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https://f1000research.com/articles/10-1279/v1
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14 Dec 21
|
{
"type": "Review",
"title": "Prediction of PM2.5 concentrations in Malaysia using machine learning techniques: a review",
"authors": [
"Naveen Palanichamy",
"Su-Cheng Haw",
"Subramanian S",
"Kuhaneswaran Govindasamy",
"Rishanti Murugan",
"Su-Cheng Haw",
"Subramanian S",
"Kuhaneswaran Govindasamy",
"Rishanti Murugan"
],
"abstract": "Particulate matter (PM), an air pollutant that is detrimental to breathing, is either emitted or formed ambiently. The exposure of respiratory system towards PM2.5, the fine particles of 2.5 micrometres diameter, causes complication for health. Thus, developing pollution control strategies requires the prediction of PM2.5 concentrations. Advancement of technology and computer science knowledge, machine learning (ML) algorithms are used for highly accurate prediction of air pollutant concentrations. Recently, air quality in Smart Cities of Malaysia has been getting worse due to industrialization, emissions from private motor vehicles, and transboundary haze pollution. Therefore, the forecasting of PM2.5 emissions to ensure they are within the statutory limits becomes necessary. Several machine learning methods have been implemented in existing research to predict air pollution concentrations in comparison to PM2.5. However, very few studies have used ML techniques to predict air quality in Malaysia when compared with global studies. Hence, to create awareness on the ML techniques and promote further research in this area, this study reviews and highlights most of the existing ML techniques for the prediction of PM2.5.",
"keywords": [
"Air Pollution",
"Particulate Matter (PM2.5)",
"Neural Network",
"Deep Learning",
"Decision Tree"
],
"content": "Introduction\n\nAir quality is important for human health, crops, vegetation, and aesthetic considerations, for example, visibility. Air pollution, in which the air is contaminated with a variety of dirt and chemicals, is detrimental to breathing and can cause a wide variety of health defects and issues. Bad air is a combination of both natural and human-made sources of perilous substances. It was estimated in 2016 that outdoor air pollution in rural and urban areas caused 4.2 million premature fatalities worldwide annually; exposure to PM is the reason for the mortality, which causes cancers, and respiratory and cardiovascular diseases [https://www.who.int/news-room/fact-sheets/detail/ambient-(outdoor)-air-quality-and-health].\n\nA complicated mixture of ultrafine particles and vaporized tiny molecules or liquid droplets is known as particulate matter (PM) [https://www.epa.gov/pm-pollution/particulate-matter-pm-basics]. PM are categorized according to their sizes. PM2.5 has a diameter of 2.5 microns or less. PM2.5 is inhalable and can travel farther into our bodies and deposit into alveoli, eventually passing into the bloodstream. They may cause cardiovascular diseases, since they start to mix into the blood stream [https://blog.breezometer.com/what-is-particulate-matter].\n\nThe health impact of exposure to PM2.5 is a nightmare which involves different age groups of people.1 The number of coughs counted by urban workers who are exposed to PM2.5 determines how badly their respiratory system is in danger. Usmani2 reviewed a paper and mentioned that environmental indicators and PM2.5 have a great impact on Malaysian health services via infant mortality rate, fertility rate, and life expectancy. He also concluded that outdoor and indoor air quality can affect the health of school children who go to school every day.\n\nTraffic pollution and industrialization are the root sources of emission of PM2.5. In Malaysia, the main sources of PM2.5 are emissions from industrial growth, motor vehicles, and recently, transboundary haze pollution. Traffic-related air pollution (TRAP), happens due to the emissions from motor vehicles.1–3 S N Brohi et al.4 concluded that industries were the main contributors to PM in Malaysia, accounting for 32%. Haze incidents have been a crucial problem in Malaysia for decades. Jaafar et al.5 concluded that PM2.5 is presumed to be one of the most critical health hazards and should be continuously monitored during haze episodes.\n\nSeveral empirical studies have identified air quality as a major concern in smart cities. The non-linear behaviour of air pollutants, combined with other significant regional factors, results in a highly complex system of air pollutant generation. According to research, capturing nonlinearity between air contaminants and their emission and dispersal sources is difficult in traditional deterministic models. As a result, to address the issue of capturing non-linearity trends in air pollution models and mitigating the impact of PM2.5, ML approaches based on statistical algorithms that are reliable and widely used should be considered.\n\nThis literature review is structured as follows. After the justification for the prediction of PM2.5, the steps involved in each ML technique are discussed first. The results and discussion of each ML approach used to predict PM2.5 concentrations are presented next. Finally, the conclusions discuss the use of ML for PM2.5 prediction.\n\n\nMethods\n\nThe following phases comprise the review of ML approaches. The first step, to find related SCOPUS indexed papers, was to use keyword combinations to find the document; which were: {‘Particulate Matter’} AND {‘PM2.5’} AND {‘Prediction’} AND {‘Machine Learning’}. The paper publishing period was limited to 2017–2021, and the study was limited to journal and conference proceedings that were published in English. We ended up with 284 documents as a result.\n\nAfter that, the studies were screened by looking at the title and abstract. Biological studies, social studies, and investigations into the relationship between PM2.5 and other air contaminants, among other topics, were omitted. The number of documents was reduced to 36. Finally, the papers that were unanimously deemed out of scope were excluded after reviewing the whole document. As a consequence, 20 manuscripts were chosen for further examination.\n\nThe five aspects are used to review the articles. The initial analysis is based on the ML type that was utilized. The researchers' method is the second point to consider. Third, the study's location as well as the dataset's characteristics. The fourth and fifth components deal with the evaluation method, performance measures such as root mean square error (RMSE), mean square error (MSE), mean absolute error (MAE), coefficient of determination (R2), and the performance of the algorithms under consideration.\n\n\nResults and discussion\n\nThe findings of the review are explained in this section. To begin, the review's findings are based on the number of studies that used machine learning approaches to forecast PM2.5 levels. Figure 3 shows the number of conference and journal articles produced in the last five years to predict PM2.5. It shows that the number of studies has been increasing in recent years, and if this trend continues, a potentially higher number of documents might be expected by the end of 2021.\n\nNext, the number of machine learning algorithms has increased significantly; however, this increase has not been evenly distributed globally. Figure 4 shows that the number of published studies in Eurasia and North America is significantly higher. While China (146 studies) and the US (109 studies) have the most published research, Malaysia only has three studies.\n\nAccording to the study, supervised machine learning techniques like neural networks (NN), deep learning (DL), decision tree (DT), and others were commonly employed. The largest percentages are for DL and NN, followed by DT, regression, and support vector machine (SVM). The following categories are used to categorise the full descriptions of the selected papers.\n\nArtificial neural networks, which are algorithms inspired by the structure and function of the brain, are used in deep learning. The papers that fall within this category are listed below.\n\nShahriar et al.6 conducted a study in three Bangladeshi air pollution hotspots to evaluate the effectiveness of two hybrid models for predicting daily PM2.5 concentrations in terms of computational efficiency and accuracy. The models presented and compared with DT and Catboost were Autoregressive Integrated Moving Average (ARIMA)-Artificial Neural Network (ANN) and ARIMA-SVM. With lower MAE and RMSE and a better R2 value, the CatBoost and ARIMA-ANN models fared well.\n\nBy comparing four prediction models, Yang et al.7 sought to anticipate PM several days in advance in 39 Seoul stations. The gated recurrent Unit (GRU) of a convolutional neural network (CNN) and the long short-term memory (LSTM) of a CNN were the two models suggested and compared. The CNN-LSTM model provided reliable prediction by capturing hidden patterns with low RMSE and MAE values. In Ref. 8 deep neural network (DNN) based hybrid model, DNN-LSTM, was proposed. The DNN-LSTM model outperformed the multiple additive regression trees (MART) and deep feedforward neural network (DFNN) models with a highest R2 and lowest values of MAE and RMSE for 48-h predictions.\n\nFor the prediction of PM2.5, Zhang et al.9 suggested a DL model including an auto-encoder (AE) and a bidirectional LSTM (Bi-LSTM). The proposed method incorporates data preprocessing to improve prediction accuracy, an AE layer to extract implicit features and increase training efficiency, and a Bi-LSTM layer to predict. The results indicate that the proposed model’s prediction was better with low RMSE and higher R2 values and a positive correlation does exist.\n\nLiu et al.10 proposed a hybrid ensemble model using DBN, LSTM, and multilayer perceptron (MLP). To reduce the model's complexity, it uses complementary ensemble empirical mode decomposition (CEEMD) to extract the features from the data series. To produce the best forecast outcomes, the imperial competition algorithm (ICA) is used to alter the weights of the predictors. Two sets of hourly PM2.5 concentrations from Shanghai are used to validate the model. According to the findings of the experiments, the proposed model performed better in terms of accuracy and resilience.\n\nThe neural network is based on the idea of classifying input observations by linearly combining datasets. For lowering difficulties and errors, Jiang et al.11 presented the group teaching optimization algorithm (GTOA): the extreme learning machine (ELM) method, which was based on a data-preprocessing strategy. Two-step decomposition is used to break down PM concentration data into high-frequency IMFs. GTOA is then used to optimise ELM. Over a 16-month period, the data covers hourly PM2.5 levels in Beijing. The findings showed that the proposed model improved prediction accuracy while maintaining a low mean absolute error and root mean square error.\n\nWith daily records from cities in Finland and Brazil, Neto et al.12 evaluated single and neural-based ensemble techniques. The values of MSE, MAPE, MAE, and RMSE were compared. MLP, the ensemble method, has the best overall performance. Suleiman et al.13 examined the performance of boosted regression trees (BRT), artificial neural networks (ANN), and support vector machines (SVM) models in forecasting roadside PM2.5 concentrations in London at nineteen monitoring sites. For performance evaluation, RMSE and other metrics were used. In general, ANN performed better.\n\nAli Shah et al.14 assessed the performance of the Phase Space Reconstruction (PSR) technique, which captures multi-time scale information, using radial and linear Support Vector Regression (SVR), Feedforward Neural Network (FFNN), and Random Forest (RF) ML. RMSE and MAE were used to assess the performance of ML techniques on a dataset collected in Saudi Arabia (Masfalah) over a 21-month period. The results showed that FFNN produced a reliable prediction.\n\nHung et al.15 conducted research to determine how transported smoke aerosols affect air quality in New York State. ANN was used in the method, and five models with distinct sets of predictors were considered during the summer seasons of 2012–2019. When the models were evaluated using RMSE and R2, the results revealed that smoke cases had higher average PM2.5 concentrations than non-smoke cases.\n\nIn the decision analysis, a decision tree can be used to visually and explicitly depict decisions and decision making. Angelin Jebamalar et al.16 created a method that combined light gradient boosting and decision tree techniques. The model breaks the tree leaf by leaf using the best fit, allowing it to handle massive amounts of data with little memory and great speed. From 2017 to 2019, the PM2.5 information for Chennai, India, was collected using IoT devices and stored in the cloud. When compared to RF, DT, and regression approaches, the suggested model outperformed with the lowest mean absolute error and root mean square error values.\n\nAnother study17 focused on PM2.5 predictions from environmental sensor data streams using a stacked boosting ensemble (STBoost) model with z-score optimization techniques. The STBoost includes Light GBM as the meta regressor and base regressors such as XGBoost and GBM regression and RF to improve the prediction accuracy. The results indicate that the STBoost model outperformed with an accuracy score of 99.52 and an RMSE value of 0.1048.\n\nTo improve PM2.5 perception, Luo et al.18 used an image-based technique that included CNN and GBM. Daily weather conditions, 6976 pictures, and hourly data from Shanghai were used to create the model (2016). With the proposed technique, the MAE, RMSE, and R2 estimations of PM2.5 are 3.56, 10.02, and 0.85, respectively.\n\nUsing a 1.5 years’ dataset of Malaysia,19 examined the performance of MLP and RF models in predicting PM2.5. Confusion matrix was utilised as a performance metric. MLP was outperformed by RF overall.\n\nThe regression model was used in a number of articles to predict particulate matter. Kleine Deters et al.20 present a machine learning technique for predicting PM2.5 based on pollution and meteorological data from two Ecuadorian cities over a six-year period. Using CGM in regression analysis, it was found that PM2.5 could be predicted more accurately during extreme weather.\n\nKowalski and Warchałowski21 provide a comparison of machine learning techniques for predicting dust-type air pollution levels. Real-time hourly data from Krakow was utilised to train and test the models using MSE and R2 over the course of a year. The best prediction approach, according to the findings, was a regression model.\n\nGu et al.22 introduced a recurrent air quality prediction (RAQP) model, which combines a recurrent framework and SVR. The model was tested on 180 hourly records from a small Chinese town. The RAQP model was found to be more successful than state-of-the-art air quality predictors with a low RMSE value.\n\nAljuaid et al.23 compared numerous forecasting approaches and strategies based on mathematics and machine learning. The one-hour and five-minute datasets were created by combining and manipulating numerous sources of Danish data. For comparison, the researchers utilised multivariate (SVR, DT, and K-nearest neighbour) and univariate (auto-regression) techniques. SVR had the lowest RMSE and MAE values for the one-hour data set, and auto-regression for the five-minutes dataset, according to the findings.\n\nFor PM2.5 ground-level forecasting in the city of Bogotá, Mogollón-Sotelo et al.24 presented SVM. Statistical validation was done using RMSE, etc. The SVM model predicts with greater accuracy. An ensemble empirical mode decomposition (EEMD), least square SVM (LSSVM), and PSR were proposed in Ref. 25 as alternative method for forecasting the following day. The empirical results reveal that the EEMD-PSR-LSSVM outperformed other models in terms of MAPE and RMSE values.\n\n\nConclusions\n\nThis study looked over 20 scientific papers that focused on machine learning algorithms for PM2.5 prediction. The use of machine learning to forecast PM2.5 has grown significantly in the previous five years, although only three research articles have been published in Malaysia. There are also several international research programmes that concentrate on more than one type of particulate matter. For predicting PM2.5, the ML techniques DL, NN, and DT are often utilised. Overall, it appears that supervised machine learning algorithms are employed to predict air pollution, notably PM2.5. The review concludes that while there have been few researches in Malaysia using machine learning to forecast PM2.5, the field can be expanded and the accuracy improved, as has been done globally using supervised machine learning methodologies.\n\n\nData availability\n\nNo data are associated with this article.\n\n\nAuthor contributions\n\nPalanichamy Naveen did the conception of the work, drafting the article, and revision to the final version. Kuhaneswaran and Rishanti did data collection, data analysis and interpretation, under the guidance of S Subramanian and their supervisors Su-Cheng Haw and Palanichamy Naveen. Palanichamy Naveen is the corresponding author for this paper.",
"appendix": "Acknowledgements\n\nNot applicable.\n\n\nReferences\n\nAwang MF, Jalaludin J, Latif MT, et al.: Exposure to PM2. 5 in urban area and respiratory health symptoms among urban workers in Klang Valley. IOP Conference Series: Earth and Environmental Science. IOP Publishing; 2019; Vol. 228(No. 1): p. 012015.\n\nUsmani RSA, Saeed A, Abdullahi AM, et al.: Air pollution and its health impacts in Malaysia: a review. Air Qual. Atmos. Health. 2020; 13(9): 1093–1118. Publisher Full Text\n\nAmeer S, Shah MA, Khan A, et al.: Comparative analysis of machine learning techniques for predicting air quality in smart cities. IEEE Access. 2019; 7: 128325–128338. Publisher Full Text\n\nBrohi SN, Pillai TR, Asirvatham D, et al.: Towards smart cities development: a study of public transport system and traffic-related air pollutants in Malaysia. IOP Conference Series: Earth and Environmental Science. IOP Publishing; 2018, June; Vol. 167(No. 1): p. 012015.\n\nJaafar SA, Latif MT, Razak IS, et al.: Composition of carbohydrates, surfactants, major elements and anions in PM2. 5 during the 2013 Southeast Asia high pollution episode in Malaysia. Particuology. 2018; 37: 119–126. Publisher Full Text\n\nShahriar SA, Kayes I, Hasan K, et al.: Potential of ARIMA-ANN, ARIMA-SVM, DT and CatBoost for Atmospheric PM2. 5 Forecasting in Bangladesh. Atmos. 2021; 12(1): 100. Publisher Full Text\n\nYang G, Lee H, Lee G: A hybrid deep learning model to forecast particulate matter concentration levels in Seoul, South Korea. Atmos. 2020; 11(4): 348. Publisher Full Text\n\nKarimian H, Li Q, Wu C, et al.: Evaluation of different machine learning approaches to forecasting PM2. 5 mass concentrations. Aerosol Air Qual. Res. 2019; 19(6): 1400–1410. Publisher Full Text\n\nZhang B, Zhang H, Zhao G, et al.: Constructing a PM2. 5 concentration prediction model by combining auto-encoder with Bi-LSTM neural networks. Environ. Model Softw. 2020; 124: 104600. Publisher Full Text\n\nLiu H, Dong S: A novel hybrid ensemble model for hourly PM2. 5 forecasting using multiple neural networks: a case study in China. Air Qual. Atmos. Health. 2020; 13(12): 1411–1420. Publisher Full Text\n\nJiang F, Qiao Y, Jiang X, et al.: MultiStep Ahead Forecasting for Hourly PM10 and PM2. 5 Based on Two-Stage Decomposition Embedded Sample Entropy and Group Teacher Optimization Algorithm. Atmos. 2021; 12(1): 64. Publisher Full Text\n\nNeto PSDM, Firmino PRA, Siqueira H, et al.: Neural-Based Ensembles for Particulate Matter Forecasting. IEEE Access. 2021; 9: 14470–14490. Publisher Full Text\n\nSuleiman A, Tight MR, Quinn AD: Applying machine learning methods in managing urban concentrations of traffic-related particulate matter (PM10 and PM2. 5). Atmos. Pollut. Res. 2019; 10(1): 134–144. Publisher Full Text\n\nAli Shah SA, Aziz W, Ahmed Nadeem MS, et al.: A novel phase space reconstruction-(PSR-) based predictive algorithm to forecast atmospheric particulate matter concentration. Sci. Program. 2019; 2019.\n\nHung WT, Lu CHS, Alessandrini S, et al.: The impacts of transported wildfire smoke aerosols on surface air quality in New York State: A multi-year study using machine learning. Atmos. Environ. 2021; 259: 118513. Publisher Full Text\n\nAngelin Jebamalar J, Sasi Kumar A: PM2.5 prediction using machine learning hybrid model for smart health. Int. J. Eng. Adv. Technol. 2019; 9(1): 6500–6504.\n\nJebamalar JA, Kamalakannan T: Enhanced Stacking Ensemble Model in Predictive Analytics of Environmental Sensor Data. 2021 International Conference on Artificial Intelligence and Smart Systems (ICAIS). IEEE; 2021, March; (pp. 482–486).\n\nLuo Z, Huang F, Liu H: PM2. 5 concentration estimation using convolutional neuranetwork and gradient boosting machine. J. Environ. Sci. 2020; 98: 85–93. Publisher Full Text\n\nMurugan R, Palanichamy N: Smart City Air Quality Prediction using Machine Learning. 2021 5th International Conference on Intelligent Computing and Control Systems (ICICCS). IEEE; 2021, May; (pp. 1048–1054).\n\nKleine Deters J, Zalakeviciute R, Gonzalez M, et al.: Modeling PM2. 5 urban pollution using machine learning and selected meteorological parameters. Int. J. Electr. Comput. Eng. 2017; 2017.\n\nKowalski PA, Warchałowski W: The comparison of linear models for PM10 and PM2. 5 forecasting. WIT Trans. Ecol. Environ. 2018; 230: 177–188.\n\nGu K, Qiao J, Lin W: Recurrent air quality predictor based on meteorology-and pollution-related factors. IEEE Transactions on Industrial Informatics. 2018; 14(9): 3946–3955. Publisher Full Text\n\nAljuaid H, Alwabel N: Air pollution prediction using machine learning algorithms. Int. J. Eng. Adv. Technol. 2019; 8(6 Special Issue 3): 160–164.\n\nMogollón-Sotelo C, Casallas A, Vidal S, et al.: A support vector machine model to forecast ground-level PM 2.5 in a highly populated city with a complex terrain. Air Qual. Atmos. Health. 2021; 14(3): 399–409. Publisher Full Text\n\nNiu M, Gan K, Sun S, et al.: Application of decomposition-ensemble learning paradigm with phase space reconstruction for day-ahead PM2.5 concentration forecasting. J. Environ. Manag. 2017; 196: 110–118. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "115273",
"date": "06 Jan 2022",
"name": "Nagender Aneja",
"expertise": [
"Reviewer Expertise Deep Learning",
"NLP"
],
"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 examines and highlights the most available ML strategies for PM2.5 prediction to raise knowledge of ML techniques and encourage additional research in this field. The articles published in Malaysia proposed supervised machine learning algorithms to predict air pollution, notably PM2.5.\nThe articles have been categorized in deep learning, neural network, decision tree, regression, and support vector machine. This is a good analysis from the perspective of Malaysia, however, the search approach seems limited and missing some references e.g. Masood and Ahmad (2020)1, Danesh et al., (2020)2, Doreswamy et al., (2020)3. Authors can include similar references and see if the techniques are applicable for Malaysia also.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": []
},
{
"id": "115274",
"date": "24 Jan 2022",
"name": "D. Devaraj",
"expertise": [
"Reviewer Expertise Machine learning",
"Smart grid"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGlobally, in the major cities, air pollution is becoming a major issue. To adopt appropriate pollution control strategies Prediction of PM 2.5 concentration is necessary. Recently, in the literature, machine learning algorithms like Decision tree algorithms, Artificial neural networks, and support vector machines have been applied for accurate prediction of PM 2.5 concentration. In this review paper, the authors have reviewed recently published articles related to the prediction of PM2.5 using Machine learning algorithms. In this review paper, the authors have highlighted the strength and weaknesses of various algorithms reported in the literature. The reviewer has the following suggestions to further improve the quality of this paper:\nInclude the review of \"Deep learning\" at the end after reviewing the papers related to the conventional machine learning algorithms, instead of reviewing that at the beginning.\n\nInclude the research gap identified in this area at the end of the review.\n\nAlso, the title of the section \"Results and Discussion\" may be changed appropriately.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1279
|
https://f1000research.com/articles/10-548/v1
|
08 Jul 21
|
{
"type": "Research Article",
"title": "Modified Kibria-Lukman (MKL) estimator for the Poisson Regression Model: application and simulation",
"authors": [
"Benedicta B. Aladeitan",
"Olukayode Adebimpe",
"Adewale F. Lukman",
"Olajumoke Oludoun",
"Oluwakemi E. Abiodun",
"Olukayode Adebimpe",
"Adewale F. Lukman",
"Olajumoke Oludoun",
"Oluwakemi E. Abiodun"
],
"abstract": "Background: Multicollinearity greatly affects the Maximum Likelihood Estimator (MLE) efficiency in both the linear regression model and the generalized linear model. Alternative estimators to the MLE include the ridge estimator, the Liu estimator and the Kibria-Lukman (KL) estimator, though literature shows that the KL estimator is preferred. Therefore, this study sought to modify the KL estimator to mitigate the Poisson Regression Model with multicollinearity. Methods: A simulation study and a real-life study were carried out and the performance of the new estimator was compared with some of the existing estimators. Results: The simulation result showed the new estimator performed more efficiently than the MLE, Poisson Ridge Regression Estimator (PRE), Poisson Liu Estimator (PLE) and the Poisson KL (PKL) estimators. The real-life application also agreed with the simulation result. Conclusions: In general, the new estimator performed more efficiently than the MLE, PRE, PLE and the PKL when multicollinearity was present.",
"keywords": [
"Linear regression model",
"generalized regression model",
"Ridge estimator",
"Liu estimator",
"KL estimator."
],
"content": "Introduction\n\nA special case of the Generalized Linear Models (GLM) is the Poisson Regression Model (PRM) which is generally applied for count or frequency data modelling. It is employed to model the relationship between a response variable and one or more independent variable where the response variable denotes a rare event or count data. The response variable also takes the form of a non-negative variable, and it is applicable in the following fields: economics, health, social and physical sciences. The Maximum Likelihood Estimation (MLE) method is popularly used to estimate the regression coefficient in a PRM. In both a Linear Regression Model (LRM) and Generalized Linear Model (GLM), MLE suffers a setback when the independent variables are correlated, which implies multicollinearity. Multicollinearity effects include large variance and regression coefficient covariances, negligible t-ratio and a high coefficient of determination (R-square) values. Alternative estimators to the MLE in the linear regression model include the ridge regression estimator by Hoerl and Kennard (1970), Liu estimator by Liu (1993), Liu-type estimator by Liu (2003), two-parameter estimator by Özkale and Kaciranlar (2007), r-d class estimator Kaçiranlar and Sakallioǧlu (2007), k-d class estimator Sakallioglu and Kaciranlar (2008), a two-parameter estimator by Yang and Chang (2010), modified two-parameter estimator by Dorugade (2014), modified ridge-type estimator by Lukman et al. (2019), modified Liu estimator by Lukman et al. (2020), Kibria-Lukman (KL) estimator by Kibria and Lukman (2020), modified new two-parameter estimator by Ahmad and Aslam (2020), the modified Liu ridge type estimator by Aslam and Ahmad (2020) and the DK estimator by Dawoud and Kibria (2020) among others. Researchers have extended some of these existing estimators in LRM to the PRM. Mansson et al. (2012) introduced the Liu estimator into the PRM. The modified jackknifed ridge estimator for the PRM was introduced by Türkan and Özel (2016). The ridge estimator was introduced into the PRM by Månsson and Shukur (2011). A new two-parameter for PRM was developed by Asar and Genç (2017). Recently, Poisson KL estimator was developed by Lukman et al. (2021) for combating multicollinearity in the PRM.\n\nIn this study, we modified the KL estimator to handle multicollinearity in PRM. Furthermore, we compared the performance of the estimator with the Poisson Maximum Likelihood Estimator (PMLE), Poisson Ridge Regression Estimator (PRE), Poisson Liu Estimator (PLE) and the Poisson KL estimator (PKLE).\n\n\nMethods\n\nGiven that the response variable, yi is in the form of count data, then it is assumed to follow a Poisson distribution as Po (μi) where μi = exp (xiβ), such that xi is the ith row of X which is a n×(p+1) data matrix with p independent variables and β is a (p+1)×1 vector of coefficients. The log likelihood of the model is given as:\n\nThe most common method of maximizing the likelihood function is to use the iterated weighted least squares (IWLS) algorithm which results to:\n\nwhere V̂=diagμ̂i and ẑ is a vector while the ith element equals z^i=log(μ^i)+yi−μ^iμ^i.\n\nThe MLE is normally distributed with a covariance matrix that is equivalent to the inverse of the second derivative as:\n\nand the mean square error is given as:\n\nwhere λj is the jth eigen value of the X′V̂X matrix.\n\nThe Poisson Ridge Estimator (PRE) was introduced by Månsson and Shukur (2011) as a solution to multicollinearity in PRM. The estimator is defined as follows:\n\nwhere k=max1mi and σ̂2αi2\n\nThe mean square error (MSE) is:\n\nMansson et al. (2012) developed the Liu estimator to the Poisson regression model as:\n\nwhere\n\nThe means square error for the Liu estimator is defined as:\n\nwhere λj is the jth eigenvalue of X′V̂X and αj is the jth element of α.\n\nThe KL estimator was proposed by Kibria and Lukman (2020) as a means of mitigating the effect of multicollinearity on parameter estimation. The estimator is defined as\n\nBy means of extension, the Poisson K-L estimator was proposed by Lukman et al. (2021) as follows:\n\nThe proposed estimator is obtained as follows: β̂MLE in equation (2.10) is replaced with the ridge estimator. Thus, we have:\n\nThe properties of the new estimator include:\n\nThe bias can be written in scalar form as:\n\nVβ̂MKL can be represented in scalar form as follows:\n\nThus, the MSE is obtained as:\n\nThe proposed estimator in (2.13) is extended to the PRM. It is referred to as the Poisson modified KL (PMKL) estimator and defined as:\n\nThe mean square error of the PMKL is defined as:\n\nThe following lemmas are adopted for theoretical comparisons among the estimators.\n\nLemma 2.1 Let A be a positive definite (pd) matrix, that is, A > 0, and a be some vector, then A−aa'≥0 if and only if (iff) a'A−1a≤1 (Farebrother, 1976).\n\nLemma 2.2 MSEM(β^1)−MSEM(β^2)=σ2D+b1b′2−b2b′2>0\n\nif and only if b′2[σ2D+b1b′1]−1b2<1 where MSE(β^j)=Cov(β^j)+b′jbj (Trenker and Toutenburg, 1990).\n\nTheorem 2.1: α̂PMKL is preferred to α^PMLE iff, MSEMα̂MLE−MSEMα̂PMKL>0 provided k > 0.\n\nProof\n\nIt is observed that λj+k4−λj2λj−k2>0 such that the expression above is non-negative for k > 0\n\nTheorem 2.2: α̂PMKL is preferred to α̂PRE iff, MSEMα̂PRE−MSEMα̂PMKL>0 provided k > 0.\n\nProof\n\nWe can observe that the difference of the variance of the estimator is non-negative since λj+k2λj−λjλj−k2>0 for k > 0.\n\nTheorem 2.3: α̂PMKL is preferred to α̂PLE iff, MSEMα̂PLE−MSEMα̂PMKL>0 provided k > 0 and 0 < d < 1.\n\nProof\n\nThe difference of the variance is non-negative since\n\nλj+kλj+d−λjλj+1λj−k>0 for 0 < d < 1 and k > 0.\n\nTheorem 2.4: α̂PMKL is preferred to α̂PKL iff, MSEMα̂PKL−MSEMα̂PMKL>0 provided k > 0.\n\nProof\n\nThe difference of the variance is non-negative since λj+kλj−k−λjλj−k>0 for k > 0.\n\nThe biasing parameter k for the estimator is obtained by differentiating the MSE with respect to k and obtained as:\n\nThe shrinkage parameter estimated by Mansson and Shukur, (2011) and Kibria and Lukman (2020) was also adopted for this study as listed:\n\nk1 is the biasing parameter for PMKL1, while k2 and k3 are the biasing parameters for PMKL2 and PMKL3.\n\n\nSimulation Design and Real-Life Application\n\nIn this section, a simulation study is carried out to compare the performance of the different estimators. The generation of the dependent variables are done using pseudo-random numbers from Po (μi) where μi=eβxii=1,2,…,n and Xi is the ith row of the design matrix with β=β0β1…βp being the coefficient vector. The generation of the independent variables with different levels of correlation is obtained using\n\nwhere ρ is the level of multicollinearity between the independent variables (Kibria et al. 2015; Kibria and Banik, 2016; Lukman et al., 2019b, Lukman et al. 2020b). zij are pseudo-random numbers generated using the standard normal distribution such that i ranges from 1 to n and j from 1 to p. As a common restriction used in simulation studies, it is assumed that ∑j=1pβj2=1 and β1=β2=…=βp. Also, the effect of the intercept value is also being investigated as values are taken to be 1, 0 and -1 (Kibria et al. 2014). The different levels of correlation taken are 0.8, 0.9, 0.95, 0.99 and 0.999. The other factors varied in the simulation study are the sample size n and the number of independent variable p. We assume n = 50, 100 and 200 observations and p = 4 and 8 independent variables.\n\nThe simulation results in Tables 1 to 6 that for each of the estimators, the simulated MSE values increase as the multicollinearity level increases, keeping other factors constant. There is also an increase in the mean square error as the sample size increases for all estimators compared while other factors were kept constant. As the intercept values varied from -1 to +1, the values of the mean square error reduced for all estimators. Result shows that the PMKL1 performed best with minimum MSE at varying sample sizes. It was closely followed by PMKL2. They are both considered more suitable for estimation of parameters in the Poisson regression model than the MLE as it performed worst when multicollinearity is a challenge. In general, the PMKL1 estimator consistently performed more efficiently than the MLE, PRE, PLE and the PKL estimators.\n\n\nReal Life Application\n\nHaving carried out a simulation study, the efficacy of the proposed estimator needs to be further investigated by considering a real-life application. The Poisson regression model has been applied to the aircraft damage dataset initially by Myers et al. (2012) and subsequently by other researchers such as Asar and Genc (2017) and Amin et al. (2020) among others. By following the Pearson chi-square goodness of fit test, Amin et al. (2020) was able to ascertain that the data fits a Poisson regression model. The test confirms the suitability of the response variable to Poisson distribution with P-value of 6.898122 (0.07521). The dataset provides some detail on two separate aircrafts: The McDonnell Douglas A-4 Skyhawk and the A-6 Grumman Itruder. The dependent variable denotes the number of locations with damage on the aircraft and this follows a Poisson distribution (Asar and Genc, 2017; Amin et al., 2020). The data set has three explanatory variables, X1 shows the type of aircraft which makes the outcome binary (A-4 is coded as 0 and A-6 is coded as 1). X2 is the bomb load in tons and X3 is the number of months of aircrew experience. Meyers et al. (2012) was able to ascertain that the data set is greatly affected by multicollinearity. The eigenvalues of the matrix X were obtained as 4.3333, 374.8961 and 2085.2251. The condition number of 219.3654 was also obtained which is an indication of the problem of multicollinearity since it is greater than 30 (Asar and Genc, 2017). The performance of the estimators is judged based on the mean square error of each of the estimators.\n\nFrom Table 7, it is evident that all of the regression coefficients had identical signs. The estimator with the highest mean squared error is the MLE due to the presence of multicollinearity. The suggested estimator (PMKL1, PMKL2, PMKL3) has the lowest MSE that has established its dominance. We also observed that the performance of the estimator is highly dependent on the biasing parameter k.\n\n\nConclusion\n\nThe parameters in the PRM are commonly estimated using the Maximum Likelihood Estimator. However, literature had shown that the estimator suffers a setback when the explanatory variables are correlated. This problem led to the implementation of alternative estimators with single shrinkage parameters such as the Poisson Ridge Regression Estimator (PRE), Poisson Liu Estimator (PLE) and the Poisson KL Estimator (PKLE). The KL estimator was generally preferred to the ridge regression and Liu estimator in the linear regression model. According to Lukman et al. (2021), the Poisson KL estimator outperforms PRE and PLE. This study modified the KL estimator to propose a new estimator called the Poisson Modified KL estimator (PMKL). The new estimator falls in the same class with the ridge, Liu and KL estimators since they possessed a single shrinkage parameter. We investigated the performance of the estimators with a simulation study and a real-life application. From the results, we observed that the new estimator consistently performed well in the presence of multicollinearity with the lowest MSE. Finally, the new estimator is more suitable to combat multicollinearity in the PRM.\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\nAhmad S, Aslam M: Another proposal about the new two-parameter estimator for linear regression model with correlated regressors. Communications in Statistics - Simulation and Computation. 2020. Publisher Full Text\n\nAmin M, Qasim M, Yasin A, et al.: Almost unbiased ridge estimator in the gamma regression model. Communications in Statistics: Simulation and Computation. 2020. Publisher Full Text\n\nAslam M, Ahmad S: The modified Liu-ridge-type estimator: a new class of biased estimators to address multicollinearity. Communications in Statistics - Simulation and Computation . 2020; 0(0): 1–20. Publisher Full Text\n\nAsar Y, Genç A: A New Two-Parameter Estimator for the Poisson Regression Model. Iranian J Science Technology, Transaction A: Science . 2017; 42(2): 793–803. Publisher Full Text\n\nDawoud I, Kibria BMG: A new biased estimator to combat multicollineatity in the Gaussian linear regression model. Publisher Full Text\n\nDorugade AV: Modified two parameter estimator in linear regression. J Stat Trans New Ser. 2014; 15(1): 23–36. Publisher Full Text\n\nFarebrother RW: Further results on the mean square error of ridge regression. J. Roy. Statist. Soc., B . 1976; 38: 248–250. Publisher Full Text\n\nHoerl AE, Kennard RW: Ridge Regression: Applications to Nonorthogonal Problems. Technometrics . 1970; 12(1): 69–82.\n\nKaçiranlar S, Sakallioǧlu S: Combining the liu estimator and the principal component regression estimator. Communications in Statistics - Theory and Methods . 2007; 30(12): 2699–2705. Publisher Full Text\n\nKibria BMG (2014): Performance of some new ridge regression estimators. Commun Stat Simul Comput. 2003; 32(2): 419–435. Publisher Full Text\n\nKibria BMG, Banik S: Some ridge regression estimators and their performances. J Modern Applied Statistical Methods . 2016; 15(1): 206–238.\n\nKibria BMG, Lukman AF: A new ridge-type estimator for the linear regression model: Simulations and applications. Scientifica . 2020; 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKibria BMG, et al.: A simulation study of some biasing parameters for the ridge type estimation of Poisson regression. Commun. Stat.-Simul. Comput. I . 2015; 44: 943–957. Publisher Full Text\n\nLiu K: A new class of biased estimate in linear regression. Communications in Statistics - Theory and Methods . 1993; 22(2): 393–402. Publisher Full Text\n\nLiu K: Using Liu-Type estimator to combat collinearity. Communications in Statistics Theory and Methods . 2003; 32(5): 1009–1020. Publisher Full Text\n\nLukman AF, Ayinde K, Binuomote S, et al.: Modified ridge-type estimator to combat multicollinearity: Application to chemical data. J Chemometrics . 2019a; 33(5): 1–12. Publisher Full Text\n\nLukman AF, Ayinde K, Sek SK, et al.: A modified new two-parameter estimator in a linear regression model. Modelling and Simulation in Engineering. 2019b.Publisher Full Text\n\nLukman AF, Ayinde K, Aladeitan BB, et al.: An Unbiased Estimator with Prior information. Arab Journal of Basic and Applied Sciences . 2020a; 27(1): 45–55. Publisher Full Text\n\nLukman AF, Ayinde K, Kibria BMG, et al.: Modified ridge-type estimator for the gamma regression model. Communications in Statistics: Simulation and Computation . 2020b; 0(0): 1–15. Publisher Full Text\n\nLukman AF, Adewuyi MK, Kibria BMG: A new estimator for the multicollinear Poisson regression model: simulation and application. Sci Rep . 2021; 11: 3732. Publisher Full Text\n\nMånsson K, Shukur G: A Poisson ridge regression estimator. Econ. Model. 2011; 28: 1475–1481. Publisher Full Text\n\nMansson K, Kibria BMG, Sjolander P, et al.: Improved Liu Estimators for the Poisson Regression Model. Int J Statistics Probability . 2012; 1(1): 2–6. Publisher Full Text\n\nMyers RH, et al.: Generalized linear models: with applications in engineering and the sciences. New York: Wiley; 2012; 791. .\n\nOzkale MR, Kaciranlar S: The restricted and unrestricted two-parameter estimators. Commun. Statist. Theor. Meth. 2007; 36: 2707–2725. Publisher Full Text\n\nQasim M, Kibria BMG, Månsson K, et al.: A new Poisson Liu Regression Estimator: method and application. J Applied Statistics. 2019; 4763. Publisher Full Text\n\nSakallıoğlu S, Kaçıranlar S: A new biased estimator based on ridge estimation. Statist. Papers . 2008; 49(4): 669–689. Publisher Full Text\n\nTrenkler G, Toutenburg H: Mean squared error matrix comparisons between biased estimators—an overview of recent results. Stat Pap. 1990; 31(1): 165–179. Publisher Full Text\n\nTürkan S, Özel G: A new modified Jackknifed estimator for the Poisson regression model. J Applied Statistics . 2016; 43: 1892–1905. Publisher Full Text\n\nYang H, Chang X: A New Two-Parameter Estimator in Linear Regression. Communications in Statistics - Theory and Methods . 2010; 39(6): 923–934. Publisher Full Text"
}
|
[
{
"id": "89260",
"date": "21 Jul 2021",
"name": "Mohammad Arashi",
"expertise": [
"Reviewer Expertise High-dimensional modeling",
"shrinkage estimation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 extends the Liu estimator in generalized linear modeling. Specifically, the authors propose a new biased estimator for the estimation of regression coefficients in the discrete Poisson regression.\nThe results are interesting and the topic is eye-catching. The theoretical results are well supported by extensive numerical analysis.\nI suggest the authors make minor revisions to improve the presentation before indexing.\nCheck the notation entirely to be consistent. For instance, in equation (2.10), \"hat\" must be added for the estimator. It happens also for (2.12).\n\nUse another notation for diagonal matrices in equations. For example, you may use \"L\" and then define the elements.\n\nExplain equation (2.21) more. Is the minimization over i?\n\nIn the simulation study, for the design generation, I suggest using another notation for \"zip\" since it is not the last element of the series of generated independent normals.\n\nProvide a reference for the accessibility of the real data use in the real-life application.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "6967",
"date": "27 Jul 2021",
"name": "BENEDICTA Aladeitan",
"role": "Author Response",
"response": "Thanks for your observations and corrections. All will be duely implemented."
}
]
},
{
"id": "89258",
"date": "03 Aug 2021",
"name": "Muhammad Amin",
"expertise": [
"Reviewer Expertise Regression Analysis",
"Biased Estimation Methods"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this paper, the authors introduced a new estimator by modified KL estimator for the Poisson regression model to overcome the effect of multicollinearity. The paper is original and deals with a topic of interest. This paper could be accepted for indexing after incorporating the following points.\n\nWrite one paragraph on count data models and their importance at the start of the Introduction and include some citations that demonstrate the importance of count data models, for example: Amin et al., 20201; Amin et al., 20212; Sami et al., 20213; Amin et al., 20214; Majid et al., 20215; Rashad et al., 20196; Algamal et al., 20157; Algamal et al., 20218; Alanaz et al., 20189.\n\nWrite the reason for your proposed estimator over other estimators in the last paragraph of the Introduction section.\n\nChange independent variables to explanatory variables in the whole study.\n\nWrite the first paragraph clearly and correct equation 2.1 of the Methods section by following Amin et al., 2020 1.\n\nChange “mean square error” to “mean squared error” in the whole manuscript.\n\nOn page 3, write the reason for adapting the Poisson ridge estimator.\n\nOn page 4, line 1, write the range of ridge parameter k.\n\nWrite the limitations of the ridge estimator after equation (2.5).\n\nWrite the range of Liu parameter d after equation (2.6).\n\nWrite different notations of the ridge parameter k, for ridge, KL, and MKL estimators and also mention the ranges of these biasing parameters.\n\nWrite the expressions for MSEs of ridge, Liu, and KL estimators.\n\nIn Lemma 2.2, define b1, b2,\n\nThe statement of Theorem 2.2 is wrong, I suggest the authors correct this.\n\nDefine e in equation (2.23). In equation (2.24), change λi to λj\n\nCorrect expressions above equation (3.1).\n\nThe interpretations of simulation results need more detailed discussion.\n\nIn real application, report the estimated values of each biasing parameter with proper citation of equations. Moreover, cite equation to compute MSE of the consider estimators.\n\nThere are some grammatical issues that should 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? 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": []
},
{
"id": "89263",
"date": "09 Aug 2021",
"name": "Nimet Özbay",
"expertise": [
"Reviewer Expertise Monte Carlo simulation",
"Linear regression model",
"Econometric models",
"Applied statistics",
"Biased estimation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 focuses on proposing a modified KL estimator to mitigate the Poisson Regression Model with multicollinearity. Some theoretical properties of the new estimator are examined. A numerical example is conducted to show the performance of the new estimator. I think the authors should give the definition of the modified KL estimator in more detail and explain its statistical necessity. The organization of the paper, grammatical mistakes, and punctuation errors should also be controlled. This article may be indexed after the major comments below are applied.\nComments:\nThe main document of the article does not contain line numbers, thus it has been quite difficult to pinpoint the location of the comments.\nThere are lots of language and punctuation errors throughout the whole article, so the authors should recheck the writing of the manuscript. For example:\n\nIn the Abstract, “the simulation result showed…” should be changed to “the simulation result showed that…”.\n\nOn page 3, a dot is required before equation (2.1).\n\nOn page 3, a comma is required before equation (2.2).\n\nOn page 5, line 1, “estimator” should be “estimators”.\n\nSection number is required for the sections, etc.\n\nThe basic punctuation marks are missing throughout the paper.\n\nOn page 3, the abbreviation “PRE” is repeated.\n\nIn the whole article, there are some inappropriate uses of the abbreviations. The authors should rearrange the use of abbreviations. In some places, previously made abbreviations are repeated.\n\nThe use of “hat” is missing while presenting some estimators.\n\nIn the Introduction section, the manuscript Defining a two-parameter estimator: a mathematical programming evidence by Üstündağ Şiray et al. (2021)1 may be mentioned since this is a more recent article in which a new biased estimator is proposed to mitigate multicollinearity.\n\nOn page 4, the authors should explain what lambdas are.\n\nOn page 6, before equation (2.8), “means square error” should be “MSE”.\n\nThere is no explanation for equation (2.11).\n\nI think, “equation (2.10)” should be “equation (2.9)” before equation (2.12) on page 4.\n\nOn page 5, the authors should explain what lambdas are. Do the authors use “V” to Show variance? If so, some explanations should be added about it.\n\nOn page 5, there is the incorrect use of “MSEM”. This abbreviation does not exist, although it is used while representing the lemmas and theorems.\n\nI think the authors employ the canonical form in the proof of the theorems. Unfortunately, I did not find some information about the canonical model.\n\nThe selection of the biasing parameter section is insufficient. A detailed derivation and more information should be given.\n\nIn the simulation section, on page 7, why does the mean square error increase as the sample size increases?\n\nIt would be better if no abbreviations were used in the title.\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? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-548
|
https://f1000research.com/articles/10-1048/v1
|
15 Oct 21
|
{
"type": "Research Article",
"title": "Reframing organizations in the digital age: A qualitative study exploring institutional social media adoption",
"authors": [
"Yusuf Yilmaz",
"Brandon Ruan",
"Priya Thomas",
"Victoria Tran",
"Teresa M. Chan",
"Yusuf Yilmaz",
"Brandon Ruan",
"Priya Thomas",
"Victoria Tran"
],
"abstract": "Background: Social media is changing the modern academic landscape; this study sought to explore how organizational structures support or inhibit the harnessing of social media use in academic contexts and knowledge translation. Methods: A qualitative study was conducted using framework analysis based on the Bolman and Deal’s Four-Frame Model—structural, human resources, political and symbolic. The research team used the snowball sampling technique to recruit participants following the completion of each participant’s semi-structured interview. A member check was completed to ensure rigour. Results: 16 social media educators and experts from several countries participated in the study. Study findings showed that within the Structural Frame, institution types were reported to have with diverse hierarchical structures, ranging from strict to malleable: hospital-based (strict), education institutional-based and online only groups (malleable). The Human Resources Frame revealed that most participants’ social media organizations operated on unpaid volunteer staff. The training of these staff was primarily via role-modeling and mentorship. Regarding the Political Frame, social media helped participants accumulate scholarly currency and influence within their field of practice. Symbolic Frame showed a wide range of traditional to non-traditional organizational supports, which interacted with both intrinsic to extrinsic motivation. Conclusions: Bolman and Deal’s Four-Frame Model framework may serve as an effective guideline for academic leaders who wish to strategically implement or enhance social media use into their organizations. The key insights that we have gained from our participants are how new emerging forms of scholarly pursuits can be more effectively enabled or hindered by the attributes of the organization within which these are occurring.",
"keywords": [
"social media",
"medical education",
"knowledge translation",
"organizational change",
"qualitative study"
],
"content": "Introduction\n\nFor billions of consumers across the world, social media continues to grow as the epicenter of both information and entertainment. The immense reach and power of social media is best exemplified during the COVID-19 pandemic, where many took to Facebook, Twitter, and other platforms to discuss, and debate the crisis1,2. Alongside these positive applications of social media, rampant usage of social media during the pandemic has also demonstrated its capacity to serve as a vehicle of mis- and dis-information3,4.\n\nAcademic health sciences centers (AHSCs), such as hospitals and universities, are considered disseminators of health information for public health and research. Many are publicly funded and seen as having a social contract for health scholarship and advocacy5. During the COVID-19 pandemic, AHSCs found themselves ill-prepared to combat this “fake news”6 and the consequences that transpired as a result of its dissemination7,8. Some AHSCs simply neglected social media as a tool to combat misinformation, while other AHSCs appeared to actively avoid communicating with their employees, who took to social media to fill the information vacuum- one that was created in the first place by AHSCs9,10.\n\nInevitably, this created considerable tension between the AHSCs and their employees, which can be traced to the lack of institutional training such as digital professionalism in alignment with instructional policies and mission statements11. The consequences of this tension were seen, for instance, when physicians who spoke out on social media about their institution’s lack of preparedness for COVID-19, were terminated12. Additionally, the absence of social media adoption in AHSCs have resulted in healthcare practitioners creating online-based organizations outside of their professional institution11,13,14. Thus, it is evident that there is misalignment between the expectations of social media usage of individual health professionals’ and their institutions at large15,16. This may be due to a lack of compatibility between personal and institutional values with respect to social media17.\n\nThere is an opportunity to bring health care organizations and their employees to bridge this apparent incompatibility in social media usage and presence18,19. This can be accomplished by reframing the institution’s organizational framework in the contexts of integrating and adopting social media utilization and training towards staff. One benefit of having organizations in supporting staff’s utilization of social media on the organizational level will allow more explicit policies for staff that allow professional behavior and conduct on social media. Furthermore, the enabling of physicians and researchers within AHSCs to utilize social media also bring academic benefits for their users, such as forming scholarly communities of practice and increased research dissemination20,21. The importance of social media adoption on the institutional level is highlighted in an era of online misinformation22,23. The need for reframing organizations in the contexts of social adoption will allow AHSCs to better prepare and combat this.\n\nReframing an institution’s organizational framework is a process by which the structure of an organization is aligned with its objectives, with the goal of improving its efficiency and effectiveness. In their book Reframing Organizations, Bolman and Deal propose a Four-Frame Model that enables leaders to see organizational issues through four lenses that, altogether, paint a complete picture of the challenge24. This approach to reframing organizations aims to prevent inefficiencies that may arise when leaders adopt only their own frame of reference, otherwise known as a leader’s Habitual Frame. The four frames outlined by Bolman and Deal are the Structural Frame, the Human Resource Frame, the Political Frame, and the Symbolic Frame, and they are described in detail in Table 1.\n\nConsidering the emerging landscape of social media-based scholarship, we sought to harness the conceptual framework proposed by Bolman and Deal to examine how organizational structures emerge or evolve around new forms of scholarship. Specifically, the purpose of this study is to explore how organizational structures support or inhibit the harnessing of social media use in academic contexts and knowledge translation.\n\n\nMethods\n\nWe used quasi-deductive thematic framework analysis approach on the amalgamated perceptions of social media clinician educators and researchers to determine organizational components that fostered the utilization of social media, and used SRQR guidelines25 while reporting the results. While we were sensitized to the work of Bolman and Deal, we did analyze and review the content with a fully inductive approach, and then sought to map our themes to the framework during axial coding. Themes that emerged outside of the framework are presented in addition to those that fit with the framework.\n\nThe research team was comprised of five individuals: three of which used social media professionally in the contexts of scholarly advancement and practice, (YY, PT, TMC) and two who only used it for personal and recreational purposes (VT, BR). Furthermore, the composition of the team consists of a senior lead (TMC) who is a medical physician with expertise in qualitative analysis, free open access medical education resource dissemination and social media stakeholdership, a postdoctoral fellow who is an expert in qualitative analysis and social media education. Two researchers (TMC, YY) have publications utilizing qualitative methods. The remaining three members are research assistants trained in qualitative analysis but are neither experts in social media nor knowledge translation (PT, VT BR). Having a mix of people with different expertise and familiarity was key to ensure that our lead and senior author did not overinterpret the transcripts and bring in their own perspectives and experiences, in keeping with our selected methodology of the framework analysis. Gender composition of the team consisted of three females (TMC, PT, VT) and two males (YY, BR).\n\nThe problem that we sought to answer required seeking experts on social media who had personal and professional backgrounds around knowledge working in AHSCs. Our initial participants were derived from the field of emergency medicine, as they were likely to have many experiences regarding social media knowledge translation and usage within academic and health institutions based on their extensive online careers26. Bolman and Deal’s Four-Frame Model guided our study design which examined structural, human resource, political, and symbolic constructs in relation to social media and knowledge translation for organizations. This study is a sub-study that was defined a priori.\n\nWe contacted a random selection of 25 individuals from a previously published list of influential physicians26 and contacted them via email or direct messaging on Twitter. The only individual excluded from this random selection was the Principal Investigator (co-author TC), who is listed in this paper. Based on the literature which identified influential online physicians using a complex set of analytics including network centrality26, we determined the most influential social media users in emergency medicine and applied a purposive, snowball sampling technique to define our study group, as snowball sampling techniques are used for populations that are ill-defined. In this instance, the landscape of social media is constantly evolving with new platforms and new people. Therefore, snowball sampling is an appropriate method to employ to augment previous lists of influencers that may only hold past relevance.\n\nHamilton Integrated Research Ethics Board granted ethics approval for the study with a reference number of HIREB-#5609.\n\nWe elected to perform interviews with our participants since we were interested in individual’s interaction with their organizations, instead of the interactions between various participants. We developed a semi-structured interview guide to assist with steering the interviews. Our interview guide was developed by two team members (EB, PT) based on the Bolman and Deal’s framework. This initial guide was reviewed by the rest of the team, then piloted with non-participatory individuals to ensure clarity. We did not modify the interview guide since our pilot testers thought that the guide was very clear, and the interviewers felt that we were able to elicit the types of answers required. The interview guide has been fully published27 and is available for full review (see references, citation 27).\n\nTwo of the team members (AM, BR) managed the data collection procedures. Each research assistant completed a practice run of data collection with the senior research lead (TMC) preceding data collection. The research team reviewed groups of 2-4 transcripts before proceeding with subsequent interviews and refined the interview questions as necessary. This process enabled the interviews to be increasingly explorative. All the transcription files and their content were anonymized. We assigned a gender-matched name for each file using a random name generator.\n\nWe informed our participants about the research, data collection process, and confidentiality procedures. Informed consent was obtained from participants via email prior to the interview, who were then asked to complete a short demographics survey (See the interview guide in the extended data). Subsequently, we invited them to be interviewed via Zoom video conferencing software (Zoom Communications Inc., San Jose, CA, USA). We used Zoom’s local audio capturing feature to record all the interviews for transcription purposes. The recordings were transcribed verbatim into Microsoft Word files (Microsoft Corp., Seattle, WA, USA) by a trained medical research transcriptionist (EC).\n\nWe followed the five-step process articulated by Ritchie and Spencer28: 1) Familiarization; Identifying a thematic framework; 3) Indexing; 4) Charting; and 5) Mapping and interpretation. Throughout the interview period, our team collaboratively analyzed transcripts. The transcripts were analyzed in batches of 2-4 transcripts at a time using Google Docs (Google Inc., Mountainview, CA, USA) to create our codebook. Key quotations were recorded in the comment feature of Google Docs to augment our codebook. After a period of familiarization, we identified that many of the emergent themes aligned with that of Bolman and Deal’s Four-Frame Model and formally began indexing our themes according to this model. Once we analyzed all transcriptions, our research team had a final charting meeting to refine our coding structure and integrated the findings into Bolman and Deal’s framework. We then asynchronously collaborated to engage in mapping and interpretation of the data.\n\nThe research team ensured the trustworthiness of the study applying several techniques. All of the members analyzed the qualitative data and served as debriefers throughout the analysis. Concepts that the participants mentioned were identified and investigated at every stage of the analysis as well as the last coding stage. The final themes were confirmed with the frames of Bolman and Deal. While reporting, we used thick descriptions to ensure our participants’ voices were represented to the readers. Participants underwent a member check process by reviewing the results of the study to ensure they resonated with their interviews and experiences. Our results and discussion were refined based on their suggestions to better represent and resonate with their experiences.\n\n\nResults\n\nThe findings section first describes the demographics of participants, and how our snowball sampling technique captured diverse populations of social media stakeholders and experts. The proceeding section describes the results of our analysis in each element of the Bolman and Deal’s framework. Participant quotations were placed in line to support our interpretations of the data in the contexts of the framework.\n\nA total of 16 participants were interviewed, with an average age of 43.3 (SD=8.32). The interviews were on average 30.3 minutes long, ranging from 22.5 minutes to 42.1 minutes. This yielded a total of 180 pages of transcripts.\n\nThe majority of participants were male (n=10/16). Most of our participants clinically or academically practiced in Western countries: 7 (44%) practiced in the USA; 4 (25%) in Australia, and 3 (19%) in Canada. Furthermore, the roles identified by our sample mostly consisted of clinicians (15.94%), teachers 14 (88%), and researchers (12.75%) which aligned with our intended target audience of capturing the perceptions of clinician educators and researchers working within organizations. We captured: 13 (81%) were affiliated with a national or international organization; 8 (50%) were affiliated with a journal or publication; and 8 (50%) identified not being affiliated with a journal or publication. Our interviewed participants utilized a wide array of social media platforms to disseminate their scholarly activities: 15 (94%) used Twitter; 8 (50%) used ResearchGate; 8 (50%) used Google Scholar; and 8 (50%) had an ORCID profile. Our recruitment process was able to capture a diverse amount of organization affiliations, allowing us to gain multiple perspectives around different organization frameworks. A full summary of participant demographics is outlined in Table 2.\n\nThe structural frame includes the governance, committee structures, policies and procedures, and organizational hierarchies present in institutions. Overall, there were several structural elements within the organizations that tended to incentivize work across all contexts. These incentives were described by participants in two ways: financial incentives, and non-financial incentives. Examples of financial incentives included grants and salary support. Most participants noted that they had little-to-no financial incentives. As one participant highlighted: “The hospital doesn't pay me to use Twitter. They pay me to write papers and to be a doctor. And Twitter … in my view should be an embellishment.”\n\nSocial media can also be seen as a lost opportunity from currently acceptable forms of scholarly activities while spending time on social media. However, many participants highlighted substantial nonfinancial incentives which were thought to include opportunities to engage in research and scholarship, to learn about new literature, and to recruit participants into their own scholarship. A participant whose primary incentive for social media use was to familiarize himself with new literature added that it is “well worth the investment of time even though it is not compensated”.\n\nSeveral structural elements were identified within organizations that supported our participants in their utilization of social media. These structural elements were grouped under three main themes: Hospital-based, Educational institutional-based, and Online organization-based structures.\n\nThere was a wide range in elements that were noted within the hospital-based structures, with more being structural barriers rather than enablers. For instance, some of the participants noted that hospitals tended to discourage their social media usage, while others were encouraged to have their own accounts. Mostly, if social media was permitted, it was usually not a high priority for organizations, and consequently participants felt that these roles were secondary to their other official roles. On the other end of the spectrum, one participant noted that their hospital had a fully integrated hospital-based social media team. Such hospitals clearly prioritized this type of communication in a fully structural way by creating infrastructure to support these activities.\n\nMany of our participants also held roles within educational institutions that may or may not have been intertwined with hospitals. Within these organizations, it was felt that structures that helped included the development of transparent policies and guidelines for social media integration into the university. One participant describes his desire for his organization to outline what social media tools they value, why, and how they value social media for promotion:\n\nAs it is in many institutions it is a rather nebulous concept that the unwritten rule is that it is not highly valued so don't waste your time here with social media. But it is not written explicitly anywhere in the anywhere in the promotions board or criteria. The only thing that is written in black and white at my institution is that if you are going to use social media then avoid politics and avoid slanderous jokes, avoid gender disparity and racial disparity comments. Very explicit statements about what not to do on Twitter but nothing about what to do or how they are going to value it.\n\nWithin this theme was the natural structural alignment between the institutional prerogatives for teaching and the methods by which this teaching could be accomplished via social media structures. Tweet chats or other online conversations or blogs for dissemination of content were seen as easy venues.\n\nOnline-based organizations tended to have the most non-hierarchical and organic structures. Participants described these structures as spaces to be creative. While some were described to have editorial systems (complete with peer review and editors), most of these organizations were outside the governance of hospitals or educational institutions. Mainly these groups arose as a mechanism to exist outside of formal structures, and yet over time had evolved to take on more structure, increasingly resembling the academic institutions with the evolution of distribution teams and some level of support/hierarchy for authors. Many had also evolved over time to go from more static entities (e.g. blogs) to more media-savvy entities that supported distribution across multiple platforms (i.e. a blog post is distributed across emails, Twitter, and Facebook), which required increased structures to support such processes. Figure 1 depicts the continuum in the level of perceived structures and policies pertaining to social media.\n\nThe human resources frame describes how an organization fulfills the needs of its members and how the organization allows the worker to express their skills and ideas to create the optimal individual-organizational alignment that benefits both parties (see Figure 2).\n\nOrganizational roles. In our interviews, it became clear that organizational roles pertaining to social media usage varied from being informal and volunteer-based, to being delegated with responsibilities, specified tasks, and embedded leadership levels. In most cases, work relating to social media was unpaid and uncompensated. In one participant’s organization, their academic work position did not require blog-writing; however, junior residents were required and expected to write blog posts, with senior residents supporting the blog through administrative tasks and a committee of residents managing the website. The residency blog of their organization has delegated roles for content managers (e.g. “putting the graphics up”, “running the website”) as well as managing editors (e.g. “administrative tasks”, “emailing people”) for coordination of content generation within their team of residents.\n\nAnother participant described their organization as having “four levels of involvement” for social media use: 1) a core executive team of individuals who run the fellowship program, the blog, the social media account, the website, and strategic initiatives; 2) the editors who lead and coordinate a series and set of resources; 3) contributors who help produce podcasts and write blog posts; and finally 4) the supporting staff and junior editors who help upload, copyedit, and perform miscellaneous tasks. Further participants were also found to have unpaid social media teams with individuals who have significant number of followers on Twitter. They are indirectly compensated through the waiving of registration fees for scientific assemblies and unlimited access to various conference sessions to tweet and disseminate information.\n\nEducational considerations of the human resources themes. Training of social media use by organizations through mentorship, role-modelling, and formal education programs within medical school curriculums are effective methods of supporting an individual’s capacity to learn and empowers members to feel supported and coached in these roles to encourage future participation in social media activities in academic work. These activities and programs are an example of how to address issues arising in the human resources frame such as how to keep individuals informed, involved, committed, and motivated in their work.\n\nA participant noted their start with social media through the role-modelling of colleagues who are experienced social media users, who “showed [them] that the typical peer reviewed journals don't have as much dissemination as would be optimal”. With the motivation to promote further dissemination, they learned how to use Twitter and grow an audience, “specifically to promote the growth of the journal and alt-metrics”. Another participant added to this notion, and suggested role-modelling through weekly discussion of blogs and podcasts with junior doctors would encourage social media involvement and knowledge on the value of these tools. This participant explains:\n\n...what might help particularly for the younger doctors is if for example: we do a blog post of the week and make it easier for younger doctors to access the blog posts and podcasts and to discuss it for example on Tuesday morning after handover. I think something like that would really help younger doctors to get more involved in social media. But also, to get an idea of which blogs and or podcasts are of higher value. And which ones to follow or read.\n\nOne participant described how social media use is being integrated in curriculums for second-year students in the medical education scholarly concentration track; in these social teaching sessions, students are taught “how to utilize [social media] for their professional brand” and as a way of networking.\n\nThe political frame articulates how various actors within the organization garner and wield influence and power. Our participants described different mechanisms and processes that influenced their behaviors surrounding social media utilization and their organizational influence, which are modeled in Figure 3.\n\nThe accumulation of scholarly currency, which we define as the gradual acquisition of political stakeholdership and influence in the respective field of practice, are the drivers for this model. Pointed arrows originating from concepts in green are enablers that promote scholarly currency accumulation, while flat-head arrows originating from concepts in red are inhibitors. Our findings in our model highlight five progressive stages with respect to the online community of practice (CoP) which will be defined further in this section: the “Self” phase, novice member of CoP, intermediate member of CoP, Expert in CoP and acknowledgement in real life.\n\nCommunity of Practice (CoP). Many participants described engaging, collaborating and networking with a larger network of “scholars” and “communities” on social media, as one interviewee eloquently puts it:\n\n“Twitter allows you to have a community that you may not have even though you are in a job around similar, like[-minded] people. It allows you to develop an even larger or very strong, connected professional community. It allows you to, you have access to other experts you can learn [from], so something […] is given to you. That is a benefit of Twitter.”\n\nAs this concept frequently emerged in our interviews, we have decided to articulate these entities as the “community of practice (CoP)”, as we felt they were aligned with the concepts originally highlighted by Lave and Wenger29. Participants described collaborations within the CoP to serve as the heart when building scholarly currency and academic stakeholdership. Interestingly, by fostering active communities around a given practice, organizations\n\nThe “Self” phase. Initial engagement of social media begins by developing a digital identity.Participants in this phase carry forward defined research interests and begin to generate forms of content related to their academic work. Utilizing social media’s ability to “reach a broader audience” and “get your message out there” allowed participants to start building an identity and status as a social media researcher. Participants primarily used Twitter as a “mechanism to promote any of the publications that [they] had at any given time.” Building metrics on other platforms such as Google Scholar or ResearchGate were also ways that contributed to solidifying an online research identity in their field of practice. As the digital identity is in its beginning stages, participants initially engage with CoP in forms of “partaking in…conversations and [getting] involved in conversations that other people have started,” “sharing articles that [they] find interesting” or “[commenting] on [the] interpretation of scientific articles.” Development from this engagement have resulted in early forms of collaborations in some participants, including sharing viewership and collaborating through “[recording] a podcast with other [podcast organizers].”\n\nThe rate at which online identity manifests was affected by the levels of organizational support received by scholars. Participants who experienced institutional support regarding their social media scholarship found their “organization keen to promote and amplify individual Twitter or individual social media outputs from people, particularly when it comes to highlighting publications,” which assisted in disseminating and promoting their work. Other participants however felt a described “lone wolf” status, where their home institutions did actively not support or engage with their scholarly social media work. These participants, despite valuing institutional support, expressed frustration in receiving lack thereof as one of our participants highlight:\n\nI have tried to engage them when there are news stories that are on the mass media that are applicable to our organization. And in that they name our organization for something good that has happened. I tag our organization social media feed—they are on Twitter. Both the hospital and the healthcare system are on Twitter. So, I send them emails saying here is the tweet that I sent. It would be helpful if the organization would retweet this or tag some high-yield folks on this. This is a good story for our organization..., [but] there has never, ever been a response, positive, negative, or thank you or anything.\n\nNovice members of CoP. As the promotion of content continues, types of content and strategies that garner followers are identified and reproduced, leading to further frequent engagement and acknowledgement with the CoP. At this point, the researcher begins to realize their field of online engagement as a social media researcher and has reached the milestone receiving a novice membership in the CoP. Participants described their intention of continuing to engage with their respective CoP by using engagement strategies to promote discussion, as one participant describes: “When I see new research coming out of any of our journals that I think have a compelling point or merit for the dissemination then I will capture the URL. And send out a tweet with some questions trying to tag a few individuals who I think are in that research field.”\n\nAs production, consumption and engagement continue to build scholarly currency, participants begin to build a “network with people who are like-minded [that] increase the chance of collaboration and future grant success,” which can result in the collaboration of a “variety of projects, things like studies, educational endeavors and all sorts of different work.”\n\nIntermediate members of CoP. Consistent engagement allows further establishment within the CoP, subsequently allowing the third phase of becoming an intermediate member of the CoP. In this phase, the researcher has also established a base audience or target following, and can identify a close group of collaborators. The roles of which participants took online towards their audience or CoP were diverse. One participant who runs an educational blog as a knowledge dissemination tool for other clinicians described:\n\nI spend an awful lot of time writing for an educational blog that I know generates discussion and has positioned me as somebody who influences the discussion around education. And some of the blog post that I am getting are having you know five or six thousand views and comments.\n\nOther participants established their platform as an education tool for the general public to teach or generate discussions. In one participant’s case, they used their professional expertise in toxicology to “teach about drug related topics” on Twitter. Utilizing the network and following now built, the previous transition mechanisms from stages 2 to 3 can be repeated to continually generate scholarly currency.\n\nExpert members of CoP. When enough scholarly currency is attained, the individual will become recognized by the CoP as an expert, experiencing academic influence that bleeds and translates into the researcher’s identity in real life: “[Twitter] allows you to brand yourself as a leader in the field and it helps you to be established at your own institution.”\n\nThese influences also take the form of many scholarly outcomes. For instance, the opportunities from social media scholarship allowed participants “to talk at international conferences and get involved in international guidelines.” Others commented on social media’s ability to bolster faculty development and find international collaborators, as one of these participants highlight:\n\nAs a [physician] working in a small community normally not the kind of person that would have a big academic career. And it was only through social media a context that I have been invited to, I have written a number of textbook chapters, I have a large number of academic publications I have been invited to like the [American Heart Association] guideline meetings to speak.\n\nOur findings from our participants also noted one unconventional academic contribution to social media regarding a grant application as they describe:\n\nTo be honest a reviewer from my grant actually commented on, like, the amount of followers etc. on my blog and podcast as a positive [factor] when they reviewed my grant application. And [they] noted that it was sort of an atypical pathway but also impressive. So even a very non-social media thing like, you know, applying for a grant for something completely unrelated to social media even that sort of helped me out there.\n\nInhibitors of scholarly growth. Meanwhile, our participants described some negative influence towards social media usage. Organizations which were anxious to control their message and utilize their hierarchy to do so, as one participant highlights: “[Institutions] seem to be very nervous about their employees or the members of the organization using it because they don't really have control over that content. And that seems to make the organizations a little bit nervous.”\n\nPolitical constraints of this type within an organization inhibit individuals from progressing through the various stages of their development from individuals to leaders in their academic spheres. Furthermore, this increases the learning curve for researchers unfamiliar with these platforms that are transitioning to use social media to augment their work. Similarly, the political ramifications (e.g. intellectual property concerns and copyright issues) around content generated within their academic or social media roles had an effect on scholarly growth, often deterring individuals from using social media platforms:\n\n...Copyright is tough! ...There are others that I know that are producing content that they feel a little bit differently about and are having trepidation about the security of that ...But certainly, privacy and the ownership of content [issues] of varying degrees, so I know that there are people who are very reluctant to venture into the realm just because of those issues.\n\nThe symbolic frame represents the motivations or sense of purpose from members within an organization. This section provides insights on various ways that organizations can use or support social media to promote their citizens’ sense of purpose and promote their organizational mission. Our analysis revealed that participants had different symbolic values for the use and integration of social media. While some participants sought ways to integrate in their practices in traditional organizations, others found non-traditional groups to associate with. They also mentioned the ways of how intrinsic and extrinsic motivation enables them to contribute to the organization values. For example, enjoyment is worth mentioning as highlighted: “I would say that I do that journal club for free. I do it as a member of the editorial board of the journal, it is sort of a service that took up a couple of years ago and I like it. I don't get paid for it.”\n\nOn the other hand, some participants mentioned social media as a manifestation of their mission as a traditional aspect. They perceive that the transition to social media can be attributed to people as well as the organization itself depending on the situation.\n\nThe symbolic frame also seemed to have impact on either intrinsic or extrinsic motivations of individuals within organizations. Organizations who supported and rewarded their members in non-traditional ways seemed to be fairly better in generating success for those individuals within the social media domain – suggesting that by supporting and rewarding these individuals, they were providing some level of extrinsic motivation.\n\nOthers were less motivated by organizational rewards and support. Many of these individuals noted that it was the other people within the organization that were key to their continued participation. The opportunity to engage in forming new organic social relationships between like-minded people in real life were examples of non-traditional methods of fostering intrinsic motivation. One participant underlined the meaning of strong connection with colleagues here:\n\n...we do lots together socially. We are [a] fairly tight-knit group and so I would say that three or four times a week we are doing things socially together and there are a couple of ways that comes to be. Either usually it will be like people who are working together so like staff and residents who are working together will after a shift decide to go out and hangout. Or sometimes it’s like third year residents are responsible for the social kind of aspect of our programs so they will organize things. Or we also have a WhatsApp group through which you know somebody will just organize something sort of casually.\n\nTraditions have a great deal of impact on social media, as participants mentioned. Organizational supports for social media enabled practices in workplace provide variety of options for their employees. For example, alternative communication options or cultivating communities of practices with organization support is found an important extrinsic motivator. This experience is described in this quote:\n\nI would say that my department overall is pretty positive on social media. There are a number of faculty members and residents who have… not [had] incredible involvement in social media but are on Twitter and do you some participation in some blog activities and other activities in the general [free open access medical education] world. … Overall, I think that the attitude is pretty positive for it.\n\nIn more traditional organizations, social media was often deemed as added activity to be engaged in on individual spare time or perhaps as an adjunct to more traditional scholarly pursuits (e.g. to engage in gaining online engagement with one’s research article). Individuals in these organizations were extrinsically motivated to strongly align their social media work with other traditional roles (e.g. journal editor, researcher) that are already valued, so as to better reap the benefits of the organizations’ support. This participant quote highlights this perceived need for alignment:\n\nThey might perceive that I spend too much time on it which is perhaps true. But I think it is fair to say that Twitter side, I am perceived as having expertise, world-class expertise I mean in my area of research. And I think that Twitter supports that in a way. And I think the university sees that.\n\nFigure 4 depicts a 2 x 2 table that highlights how the traditional vs. non-traditional and intrinsic vs. extrinsic motivators intersect.\n\nAlthough the following topics were not considered in the scope of this study, we also found some non-organizational personal perspectives with regards to social media usage that were shared by some respondents. For example, not all respondents were convinced that social media was a useful tool. This might be related to another shared belief that social media promotes interaction without any real emotional investment. Finally, some reported that they are not sure how to use platforms such as Instagram, although they do consider them to be visually appealing.\n\n\nDiscussion\n\nThis study focused on how institutions have been reframing their organizations for using social media, specifically harnessing the lens afforded to us by the Bolman and Deal’s Four-Frame Model24. Our findings provide insights about how a new form for scholarship (e.g. social media) interacts with hospital-based, academic, and online-only organizations.\n\nSocial media has the power to boost organizations’ productivity or visibility30 and applying the four-frame model allows us to identify the structures, human resources, political mechanisms, and symbols that will best enable this. Setting forth a solid structural foundation that acknowledges the existence of social media within an organization is a first step. Subsequently, supporting those structures with adequate human resources to engage in social media opportunities is the next step. Proceeding this, navigating the politics and influence of various forces (such as academic or scholarly credit) is important to bear in mind when aiming to foster social media within health- and academic-based organizations. And finally, symbolic alignment of organizations and individuals can help even greater to build up shared values. Clearly, emerging forms of scholarly work (such as teaching on social media) can be integrated into our existing structures and applying the Four-Frame model may help us to expedite this for other forms of new scholarship.\n\nBolman and Deal’s Four-Frame Model24 allow us to identify the weaknesses within organizations for any aspect, but in our particular study, we have used it as a lens to explore social media usage. Our approach of using this framework to analyze social media is a worked example of how one might also investigate the current status of any new phenomenon in their organizations. One might similarly have asked clinicians and researchers about how we may use artificial intelligence within medicine through using the Bolman and Deal’s model to examine how institutions are adopting this technology or lack thereof (or not). While this framework is originally meant for leaders who want to change or to build capacity in the organizations, it can also be used by those interested in examining emergent phenomena in our organizations.\n\nThe key insights that we have gained from our participants are how new emerging forms of scholarly pursuits can be more effectively enabled or hindered by the attributes of the organization within which these are occurring.\n\nOther change frameworks such as Kotter’s Eight Steps for Leading Organizational Change31 or Roger’s Diffusion of Innovation32 certainly have some resonance with our present topics. However, Kotter’s framework can be seen more as a playbook for leaders who are implementing an organizational change, and does not provide the necessary ingredients to outline how one might ensure they comprehensively prepare their organization for the change, addressed by the way that Bolman and Deal’s Four-Frame Model outlines how one might ensure they comprehensively prepare their organization for the change. Meanwhile, Roger’s model more aptly describes how innovations move throughout society. It has been criticized as a framework for organizations to examine their technology adoption33. In our present study, one of the key insights is that an individual’s choice to pursue new forms of scholarship may have more to do with the organization perspective on change or innovation, and less to do with their personal attributes.\n\nIn our study, harnessing the power of Bolman and Deal’s framework maps well to organizational changes as observed by frontline champions of a new technology (i.e. social media). Our findings suggest that others may find it useful for analyzing their organization’s structural, human resources, political, and symbolic components when enacting change. For instance, in the wake of the pandemic many educators are cognizant that there is a need for greater health advocacy34, physician wellness, and equity work35. Our study suggests that organizations seeking to implement changes to enable great health advocacy, physician wellness, or health equity work may find the Bolman and Deal’s framework useful to review the organizational structures that can enable this type of work to be done. In this study, we have mapped the social media work of emerging digital scholars to the Four Frames, others may find this framework similarly useful for mapping the experiences of those in these other new and emerging streams of scholarly work. Strategically, when fostering new lines of scholarship, we propose that our present study shows how relevant the Four Frames can be for improving conditions for those engaging in novel academic work. As seen in our study, when academic leaders attempt to foster new initiatives, there can be gaps in the support for these endeavors (e.g. a mandate is created without the human resources or budgetary support) leading to unsustainable.\n\nWe worked on eliminating the limitations of the study. Our senior author (TMC) is a social media expert and is highly engaged in organization change strategies as administrator. She was not involved in data collection and was blinded to participants’ identities in this study. While her expertise helped to improve understanding concepts as a leader and social media user, we ensured that her interpretation was aligned with the participants’ views. Participants included international stakeholders who are members of international organizations. Potential cultural differences between organizational structures and hierarchies may affect direct transferability of our findings. Our sampling technique may also omit some emerging leaders on social media during the sampling process. Due to the rapidly changing landscape of users and conversations on social media, we may not have included other relevant leaders in our study.\n\n\nConclusions\n\nSocial media was originally a user-based platform, but increasingly has a greater role in our academic health sciences organizations for knowledge translation and education. Our findings show that Bolman and Deal's Four-Frame Model may serve an effective guideline for academic leaders who wish to strategically implement or enhance social media into their organizations. Further research is required to elucidate whether enhancing components of the Four-Frame Model may be tactically implemented to improve the capacity of academic institutions to engage in higher quality education or knowledge translation.\n\n\nData availability\n\nDue to confidentiality reasons our institutional review board does not allow open data sharing of the qualitative data from this study (i.e. the transcripts). For those interested in accessing this dataset, please contact the corresponding author Teresa Chan (teresa.chan@medportal.ca), who will arrange access to our dataset after institutional protocols including a non-disclosure agreement and/or formal institutional inter-institution agreement are completed.",
"appendix": "Acknowledgements\n\nWe would like to thank Aisha Mohamed and Emma Bridgwater for their assistance in the development and early recruitment phases of this study. We also thank Elizabeth Clow for her services as a transcriptionist for our project.\n\n\nReferences\n\nAhmad AR, Murad HR: The Impact of Social Media on Panic During the COVID-19 Pandemic in Iraqi Kurdistan: Online Questionnaire Study. J Med Internet Res. 2020; 22(5): e19556. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeschamps T: Platforms struggle to keep up with moderating content amid COVID-19. CTVNews. Published June 7, 2020, Accessed July 17, 2020. Reference Source\n\nOhlheiser A: Doctors are now social-media influencers. They aren’t all ready for it. MIT Technology Review. Published 2020, Accessed July 17, 2020. Reference Source\n\nPazzanese C: Battling the ‘pandemic of misinformation.’ Harvard Gazette. Published May 8, 2020. Accessed July 17, 2020. 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PubMed Abstract | Publisher Full Text\n\nSingh L, Bansal S, Bode L, et al.: A first look at COVID-19 information and misinformation sharing on Twitter. ArXiv200313907 Cs. 2020. Accessed July 17, 2020. PubMed Abstract | Free Full Text\n\nLu D, Ruan B, Lee M, et al.: Good practices in harnessing social media for scholarly discourse, knowledge translation, and education. Perspect Med Educ. 2021; 10(1): 23–32. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRead R: Doctor fired after criticizing his hospital for coronavirus response. Los Angeles Times. Published April 4, 2020. Accessed July 17, 2020. Reference Source\n\nCadogan M, Thoma B, Chan TM, et al.: Free Open Access Meducation (FOAM): the rise of emergency medicine and critical care blogs and podcasts (2002– 2013). Emerg Med J. 2014; 31(e1): e76–e77. PubMed Abstract | Publisher Full Text\n\nTing DK, Thoma B, Luckett-Gatopoulos S, et al.: CanadiEM: Accessing a Virtual Community of Practice to Create a Canadian National Medical Education Institution. AEM Educ Train. 2019; 3(1): 86–91. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCheston CC, Flickinger TE, Chisolm MS: Social media use in medical education: a systematic review. Acad Med. 2013; 88(6): 893–901. PubMed Abstract | Publisher Full Text\n\nFenwick T: Social Media and Medical Professionalism: Rethinking the Debate and the Way Forward. Acad Med. 2014; 89(10): 1331–1334. PubMed Abstract | Publisher Full Text\n\nLopez M, Chan TM, Thoma B, et al.: The Social Media Editor at Medical Journals: Responsibilities, Goals, Barriers, and Facilitators. Acad Med. 2019; 94(5): 701–707. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChretien KC, Kind T: Climbing Social Media in Medicine’s Hierarchy of Needs. Acad Med. 2014; 89(10): 1318–1320. PubMed Abstract | Publisher Full Text\n\nHamm MP, Chisholm A, Shulhan J, et al.: Social Media Use by Health Care Professionals and Trainees: A Scoping Review. Acad Med. 2013; 88(9): 1376–1383. PubMed Abstract | Publisher Full Text\n\nRoland D, Spurr J, Cabrera D: Preliminary Evidence for the Emergence of a Health Care Online Community of Practice: Using a Netnographic Framework for Twitter Hashtag Analytics. J Med Internet Res. 2017; 19(7): e252. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRuan B, Yilmaz Y, Lu D, et al.: Defining the Digital Self: A Qualitative Study to Explore the Digital Component of Professional Identity in the Health Professions. J Med Internet Res. 2020; 22(9): e21416. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBehringer N, Sassenberg K: Introducing social media for knowledge management: Determinants of employees’ intentions to adopt new tools. Comput Hum Behav. 2015; 48: 290–296. Publisher Full Text\n\nNamisango F, Kang K: Organization-public relationships on social media: The role of relationship strength, cohesion and symmetry. Comput Hum Behav. 2019; 101: 22–29. Publisher Full Text\n\nBolman LG, Deal TE: Reframing Organizations: Artistry, Choice and Leadership. 6th edition. Jossey-Bass & Pfeiffer Imprints, Wiley; 2017. Reference Source\n\nO’Brien BC, Harris IB, Beckman TJ, et al.: Standards for Reporting Qualitative Research: A Synthesis of Recommendations. Acad Med. 2014; 89(9): 1245–1251. PubMed Abstract | Publisher Full Text\n\nRiddell J, Brown A, Kovic I, et al.: Who Are the Most Influential Emergency Physicians on Twitter? West J Emerg Med. 2017; 18(2): 281–287. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChan T: Social Media & Knowledge Translation: A Qualitative Study - Interview Guide. Preprints; 2021.\n\nRitchie J, Spencer L: Qualitative data analysis for applied policy research. In: Bryman A, Burgess RG, eds. Analyzing Qualitative Data. Routledge; 1994; 173–194. Publisher Full Text\n\nLave J, Wenger E: Situated Learning: Legitimate Peripheral Participation. 1st ed. Cambridge University Press; 1991. Reference Source\n\nNascimento AM, da Silveira DS: A systematic mapping study on using social media for business process improvement. Comput Hum Behav. 2017; 73: 670–675. Publisher Full Text\n\nKotter JP: Leading Change. Harvard Business Press; 2012. Reference Source\n\nRogers EM: Diffusion of Innovations, 5th Edition. Simon and Schuster; 2003; 576. Reference Source\n\nLundblad JP: A Review and Critique of Rogers’ Diffusion of Innovation Theory as It Applies to Organizations. Organ Dev J. 2003; 21(4): 50. Reference Source\n\nChesley C, Lee JT, Clancy CB: A Framework for Commitment to Social Justice and Antiracism in Academic Medicine. ATS Sch. 2021; 2(2): 159–162. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGateau KL: White Coats for Black Lives. J Grad Med Educ. 2021; 13(3): 327–328. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "97582",
"date": "15 Nov 2021",
"name": "Alice Fornari",
"expertise": [
"Reviewer Expertise health professions education",
"faculty development",
"mentoring",
"teaching and 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 qualitative study presents data very relevant to medical education today. Social media is a part of daily personal lives and for many has entered their professional lives as a source of colleagueship, resources and recognition of accomplishments. The attempt by the authors to frame the approval, use and extent of institutional support for social media across institutions through semi-structured interviews is definitely out of the box thinking and fills a gap in the literature specific to academic and scholarly activities. Their selection of Bolman and Deal as a leadership and organizational framework is evidenced based outside of academic health centers and is certainly applicable to the academic healthcare institutions and this is evidenced in their results and discussion. Which author made this connection of using this framework should be applauded for connecting an organizational psychology approach to academic healthcare. The introduction fills a gap and captures the reader with a hook. The methods are detailed and follow all \"rules\" of qualitative research. The results are supported and quotes selected to report engaging are applicable to the original intent of the article. The figures are additive and clarifying and supported by the research process and data collected.\n\nI look forward to this article being indexed and shared.\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": "7444",
"date": "01 Dec 2021",
"name": "Teresa Chan",
"role": "Author Response",
"response": "Thank you Dr. Fornari for your supportive review of this work."
}
]
},
{
"id": "99753",
"date": "02 Dec 2021",
"name": "Catherine M. Giroux",
"expertise": [
"Reviewer Expertise Social media",
"Health Professions Education",
"Knowledge Translation",
"Qualitative Research",
"Mixed Methods 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 the opportunity to review this interesting and timely qualitative study of social media use within Academic Health Science Centers (AHSCs) based on Bolman and Deal’s Four-Frame model. The article starts with an overview of the role of AHSCs in communicating health-related information and describes social media as one way of doing so. The authors discuss communication challenges that exist between physicians and AHSCs, especially throughout the COVID-19 pandemic and on social media. The authors interviewed 16 emergency physicians to explore how organizational structures emerge or evolve around new forms of scholarship. Specifically, the authors used Bolman and Deal’s framework to explore the hierarchical structures, human resource and training needs, impacts on scholarly currency, and organizational supports for integrating social media within AHSCs. This topic is timely and relevant to a medical education audience.\nI think that this article has merit and should be accepted with reservations. There are a few major and minor points for the authors to address prior to the article being indexed. I will explain my concerns in more detail.\nMajor comments:\nThis study is framed broadly at the institutional level (i.e., academic health sciences centers) but is derived from 16 semi-structured interviews with emergency physicians. Based on the population and sample size, I recommend framing the study as one of emergency physicians’ perceptions of institutional social media adoption since the findings cannot be generalized or easily transferred to specific institutional contexts or to entire institutions.\n\nWhat is missing from both the introduction and discussion section is contextual information about how communications work in AHSCs. For instance, many have designated communications teams that handle social media for the institution. Others may have specific social media policies that are publicly or internally articulated. What implications does this study of emergency physicians’ use of social media and/or perceptions of institutional adoption of social media have for AHSCs with diverse structures and policies? Would the findings of this study be relevant to all groups within an AHSC (e.g., other medical specialties, nursing, rehab, admin, communications)? As written, the study appears to address the barriers and facilitators to physician uptake of social media within AHSCs rather than broad AHSC uptake of social media.\n\nMinor Comments:\nGeneral comments:\nKnowledge translation appears in the abstract and throughout the paper but is not defined or operationalized. Including a definition of knowledge translation and explicit connection between social media and knowledge translation would be beneficial.\n\nThere is inconsistency in the lead author’s initials throughout the paper. Sometimes they include an M and sometimes they do not.\n\nProviding a definition of social media would be beneficial; for instance, why is ORCID considered social media in this instance? By some definitions, it might not be.\n\nThe Findings section is not just a presentation of the findings but rather, includes the authors’ interpretations of the findings. To that end, the authors might wish to consider merging the findings and discussions sections so that they can present their findings and discuss them simultaneously.\n\nAbstract:\nP. 1 - There is some awkward wording in the results section of the abstract. In the structural frame section, the wording “institution types were reported to have with diverse hierarchical structures” is unclear.\n\nP. 1 - There is inconsistency in the use of ‘the’ when referring to the frames in the abstract. Including the word ‘the’ before stating each frame (i.e., the symbolic frame) is how it is most commonly presented throughout the manuscript.\n\nIntroduction:\nP. 3 – The argument in the second paragraph related to AHSCs could be expanded on further for clarity. The current phrasing appears to draw a cause and effect relationship between misinformation and the lack of communication between AHSCs and their employees. Expanding further on why AHSCs were unprepared to tackle misinformation, who the employees referred to are (e.g., communications teams? Physicians?), and who the target audience of communication about misinformation is (i.e., patients/public? Employees?) would be beneficial here.\n\nP. 3 - The term ‘online based organizations outside of their institution’ would benefit from definition or examples of what these might be. Operationally defining this term will help the reader differentiate these organizations from formal institutional structures.\n\nP. 3 – The sentence “This can be accomplished by reframing the institution’s organizational framework in the contexts of integrating and adopting social media utilization and training towards staff” might benefit from being rephrased or split into two sentences.\n\nP. 3 – The sentence “One benefit of having organizations in supporting staff’s utilization of social media on the organizational level will allow more explicit policies for staff that allow professional behaviour and conduct on social media” could also benefit from rephrasing or being split into two sentences.\n\nP. 3 – The sentence “The need for reframing organizations in the contexts of social adoption will allow AHSCs to better prepare and combat this” is missing the word ‘media’ following ‘social’. The authors may also consider adding the word ‘for’ following the word ‘prepare’.\n\nThe overview of Bolman and Deal’s four-frame model is well articulated, especially for those who are unfamiliar with the concept.\n\nMethods:\nP. 3 - Including a short explanation and justification of the quasi-deductive thematic framework analysis approach would be beneficial.\n\nP. 3 – SRQR should be written out in full on first use and abbreviated thereafter.\n\nP. 4 – the Research Team Reflexivity paragraph switches between past and present tense. Editing for consistency is recommended.\n\nP. 4 – The sentence “Furthermore, the composition of the team consists of a senior lead (TMC) who is a medical physician with expertise in qualitative analysis, free open access medical education resource dissemination and social media stakeholdership, a postdoctoral fellow who is an expert in qualitative analysis and social media education” would benefit from being split into two sentences with each sentence reflecting each researcher. The postdoctoral fellow could have their initials identified for consistency since the rest of the team does.\n\nP. 4 – The authors indicate that the present study is a sub-study. Additional details regarding the initial inquiry and how this work fits within the overall program of research would be beneficial.\n\nP. 4 – A citation supporting the use of snowball sampling for ill-defined populations is recommended.\n\nP. 4 – In the first sentence of the Data Collection and Processing section, the apostrophe on the word ‘individuals’ should be placed after the s for a plural possessive (i.e., individuals’).\n\nP. 5 – In the Rigour and Trustworthiness section, the sentence “The research team ensured the trustworthiness of the study applying several techniques” would benefit from adding the word ‘by’ before the word ‘applying’.\n\nResults:\nP. 6 – In the Structural Frame section, the sentence “Overall, there were several structural elements within the organizations that tended to incentivize work across all contexts” requires clarification. Is this work related to social media? If not, what kind of work?\n\nP. 6 – the sentence “social media can also be seen as a lost opportunity from currently acceptable forms of scholarly activities while spending time on social media” is circular. Why is social media currently not incentivized as a scholarly activity? Alternatively, is the perception that social media is a waste of time?\n\nP. 7 – In the second paragraph of the Organizational Roles section, the sentence “further participants were also found to have unpaid social media teams with individuals who have significant number of followers on Twitter” suggests that the participants have their own social media teams. Is this the case?\n\nP. 7 – The first sentence of the Educational Considerations section would benefit from being split into two or more separate sentences.\n\nThe results section alternates between past and present tense. Consistently using the past tense is recommended.\n\nP. 9 – The word ‘media’ appears to be missing from the sentence “in these social teaching sessions, students are taught ‘how to utilize [social media] for their professional brand’ and as a way of networking”. Media could be inserted between the words ‘social’ and ‘teaching’ in this instance.\n\nP. 10 – Adding a brief operational definition of Communities of Practice as conceptualized by Lave & Wenger would be helpful.\n\nP. 10 – The words “of which” could be removed from the following sentence for clarity: “The roles of which participants took online towards their audience or CoP were diverse”.\n\nP. 11 – In the Inhibitors of Scholarly Growth section: The word ‘which’ could be removed from the following sentence for clarity: “Organizations which were anxious to control their message and utilize their hierarchy to do so…”.\n\nP. 12 – The first participant quote is worded in the following way “… not [had] incredible involvement in social media but are on Twitter and do you some participation…” Is this accurate?\n\nDiscussion:\nP. 13 - The sentence “While this framework is originally meant for leaders who want to change or to build capacity in the organizations, it can also be used by those interested in examining emergent phenomenon in our organizations” requires a citation.\n\nP. 13 – The sentence “The key insights that we have gained from our participants are how new emerging forms of scholarly pursuits can be more effectively enabled or hindered by the attributes of the organization in which they are occurring” appears vague. Including specific examples of the key insights and organizational attributes would be beneficial.\n\nP. 13 – The final sentence of the discussion appears incomplete: “As seen in our study, when academic leaders attempt to foster new initiatives, there can be gaps in the support for these endeavours leading to unsustainable”. Unsustainable what?\n\nP. 13 – Limitations: Are there any limitations from using a predefined list of social media influencers? Are there any limitations of including only emergency physicians’ perspectives? Are there any geographic limitations regarding who is considered an influencer and is therefore included in the study (i.e., the prevalence of US, Australia, and Canada as compared to how social media is used in institutions elsewhere)?\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? Partly",
"responses": [
{
"c_id": "7534",
"date": "13 Dec 2021",
"name": "Teresa Chan",
"role": "Author Response",
"response": "Dear Dr. Giroux, Thank you for taking the time to provide us with such a detailed review of our paper. We know that this paper has been enhanced by your time and care, and we are greatly indebted to you for this. For the record, we have placed our replies to your thoughtful suggestions alongside your initial reviews. Our replies are indicated by the term \"Reply:\" to differentiate our responses from your initial reviews for future readers. Thank you for the opportunity to review this interesting and timely qualitative study of social media use within Academic Health Science Centers (AHSCs) based on Bolman and Deal’s Four-Frame model. The article starts with an overview of the role of AHSCs in communicating health-related information and describes social media as one way of doing so. The authors discuss communication challenges that exist between physicians and AHSCs, especially throughout the COVID-19 pandemic and on social media. The authors interviewed 16 emergency physicians to explore how organizational structures emerge or evolve around new forms of scholarship. Specifically, the authors used Bolman and Deal’s framework to explore the hierarchical structures, human resource and training needs, impacts on scholarly currency, and organizational supports for integrating social media within AHSCs. This topic is timely and relevant to a medical education audience. Reply: Thank you. I think that this article has merit and should be accepted with reservations. There are a few major and minor points for the authors to address prior to the article being indexed. I will explain my concerns in more detail. Reply: Thank you for your suggestions. Major comments: This study is framed broadly at the institutional level (i.e., academic health sciences centers) but is derived from 16 semi-structured interviews with emergency physicians. Based on the population and sample size, I recommend framing the study as one of emergency physicians’ perceptions of institutional social media adoption since the findings cannot be generalized or easily transferred to specific institutional contexts or to entire institutions. Reply: Thank you for this comment, as you can see from the first table, our snowball sampling allowed us to start with emergency physicians, but evolved via the snowball sampling to include others. We had physicians from other specialties and also non-physician researchers. We have changed the initial part of the results to explain that 12/16 were emergency physicians. We have changed the title to clarify that this was a study in emergency physicians and other researchers. What is missing from both the introduction and discussion section is contextual information about how communications work in AHSCs. For instance, many have designated communications teams that handle social media for the institution. Others may have specific social media policies that are publicly or internally articulated. What implications does this study of emergency physicians’ use of social media and/or perceptions of institutional adoption of social media have for AHSCs with diverse structures and policies? Would the findings of this study be relevant to all groups within an AHSC (e.g., other medical specialties, nursing, rehab, admin, communications)? As written, the study appears to address the barriers and facilitators to physician uptake of social media within AHSCs rather than broad AHSC uptake of social media. Reply: Thank you for pointing this out. We have altered the initial framing and discussion to highlight this. In the introduction we mention physicians only once pertaining to a specific example, the rest of the framing is around healthcare practitioners more broadly. We have aimed to be both more specific and more broad in our articulation of our intended target audience. We have highlighted how the barriers and facilitators of individuals like our participants engaged in social media are key to broader uptake. We have explained our perspective in this statement within the discussion: “For organizations such as AHSCs to adopt these technologies for the improvement of healthcare, new policies or structures must be created to enable individuals within an organization to thrive – after all, most organizations are groupings of individuals who are connected within a system.” Minor Comments: General comments: Knowledge translation appears in the abstract and throughout the paper but is not defined or operationalized. Including a definition of knowledge translation and explicit connection between social media and knowledge translation would be beneficial. Reply: Thank you for the suggestion. This has been done. There is inconsistency in the lead author’s initials throughout the paper. Sometimes they include an M and sometimes they do not. Reply: Thank you for the suggestion. This has been done. Providing a definition of social media would be beneficial; for instance, why is ORCID considered social media in this instance? By some definitions, it might not be. Reply: Thank you for the suggestion. This has been done. We have placed our definition in the introduction in parentheses now – “social media (broadly described as internet enabled applications that allow users to share/create content and participate in shared networking)” The Findings section is not just a presentation of the findings but rather, includes the authors’ interpretations of the findings. To that end, the authors might wish to consider merging the findings and discussions sections so that they can present their findings and discuss them simultaneously. Reply: The discussion has been kept in this format as we felt it would be important to zoom out again to help readers contextualize our findings. As we are using a framework analysis and a constructivist orientation, our interpretation of the findings are certainly interwoven throughout the paper’s results section. Abstract: P. 1 - There is some awkward wording in the results section of the abstract. In the structural frame section, the wording “institution types were reported to have with diverse hierarchical structures” is unclear. Reply: This has been clarified as best we could. P. 1 - There is inconsistency in the use of ‘the’ when referring to the frames in the abstract. Including the word ‘the’ before stating each frame (i.e., the symbolic frame) is how it is most commonly presented throughout the manuscript. Reply: This has been done. Introduction: P. 3 – The argument in the second paragraph related to AHSCs could be expanded on further for clarity. The current phrasing appears to draw a cause and effect relationship between misinformation and the lack of communication between AHSCs and their employees. Expanding further on why AHSCs were unprepared to tackle misinformation, who the employees referred to are (e.g., communications teams? Physicians?), and who the target audience of communication about misinformation is (i.e., patients/public? Employees?) would be beneficial here. Reply: This has been clarified. Generally, the literature cited had a broad target audience so the term employees would be quite broadly applicable. We changed the term to “citizens” to make this more clear. P. 3 - The term ‘online based organizations outside of their institution’ would benefit from definition or examples of what these might be. Operationally defining this term will help the reader differentiate these organizations from formal institutional structures. Reply: This has been added. P. 3 – The sentence “This can be accomplished by reframing the institution’s organizational framework in the contexts of integrating and adopting social media utilization and training towards staff” might benefit from being rephrased or split into two sentences. Reply: We have rephrased this as requested. P. 3 – The sentence “One benefit of having organizations in supporting staff’s utilization of social media on the organizational level will allow more explicit policies for staff that allow professional behaviour and conduct on social media” could also benefit from rephrasing or being split into two sentences. Reply: This has been rephrased. P. 3 – The sentence “The need for reframing organizations in the contexts of social adoption will allow AHSCs to better prepare and combat this” is missing the word ‘media’ following ‘social’. The authors may also consider adding the word ‘for’ following the word ‘prepare’. Reply: This has been rephrased. The overview of Bolman and Deal’s four-frame model is well articulated, especially for those who are unfamiliar with the concept. Reply: Thank you. Methods: P. 3 - Including a short explanation and justification of the quasi-deductive thematic framework analysis approach would be beneficial. Reply: This has been done. P. 3 – SRQR should be written out in full on first use and abbreviated thereafter. Reply: This has been done. P. 4 – the Research Team Reflexivity paragraph switches between past and present tense. Editing for consistency is recommended. Reply: This has been corrected. P. 4 – The sentence “Furthermore, the composition of the team consists of a senior lead (TMC) who is a medical physician with expertise in qualitative analysis, free open access medical education resource dissemination and social media stakeholdership, a postdoctoral fellow who is an expert in qualitative analysis and social media education” would benefit from being split into two sentences with each sentence reflecting each researcher. The postdoctoral fellow could have their initials identified for consistency since the rest of the team does. Reply: This has been done. P. 4 – The authors indicate that the present study is a sub-study. Additional details regarding the initial inquiry and how this work fits within the overall program of research would be beneficial. Reply: We have done this. We have cited our previous work in the program of research as well. P. 4 – A citation supporting the use of snowball sampling for ill-defined populations is recommended. Reply: This has been added. We have cited previous work within our program which has similar techniques. P. 4 – In the first sentence of the Data Collection and Processing section, the apostrophe on the word ‘individuals’ should be placed after the s for a plural possessive (i.e., individuals’). Reply: This has been done. P. 5 – In the Rigour and Trustworthiness section, the sentence “The research team ensured the trustworthiness of the study applying several techniques” would benefit from adding the word ‘by’ before the word ‘applying’. Reply: Thank you for the careful read. Results: P. 6 – In the Structural Frame section, the sentence “Overall, there were several structural elements within the organizations that tended to incentivize work across all contexts” requires clarification. Is this work related to social media? If not, what kind of work? Reply: We were referring to academic work. This has been clarified. P. 6 – the sentence “social media can also be seen as a lost opportunity from currently acceptable forms of scholarly activities while spending time on social media” is circular. Why is social media currently not incentivized as a scholarly activity? Alternatively, is the perception that social media is a waste of time? Reply: This has been clarified – there is an opportunity cost created by the incentives structures. We have clarified this. P. 7 – In the second paragraph of the Organizational Roles section, the sentence “further participants were also found to have unpaid social media teams with individuals who have significant number of followers on Twitter” suggests that the participants have their own social media teams. Is this the case? Reply: We have clarified. It is more that they were part of social media teams. P. 7 – The first sentence of the Educational Considerations section would benefit from being split into two or more separate sentences. Reply: This has been done. The results section alternates between past and present tense. Consistently using the past tense is recommended. Reply: We have done our best to adhere to this recommendation. Some sentences are still in present tense because they refer to the Bolman & Deal framework, which we felt was appropriate to keep in present tense. P. 9 – The word ‘media’ appears to be missing from the sentence “in these social teaching sessions, students are taught ‘how to utilize [social media] for their professional brand’ and as a way of networking”. Media could be inserted between the words ‘social’ and ‘teaching’ in this instance. Reply: This has been added. P. 10 – Adding a brief operational definition of Communities of Practice as conceptualized by Lave & Wenger would be helpful. Reply: This has been added. P. 10 – The words “of which” could be removed from the following sentence for clarity: “The roles of which participants took online towards their audience or CoP were diverse”. Reply: This has been deleted. P. 11 – In the Inhibitors of Scholarly Growth section: The word ‘which’ could be removed from the following sentence for clarity: “Organizations which were anxious to control their message and utilize their hierarchy to do so…”. Reply: This has been deleted. P. 12 – The first participant quote is worded in the following way “… not [had] incredible involvement in social media but are on Twitter and do you some participation…” Is this accurate? Reply: There was a section that was unclear that resulted in dropping words. We have added bracketed words now for clarity. Discussion: P. 13 - The sentence “While this framework is originally meant for leaders who want to change or to build capacity in the organizations, it can also be used by those interested in examining emergent phenomenon in our organizations” requires a citation. Reply: We have cited Bolman and Deal here. P. 13 – The sentence “The key insights that we have gained from our participants are how new emerging forms of scholarly pursuits can be more effectively enabled or hindered by the attributes of the organization in which they are occurring” appears vague. Including specific examples of the key insights and organizational attributes would be beneficial. Reply: We have clarified this statement now. P. 13 – The final sentence of the discussion appears incomplete: “As seen in our study, when academic leaders attempt to foster new initiatives, there can be gaps in the support for these endeavours leading to unsustainable”. Unsustainable what? Reply: We have rephrased and added an example for clarity. P. 13 – Limitations: Are there any limitations from using a predefined list of social media influencers? Are there any limitations of including only emergency physicians’ perspectives? Are there any geographic limitations regarding who is considered an influencer and is therefore included in the study (i.e., the prevalence of US, Australia, and Canada as compared to how social media is used in institutions elsewhere)? Reply: These have been added."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1048
|
https://f1000research.com/articles/10-1275/v1
|
13 Dec 21
|
{
"type": "Research Article",
"title": "Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies",
"authors": [
"Mariana Xavier",
"Nayla Farez",
"Paola Luciana Salvatierra",
"Andre Luiz Jardini",
"Paulo Kharmandayan",
"Sara Feldman",
"Nayla Farez",
"Paola Luciana Salvatierra",
"Andre Luiz Jardini"
],
"abstract": "Background: The biomaterials engineering goal is to manufacture a biocompatible scaffold that adequately supports or improves tissue regeneration after implantation of the biomaterial in the injured area. Many requirements are demanded for a biomaterial, such as biocompatibility, elasticity, degradation time, and a very important factor is its cost of importation or synthesis, making its application inaccessible to some countries. Studies about biomaterials market show that Polylactic acid (PLLA) is one of the most used polymers, but expensive to produce. It becomes important to prove the biocompatibility of the new PLLA and to find strategies to produce biocompatible biopolymers at an acceptable production cost. Methods: In this work, the polylactic acid biomaterial was synthesized by ring-opening polymerization. The polymer was submitted to initial in vivo biocompatibility studies in 12 New Zealand female rabbits, assigned to two groups: (1) Lesion and PLLA group (n = 6), (2) Lesion No PLLA group (n = 6). Each group was divided into two subgroups at six and nine months post-surgical time. Before euthanasia clinical and biochemical studies were performed and after that tomographic (CT), histological (Hematoxylin and Eosin and Masson's trichrome) and histomorphometric analyses were performed to evaluate the injury site and prove biocompatibility. The final cost of this polymer was analyzed. Results: The statistical studies of hemogram and hepatocyte enzymes, showed that there were no significant differences between the groups for any of the times studied, in any of the variables considered and the results of CT and histology showed that there was an important process of neoregeneration. The cost analysis showed the biopolymer synthesis is between R$3,06 - R$5,49 cheaper than the import cost. Conclusions: It was possible to synthesize the PLLA biopolymer by cyclic ring opening, which proved to be biocompatible, potential osteoregenerative and cheaper than other imported biopolymers.",
"keywords": [
"biomaterials",
"material synthesis",
"PLLA",
"polymers",
"orthopedic",
"tissue-engineering",
"biofabrication"
],
"content": "Introduction\n\nTissue regeneration has currently attracted significant attention because it offers potential solutions for the treatment of many diseases. To produce scaffolds and other structures, it is essential to understand biomaterials because they must mimic the body's natural structures1 The use of these materials is significant in cardiology, orthopedics, plastic surgery, wound healing and other areas. Bone substitutes are being increasingly used especially in oncologic surgery, traumatology, revision prosthetic surgery, and spine surgery2. Bone grafting frequency is indeed the second most frequent tissue transplantation worldwide, with more than 500,000 implanted in the US alone3.\n\nA wide variety of bone substitutes have been employed over the past 50 years. Bone substitutes can be broadly categorized into bone grafts (autograft, allograft, xenograft) and the biomaterials can be titanium, ceramics (hydroxyapatite, TCP, calcium sulphate), natural polymers, synthetic polymers and many others4. Work worldwide is focusing on the construction of bioactive, osteoconductive, biodegradable, bioabsorbable scaffolds in order to stimulate osteoprogenitor cells at the injury site without hyper stimulating unwanted cellular responses5.\n\nThere are many different types of polymers used in tissue engineering, each of which has completely different properties from other bone substitutes, and can be divided into biopolymers and synthetic polymers. Biopolymers of natural origin (collagen, gelatin, chitosan) are used for this purpose, as they mimic the structure and biochemical properties of the natural bone organic matrix, are able to stimulate a proper cellular response and function, on the other side it has some disadvantages, such as pure collagen scaffolds that remain their poor mechanical properties and pose a higher risk of infection and allergic reactions6.\n\nA large number of tissue engineering materials based on synthetic polymers have been developed, including poly (ε-caprolactone) (PCL), polylactic acid (PLLA), polyglycolide (PGA), poly (lactide-coglycolide) (PLGA), poly (propylene fumarate) (PPF) and polyhydroxyalkanoates (PHA)4 The benefit is that they improve healing without any foreign body residues remains. These polymers can be synthesized in large quantities under controlled conditions, ensuring uniform and reproducible properties while reducing the risks of infection and immunogenicity6. Another important factor is how the body eliminates the remains of the biomaterial, in this case, biopolymers are degraded through simple hydrolysis, breaking the molecule into small units, and so their products can then be eliminated from the body through natural metabolic pathways, such as the citric acid cycle, or through renal excretion7,8.\n\nDepending on the required application, PLLA has better physicochemical characteristics than other polymers. It also presents a diversification of applications, since simple changes in its physical and chemical structure can make it useful in different areas. Depending on the application, different products can be obtained using specific polymerization routes9.\n\nPrior works done by our group10–12 have shown that the PLLA can be obtained using different routes (Figure 1). In general, three methods can be used to produce high molecular mass PLLA of about 100,000 Daltons: (a) direct condensation polymerization; (b) azeotropic dehydrative condensation and (c) polymerization through lactide formation, the ring-opening polymerization. Currently, direct condensation and ring-opening polymerization are the most used production techniques.\n\nWhile there are different ways to manufacture PLLA, its production is not easy. The synthesis of PLLA demands severe control of conditions such as temperature, pressure and pH, just as well as the use of catalysts and long polymerization time, which lead to a high-energy consumption to achieve the final product.\n\nIn addition to the intrinsic biomaterial characteristics previously mentioned, the cost of synthesizing or importing a specific polymer may affect its acquisition, application, or scientific study in some countries. The increase in the use of biomaterials around the world is evident and this expansion must be supported by strategies of biomaterial accessibility13\n\nThe global biomaterials market size was estimated at USD 106.5 billion in 2019, USD 121.1 billion in 2020, and is expected to reach USD 151.5 in 2021 as reported in the latest study by Grand View Research and polymers is the segment with the largest share in this statistic a participation of 40.8% in 2019.(Graph 1)14\n\nThe data show that PLLA polymer has significant participation in the economic market of biomaterials, when analyzed the prices of biopolymer values are from USD 1800 to USD 3200 per kilogram of PLLA. In addition to the cost of the biopolymer as a raw material, packs of a few grams of PLLA for facial esthetic treatments cost USD 60 and a PLLA biofilm 300×300mm costs from USD 159 to USD 20315,16.\n\nOne possible solution to reduce the costs of biomaterials studies is to import the monomer and then perform the polymerization, this strategy allows the material to be synthesized in a cheaper and more accessible way, thus opening the possibility to learn more about the material and discover new ways of polymerization and even to obtain its monomer.\n\nBased on the above mentioned strategy, after studies, the national PLLA polymerization was produced and the results published in previous works10, subsequently hemocompatibility and cytotoxicity studies proved the in vitro biocompatibility of the material, in order to verify if it could have a medical application. These studies showed that the strategy of elaborating a polymerization from imported monomers was viable and that the PLLA biopolymers produced could be an accessible solution for use11.\n\nThe in vivo biocompatibility study is a crucial requirement to prove that the polymer manufactured will have the same medical applicability as the biomaterial polymerized elsewhere. When referred to biocompatibility analysis means the ability of a material to produce an appropriate host response when applied as designed, and it is this response that must be evaluated17.\n\nThis work evaluates the in vivo biocompatibility of biomaterial synthetized from Lactide monomer polymerization, showing the possibility of synthesis at low cost with a quality final product that can bring real benefits to research and the application of its results in the health of parents with less financial possibilities for scientific research.\n\nThis work aims to evaluate the in vivo biocompatibility of biomaterials synthesized from the polymerization of Lactide monomers and compare the final synthesis cost to the PLLA biopolymer import price.\n\n\nMethods\n\nThis study has been reported using CONSORT guidelines and ARRIVE guidelines.\n\nPoly-lactic acid synthesis. The synthesis of PLLA was conducted by bulk polymerization by adding L-lactide monomer into a glass reactor containing the catalyst Sn (Oct) 2 (Sigma). The proportion monomer/catalyst was 0.5%. The mixture was immersed in an oil bath at 140°C for 2 hours under nitrogen flow. The produced polymer was dissolved in chloroform, CHCl3 (Merck), precipitated in ethyl alcohol and dried in a vacuum oven at 60°C for 12 hours. After the synthesis were manufacture tablets of PLLA.\n\nManufacturing PLLA tablet. The scaffold size was determined by reviewing previously published studies that determine the size of critical lesions for osseointegration and biocompatibility studies in rabbits18,19. PLLA tablets (Figure 2) of 3mm × 15mm were produced by compression of the polymerized raw material under a hydraulic press.\n\nA – 3D representative image and dimensions of the PLLA tablet. B - photo of a compacted PLLA pellet, ready for insertion into a rabbit lesion.\n\nStudy design. The animals were selected and divided into groups, at the post-surgical time determined for each group the initial number of animals was not changed as shown in the study flow diagram.\n\nExperimental models - eligibility criteria. 12 New Zealand female rabbits (age = 16–20 weeks) were assigned to two groups:(1) Injury + PLLA group (n = 6), (2) Injury no PLLA group (n = 6). Each group was divided into two subgroups at six and nine months post-surgical procedure. Rabbits were kept in individual cages with food (PROVIFE, Argentina) and water ad libitum. All procedures were made according to the approval of the ethics committee nº44371/0028 of 1MED423- University National of Rosary, Argentina. Their regulations are in accordance with well-established guidelines for the care and handling of animals to minimize animal pain and suffering according to the 3Rs (replacement, reduction and refinement) and follow international regulations for the care and use of laboratory animals. All efforts were made to ameliorate harm to animals\n\nPre-surgical preparation. Antibiotic prophylaxis and anesthetic treatment were performed. Before the surgical procedure, rabbits received antibiotic prophylaxis Cefazolin 50mg/Kg/day (administered intramuscularly). Anesthetic treatment was performed using a combination of two drugs administered intramuscularly: ketamine hydrochloride 35mg/kg animal, xylazine hydrochloride 2% 18mg/kg animal, and acepromazine maleate 1mg/kg animal. The anesthetic effect lasted 45 – 60 minutes.\n\nSurgical procedure. The surgeries were performed under aseptic conditions. A longitudinal incision of 3 cm total length was made parallel to the sagittal suture below the Lambdoid suture (5–6 cm long). The central perfuration point is marked with a surgical marker, the drilling was done with a 15 mm drill, made of stainless steel with laser engraving, generating a hole of 15 mm in diameter and +/-3 mm in depth. After dissection of the periosteum, the defect was made in the center of the sagittal suture, 2 mm below the Lambda suture. In one group of animals PLLA was introduced in the center of the lesion (Lesion + PLLA Group) and in the other group the bone lesion was maintained (Lesion without PLLA Group) (Figure 4).\n\nPost-surgical procedure. The rabbits were clinically monitored daily in basis as to overall status, mobility and food intake. Post-surgical analgesia was performed using tramadol every 12 hours, (6 mg / kg / day) intramuscularly during three days. Antibiotic cephalexin, 50mg/kg/day and anti-inflammatory meloxicam 0,75mg/kg/day intramuscularly on the day of surgery and 3 days following surgery.\n\nHemogram. Blood samples were collected before sacrifice. The blood samples were collected in EDTA tubes to perform hemogram, after homogenization of the samples. Red blood cells (RBC), white blood cells (WBC), hemoglobin (Hb), hematocrit (Hto), mean corpuscular volume (MCV) and platelets were evaluated.\n\nTransaminases. The serological study was performed on blood samples without anticoagulant, centrifuged for 10 minutes at 10,000 rpm, to separate the serum fraction from the blood, where the values of the enzymes transaminases, glutamate-oxalacetic transaminase (GOT) and glutamate pyruvate transaminase (GPT) were determined. All determinations were performed with Wiener lab Kids (Argentina).\n\nBiochemical statistical evaluation was performed with non-parametric analysis of variance (Wilcoxon). A p value <0.05 was considered significant\n\nThe animals were euthanized in the 50 % of each group at six-month post-surgery and the others at nine months, with an intraperitoneal injection of five times the value of the anesthesia dose. Then, cranial were obtained by axially cutting the neck near the base of the skull with a bench saw, which were immediately used for tomographic, macroscopy and histology studies.\n\nPrior to sacrifice, each implanted area was inspected. Surface characteristics such as skin color, scarring, edema, erythema, and elevations were evaluated. A sagittal incision was then made at the scar site and the lesion area was cut with a 5 mm margin from the edges to remove a portion of bone with the central lesion. After removal of the skull fragment containing the central lesion, the endocranial and exocranial side of the fragment was evaluated for edema, surface characteristic, implant position, exudate or other signs of infection.\n\nTomographic studies were performed on the day of sacrifice of the group of animals, each skull obtained from the axial section was immediately used for tomographic study with a 16-channel Toshiba multislice CT scanner for qualitative analysis of the characteristics of the lesion edge and the progression of the tissue around the biomaterial.\n\nAfter euthanasia, tissue preparation was conducted according to a previously described method. Briefly, the lesion area was explanted with a 5 mm margin around, fixed in 4% formaldehyde for 24 hours and then dehydrated in a series of increasing concentrations of alcohol and xylene. After that, the samples were serially cut (5 µm thick) using a manual rotary microtome (Micron-Zeiss, Germany), and stained with hematoxylin and eosin and by Masson trichrome staining. All samples were examined by light microscopy and evaluated. Photomicrographs were taken from slides of each specimen using a digital camera mounted on an Olympus CH30 microscope.\n\nStudies were conducted to consider if the proportion of regenerated bone in animals in the group implanted with the scaffold under study was greater relative to animals in the group not implanted with PLLA at each of the time points considered for this experiment, six months and nine months, respectively.\n\nThree histological sections were studied for each animal in each of which three sites were randomly selected. ImageJ software was used for the observation of de novo regenerated bone. The New bone formation was quantified and expressed as a percentage of total bone (% BV/TV) in the area surrounding the lesion.\n\nData were analyzed using linear mixed models implemented in Infostat software. Outliers were removed before the analysis was performed.\n\nStatistical analyses: The variable of interest is worked out in original scale, in proportion between 0 and 1. To detect significant differences between Groups, linear mixed models20 were fitted and the Bayesian information criterion21 was used to select the best fit. Fisher's a posteriori test was used with a significance level of 0.05. The software used for the analysis was Infostat22. These procedures were followed for both the evaluation at six months and nine months and between six months.\n\nThe cost of the raw material needed to synthesize the biomaterial from the lactide monomer was compared with the cost of importing the PLLA polymer. The currency conversion of the prices in dollars (US$) to real (R$) was performed. To analyze the cost of synthesizing 1 gram of PLLA, the price of 100g of lactide monomer, dudecanol, octanoate and the Nitrogen (N2) cylinder was obtained, and then the cost of each quantity used in the synthesis was determined. The costs of each material were added up to obtain the price of 1g of synthetized polymer. This value was compared to the cost of 1g of the imported material by dividing the price of the material by the content of 100 grams of the package. (Figure 3)\n\nViolet square representing cost calculations of each gram of already synthesized imported PLLA. Yellow square represents comparison of costs of laboratory synthesized material and imported biomaterial.\n\n\nResults\n\nThe PLLA was synthesized by opening of the cyclic dimer of L-lactide in order to obtain high molecular weight polymer. The synthesis temperature was maintained at 140 °C/ thus avoiding, high temperatures, which lead to a depolymerization process which allows the decrease of the molecular weight of the polymer23.\n\nThe obtained polymer had the PLLA molecular weight 86.93 g/mol as mentioned in previous works10.\n\nAs can be seen in Figure 4, the surgical procedure with the selected drill allowed the achievement of a central lesion with a diameter considered as a critical lesion, and it was also possible for the biopolymer to be placed in the center in order to analyze its biocompatibility with the edge of the bone in question in the group (Injuria +PLLA).\n\nA 3-cm full-thickness longitudinal incision (A). The central drilling point (B). Defect in the center of the sagittal suture, 2mm below the Lambda suture (C).\n\nIn Figure 4-A, after asepsis with iodopovidone and covering the surgical area on top of the head, a sagittal cut was made with a scalpel. After removal of the periosteum, the start of the circumferential lesion can be seen through a 15mm trephine, before the central bone is removed (Figure 4-B). After total removal of the central bone, a part of the brain can be seen in Figure 4-C, covered by the meninges.\n\nHemogram. The hemogram statistical studies showed that there were no significant differences between the groups at any of the times studied, in any of the variables considered. In Figure 5 and Figure 6 we can observe the results obtained the day before euthanasia. Each of the results obtained for each variable applied to each sample, were always within normal ranges for animals of this line and age24\n\n1: Lesion + PLLA group. 2: Lesion No PLLA group.\n\n1: Lesion + PLLA group. 2: Lesion No PLLA group.\n\nTransaminases. Statistical studies of transaminase levels showed that there were no significant differences between the groups for any of the variables considered. Each of the results obtained for each variable applied to each sample (Figure 7).\n\nGroup 1: Injury No PLLA. Group 2: Injury + PLLA.\n\nThe images observed on the CT scans allowed an analysis of the lesion border in the Injury+PLLA group and the Injury No PLLA group.\n\nIn the Injury No PLLA group at 6 and 9 months, it is possible to observe the formation of a small fragmented layer of bone tissue over the meninges, however, there are no differences in bone formation activity at the edge of the lesion. The analyses of the animals that have the PLLA implant in their lesion, showed hyperdense borders with signs of bone regeneration. In addition, it can be seen that under and above the implant there are hyperdense sectors, also indicating the formation of a layer of bone tissue around the implanted matrix. (Figure 8)\n\nThe larger images represent a coronal slice and the smaller images in the lower right corner represent axial cuts. On the left images, represent the animals that did not receive the PLLA implant, where the red line shows the lesion area. The right images represent animals that received PLLA implantation in the center of the lesion (yellow arrow) and the red line shows the lesion area.\n\nAfter sectioning the area with the central lesion, a clinical presentation of the groups examined at six and nine months is shown in Figure 9. A fibrous scar covered the entire area of the defect. From the Exocraneal view much of the polymer can be visualized below a thin layer of subcutaneous tissue. In the endocranial view it was covered by the adhered meninges, where the biopolymer could hardly be assessed. No apparent indications of infection were detected in any of the experimental groups macroscopically.\n\nCranial gross appearance of the defects, showing the fibrous scar covering the defect area (A), exocranial (B) and endocranial face (C).\n\nHematoxilin and eosin. In the hematoxylin and eosin staining results, at a 10X magnification it is possible to analyze the cell types present at the margin of the lesion and compare them with the group of animals that did not receive the PLLA biopolymer implant. In the six-month-old animals without implantation, it is possible to observe the scarce formation of connective tissue and some inflammatory cells and the irregular and undefined border of the lesion.\n\nWhen analyzing the six-month-old animals with bone implant, there is a thick layer of connective tissue at the margin of the biomaterial, with an evident and well-defined border. In the region of contact with the polymer, groups of inflammatory cells can be seen around the fragments of biomaterial. In the surrounding connective tissue, besides fibroblasts, it is possible to see bone tissue formation, with the presence of osteoblasts, osteocytes and osteoclasts. (Figure 10 – A and C)\n\nHE staining- original magnification 10x – A 6 months, Injury No PLLA animal. B nine months, Injury No PLLA animal. C six months, Injury + PLLA animal. D 9 months, Injury + PLLA animal. Bone is presented as a compact structure in a pink color, connective tissue in light pink and the scaffold structure (PLLA) in light grey. OSB, osteoblast; OTC, osteoclast; OST, osteocyte; FB, fibroblast; BV, blood vessel; NB, new bone and Defect Margin indicates edge the tissue boundary.\n\nWhen comparing and analyzing the nine-month-old animals, it is possible to verify that the animals with a critical lesion without implant have an increased layer of connective tissue around the edge of the lesion, the presence of adipose tissue, and few inflammatory cells. In the animals nine months old with implants, the plaque fragments are surrounded by phagocytic cells, surrounded by abundant connective tissue and new bone tissue, and abundant osteoblastic and osteoclastic cells can be seen. Blood vessels are also present and distributed around the PLLA biopolymer. In none of the animals is there the formation of thick connective tissue suggestive of fibrous capsule. (Figure 10 – B and D)\n\nWhen analyzed at 40x magnification, the cell types present at the edge of the lesion are observed. The six-month-old animals with lesions without polymer have the formation of abundant dense connective tissue, without signs of intense inflammation or signs that indicate regenerating cellular activity such as the presence of new bone tissue. When compared to the six-month-old animals, at the same 40x magnification, we see the presence of inflammatory tissue surrounded by fragments of polymer and also abundant blood vessels throughout the area.\n\nThe collagen is seen in blue or greenish color, while the bone acquires a red color. through this differentiation we can delimit the color margin in the ImageJ program, quantifying the percentage of bone present at the edge of the lesion and comparing the different groups and times.\n\nAfter Masson staining and quantification of the area in pixels represented by dark blue and red colors, the area of bone growth bordering the lesion can be seen. In a qualitative analysis of the Masson staining, it can be inferred, together with what was observed in the hematoxylin and eosin staining, that the animals implanted with PLLA present a greater amount of bone tissue surrounding the lesion.\n\nTogether with the images, we can analyze below the statistical data that represents the area of bone and connective tissue of the analyzed groups (Figure 12)\n\n-Histomorphometric analysis of connective tissue lesion area and bone tissue area in six- and nine-month-old animals with and without PLLA. First row with original photos at 10X magnification with Masson staining. Second row with total tissue area in red by image analysis software image J. Third row representing bone tissue area in red.\n\nSignificant differences were detected between the groups at both six and nine months of post-surgical evaluation. The Injury+PLLA group achieved 62% bone regeneration at six months, while the Lesion+PLLA group achieved only 30% bone regeneration (Graph 2). At nine months of evaluation, the Injury+PLLA Group achieved 66% of both regenerations, compared to 31% in the Injury No. PLLA Group (Graph 3).\n\nDifferent letters indicate significant differences in LSD Fisher test with a significance of 0.05.\n\nDifferent letters indicate significant differences in LSD Fisher test with a significance of 0.05.\n\nThe prices of the raw material for the polymerization of the biomaterial in the laboratory were obtained through quotations in Sigma Aldrich. and Corbion.\n\nThe price of synthesizing 50g of PLLA was first calculated by dividing the value of R$7. 559.00 per 50 grams of the lactide monomer (1kg) Purasorb L, R$1413.00 of the Tin Octanoate (1kg) divided by the 0.75 grams needed, R$138.00 of the CHCl3 (1L) cost was divided by the 0.00057ml used and the nitrogen used for 150 minutes of reaction corresponds to 3 liters, where the cost per liter of N2 was calculated by dividing the R$143.60 by the 10L and then multiplied by the 3 liters needed. Once the cost of producing 50 grams of polymer was obtained, this cost was divided by the value of 50 and the cost for each gram of polymer synthesized in the laboratory was found (Table 1).\n\nThe price of the imported PLLA polymer was quoted by two companies: TCI America and ACROS Organics. The packages contained 25g of PLLA polymer each. The cost per gram of imported polymer was calculated by dividing the package price by 25, where the costs found for each brand were: R$11.49/g of PLLA polymer (L-Lactide 98.0+%, TCI America™) and R$13.92 of the polymer (L-Lactide, 98%, ACROS Organics™) (Table 2).\n\n*The dollar values were converted to real with WestenUnion quotation of August 05, 2021 where 1US$= R$5.223.\n\nComparing the costs for each imported gram of PLLA of R$11.49 and R$13.92 to the obtained value of R$8.43 for laboratory synthesized PLLA, a difference of R$3.06 is calculated between synthesized PLLA and imported PLLA (TCI America™) and a difference of R$5.49 for laboratory synthesized PLLA compared to imported PLLA (ACROS Organic™).\n\n\nDiscussion\n\nFrom the work performed, it was possible to synthesize the polymerization of PLLA from lactide monomers using the cyclic ring opening technique and subsequently create implants with the exact size and shape of the lesion to be repaired. The implants developed had characteristics that allowed them to be easily implanted perfectly into the lesion site by means of simple manipulation. This makes the material obtained a potential scaffold that can be synthesized in a three-dimensional way and be applicable for different injury shapes.\n\nAs published by other authors, implantation of a biomaterial could induce a host reaction to the implant that determines the integration outcome and the biological performance of the implant25. Based on these statements, clinical observations of the animals were performed and the results provided evidence that there were no inflammatory events. In this work it is very important to remark the hemogram monitoring level of the implanted animals, compared to the injured animals that did not receive the implant, since this allows to evaluate some syntemic responses. The normal red blood cell values did not suggest hemolysis, and the white blood cell parameters remained within normal ranges.\n\nAnother important study when dealing with bioabsorbable biomaterials is to analyze transaminases, indicators of possible hepatoxicity, because the degradation of polymers into their respective monomers can give rise to the systemic circulation of these biomolecules, requiring hepatic biotransformation for waste disposal26. The terminology used for the word biodegradable is often misapplied as a synonym for bioabsorbable in many literatures. It is important to infer that biodegradation does not mean that the material will leave the organism, it will just lose its primary conformation. When we mention the word bioabsorption, we are referring to the power of metabolization or excretion that the body has in relation to this biomaterial.\n\nThus, the analysis of transaminases allows us to evaluate the co-participation of the liver and verify whether it may be suffering damage from the presence of systemic circulation of biomolecules27. Therefore, it was important that in the experimental model presented in this work, the variables of both transaminases were not altered, without significant intergroup differences, with values within the range of animals of the same line and age, reinforcing the primary idea of biocompatibility without systemic damage by biodegradation.\n\nWhen it comes to analyzing the degradation surface of the biomaterial it is important to take into account that PLLA has a degradation time ranging from 6–24 months, depending on temperature, ph, humidity and others28. This means that the period covered by the current study is limited in data to make any statement in this respect.\n\nThus, the analysis of the lesion site through tomographic images were qualitative (Figure 8) showed that the biomaterial allows bone regeneration in a centripetal way, performing the osteointegration process from the edge of the lesion towards the biopolymer. In animals without PLLA implantation, no significant change in the lesion was verified.\n\nThe inflammatory process occurs in phases, and it is important to analyze the macroscopic site of injury, looking for signs of inflammation, such as fibrotic capsule formation, and any indicator of biocompatibility failure. In the macroscopic evaluation (Figure 9), no signs indicative of regenerative failure or exacerbated inflammatory response were observed. This information is in accordance with other published papers that affirm that several factors are taken into consideration in a biocompatibility study. We know that the insertion of a biomaterial can naturally produce a local inflammatory response with attempts to eliminate the inflammatory agent and regenerate the affected tissue. However, this inflammatory response must be within expected limits at each post-injection time point29.\n\nIn biocompatibility studies, performing histological analysis is crucial to understand the interaction of the implant site with the implanted polymer. The interaction between the host immune system and the implanted material depends on the tissue surrounding the implant, which will drive tissue-specific innate defenses and the following induction of adaptive immune responses, so analyzing the type of cellularity is indicated30,31.\n\nIn this work, histological studies allow us to analyze the type of cell present at the edge of the lesion. We can infer that, in the absence of biomaterial, the critical lesion evolves to a sclerotic border. In the animals (Figure 10) that received the biomaterial, not only showed biocompatibility and absence of fibrotic capsule, but also showed formation of connective repair tissue and the beginning of bone tissue formation, which can be confirmed with further staining and analysis\n\nKnowing that the inflammatory response changes its profile over time and according to the type of biomaterial present, taking weeks or even months for an acute response to change to a chronic one32,33, we seek to verify a difference between the tissue profile in animals six and 9 months post-surgery. it is evident that when analyzing the margin and the center of the lesion at 40x magnification in the animals nine months without implantation, the center of the lesion was taken by adipose tissue, the border contains connective tissue and little sign of neovascularization or bone regeneration, the cells present indicate a process of repair of the border without possible regeneration of the lesion. When the center and the edge of the lesion are checked in the animals with implanted polymer, the initial acute inflammatory process has given way to the degradation of the polymeric matrix and the connective tissue surrounding the polymer is occupied by bone tissue cells. In the center of the lesion, islands of biomaterial fragments can be seen, completely surrounded by a new bone matrix, as shown in Figure 10 and Figure 11.\n\n– A 6 months, Injury No PLLA animal. B 9 months, Injury No PLLA animal. C 6 months, Injury + PLLA animal. D 9 months, Injury + PLLA animal. Bone is presented as a compact structure in a pink color, connective tissue in light pink and the scaffold structure (PLLA) in light grey. BV – Blood Vessel. Defect Margin indicates edge the tissue boundary.\n\nThe PLLA implant promoted a very significant increase in the percentage of bone tissue formation. This would reinforce the proposal to promote our material in the field of regenerative medicine, since it would not only show biocompatibility characteristics, but would also promote bone tissue regeneration in a gradual manner.\n\nAnalyzing the strong economic impact nowadays generated by biomaterials and their very important applications in the medical sector, one can verify that any strategy that seeks to reduce their cost and simplify their synthesis process will be considered a mechanism to promote the accessibility to biomaterials.\n\nThrough the cost analysis mentioned, the synthesized biomaterial has a difference of $3.06 between synthesized PLLA and imported PLLA (TCI America™) and a difference of $5.49 for laboratory synthesized PLLA compared to imported PLLA (ACROS Organic™) Per gram of biomaterial. Confirming that the synthesized biomaterial, besides completing with the expected biocompatibility requirements, also proved to be cheaper than the import process.\n\n\nConclusion\n\nThis study proved that ring-opening polymerization is a feasible process for the production of lactic acid-derived PLLA, the results demonstrated that the synthesized polymer presents the characteristics of biocompatibility and osteoregenerative potential, as well as being a low-cost and accessible procedure, as an initial proposal to become cheaper.\n\n\nData availability\n\nZenodo: ARRIVE Questionnaire, CONSORT Check-list and Flow Diagram + TGO, TGP, HEMOGRAMA AND OSTEOREGENERATIVE DATA - Paper: \"Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies\", https://doi.org/10.5281/zenodo.539692123.\n\nThis project contains the following underlying data:\n\n- Biochemistry transaminases Data - GOT & GTP.xlsx\n\n- Data - Hemogram 6 months animals.xlsx\n\n- Data - Hemogram 9 months animals.xlsx\n\n- Osteoregenerative Masson Staining bone area.xlsx\n\nZenodo: Images, graphs and tables from the article: Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies - https://doi.org/10.5281/zenodo.5216707.\n\nThis project contains the following underlying data:\n\n- TAC CONEJO 41 - 6 MESES+PLLA600.tif\n\n- TAC CONEJO 44 - 9MESES CONTROL600.tif\n\n- TAC CONEJO 45 - 6 MESES CONTROL600.tif\n\n- TAC CONEJO 45 - 9MESES +PLLA600.tif\n\nZenodo: Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies - HEMATOXYLIN&EOSIN, MASSON AND CT SCAN IMAGES, https://doi.org/10.5281/zenodo.5396584.\n\nZenodo: ARRIVE Questionnaire, CONSORT Check-list and Flow Diagram + TGO, TGP, HEMOGRAMA AND OSTEOREGENERATIVE DATA - Paper: \"Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies\", https://doi.org/10.5281/zenodo.5396921.\n\nThis project contains the following reporting guidelines:\n\n- File 1 CONSORT 2010 Checklist - PLLA.pdf\n\n- File 2 ARRIVE Compliance Questionnaire - PLLA Animals.pdf\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nThe authors wish to acknowledge the financial support provided by the Scientific Research Foundation for the State of São Paulo (FAPESP Process 2017/03249-0), National Rosario University, National Institute of Biofabrication (BIOFABRIS – Brasil) and Sierra Laboratory – Argentina.\n\n\nReferences\n\nStratakis E: Novel Biomaterials for Tissue Engineering 2018. Int J Mol Sci. 2018; 19(12): 3960. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBhatt RA, Rozental TD: Bone graft substitutes. Hand Clin. 2012; 28(4): 457–68. PubMed Abstract | Publisher Full Text\n\nCampana V, Milano G, Pagano E, et al.: Bone substitutes in orthopaedic surgery: from basic science to clinical practice. J Mater Sci Mater Med. 2014; 25(10): 2445–61. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArner JW, Santrock RD: A historical review of common bone graft materials in foot and ankle surgery. Foot Ankle Spec. 2014; 7(2): 143–51. PubMed Abstract | Publisher Full Text\n\nCicero AM, Issa JPM, Feldman S: Matrices de tercera generación en la ingeniería de tejidos óseos. Asociación Argentina de Osteología y Metabolismo Mineral; Actual Osteol. 2017; 13(2): 157–176. Reference Source\n\nThrivikraman G, Athirasala A, Twohig C, et al.: Biomaterials for Craniofacial Bone Regeneration. Dent Clin North Am. 2017; 61(4): 835–856. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSantos AR Jr, Wada MLF: Bioreabsorbable polymers for cell culture substrate and tissue engineering. Polímeros: Ciênc Técnol. 2007; 17(4): 308–17. Publisher Full Text\n\nMiddleton JC, Tipton AJ: Synthetic biodegradable polymers as orthopedic devices. Biomaterials. 2000; 21(23): 2335–46. PubMed Abstract | Publisher Full Text\n\nFukushima K, Kimura Y: An efficient solid-state polycondensation method for synthesizing stereocomplexed poly(lactic acid)s with high molecular weight. J Polym Sci Part A-Polym Chem. 2008; 46(11): 3714–3722. Publisher Full Text\n\nLopes MS, Jardini AL, Filho RM: Synthesis and Characterizations of Poly (Lactic Acid) by Ring-Opening Polymerization for Biomedical Applications. Chem Eng Trans. 2014; 38: 331–336. Publisher Full Text\n\nXavier MV, Macedo MF, Benatti ACB, et al.: PLLA Synthesis and Nanofibers Production: Viability by Human Mesenchymal Stem Cell from Adipose Tissue. Procedia CIRP. 2016; 49: 213–221. Publisher Full Text\n\nBenatti ACB, Xavier MV, Macedo MF, et al.: Comparative Analysis of Biocompatibility between Poly (L-lactic Acid) (PLLA) and PLDL Purac® Nanofibers for use in Tissue Engineering. Chem Eng Trans. 2016; 49: 199–204. Publisher Full Text\n\nBiswas MC, Jony B, Nandy PK, et al.: Recent Advancement of Biopolymers and Their Potential Biomedical Applications. J Polym Environ. 2021. Publisher Full Text\n\nGrand View Reseach. Biomaterials Market Size, Share & Trends Analysis Report By Product (Natural, Metallic, Polymer), By Application (Cardiovascular, Orthopedics, Plastic Surgery), By Region, And Segment Forecasts, 2020 – 2027. Reference Source\n\nNational Center for Biotechnology Information: \"PubChem Substance Record for SID 24890061, SID 24890061, Source: Sigma-Aldrich\". PubChem, Accessed 27 July, 2021. Reference Source\n\nNational Center for Biotechnology Information: \"PubChem Substance Record for SID 24858300, 3,6-Dimethyl-1,4-dioxane-2,5-dione, Source: Sigma-Aldrich\". PubChem, Accessed 27 July, 2021. Reference Source\n\nShahi S, Rahimi S, Lotfi M, et al.: A Comparative Study of the Biocompatibility of Three Root-end Filling Materials in Rat Connective Tissue. J Endod. 2006; 32(8): 776–780. PubMed Abstract | Publisher Full Text\n\nFilardo G, Perdisa F, Gelinsky M, et al.: Novel alginate biphasic scaffold for osteochondral regeneration: an in vivo evaluation in rabbit and sheep models. J Mater Sci Mater Med. 2018; 29(6): 74. PubMed Abstract | Publisher Full Text\n\nPearce AI, Richards RG, Milz S, et al.: Animal models for implant biomaterial research in bone: a review. Eur Cell Mater. 2007; 13: 1–10. PubMed Abstract | Publisher Full Text\n\nHenderson CR: Estimation of genetic parameters. Annals of Mathematical Statistics. 1950; 21: 309–310. Reference Source\n\nAkaike H: Information theory and an extension of the maximum likelihood principle.proceedings of the 2nd international symposium on information, bn petrow, f. Czaki, Akademiai Kiado, Budapest, 1973. Reference Source\n\nDi Rienzo JA, Casanoves F, Balzarini MG, et al.: InfoStat versión 2020. Centro de Transferencia InfoStat, FCA, Universidad Nacional de Córdoba, Argentina. Reference Source\n\nXavier MV, Farez N, Salvatierra PL, et al.: ARRIVE Questionnaire, CONSORT Check-list and Flow Diagram + TGO, TGP, HEMOGRAMA AND OSTEOREGENERATIVE DATA - Paper: \"Biological performance of a bioabsorbable Poly (L-Lactic Acid) produced in polymerization unit: in vivo studies\". [Data set]. Zenodo. 2021. http://www.doi.org/10.5281/zenodo.5396921\n\nColetta DJ, Lozano D, Rocha-Oliveira AA, et al.: Characterization of Hybrid Bioactive Glass-polyvinyl Alcohol Scaffolds Containing a PTHrP-derived Pentapeptide as Implants for Tissue Engineering Applications. Open Biomed Eng J. 2014; 8: 20–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRentsch C, Schneiders W, Manthey S, et al.: Comprehensive histological evaluation of bone implants. Biomatter. 2014; 4: e27993. 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\n\nVert M, Mauduit J, Li S: Biodegradation of PLA/GA polymers: increasing complexity. Biomaterials. 1994; 15(15): 1209–13. PubMed Abstract | Publisher Full Text\n\nKroeze RJ, Helder MN, Govaert LE, et al.: Biodegradable Polymers in Bone Tissue Engineering. Materials. 2009; 2(3): 833–856. Publisher Full Text | Free Full Text\n\nDomingues RCC, Pereira CC, Borges CP: Morphological control and properties of poly(lactic acid) hollow fibers for biomedical applications. J Appl Polym Sci. 2017; 134(47): 45494. Publisher Full Text\n\nWitherel CE, Abebayehu D, Barker TH, et al.: Macrophage and Fibroblast Interactions in Biomaterial-Mediated Fibrosis. Adv Healthc Mater. 2019; 8(4): e1801451. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMariani E, Lisignoli G, Borzì RM, et al.: Biomaterials: Foreign Bodies or Tuners for the Immune Response? Int J Mol Sci. 2019; 20(3): 636. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWilson CJ, Clegg RE, Leavesley DI, et al.: Mediation of biomaterial-cell interactions by adsorbed proteins: a review. Tissue Eng. 2005; 11(1–2): 1–18. PubMed Abstract | Publisher Full Text\n\nCarnicer-Lombarte A, Chen ST, Malliaras GG, et al.: Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics. Front Bioeng Biotechnol. 2021; 9: 622524. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "118627",
"date": "03 Feb 2022",
"name": "Gustavo Roberto Cointry",
"expertise": [
"Reviewer Expertise Bone structure",
"Bone Biology",
"bone tomography",
"bone-muscle relationship"
],
"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 seems interesting. The authors aimed to evaluate the in vivo compatibility of biomaterial synthetized from lactide monomer to replace biopolymer imported to reduce the cost of biomaterial. I think that the paper is well designed and the methodology is correct and appropriate for the objectives. I consider that the paper is very well written and adequate to be indexed. The work is very well done and can be useful for public health in the country of origin, reducing the costs of importing the biomaterial and avoiding the procedures that can often be very slow and make it difficult to treat patients. It is not an original proposal that allows the advancement of knowledge in this field, but rather it proposes the possibility of a practical application that favors local public health.\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": []
},
{
"id": "139121",
"date": "23 Jun 2022",
"name": "Andrea Nitti",
"expertise": [
"Reviewer Expertise organic synthesis",
"polymer science"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this report, the authors evaluate the in vivo performance of PLA scaffolds studying its biodegradation, bioabsorptivity/biocompatibility, and benefit in bone tissue regeneration in implanted animals. A comparison of the PLA cost coming from lab synthesis to those bought from TCI and Across Organics was reported.\nI consider the paper well written. The experimental design and data collection, as well as their presentation, are in conformity with its purposes. This work does not present a high level of originality, but rather it proposes practical applications studied in detail.\n\nI suggest indexing after minor revision:\nA general references revision of the introduction section. There are several issues: (a) Ref 1 is an editorial paper, more appropriate would be a review article such as O'Brien (2011)1 (b) Substitute Ref 6 with specific papers, that help readers to better understand the state-of-art, some examples are works of P. Nitti et al. 2,3,4 and others. (c) Ref 4 was cited two times. Substitute the second citation with specific works, as well as the previous one. For instance, the work of C. Zaccaria et al. 5 and others. (d) After the sentence 'Depending on the required application, PLLA has better physicochemical characteristics than other polymers.' would be better to cite the book chapter from which figure 1 was copied (see followed note).\n\nModify Figure 1 with another original figure. Figure 1 was integrally copied from 'Handbook of biopolymers and biodegradable plastics 2012-cap 2: synthesis and production of PLA'\n\nThe polydispersity index of PLA synthesized is missing.\n\nwith the sentence 'molecular weight of 86.9 KDa' do the authors refers to Mn or Mw? Specify this one.\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/10-1275
|
https://f1000research.com/articles/10-1274/v1
|
13 Dec 21
|
{
"type": "Research Article",
"title": "Customer churn prediction for telecommunication industry: A Malaysian Case Study",
"authors": [
"Nurulhuda Mustafa",
"Lew Sook Ling",
"Siti Fatimah Abdul Razak",
"Nurulhuda Mustafa",
"Siti Fatimah Abdul Razak"
],
"abstract": "Background: Customer churn is a term that refers to the rate at which customers leave the business. Churn could be due to various factors, including switching to a competitor, cancelling their subscription because of poor customer service, or discontinuing all contact with a brand due to insufficient touchpoints. Long-term relationships with customers are more effective than trying to attract new customers. A rise of 5% in customer satisfaction is followed by a 95% increase in sales. By analysing past behaviour, companies can anticipate future revenue. This article will look at which variables in the Net Promoter Score (NPS) dataset influence customer churn in Malaysia's telecommunications industry. The aim of This study was to identify the factors behind customer churn and propose a churn prediction framework currently lacking in the telecommunications industry.\n\nMethods: This study applied data mining techniques to the NPS dataset from a Malaysian telecommunications company in September 2019 and September 2020, analysing 7776 records with 30 fields to determine which variables were significant for the churn prediction model. We developed a propensity for customer churn using the Logistic Regression, Linear Discriminant Analysis, K-Nearest Neighbours Classifier, Classification and Regression Trees (CART), Gaussian Naïve Bayes, and Support Vector Machine using 33 variables.\n\nResults: Customer churn is elevated for customers with a low NPS. However, an immediate helpdesk can act as a neutral party to ensure that the customer needs are met and to determine an employee's ability to obtain customer satisfaction.\n\nConclusions: It can be concluded that CART has the most accurate churn prediction (98%). However, the research is prohibited from accessing personal customer information under Malaysia's data protection policy. Results are expected for other businesses to measure potential customer churn using NPS scores to gather customer feedback.",
"keywords": [
"Customer Churn",
"Net Promoter Score (NPS)",
"Data Mining Techniques",
"Classification and Regression Trees (CART)"
],
"content": "Introduction\n\nCustomer retention and customer satisfaction are essential for a business to succeed.1 Customer satisfaction is improved by repeating businesses, brand loyalty, and positive word of mouth.2 Consumers prefer to stay with their current providers due to quality and price. Therefore, new anti-churn strategies must be constantly developed.3 Data processing automates analytical model building. Machine learning algorithms improve the dataset iteratively to find hidden patterns.4 Several studies show that machine learning can predict churn and severe problems in competitive service sectors. Predicting churning customers early on can be a valuable revenue source.5 The results of the mediating effects of a customer's partial defection on the relationship between churn determinants and total defection show that some churn determinants influence customer churn, either directly or indirectly through a customer's status change, or both; thus, a customer's status change explains the relationship between churn determinants and the probability of churn.6 This study hypothesised that changes in Net Promoter Score (NPS) can indicate whether churn determinants directly or indirectly influence churn.\n\nFigure 1 presents the revenue generated by telecommunications in Malaysia. Telekom Malaysia (TM) has made RM11.43 million in 2019 and ranked top.7\n\nMalaysia's mobile, fixed broadband, and household penetration are expected to grow further between 2019 and 2025, providing 30 to 500 Mbps fibre internet for cities, with gigabit connections for industries.8 As a result, customers expect the same or better service from providers. This statistic is also used to compare a company's performance to competitors.9\n\nTotal customer turnover is the number of customers leaving the provider.10 In the telecommunications industry, market competitiveness is measured by churn rate. Telephone, internet, and mobile services are all part of telecommunications. For example, one of the Internet Service Provider (ISP) from 20 subscribers will cancel, reducing annual revenue by 5%.11 Every day, the telecom industry loses 20%-40% of its customers.12 Without pricing and subscription plans, 83% of Malaysians would switch telecom providers. On the other hand, 66% had no problem cancelling their existing service provider subscription.13 Customer satisfaction metrics would help providers to sustain their customers.\n\nNet Promoter Score (NPS) measures customer satisfaction and loyalty using a 10-point Likert scale.14 Consistency in purchases shows commitment regardless of performance and fulfilment.15 Risk scores are used to predict customer churn. Churn is predicted using customer profiles and transaction patterns—predictive analytics use demographic, transactional data and NPS.16 The NPS outperforms customer satisfaction.17 A high NPS indicates that word of mouth can help businesses thrive. Customers are classified as promoters, detractors, or passives after receiving assistance from the helpdesk (Table 1).\n\nCustomer satisfaction\n\nCustomer satisfaction is defined as customers being happy with a company's products, services, and capabilities.18 Customers' satisfaction is influenced by buyer experience.19 Satisfied customers lead to more sales and referrals. Proactive personal helpdesk and staff assistance require a company's ability to anticipate customer needs. Most businesses benefit from happy customers. In this study, the NPS measures customer satisfaction.\n\nAn excellent service exceeds consumer expectations and satisfaction by providing high-quality services. Those are ability, attitude, appearance, attention, action, and accountability.20 A customer-centric approach benefits both private and public companies. Using this mindset also helps providers win customers and save money. In addition, customers will stay loyal regardless of market choice if companies treat them well.\n\nTransparent subscriptions\n\nIn 2019, accountability was the key to sustaining a profitable company. Authenticity trumps traditional priorities like price and brand recognition.21 In addition, transparency promotes trust, peace of mind and openness. Happy customers are more pleasant than dissatisfied customers, As such, individual customers feedback counts.\n\nCompanies can classify potential customers who leave the services using advanced machine learning (ML) technology. Then, using existing data, the company can identify potential churn customers. This knowledge would allow the company to target those customers and recover them. Table 2 and Table 3 summarise the most recent churn prediction and framework studies.\n\nMachine learning can predict customer churn by identifying at-risk clients, pain points and interpreting data. Table 3 identifies dependent and independent variables in prior research on customer churn prediction. The cause is an independent variable, and the effect is a dependent variable. As such, the factors included in this study are customer churn, defection, demographics, and the voice of the customer (NPS rating).\n\nThe traditional statistics approaches are used to solve problems involving less linear and repeatable data. They work well in environments with stable data and relationships. This is still widely used for medium- to long-term sales forecasting, where a reasonable forecast can be made with a few hundred or even fewer data points. Machine learning and statistics differ significantly. Machine learning models are created to make the most precise predictions possible. The purpose of statistical models is to make inferences about the relationships between variables.31 Machine Learning is a data-driven algorithm that does not rely on rules-based programming. Statistical modelling is the use of mathematical equations to formalise relationships between variables.32 This study applied machine learning and statistical approaches to analyse the potential churn and the mediation relationship between variables.\n\nMachine Learning (ML) is a branch of artificial intelligence. ML uses existing algorithms and data sets to classify patterns.33 This study adopts six widely used churn prediction techniques. All these algorithms were evaluated based on the performance accuracy when applied to the same data for a fair comparison. Table 4 describes the well-known churn prediction techniques.\n\n\nResearch model\n\nThe following paragraphs explain the determinants of customer churn considered in this study. Figure 2 depicts four primary structures that may influence potential customer churn and the indirect effects of NPS feedback.\n\nService Request\n\nCompanies recognise that poor customer service jeopardises customer relationships and revenue in the highly competitive telecommunications industry. Therefore, the degree to which telecommunications companies disconnect services indicates customer satisfaction and is directly proportional to customer turnover40 (Table 5).\n\nAs competition grows and consumers place a higher value on service quality, service providers may find it increasingly difficult to succeed unless they pay greater attention to consumer reviews and concerns.41\n\nHelpdesk Staff\n\nSeveral customers stop doing business with a company when they feel unappreciated, unable to get the information they want to speak to them or an unreasonably rude and unhelpful employee42 (Table 6).\n\nPoor customer service, such as rude employees, delays in service, or incorrect details, can cause customer frustration and increase the churn rate.43\n\nOutlet\n\nProfessionalism, friendliness, knowledge, communication, and sales skills are a few examples. Additionally, providers can reduce customer churn by adjusting service prices, policies, and branching44 (Table 7).\n\nAn important management assumption is that employee attitudes and reactions to organisational changes are related to department performance.45\n\nNPS score feedback\n\nCollecting NPS surveys is a great way to get customer feedback and send them to the right team. For example, promoters should send a customer's name to the team for testimonials and case studies or sign up for a customer loyalty programme.46 The survey divided over a thousand NPS feedback types into three categories: distractor, passive, and promoter (Table 8).\n\nA mediating variable links the independent and dependent variables. Its existence explains why the other two variables have a mediator relationship.47 Some churn predictors may impact customer churn directly, indirectly, or both. This study defines partial defection as an NPS feedback rating from promoter to passive and total defection as passive to the distractor. Thus, it acts as a link between churn predictors and customer loss. Partial defection's mediation effects on churn determinants and total defection are investigated. Hence, an NPS feedback status is hypothesised to mediate the relationship (Table 9).\n\n\nMethods\n\nThis empirical study used 7776 random samples from a database of one of Malaysia's leading telecommunications service providers, spanning from two datasets ((MTD) September 2019 and (MTD) September 2020)) (Table 10). The primary key results from the discovery process can be seen in Table 11.\n\nThe dependent variables for potential churner are binary, with 1 representing “yes” and 0 representing “no”. In addition, a multinomial variable for each account indicates promoter, passive, and distractor NPS feedback. Thus, a positive correlation coefficient implies a direct relationship between the two variables. Conversely, inverse correlation occurs when one variable rises while the other falls.48 Finally, after data pre-processing, eight irrelevant variables were dropped, and 25 variables were selected and converted numerically to avoid unstable coefficient estimates and difficult model interpretation (Table 12) (Underlying data).49\n\nThe study found high correlations between variables. Figure 3 shows the most positive correlation between helpdesk staff and assigned officer in charge (r = 0.98 & 0.96) and the most negative correlation between NPS feedback and potential churner (r = −0.85 & −0.91). The potential churner is found to be negatively related to NPS Feedback. Customers with lower NPS ratings are more likely to churn than those with higher ratings.\n\n\nResults\n\nThis study tested a harness to use 10-fold cross-validation, builds multiple models to predict measurements, and selects the best model. As a result, CART has the highest estimated accuracy score of 0.98 or 98% (Table 13).\n\nIn Figure 4, the box and whisker plots at the top of the range, with CART, SVM, and KNN evaluations achieving 100% accuracy and NB, LDA, and LR evaluations falling into the low 41% accuracy range.\n\nTable 14 shows the findings of the mediation effects, with statistical significance presented as a p-value less than 0.05. According to the results of this study, the NPS feedback rating appears to be a partial mediator between some churn determinants and customer churn. NPS Feedback is found to be a significant mediator of several churn determinants. The NPS feedback rating change partially mediates the following variables' effects on the probability of customer churn, Duration, Reply Shift, Service Request Type, Helpdesk Staff ID, and Assigned Officer to handle the task have a significant relationship with potential churn customer.\n\n* p-value (<.05).\n\nH1b reveals that SR TYPE (Service Request Type) has a significant impact on the probability of churn (Table 15). This finding is supported by Solution Partner (2019) that customers' requests should be centralised to avoid multiple ticket opening sources. One-stop-centre to answer requests, provide helpful information, and engage with customers until the problem is solved.50\n\nH1f reveals that REPLY SHIFT (Respond Day Shift) significantly impacts the probability of churn. It is consistent with past research; the speed of customer service responses is also important. Thus, the solution can influence employee and customer engagement when seeking solutions.51\n\nH1j reveals that DURATION (Respond Time Duration) has a significant impact on the probability of churn. This result supports Scout (2020) that time is an important factor in determining customer service quality. According to Forrester Research, 77% of customers believe that respecting their time is the most important online customer service.52\n\nH2d reveals that USERNAME ASSIGNED (Officer in Charge Username) significantly impacts the probability of churn. However, H2f does not. As a result, help desk staff must assign problems to experts based on case-by-case categories. Adebiyi et al. (2016) found that failing to respond to customer complaints or provide solutions may result in poor service delivery and contract termination.53\n\n\nDiscussion\n\nThis study found that customer satisfaction with helpdesk service affects NPS scores. Each rating meets customers' expectations. Understanding the provider's potential churner will also reveal how the company operates, whether it provides a high-quality product with excellent customer service or needs to improve significantly to compete.\n\nIt is important to acknowledge customers' contributions to the product or service's value. Responding to complaints is a good start, but if the provider wants to stay in business, they will need to do more. Providers will be delighted if they meet all customers' needs while providing the highest quality services.54\n\nFrom 7776 records, 5% of customers with NPS ratings below 6 are potential churners. The Customer Relationship Management (CRM) team will find potential churners with the initiative and techniques to retain customers using the same framework. Pope (2020) research the customers' lifetime value entirely depends on how hard the businesses work to maintain them. Providing a personalised customer experience will keep them coming back. It will also turn ardent supporters into online, social media, and in-person brand advocates. But building the brand momentum through happy customers takes time and effort. A good product is not enough. When consumers make purchases, they anticipate an experience. Numerous businesses use retention marketing to ensure brand consistency. The third and final phase, retention marketing, is the most critical. Providers must focus on customer relationships.55\n\n\nConclusions\n\nThis research used data from September 2019 and September 2020 to predict churn potential among Malaysian telecommunications customers. According to the results, the immediate helpdesk response can ensure that customers' needs are met and act as mediators in determining an employee's ability to satisfy customers. This study evaluated six machine learning algorithms, with CART having the most accurate performance (98%). The NPS feedback rating partially mediates customer churn. The proposed framework will help providers accurately predict potential churn customers and help CRM teams offer targeted churning customers win-back programmes. For better findings and analysis, more research should be done on NPS rating and provided customer feedback.\n\n\nData availability\n\nZenodo: Customer Churn Prediction for telecommunication Industry: A Malaysian Case Study.\n\nDOI: https://doi.org/10.5281/zenodo.5758742.49\n\nThis project contains the following underlying data:\n\n• Dataset MTD Sept 2019.csv (The file contains Net Promoter Score (NPS) in Month to Date (MTD) September 2019 of a telecommunication company. 25 variables were used to determine potential churn customer).\n\n• Dataset MTD Sept 2020.csv (The file contains Net Promoter Score (NPS) in Month to Date (MTD) September 2020 of a telecommunication company. 25 variables were used to determine potential churn customer).\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nAuthor contributions\n\nNurulhuda, M., Lew, S. L., & Siti, F. A. R. comprehended the idea and contributed to the research article. All authors contributed to the writing, editing, and consent of the final manuscript.",
"appendix": "Acknowledgements\n\nFirst and foremost, I must thank Multimedia University, for the sponsorship towards my Master of Science (Information Technology). Lastly, special thanks to all my family members and friends for their continuous support and understanding.\n\n\nReferences\n\nTamaddoni Jahromi A, Stakhovych S, Ewing M: Managing B2B customer churn, retention and profitability. Ind. Mark. Manag. 2014; 43(7): 1258–1268. Publisher Full Text\n\nAngelova B, Zekiri J: Measuring Customer Satisfaction with Service Quality Using American Customer Satisfaction Model (ACSI Model). International Journal of Academic Research in Business and Social Sciences. 2011; 1(3): 27. Publisher Full Text\n\nHejazinia R, Kazem M: Prioritising factors influencing customer churn. Interdisciplinary Journal of Contemporary Research in Business. 2014; 5(12): 1–10. Reference Source\n\nKumar S, Chandrakala D: A Survey on Customer Churn Prediction using Machine Learning Techniques. Int. J. Comput. Appl. 2016; 154(10): 13–16. Publisher Full Text\n\nAhmad AK, Jafar A, Aljoumaa K: Customer churn prediction in telecom using machine learning in big data platform. J. Big Data. 2019; 6(1): 6–28. Publisher Full Text\n\nAhn J-H, Han S-P, Lee Y-S: Customer churn analysis: Churn determinants and mediation effects of partial defection in the Korean mobile telecommunications service industry. Telecommun. Policy. 2006; 30(10–11): 552–568. Publisher Full Text\n\nGlobal Legal Group: Telecoms, Media & Internet 2021|Malaysia|ICLG. International Comparative Legal Guides International Business Reports.2020, 11th December. Reference Source\n\nIdem Est Advisory & Research: Latest Malaysia Telecoms Industry Report – 2020-2025. Idem Est Research & Advisory.2020, 31st August. Reference Source\n\nMarkets RA: Malaysia Telecoms Industry Report 2020-2025 - Market Sizing, Insights, Key Telecom Trends, 5G, IoT, and More. GlobeNewswire Newsroom.2020, 21st February. Reference Source\n\nChurn Rate: Investopedia.2021, 1st March. Reference Source\n\nReading Churn Rates: Investopedia.2020, 25th May. Reference Source\n\nThe Influence of Perceived Organisational Justice on Customer's Trust: An Overview of Public Higher Educational Students. Int. J. Bus. Manag. 2019; 3(3): 01–08. Publisher Full Text\n\n83% of consumers in Malaysia may switch telco provider: Frost: Digital News Asia.2015, 7th April. Reference Source\n\nWhat is Net Promoter Score? (Updated 2020): Qualtrics AU.2020, 12th October. Reference Source\n\nGadkari D: Factors Influencing the Net Promoter Score. UPPSALA UNIVERSITET; 2018, June. Reference Source\n\nKeiningham TL, Aksoy L, Cooil B, et al.: A holistic examination of Net Promoter. J. Database Mark. Cust. Strategy Manag. 2008; 15(2): 79–90. Publisher Full Text\n\nWhat is Net Promoter Score (NPS)? 2021 Guide & Definition: Hotjar.2021. Reference Source\n\nNunkoo R, Teeroovengadum V, Ringle CM, et al.: Service quality and customer satisfaction: The moderating effects of hotel star rating. Int. J. Hosp. Manag. 2020; 91: 102414. Publisher Full Text\n\nRajeev M: What is Customer Satisfaction? Freshcaller Blog.2020, 18th May. Reference Source\n\nCalvert GA, Pathak A, Ching LEA, et al.: Providing Excellent Consumer Service Is Therapeutic: Insights from an Implicit Association Neuromarketing Study. Behav. Sci. 2019; 9(10): 109. PubMed Abstract | Publisher Full Text\n\nKundeliene K, Leitoniene S: Business Information Transparency: Causes and Evaluation Possibilities. Procedia. Soc. Behav. Sci. 2015; 213: 340–344. Publisher Full Text\n\nAhmad AK, Jafar A, Aljoumaa K: Customer churn prediction in telecom using machine learning in big data platform. Journal of Big Data. 2019; 6(1): 1–5. Publisher Full Text\n\nHöppner S, Stripling E, Baesens B, et al.: Profit-driven decision trees for churn prediction. Eur. J. Oper. Res. 2020; 284(3): 920–933. Publisher Full Text\n\nYang L: Prediction Modeling and Analysis for Telecom Customer Churn in Two Months. ArXiv.Org. 2019, 1st November. https://arxiv.org/abs/1911.00558\n\nAhmed AAQ, Maheswari D: Churn prediction on huge telecom data using hybrid firefly-based classification. Egypt. Inform. J. 2017; 18(3): 215–220. Publisher Full Text\n\nEria K, Marikannan BP: Systematic Review of Customer Churn Prediction in the Telecom Sector. ResearchGate. 2018, September 27. Reference Source\n\nAhn J-H, Han S-P, Lee Y-S: Customer churn analysis: Churn determinants and mediation effects of partial defection in the Korean mobile telecommunications service industry. Telecommun. Policy. 2006; 30(10–11): 552–568. Publisher Full Text\n\nClemes MD, Gan C, Zhang D: Customer switching behaviour in the Chinese retail banking industry. Int. J. Bank Mark. 2010; 28(7): 519–546. Publisher Full Text\n\nGeetha M, Abitha Kumari J: Analysis of churn behavior of consumers in Indian telecom sector. J. Indian Bus. Res. 2012; 4(1): 24–35. Publisher Full Text\n\nKim M-J, Kim J, Park S-Y: Understanding IPTV churning behaviors: focus on users in South Korea. Asia Pacific Journal of Innovation and Entrepreneurship. 2017; 11(2): 190–213. Publisher Full Text\n\nStewart MPR: The Actual Difference Between Statistics and Machine Learning. Medium. 2020, July 30. Reference Source\n\nSrivastava T: Machine Learning vs. Statistical Modeling. Analytics Vidhya. 2020, June 26. Reference Source\n\nAnalytics P: What Is Machine Learning: Definition, Types, Applications and Examples. Potentia Analytics. 2019, December 19. Reference Source\n\nBertoncelli CM, Altamura P, Vieira ER, et al.: PredictMed: A logistic regression–based model to predict health conditions in cerebral palsy. Health Informatics J. 2020; 26(3): 2105–2118. Publisher Full Text\n\nTharwat A, Gaber T, Ibrahim A, et al.: Linear discriminant analysis: A detailed tutorial. AI Commun. 2017; 30(2): 169–190. Publisher Full Text\n\nCunningham P, Delany SJ: K-Nearest Neighbour Classifiers. 2nd ed.Machine Learning; 2020; 2. : 1–15. (with Python examples). Reference Source\n\nFearn T: Classification and Regression Trees (CART). NIR News. 2006; 17(6): 13–14. Publisher Full Text\n\nMoraes RM, Machado LS: Gaussian Naive Bayes for Online Training Assessment in Virtual Reality-Based Simulators. Mathware & Soft Computing. 2009; 16(2009): 123–132. Reference Source\n\nJakkula V: Tutorial on Support Vector Machine (SVM). School of EECS, Washington State University. 2006; 1–13. Reference Source\n\nAdsit DJ, London M, Crom S, et al.: Relationships between employee attitudes, customer satisfaction and departmental performance. J. Manag. Dev. 1996; 15(1): 62–75. Publisher Full Text\n\nKierczak L: Customer Satisfaction: Why It's Still Important in 2021. Survicate. 2021, January 21. Reference Source\n\nCouncil YE: The Customer Is Not Always Right: Here Are Five Reasons Why. Forbes. 2019, May 23. Reference Source\n\nMacDonald S: Customer Complaints: Why Angry Customers Are Good for Business. SuperOffice. 2021, May 4. Reference Source\n\nHammah CA: A customer retention strategy for Phoenix Insurance Company. Ashesi Institutional Repository. 2021, July 20. Reference Source\n\nLin CY, Huang CK: Employee turnover intentions and job performance from a planned change: the effects of an organisational learning culture and job satisfaction. Int. J. Manpow. 2020; 42(3): 409–423. Publisher Full Text\n\nBaehre S, O'Dwyer M, O'Malley L, et al.: The use of Net Promoter Score (NPS) to predict sales growth: insights from an empirical investigation. J. Acad. Market. Sci. 2021. Publisher Full Text\n\nWalters GD: Why are mediation effects so small?. Int. J. Soc. Res. Methodol. 2018; 22(2): 219–232. Publisher Full Text\n\nSchober P, Boer C, Schwarte LA: Correlation Coefficients. Anesth. Analg. 2018; 126(5): 1763–1768. Publisher Full Text\n\nMustafa N: Customer Churn Prediction for Telecommunication Industry: A Malaysian Case Study [Data set]. Zenodo. 2021; Publisher Full Text\n\nSolution Partner: Best practices for Service Request Management. E-Core Consulting. 2019, 20th August. Reference Source\n\nTri Marwanto S, Komaladewi R: How to Restrain Customer Churn in Telecommunication Providers: Study in West Java Indonesia. Review of Integrative Business and Economics Research. 2017; 6(1): 51–59. Reference Source\n\nScout H: Email Response Times: Benchmarks and Tips for Support. HelpScout. 2020, June 9. Reference Source\n\nAdebiyi SO, Oyatoye EO, Amole BB: Relevant Drivers for Customers` Churn and Retention Decision in the Nigerian Mobile Telecommunication Industry. Journal of Competitiveness. 2016; 6(3): 52–67. Publisher Full Text\n\nSuchánek P, Králová M: Customer satisfaction, loyalty, knowledge and competitiveness in the food industry. Economic Research-Ekonomska Istraživanja. 2019; 32(1): 1237–1255. Publisher Full Text\n\nPope L: How to Prevent Customer Churn with Retention Marketing. G2. 2020, 27th August. Reference Source"
}
|
[
{
"id": "109266",
"date": "04 Jan 2022",
"name": "Catur Supriyanto",
"expertise": [
"Reviewer Expertise Machine learning"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe research paper title on “Customer churn prediction for telecommunication industry: A Malaysian Case Study” is well organized and the originality of the paper is good. The main objective of the paper is to compare some machine learning (ML) algorithms for customer churn prediction in telecommunication industry.\nIn experiment the authors analyzed that the data were collected from one of the Malaysia's leading telecommunications service providers. The authors hypothesized that changes in Net Promoter Score (NPS) can indicate whether churn determinants directly or indirectly influence churn. Hence, they decided to execute many algorithms such as Logistic Regression, K-Nearest Neighbor (KNN), Support Vector Machine (SVM), Linear Discriminant Analysis (LDA), Classification and Regression Trees (CART), Gaussian Naive Bayes (NB) algorithms.\nThe authors concluded that the CART outperforms with an accuracy of 98% than other ML algorithms. The structure of the paper and result findings are good. Finally, the outcome of the paper is good and suggested to other businesses to measure potential customer churn using NPS scores to gather customer feedback in near future.\nHence, I have recommended this paper to be indexed.\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": "129495",
"date": "28 Apr 2022",
"name": "D. I. George Amalarethinam",
"expertise": [
"Reviewer Expertise Cloud Scheduling & Security",
"Data Mining",
"Network 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\nThe salient features of gait are analysed to predict churn potential using the data from one of the Malaysia's standard telecommunications service providers with the specific period from September 2019 to September 2020.\nAdditional explanation to be provided towards data called for in tables.\n\nThough the paper is technically sound, the limitations or negative aspects of the proposed methodology needs to be included.\n\nThe recent year references may be provided towards strengthening of the paper.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1274
|
https://f1000research.com/articles/10-1272/v1
|
13 Dec 21
|
{
"type": "Research Article",
"title": "Performance profiling of the unit trust funds in Malaysia with data mining techniques",
"authors": [
"Aida Farah Khairuddin",
"Keng-Hoong Ng",
"Kok-Chin Khor",
"Aida Farah Khairuddin",
"Kok-Chin Khor"
],
"abstract": "Background: Millennials are exposed to many investment opportunities, and they have shown their interest in gaining more income via investments. One popular investment avenue is unit trusts. However, analysing unit trusts’ financial data and gaining valuable insights may not be as simple because not everyone has the required financial knowledge and adequate time to perform in-depth analytics on the numerous financial data. Furthermore, it is not easy to compile the performance of each unit trust available in Malaysia. The primary objective of this research is to identify unit trust funds that provide higher returns than their average peers via performance profiling. Methods: This research proposed a performance profiling on Malaysia unit trust funds using the two data mining techniques, i.e., Expectation Maximisation (EM) and Apriori, to assist amateur retail investors to choose the right unit trust based on their risk tolerance. EM clustered the unit trust funds in Malaysia into several groups based on their annual financial performances. This was then followed by finding the rules associated with each cluster by applying Apriori. The resulted rules shall serve the purpose of profiling the clustered unit trust funds. Retail investors can then select their preferred unit trust funds based on the performance profile of the clusters. Results: The yearly average total return of the financial year 2018 and 2019 was used to evaluate unit trust funds’ performance in the clusters. The evaluation results indicated that the profiling could provide valuable and insightful information to retail investors with varying risk appetites.\n\nConclusions: This research has demonstrated that the financial performance profiling of unit trust funds could be acquired via data mining approaches. This valuable information is crucial to unit trust investors for selecting suitable funds in investment.",
"keywords": [
"unit trust funds",
"expectation maximisation",
"apriori",
"performance profiling"
],
"content": "Introduction\n\nIn Malaysia, different investment securities or schemes are publicly available to investors. The common securities include stocks, bonds, deposits, properties, unit trusts and commodities. Youngsters nowadays are more aware of the importance of earning passive income from investment. Bursa Malaysia recorded a 36% rise in the new Central Depository System (CDS) account holders aged below 25 in 2016, totalling more than 25.2 thousand account holders at the end of this year.1 Recently, the fast-growing trend has driven more financial products to be brought to the market to attract investors.\n\nUnit trusts are investment options with lower risk2 than equities because they are well-diversified financial instruments that fund managers handle. Each unit trust fund has its investment objective and strategy. Hence an amateur needs to pick the suitable funds to be included in their portfolio. However, it is not easy to choose suitable unit trust funds that meet the investor’s requirements, especially from a large pool of unit trust funds available in Malaysia. As of December 2019, the Security Commission of Malaysia (www.sc.com.my/analytics/fund-management-products) reported that Malaysia’s total launched unit trust funds are 685.\n\nAmateur investors always find it challenging to identify appropriate unit trust funds that meet their investment strategies and risks. The task requires much time and effort to complete, looking at the abundance of data to be searched and analysed. Most amateur investors are usually busy with their full-time jobs or running their own business. As a result, they cannot screen and perform in-depth analysis on many unit trust funds.\n\nAnother typically encountered problem is the low financial literacy among amateur investors. Thus, they cannot carry out a thorough analysis to extract meaningful information or knowledge from the annual reports they read. Subsequently, they find it challenging to analyse unit trust funds’ performance, and usually, their findings are inconclusive and indecisive. Amateur investors also face obstacles when they are looking for unit trust funds to fulfil their risk appetite. Hence, it is difficult for them to make investment decisions.\n\nConsidering the mentioned problems, this article aims to propose a data mining model that could build the performance profiles of unit trust funds using clustering and association rules mining algorithms. The model could mitigate the problems because: (i) the performance profiles could be generated rapidly, (ii) the financial information in the profile is intuitive and easy to understand by amateur investors, and (iii) the profiles also provide risk information.\n\n\nLiterature review\n\nThe research by F. Cai et al.3 evaluated 904 investment funds from financial datasets (time series and transactions) retrieved from the Morningstar using k-means and density-based clustering. The finding indicated that k-means performed better than the latter, giving the best number of clusters. In the research by T. Sakakibara et al.,4 clustering of mutual funds was done based on investment similarity instead of using historical performance similarity. The proposed approach was tested on 551 Japanese mutual funds. The result claimed that the approach could acquire the optimal number of clusters, even better than the classification provided by Morningstar Inc.\n\nK. H. Ng et al.5 adopted association rules mining to find frequent financial patterns in outlier stocks listed on Bursa Malaysia. The outliers were identified via a score-based approach, and they were manually grouped into superior and poor outliers. The research produced nine rules associated with outstanding stocks and four rules for the poor performing stocks. Investors can refer to these rules for decision making. Another study applied clustering to construct an efficient stock portfolio in the Warsaw Stock Exchange.6 The study utilised k-means and Partitioning Around Medoids (PAM) methods for this purpose and showed satisfactory returns.\n\n\nMethods\n\nThis research applies data mining techniques to profile the unit trust funds available in Malaysia. The entire process consisted of five key steps. The first step was to collect the financial data of the unit trust funds from annual reports. The next step involved a normalisation technique to ensure that the financial attributes share the same scale. The third step was grouping unit trust funds using a clustering algorithm. This was followed by profiling the clusters to find the common rules/characteristics associated with each cluster. In the final step, evaluation was conducted to study the efficiency of the proposed profiling method. The research overview is shown in Pseudocode 1.\n\nThe financial data of the unit trust funds were gathered from the annual report of each unit trust fund. From the annual report, six common financial variables were identified as crucial in the study: Net Asset Value (NAV) per unit, total growth rate, capital growth rate, income distribution rate, management expense ratio (MER), and portfolio turnover ratio (PTR). The detail of each financial attribute is shown in Table 1. In this study, 326 local unit trust funds’ data from 26 financial institutions were collected (Underlying data).7 Examples of financial institutions were CIMB Bank, Maybank, Prudential Insurance, Kenanga Investment Bank, etc.\n\nThe created dataset underwent the z-score normalisation before the clustering process. This was to prevent features with a larger scale from outweighing smaller-scaled features in the data mining process. This normalisation technique produced equal weight features within the range of [−1,1]. The formula for the z-score normalisation8 is shown in the following:\n\nVariable p denotes the original financial data value. The mean and the standard deviation of the financial data are represented by μ and σ, respectively.\n\nIn this step, the normalised dataset was partitioned into clusters based on their feature similarity. The use of EM clustering in this study could be justified with the following: (i) No predefined number of clusters, and (ii) It could handle missing values.9 EM clustering assigns each unit trust fund a probability distribution that represents the probability it belongs to each cluster. By maximising the log-likelihood of the data, EM finds the optimised parameters of a probability distribution.\n\nEM has two major steps, i.e., E-step (expectation) and M-step (maximisation). The detailed explanation of the algorithm is illustrated in Pseudocode 2. EM begins with initialising random values to parameters mean, variance, and a fraction of the data in each cluster c (line 2). Subsequently, E-step (line 3-7) computes the expected likelihood for the unit trust dataset. This is followed by maximising the likelihood of the data by re-estimating the parameter values in the M-step (lines 8-10). Both steps are repeated until the likelihood converges and reaches a local maximum. This means that the iteration will halt once the likelihood cannot be improved further.\n\nThe original format of the financial features in the dataset is numeric. Thus, these data were required to undergo discretisation before being processed by the association rules algorithm. The binning method was applied to discretise the financial features into three categories, i.e., low, medium and high. They were divided using the quartile range. The data was discretised to “low” if it was less than Q1 of the data (quartile 1). “Moderate” referred to data that was more than or equal to Q1 and less than or equal to Q3. Any data greater than Q3 was discretised as “high”.\n\nAssociation Rules Mining (ARM) is useful to discover frequent rules or patterns among groups of objects in a dataset. In this study, CAR10 mining was adopted to find a subset of rules associated with each cluster. The primary intention was to uncover a set of financial behaviours that are associated with each cluster uniquely. The financial behaviours can be used to build the cluster profile. CAR mining could be divided into two major steps, i.e. (i) discover all frequent k-itemsets in a dataset that comply with the user-defined minimum support, (ii) find the frequent k + 1 itemsets with the help of k-itemsets by applying a self-join rule. The detailed steps of the CAR are described in Pseudocode 3.\n\n\nResults and discussion\n\nThis study used a unit trust dataset that contained six normalised financial variables of the year 2017. It started with the clustering process using the Expectation Maximisation (EM) method. As a result, eight clusters were produced. Table 2 shows the detail of each cluster, including the number of assigned unit trust funds and the means of the six financial features. Cluster 2 was the largest cluster with 63 unit trust funds, and the smallest was Cluster 5 with only 14 members.\n\nThe smallest cluster has 14 funds (cluster 5), and the largest cluster contains 63 funds (cluster 2).\n\nEven though the mean of each financial variable is produced and displayed in the table, it is not an easy task for an amateur investor to analyse and interpret the generated information correctly. This is because the financial variables have been normalised before the clustering. Hence, a further step was taken to process this information by employing the Association Rules Mining technique so that the generated profile information on each cluster would be more intuitive and easier to understand. To perform the ARM, the continuous financial data was discretised into three bins, i.e., high, moderate, low, using the binning method.\n\nARM was conducted on each cluster to discover a set of rules associated with each cluster. Two parameters, i.e., minimum support and minimum confidence, were predefined. The first parameter was set to 50%,11 and a higher threshold of 90% was applied to the minimum confidence. ARM only yielded meaningful outcomes on three clusters: Cluster 8, Cluster 4, and Cluster 5. The remaining clusters did not demonstrate any strongly associated rules after the process.\n\nCluster 8 produced two frequent 3-itemsets (Table 3). The result strongly indicates that unit trust funds in this cluster belong to the type of high total return, high capital growth, and high portfolio turnover. Upon examining the portfolios of some unit trust funds in the cluster, it was discovered that these funds prioritise stock investment in their investment baskets. This finding was sufficient to justify the derived rules associated with the cluster because the return and capital growth of stock investment were relatively higher than the fixed income securities such as bonds, fixed deposits, etc. High portfolio turnover is also expected in these unit trust funds because the fund managers must always fine-tune their portfolios to maximise the returns. As such, the financial profile of this cluster can be summarised as “Aggressive”. This cluster is appropriate for investors who are risk-takers and aim for a high growth rate and return.\n\nThe rules associated with Cluster 4 are illustrated in Table 4, displaying the three frequent 3-itemsets derived from the cluster. The financial profile of Cluster 4 might not have been as outstanding as Cluster 8, but it is noteworthy to describe the unit trust funds in Cluster 4 as average and Defensive. Even though they have average performance among their peers in total return, capital growth, and income distribution, they give stable returns over the years.\n\nA thorough analysis of some of the unit trust funds in Cluster 4 revealed conservative investment approaches. They adopted a more diverse investment strategy by pooling their funds into a basket of securities consisting of shares and bonds, deposits, and properties. Combining these investment securities can lower the downside risk due to market volatility. In short, Cluster 4 was considered “Defensive”, and therefore suitable for investors with a low-risk tolerance.\n\nCluster 5 exhibited inferior financial performance. Table 5 shows the six frequent 2-itemsets derived after the ARM process. The associated rules in this cluster included low total return, low capital growth, high portfolio turnover, and high-income distribution. The phenomena of low total return but high-income distribution was due to poor capital growth. Stagnant or negative growth in the investment capital significantly outweighed the income distribution. Hence, this cluster was deemed as an inferior type. Investors are advised to avoid such unit trust funds at all costs.\n\nThe financial profiles created for the three clusters were further assessed and validated using the average total return (yearly) for the financial year 2018 and 2019 (Table 6). For 2018, the best performer was the Defensive cluster, which was the only one that still delivered a positive return (+1.17%). Both Aggressive and Inferior clusters were in the negative territory. Thorough investigation revealed that the unsatisfactory performance in 2018 was mainly attributed to the tumble of the Bursa market (Figure 1) affected by the three factors: general election, funds pulled out by foreign investors, and negative investor sentiment.\n\nThe 14th Malaysia general election has shaken investors’ confidence to invest in Malaysia’s equity markets. As a result, many investors withdrew their securities investments, and their action caused a sharp fall in the Bursa Index.12 The stock market was still in higher volatility mode in the second half of 2018. Many stocks could not recover their prices in the first half of the year.13 Funds pulled out by foreign fund managers also attributed to the stock market fall. It has been reported that the net foreign fund outflow in 2018 for Malaysia totalled RM11.65 billion.14 The last factor that adversely impacted the stock market was investor sentiment. Issues such as unresolved trade wars, lower oil prices, and geopolitical tension had refrained investors from securities investment.\n\nIn 2019, the volatility of the Malaysian stock market had subsided. Hence, all three clusters showed improvement in the total return as compared to the preceding year. The average total return (+4.65%) of Cluster 4 outperformed the others. Cluster 8 managed to gain a positive return of +3.52%. The worst performer (−2.98%) was still Cluster 5. The evaluation of two financial years for the three cluster profiles has strongly demonstrated that Cluster 4, with a Defensive profile, was resilient in the harsh economic climate that included market downturn, high market volatility, etc. This cluster may not have performed as well as Cluster 8 with an Aggressive profile during the economic boom, but it did provide steady passive income with lesser risk in the long run. Lastly, it could be summarised that investors with lower risk tolerance could aim at the defensive unit trust funds in Cluster 4. On the other hand, high-risk investors could identify the Aggressive unit trust funds in Cluster 8.\n\n\nConclusions\n\nThis study used data mining techniques to generate a financial profile for unit trust funds. The profile information is intuitive and easily understood by an investor. The investor could narrow down the number of unit trust funds for analysis. Investors could focus on just a single cluster for making an investment decision. For instance, the investor could identify aggressive unit trust funds from Cluster 8 if he/she is a high risk-taker.\n\nOn the contrary, investors could use Cluster 4 for steady and average passive incomes. The finding from this study will have significant implications for unit trust investors. To the best of our knowledge, no published work has applied data mining approaches to profile unit trust funds in Malaysia. We hope to continue and extend the study to include non-financial factors, e.g., fund manager profile and time-series data, in the future.\n\n\nData availability\n\nZenodo: Malaysia unit trust funds dataset, https://doi.org/10.5281/zenodo.5291931.7\n\nLocal unit trust checked version 1: The dataset contained 326 unit trust funds with their six financial attributes.\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (Attribution 4.0 International)\n\n\nAuthor contributions\n\nAll authors contributed equally to the conceptualisation of this study. Data curation, methodology, analysis and investigation, were performed by Aida Farah Khairudin. Keng-Hoong Ng and Kok-Chin Khor supervised the study and validated the evaluation results. Keng-Hoong Ng and Aida Farah Khairudin wrote the first draft of the manuscript. Kok-Chin Khor reviewed and edited the manuscript. All authors checked and approved the final manuscript.",
"appendix": "References\n\nAruna P: More young investors entering into Malaysia market. The Star Online. May 2017. Reference Source\n\nAnnamalah S, Raman M, Marthandan G, et al.: An empirical study on the determinants of an investor’s decision in unit trust investment. Economies. 2019; 7(3): 80. Publisher Full Text\n\nCai F, Le-Khac NA, Kechadi T: Clustering approaches for financial data analysis: a survey. arXiv preprint arXiv:1609.08520 2016.\n\nSakakibara T, Matsui T, Mutoh A, et al.: Clustering mutual funds based on investment similarity. Procedia Comput. Sci. 2015; 60: 881–890. Publisher Full Text\n\nNg KH, Khor KC, Tong GK: Class Association Rules for Profiling Outlier Stocks. Int. J. Advance Soft Compu. Appl. 2017; 9(3): 114–131.\n\nKorzeniewski J: Efficient Stock Portfolio Construction by Means of Clustering. Acta Universitatis Lodziensis. Folia Oeconomica. 2018; 1(333): 85–92. Publisher Full Text\n\nNg KH, Khairuddin AF, Khor K-C: Malaysia unit trust funds dataset [Data set]. Zenodo. 2021. Publisher Full Text\n\nOthman J, Asuta M, Jamilan N: Comparing the determinants of fund flows in domestically managed Malaysian Islamic and conventional equity funds. J. Islam. Account. Bus. Res. 2018; 9(3): 401–414. Publisher Full Text\n\nSaranya C, Manikandan G: A study on normalization techniques for privacy preserving data mining. Int. J. Eng. Technol. 2013; 5(3): 2701–2704.\n\nJung YG, Kang MS, Heo J: Clustering performance comparison using K-means and expectation maximisation algorithms. Biotechnol. Biotechnol. Equip. 2014; 28(sup 1): S44–S48. PubMed Abstract | Publisher Full Text\n\nNguyen D, Nguyen LT, Vo B, et al.: Efficient mining of class association rules with the itemset constraint. Knowl.-Based Syst. 2016; 103: 73–88. Publisher Full Text\n\nAbdulsalam SO, Adewole KS, Akintola AG, et al.: Data mining in market basket transaction: An association rule mining approach. International Journal of Applied Information Systems (IJAIS). 2014; 7(10): 15–20.\n\nNadzri MMN: The 14th General Election, the Fall of Barisan Nasional, and Political Development in Malaysia, 1957-2018. J. Curr. Southeast Asian Aff. 2018; 37(3): 139–171. Publisher Full Text\n\nMisman FN, Roslan S, Aladin MIM: General Election and Stock Market Performance: A Malaysian Case. Int. J. Financ. Res. 2020; 11(3): 139–145. Publisher Full Text\n\nMurugiah S: Foreign selling narrowed to RM127.6m last week, says MIDF Research. The Edge Markets. Dec 2018."
}
|
[
{
"id": "109286",
"date": "23 Feb 2022",
"name": "Lay Ki Soon",
"expertise": [
"Reviewer Expertise Text and data mining"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article reports the experiments on profiling selected unit trust funds in Malaysia using EM and CAR algorithms. While the results were as expected, the overall work is decent and the experimental validation is quite thorough. Some minor suggestions to improve the article:\n1. More details should be provided on the dataset collection. For instance, the source for the raw data (annual report), the year of the annual report collected, and how were the 326 funds selected.\n2. In terms of the features, why were only six variables used? Any empirical results to support this?\n3. For the discretization, which binning method was used?\n4. In results analysis, details were given on the impact of general elections to the stock market in Malaysia. It would be good to include relation between the stock market and unit trust funds.\n5. The results were good in the sense that similar unit trust funds are grouped in the same clusters. These were expected. Any outliers (something that is unexpected but discovered by the method used) found in the experimental results? That would be interesting to discuss.\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": "109294",
"date": "27 Jun 2022",
"name": "Wen Cheong Chin",
"expertise": [
"Reviewer Expertise Financial time series and risk management."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis article aims to use 2 data mining methodologies to profile the performance of 326 unit trust funds in Malaysia. 6 financial attributes have been selected and has being normalized as an Z-score before the clustering processes. The outcome of the analysis is able to assist investors in their investments based on their risk and return preferences by selecting their desired Cluster.\n\nSuggestion: 1. Provide more literature review related to this similar study in profiling performance. 2. It is good to provide some risk indicator (eg. Sharpe ratio) for each cluster. Therefore investors can consider how risky each cluster. 3. It is good for this study to extend to predictive analysis, where investors are given some guides for their future investments.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1272
|
https://f1000research.com/articles/10-1269/v1
|
10 Dec 21
|
{
"type": "Case Report",
"title": "Case Report: Aortic to right ventricular fistula after TAVR in a patient with transthyretin cardiac amyloidosis",
"authors": [
"Sergio Garcia-Gomez",
"Esther Gonzalez-Lopez",
"Juan Francisco Oteo",
"Esther Gonzalez-Lopez",
"Juan Francisco Oteo"
],
"abstract": "Aortic to right ventricular fistula formation after transcatheter aortic valve replacement (TAVR) is a rare complication. We describe the first case of an aorto-RV fistula after TAVR, conservatively managed, in a patient with concomitant aortic stenosis and wild-type transthyretin cardiac amyloidosis. Given that the underlying pathology may have implications, transthyretin cardiac amyloidosis screening in patients undergoing TAVR is warranted.",
"keywords": [
"Transthyretin cardiac amyloidosis",
"Aortic stenosis",
"Transcatheter aortic valve replacement",
"Ventricular fistula"
],
"content": "Abbreviations\n\nAS: aortic stenosis\n\nATTRwt: wild-type transthyretin cardiac amyloidosis\n\nCA: cardiac amyloidosis\n\nCTS: carpal tunnel syndrome\n\nHF: heart failure\n\nRV: right ventricular\n\nTAVR: transcatheter aortic valve replacement\n\n\nIntroduction\n\nThere is a high prevalence of wild-type transthyretin cardiac amyloidosis (ATTRwt) among patients with degenerative aortic stenosis (AS). We describe the first case of an aortic to right ventricular (RV) fistula after transcatheter aortic valve replacement (TAVR).\n\n\nPatient information\n\nAn 88-year-old Caucasian, retired, male patient was referred for transcatheter aortic valve replacement (TAVR) due to degenerative severe AS and heart failure (HF). He was first evaluated in 2015, following the diagnosis of atrial fibrillation and a systolic murmur.\n\nRegarding his past medical history, he was a former smoker and had known dyslipidemia. Additionally, he had undergone bilateral carpal tunnel syndrome (CTS) intervention in 2015 and 2016.\n\n\nClinical findings\n\nOn top of moderate-to-severe aortic stenosis (maximal mean gradient: 32 mmHg; area: 0.9 cm2), his first echocardiogram revealed mild left ventricular hypertrophy, preserved systolic function and a severely dilated left atrium.\n\nGiven his previous history of CTS, cardiac amyloidosis diagnosis workup was started. Plasma cell dyscrasia was ruled out and technetium-99m (99m-Tc) 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy showed an intense myocardial uptake, establishing a non-invasive diagnosis of concomitant ATTRwt, after excluding transthyretin (TTR) mutations.\n\nAt that time, the patient was in the New York Heart Association class II, denying angina or syncope but in 2016 he developed HF symptoms and required admission. During hospitalization, a new echocardiogram revealed mild systolic dysfunction (left ventricular ejection fraction (LVEF) 45%) and a stress echo was requested. Following dobutamine infusion, despite no cardiac output improvement, systolic function and mean transaortic gradient increased up to an LVEF of 59% and 40 mmHg, respectively, confirming the severity of AS.\n\nIn spite of the optimal medical therapy being used, HF decompensation recurred and TAVR was considered, so a computed tomography was performed to obtain different measurements including the aortic annulus: mean diameter (24.9 mm) and area (514 mm2).\n\nThe TAVR procedure was performed using femoral access and standard technique. Since previous aortic annulus measurement corresponded to lower limits for 29 mm Sapien 3 (Edwards) prosthesis and the aortic valve was a little calcified, that prosthesis was chosen and a balloon was inflated using 2 mL less than the nominal value. Although the TAVR was correctly implanted, during the intervention, the patient suffered a complete atrioventricular block requiring pacemaker implantation and an aortic to right ventricular (RV) fistula was observed by control angiography immediately after implantation (Figure 1).13\n\nA conservative management style was implemented for further interventions, with imaging and clinical follow-up. The patient presented no complications during a 2-year-follow-up. Repeated transthoracic echocardiograms revealed stable aortic to RV fistula, without hemodynamic changes (Figure 2).14–18\n\nControl echocardiogram (subcostal view) during follow-up.\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nDiscussion\n\nAS is the most common valve disease in the elderly population. Nearly 5% of patients aged 75 years and over have at least moderate AS,1 with a prevalence of >4% in octogenarians.\n\nCardiac amyloidosis (CA) has been traditionally associated to a restrictive cardiomyopathy, caused by the extracellular deposition of proteins in the myocardium. Primary or amyloid light-chain (AL) amyloidosis and transthyretin cardiac amyloidosis (in its hereditary or wild-type (ATTRwt) forms) are the most common subtypes of CA. Recently, transthyretin amyloidosis (ATTR) has been considered much more prevalent than AL.2\n\nAmyloid can infiltrate all components of the heart, from the conduction system to vessels. Amyloid infiltration has typically been associated with atrioventricular valve infiltration, but recently, the coexistence of AS and ATTRwt has emerged as a very prevalent clinical scenario.2\n\nIn 2016 a histological report revealed that occult ATTRwt had a prevalence of 5.3% among patients undergoing surgical aortic valve replacement due to severe calcific aortic stenosis. The subjects in the report were predominantly males, with a mean age of 75 years old.3\n\nA higher prevalence was found later in screened populations undergoing TAVR as these patients tend to be older.3 An American study prospectively screened AS patients undergoing TAVR, using technetium pyrophosphate scintigraphy and found a prevalence of 16% among them.4 More recently, a European study observed that the combination of AS and amyloid is common and affects around one in eight elderly patients with severe AS being considered for TAVR.5 Therefore, clinical, ECG and imaging red flags for CA should be systematically searched for in patients with AS to identify concomitant ATTRwt.\n\nBoth entities, AS and ATTRwt, share a common demographic and clinical profile, being considered part of the aging process.6 There is increasing data pointing out to a causative link between them though.6 Oxidative stress, inflammation and extracellular remodeling may be involved in TTR amyloidogenic process6 and these factors are also a central part of AS’ pathophysiology. Thus, it is possible that amyloid deposits could be induced or accelerated in patients with AS.\n\nThe association between AS and CA is not just prevalent, but also dangerous. Some authors3,7 have described a higher mortality in patients with AS and CA compared to those with isolated AS, while in a recent cohort, mortality was not affected among those patients with ATTR and AS undergoing TAVR.8 The worse prognosis in these patients could be mainly caused by CA, even after valve replacement. To support this, the latest cohort was presented with an increase of HF admissions after TAVR.8\n\nAccording to different groups,9,10 either repeated balloon valvuloplasties or TAVR is the best therapeutical options considering these patients’ frailty. Nowadays, TAVR is a procedure that commonly sees favorable outcomes, but some frequent complications (conduction disturbances, ...) might occur. Nonetheless, aortic to RV fistula formation is a rare complication (0.004% according to reported cases).11 This unusual complication does not often require repair and is reversible in most cases.\n\nThis case represents a typical example of diagnosis and management of AS and concomitant ATTRwt in an elderly patient. Low-flow, low-gradient AS has been shown to be a frequent form of AS presentation in ATTR.4 In this setting, the dobutamine stress test plays a crucial role in order to correctly evaluate AS’s severity and guide management. Attitude regarding AS in patients with CA should be personalized.\n\nOur case illustrates a rare complication of an aortic to RV fistula. Although similar cases have been previously reported,11 to our knowledge, this is the first case of an aorto-RV fistula after TAVR in a patient with concomitant AS and ATTRwt. Aortic to RV fistula seems to be a rare complication, and cardiac amyloidosis was confirmed in just this case out of the four at our own center. Of note, it is the only one in which the fistula did not resolved during follow-up and we hypothesize its relationship with tissue’s fragility due to amyloid deposition.\n\nThe exact mechanism for fistula development after TAVR is not fully understood. Possible reasons to justify its development include congenital or acquired sinus of Valsalva aneurysms, trauma, or infections. Most cases of aortic to RV fistulas have been described in patients in whom a balloon-expanded transcatheter valve was used,11 possibly conditioned by trauma and oversizing. In this case, we believe that amyloid deposits on the aortic valve annulus might have led to a more friable substratum, making this case prone to complications, mainly complete AV block and aortic to RV fistula.\n\nSeveral studies have found myocardial amyloid deposits in a significant percentage of patients with AS. Different authors have identified amyloid deposits in prosthetic valves explanted3 and in endomyocardial biopsies from basal left ventricle septum.3 Histological analysis of the interventricular septum performed by Moreno et al12 in a patient who developed a complete AV block after TAVR discovered two different potential mechanisms to explain the patient’s complication: a localized hematoma at the site of aortic valve prosthesis expansion, which could justify trauma damage on the conduction system; and amyloid deposits.\n\n\nConclusions\n\nGenerally, conservative management with annual re-evaluation is accepted in ventricular fistulas. Except when significant symptom development or hemodynamic instability occurs. Based on our own experience, a conservative approach is an adequate option, even in cases with concomitant ATTRwt.\n\n\nLearning objectives\n\n\n\n1. To remind the importance of extensive clinical and imaging evaluation before transcatheter aortic valve replacement.\n\n2. To emphasize the high prevalence of ATTRwt among patients with degenerative aortic stenosis undergoing TAVR and the need of amyloid screening in this clinical scenario.\n\n3. To highlight the role of dobutamine stress echocardiogram in this setting.\n\n4. To increase awareness about possible TAVR complications in patients with concomitant AS and ATTRwt and how to approach these cases in order to minimize 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\nFigshare: Video 1: Aortic to right ventricular fistula after transcatheter aortic valve replacement observed by fluoroscopy, https://doi.org/10.6084/m9.figshare.17122124.v1.13\n\nFigshare: Video 2: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (subcostal view) during follow-up, https://doi.org/10.6084/m9.figshare.17122181.v1.14\n\nFigshare: Video 3: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (parasternal long axis view) during follow-up, https://doi.org/10.6084/m9.figshare.17122211.v1.15\n\nFigshare: Video 4: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (parasternal short axis view) during follow-up, https://doi.org/10.6084/m9.figshare.17122226.v1.16\n\nFigshare: Video 5: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (apical five chamber view) during follow-up, https://doi.org/10.6084/m9.figshare.17122241.v1.17\n\nFigshare: Video 6: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (zoom on apical five chamber view) during follow-up, https://doi.org/10.6084/m9.figshare.17122265.v1.18\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nWritten informed consent\n\nWritten informed consent from the patient for the use and publication of the patient’s data was obtained.",
"appendix": "References\n\nThaden JJ, Nkomo VT, Enriquez-Sarano M: The global burden of aortic stenosis. Prog. Cardiovasc. Dis. 2014; 56: 565–571. Publisher Full Text\n\nGarcia-Pavia P, Domínguez F, Gonzalez-Lopez E: Transthyretin amyloid cardiomyopathy. Med. Clin. (Barc.). 2020; 156: 126–134. Publisher Full Text\n\nTreibel TA, Fontana M, Gilbertson JA, et al.: Occult Transthyretin Cardiac Amyloid in Severe Calcific Aortic Stenosis: Prevalence and Prognosis in Patients Undergoing Surgical Aortic Valve Replacement. Circ. Cardiovasc. Imaging. 2016; 9: e005066. Publisher Full Text\n\nCastaño A, Narotsky DL, Hamid N, et al.: Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur. Heart J. 2017; 38: 2879–2887. PubMed Abstract | Publisher Full Text\n\nScully PR, Patel KP, Treibel TA, et al.: Prevalence and outcome of dual aortic stenosis and cardiac amyloid pathology in patients referred for transcatheter aortic valve implantation. Eur. Heart J. 2020; 41: 2759–2767. PubMed Abstract | Publisher Full Text\n\nGalat A, Guellich A, Bodez D, et al.: Aortic stenosis and transthyretin cardiac amyloidosis: the chicken or the egg?. Eur. Heart J. 2016; 37: 3525–3531. Publisher Full Text\n\nCavalcante JL, Rijal S, Abdelkarim I, et al.: Cardiac amyloidosis is prevalent in older patients with aortic stenosis and carries worse prognosis. J. Cardiovasc. Magn. Reson. 2017; 19: 98. PubMed Abstract | Publisher Full Text\n\nRosenblum H, Masri A, Narotsky DL, et al.: Unveiling outcomes in coexisting severe aortic stenosis and transthyretin cardiac amyloidosis. Eur. J. Heart Fail. 2020; 23: 250–258. PubMed Abstract | Publisher Full Text\n\nBordoni B, Moretti C, Marrozzini C, et al.: Repeated Aortic Balloon Valvuloplasty in Elderly Patients With Aortic Stenosis Who Are Not Candidates for Definitive Treatment. J. Invasive Cardiol. 2015 Dec; 27(12): E277–84. PubMed Abstract\n\nAlsamarrai A, Wang TKM: Balloon aortic valvuloplasty for severe aortic stenosis: single-centre contemporary patterns and experience. N. Z. Med. J. 2021 Sep 3; 134(1541): 123–129. PubMed Abstract\n\nKonda MK, Kalavakunta JK, Pratt JW, et al.: Aorto-right Ventricular Fistula Following Percutaneous Transcatheter Aortic Valve Replacement: Case Report and Literature Review. Heart Views. 2017; 18: 133–136. PubMed Abstract | Publisher Full Text\n\nMoreno R, Dobarro D, López de Sá E, et al.: Cause of complete atrioventricular block after percutaneous aortic valve implantation: insights from a necropsy study. Circulation. 2009; 120: e29–e30. PubMed Abstract | Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 1: Aortic to right ventricular fistula after transcatheter aortic valve replacement observed by fluoroscopy. f1000research.com. Media. 2021. Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 2: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (subcostal view) during follow-up. f1000research.com. Media. 2021. Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 3: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (parasternal long axis view) during follow-up. f1000research.com. Media. 2021. Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 4: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (parasternal short axis view) during follow-up. f1000research.com. Media. 2021. Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 5: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (apical five chamber view) during follow-up. f1000research.com. Media. 2021. Publisher Full Text\n\nGomez SG, Gonzalez-Lopez E, Oteo JF: Video 6: Aortic to right ventricular fistula after transcatheter aortic valve replacement. Control echocardiogram (zoom on apical five chamber view) during follow-up. f1000research.com. Media. 2021. Publisher Full Text"
}
|
[
{
"id": "120430",
"date": "07 Feb 2022",
"name": "Andreas A. Kammerlander",
"expertise": [
"Reviewer Expertise cardiovascular imaging",
"valvular heart disease",
"cardiac amyloidosis",
"coronary heart disease",
"cardiovascular magnetic resonance imaging."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nNice case of severe AS and concomitant cardiac TTR-Amyloidosis.\nI would suggest the following:\n- Currently, only the bilateral carpal tunnel syndrome is presented as hint for cardiac amyloidosis (CA). This should be expanded to: discordance of ECG and LV hypertrophy on imaging, apical sparing in strain analysis, etc.\n- Aortic to RV fistula is a rare but known complication. It is a valid hypothesis that CA patients may be more prone to such an adverse event, however, there is no data to back this up. Hence, this is speculative and should be stated as such.\n- I would include the scintigraphy image for the readers.\n- Your comment that CA in patients with AS is \"dangerous\" should be revised and discussed more critically. See e.g. 10.1016/j.jacc.2020.11.006 where treated (with TAVR) CA-AS patients performed similarly to lone AS patients.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1269
|
https://f1000research.com/articles/10-1264/v1
|
09 Dec 21
|
{
"type": "Research Article",
"title": "Predictive modelling of arsenate (As(V)) adsorption onto surface-engineered magnetite nanoparticles",
"authors": [
"Nisha Kumari Devaraj",
"Ameer Al Mubarak Hamzah",
"Nisha Kumari Devaraj"
],
"abstract": "Background: Since adsorption is a complex process, numerous models and theories have been devised to gain general understanding of its underlying mechanisms. The interaction between the adsorbates and adsorbents can be identified via modelling of the adsorption data with different adsorption isotherms as well as kinetic models. Many studies are also focused on developing predictive modelling techniques to facilitate accurate prediction of future adsorption trends. Methods: In this study, a predictive model was developed based on a multiple linear regression technique using existing data of As(V) adsorption onto several coated and uncoated magnetite samples. To understand the mechanisms and interactions involved, the data was first modelled using either Temkin or Freundlich linear isotherms. The predicted value is a single data point extension from the training data set. Subsequently, the predicted outcome and the experimental values were compared using multiple error functions to assess the predictive model’s performance. Results: In addition, certain values were compared to that obtained from the literature, and the results were found to have low error margins. Conclusion: To further gauge the effectiveness of the proposed model in accurately predicting future adsorption trends, it should be further tested on different adsorbent and adsorbate combinations.",
"keywords": [
"Arsenate adsorption",
"adsorption predictive technique",
"surface-engineered magnetite nanoparticles",
"linear regression technique",
"error function"
],
"content": "Introduction\n\nHeavy metal ions are toxic and dangerous towards living organisms depending on the concentration and duration of exposure. Among the most toxic heavy metals are chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), cadmium (Cd), lead (Pb), mercury (Hg) and arsenic (As)1. The metalloid As itself has been considered as the highest priority pollutant to be controlled in China since 2009 together with four other heavy metal ions2. Heavy metals come from two major sources, namely natural and anthropogenic activities. Natural sources include volcanic-related occurrences, soil erosion, eroded rocks and minerals whilst anthropogenic sources involve landfills, sewage, agricultural activities, industrial pollutants, as well as mining3. The increased discharge of heavy metals into the environment may be attributed to global industrialisation and increased urbanisation processes1. In addition, the metalloid As is a ubiquitous element which exists naturally in the environment, hence resulting in enhanced exposure that could prove to be fatal if not controlled. A recent spate of toxic waste dumping incidences into rivers in Peninsular Malaysia necessitates the development of more effective water remediation methods. Adsorption is one of the numerous solutions that has gained popularity lately due to its effectiveness and low cost, especially adsorption using nanoparticles (NPs) as adsorbents. Extensive research is being carried out to improve the adsorption capacity of the wide range of NPs available. However, the comprehension of the adsorption mechanism by NPs is still on-going, thus isotherm and kinetic equations are continuously being formulated4. Having the ability to predict certain outcomes especially regarding the behaviour of particles involved in the process of adsorption or desorption would be beneficial for the effective design of experiments. An accurate prediction will bring forth a great breakthrough not only for the understanding of the underlying mechanisms but for future experiments as well.\n\nIn this project, existing arsenate (As(V)) adsorption data onto uncoated, humic acid-coated and ceria-coated magnetite samples were initially modelled. As for the predictive model, multiple linear regression was implemented to predict the equilibrium adsorption capacity, qe of each sample. The predicted results were compared to the experimental qe results and the model’s accuracy was thus ascertained.\n\n\nLiterature review\n\nIn general, the first step involved in predicting an adsorption process is to emulate the process itself. An example is the study by Mandal et al.5, in which a hybrid material was synthesised to run an actual As adsorption experiment. The optimum parameters such as adsorbent dose, pH and initial concentration were varied for the predictive model’s design.\n\nA predictive model consists of a set of data framework which is correlated to the experimental variables. In the same study by Mandal et al. the evolutionary Genetic Programming (GP) and Least Squares Support Vector Machine (LS-SVM) models were utilised. The optimal physical parameters were inserted into these models for computation. The result was a model that could predict the adsorption process with a certain degree of confidence in emulating the actual adsorption process results.\n\nAnother study by Onur et al.6 implemented Quantitative Structure-Activity Relationship (QSAR) and Linear Solvation Energy Relationship (LSER) techniques to develop a predictive model for aromatic contaminants adsorption onto multi-walled carbon nanotubes. In the study, 29 aromatic adsorption datasets obtained from literature and experiments were used in developing the predictive model. A few variables such as the molecular connectivity indices and solvatochromic descriptors were included for both the QSAR and LSER models, thus increasing the accuracy of predicting future trends. Besides that, Sisi et al.7 predicted the adsorption of As(V) onto iron-coated sand, which was based on a model known as surface complexation. The input parameters were the experimental maximum adsorption capacities as well as results from an extended X-ray absorption fine structure spectroscopy (EXAFS) as a function of pH and adsorbent dose. The goal was to derive a model that could predict and determine the adsorption performance over a pH range of 5–8. This indicates that the predictive model can be implemented to determine the other factors of adsorption as well. Meanwhile, a study by Fukushi et al.8 implemented the extended triple layer model (ETLM), which is also a form of the surface complexation model. The model was used to predict As(V) adsorption onto oxides with the aid of in situ spectroscopic evidence as well as molecular theories and calculation. Based on the various studies reviewed, it can be surmised that there are multiple techniques that could be applied in predicting the outcomes of an adsorption process. The understanding of the adsorption process and as well as the availability of data parameters are the deciding factors of the suitable predictive model(s) to be selected and implemented.\n\n\nMethods\n\nThe flow of executing the predictive model from providing input to acquiring the output is shown in Figure 1. After determining the best model that fits the experimental data obtained from our previous experiments involving the different types of magnetite samples9,10, that specific model’s equation was used to provide the linearity in determining the equilibrium adsorption capacity, qe. Aside from the model’s parameters, the other values which acted as input are the raw data (the experimental qe) that was linearised by the model chosen and the value of physical parameters such as concentration, temperature and the adsorbent sizes.\n\nThe respective particles’ adsorption data: humic-acid coated magnetite NPs (modelled with Temkin isotherm), uncoated magnetite and ceria-coated magnetite particles (both modelled with Freundlich) were chosen as inputs to the predictive model. The summary of the choice of the isotherm parameters such as Ce (equilibrium concentration of adsorption), b (Temkin constant), 1/n (intensity of adsorption) as well as KF (Freundlich constant) and the physical parameters are as shown in Table 1. Y-axis parameter values, which are forms of qe (dependant on the chosen isotherm model), were predicted and compared to the experimental Y-axis parameter values.\n\nLinear predictive analysis was implemented using the software Python 3.0 (Python Programming Language, RRID:SCR_008394) to code the model’s framework. Below are some key points of the linear regression model:\n\nSample size of four including the starting point.\n\nThe first three rows of data were the training data set while the last one was the test set.\n\nNo iterations involved.\n\nThe performance of the developed predictive model was validated using multiple error functions: mean squared error (MSE), mean absolute percentage error (MAPE), average absolute relative error (AARE), non-linear chi-squared value (χ2) and root mean squared error (RMSE) as shown in Equation 1, Equation 2, Equation 3, Equation 4 and Equation 5 respectively5. These values were also compared to other models’ results from the literature to benchmark our model’s performance. Besides that, Equation 6 and Equation 7 are the absolute error (AE) and percentage error (PE) calculation formulae.\n\n\nResults\n\nTable 2, Table 3 and Table 4 depict the predicted results which are based on the actual data sets provided as input. The overall absolute error is particularly low. However, this may be because linearity is the main component for the model framework, where almost zero error is possible so as long as the provided input gives good data fit as well. In short, the data simply stretches out linearly and can predict values for every additional 20 minutes beyond the modelled data’s duration. In addition, the linearity extends indefinitely, which neglects the fact that there is an adsorption equilibrium capacity. Further analysis based on the results from the Table 2–Table 4 is tabulated and summarised in Table 5.\n\nFrom Table 2 it can be observed that the lowest absolute error of 0.000805 was obtained for the 2238 nm particle, while the largest error, 0.087876 was for the 3203 nm particle. Also observed is that at a constant humic acid concentration, the predicted value increased with increasing particle sizes and surpasses the actual value.\n\nBased on the tabulated results in Table 3, the lowest absolute error was for the 998.3 nm particle under a sonication temperature of 70°C, while the largest was for the 782 nm particle at 30 °C. At 50°C, the absolute errors for the 442 nm and 782 nm particles are lower compared to the other temperatures. On the other hand, the absolute error was the highest at the same temperature for the 998.3 nm particle. In addition, at 70°C, as the particle size increased, the absolute error values decreased. From Table 4, the lowest and the highest values of absolute error are observed for the 617 nm particle at 30°C and 1259 nm particle at 70°C, respectively.\n\nThe validated results are shown in Table 6. The value of RMSE obtained from various predictive models in the literature to compare against our predictive model’s accuracy are as shown in Table 7.\n\n\nDiscussion\n\nCompared to other studies5,11–13 shown in Table 7, our predictive modelling has lower error percentages, which may imply a higher prediction accuracy. However, this was only because our model is based solely on linearity, given very few input data sets with no iterations and no complex theories derived. The isotherm model’s linear regression was simply recycled and transformed to a multiple linear regression by adding in a few X-axis parameters (including the chosen isotherms model’s parameters) to predict the qe value. Compared to other methodologies employed as outlined in Table 75,11–13, their results were simulated and obtained from a more complex framework of codes, not to mention having many data sets as well as multiple repetitions of trial and error. Nonetheless, the framework of the predictive technique developed here could act as a foundation in the formulation of a more complex model with more input datasets to improve its reliability.\n\nTo explain further, since the linear isotherm model chosen for each sample provided the best fit to the adsorption data, the assumptions and theories of the model would be applicable for our samples as well. Hence, the existing the model’s equation can be used as a basis to predict future adsorption trends under different experimental variables once the preliminary adsorption data has been modelled. This is crucial especially as the linearity of the modelled data is the input to the predictive model analysis. Hence, this would reduce the need to derive or formulate new complex theories to emulate the adsorption process. The simplicity and straight-forward nature of the predictive model developed herein makes it attractive for further development and testing with the adsorption data of numerous types of samples under different experimental parameters for a more effective design of experiment.\n\n\nConclusions\n\nMany predictive modelling techniques were researched to emulate the actual adsorption process. In this project, a simple and straightforward multiple linear regression method was implemented. Satisfactory results were obtained with small error values. Despite lacking in theoretical derivations, choosing an existing model may prove to be sufficient to predict the qe values as long as sufficient experimental data are available, and the best-fit model is decided beforehand.\n\n\nData availability\n\nOpen Science Framework: Underlying data for ‘Predictive modelling of As(V) adsorption onto surface-engineered magnetite nanoparticles’, https://doi.org/10.17605/OSF.IO/3ZMKR10\n\nThis project contains the following underlying data:\n\n- Data file 1: CM1.2.csv\n\n- Data file 2: CM234.csv\n\n- Data file 3: ErrorCalc_ceria magnetite.csv\n\n- Data file 4: ErrorCalc_Humic acid.csv\n\n- Data file 5: ErrorCalc_Magnetite.csv\n\n- Data file 6: HA1_6.csv\n\n- Data file 7: M1234.csv\n\n- Data file 8: Magnetite As(V) adsorption data.pdf\n\nData are available under the terms of the CC0 1.0 Universal.\n\n\nSoftware availability\n\nSource code available from: https://github.com/Nishadevaraj/Phyton-source-code-Manuscript-73260-.git14\n\nArchived source code at time of publication:\n\nLicense: Apache-2.0 License.",
"appendix": "References\n\nAli H, Khan E, Ilahi I: Environmental Chemistry and Ecotoxicology of Hazardous Heavy Metals: Environmental Persistence, Toxicity, and Bioaccumulation. Journal of Chemistry. 2019; 2019: 1–14. Publisher Full Text\n\nFu Z, Guo W, Dang Z, et al.: Refocusing on nonpriority toxic metals in the aquatic environment in China. Environ Sci Technol. 2017; 51(6): 3117–3118. PubMed Abstract | Publisher Full Text\n\nBurakov AE, Galunin EV, Burakova IV, et al.: Adsorption of heavy metals on conventional and nanostructured materials for wastewater treatment purposes: A review. Ecotoxicol Environ Saf. 2018; 148: 702–712. PubMed Abstract | Publisher Full Text\n\nLópez-Luna J, Ramírez-Montes LE, Martinez-Vargas S, et al.: Linear and nonlinear kinetic and isotherm adsorption models for arsenic removal by manganese ferrite nanoparticles. SN Applied Sciences. 2019; 1: 950. Publisher Full Text\n\nMandal S, Mahapatra SS, Adhikari S, et al.: Modeling of Arsenic (III) Removal by Evolutionary Genetic Programming and Least Square Support Vector Machine Models. Environmental Processes. 2015; 2(1): 145–172. Publisher Full Text\n\nApul OG, Wang Q, Shao T, et al.: Predictive Model Development for Adsorption of Aromatic Contaminants by Multi-Walled Carbon Nanotubes. Environ Sci Technol. 2013; 47(5): 2295–2303. PubMed Abstract | Publisher Full Text\n\nQue S, Papelis C, Hanson AT: Predicting Arsenate Adsorption on Iron-Coated Sand Based on a Surface Complexation Model. Journal of Environmental Engineering. 2013; 139(3): 368–374. Publisher Full Text\n\nFukushi K, Sverjensky DA: A predictive model (ETLM) for arsenate adsorption and surface speciation on oxides consistent with spectroscopic and theoretical molecular evidence. Geochimica et Cosmochimica Acta. 2007; 71(15): 3717–3745. Publisher Full Text\n\nDevaraj NK, Elghazali SR, Ganapathe LS, et al.: As (V) adsorption kinetics of humic acid-coated magnetite particles. Applied Mechanics and Materials. Trans Tech Publications Ltd, 2019; 892: 72–78. Publisher Full Text\n\nDevaraj NK: Predictive modelling of As(V) adsorption onto surface-engineered magnetite nanoparticles. Open Science Framework. 2021. http://www.doi.org/10.17605/OSF.IO/3ZMKR\n\nNguyen VD, Nguyen HTH, Vranova V, et al.: Artificial neural network modeling for Congo red adsorption on microwave-synthesized akaganeite nanoparticles: optimization, kinetics, mechanism, and thermodynamics. Environ Sci Pollut Res Int. 2021; 28(8): 9133–9145. PubMed Abstract | Publisher Full Text\n\nHafsa N, Al‐Yaari M, Rushd S: Prediction of arsenic removal in aqueous solutions with non‐neural network algorithms. Can J Chem Eng. 2021; 99(S1): S135–S146. Publisher Full Text\n\nBullen JC, Kenney JPL, Fearn S, et al.: Improved accuracy in multicomponent surface complexation models using surface-sensitive analytical techniques: Adsorption of arsenic onto a TiO2/Fe2O3 multifunctional sorbent. J Colloid Interface Sci. 2020; 580: 834–849. PubMed Abstract | Publisher Full Text\n\nDevaraj NK: Phyton source codes for manuscript 73260. GitHub. 2021. https://github.com/Nishadevaraj/Phyton-source-code-Manuscript-73260-.git"
}
|
[
{
"id": "102407",
"date": "10 Dec 2021",
"name": "Claudia Maria Simonescu",
"expertise": [
"Reviewer Expertise Environmental engineering and protection"
],
"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 manuscript presents new data regarding development of a predictive model based on a multiple linear regression technique using existing data of As(V) adsorption onto several coated and uncoated magnetite samples. Temkin and Freundlich linear isotherms were used to model the experimental results. The predictive model’s performance was assessed by comparing of predicted outcome and the experimental values using multiple error functions.\nThis work has enough content to be published in the journal, is well-argued, well-written and well organized information. The organization of the article is satisfactory. The paper's title is brief and reflects the main theme of the paper.\nThe abstract is sufficiently informative. It is completely self-explanatory, briefly presents the topic, states the scope of the experiments, indicates significant data, and points out major findings and conclusions.\n\nThe keywords are suitable so the article can be found in the current registers or indexes.\n\nThe introduction shows how this work builds on previous work on the subject. Introduction clearly states the problem being investigated. The purpose and objectives of the manuscript are adequate and appropriate in view of the subject matter. The authors highlighted the novelty of the paper.\n\nThe authors accurately explain how the model was developed.\n\nThe input parameters, the key points of the linear regression model and multiple error functions determined are specified. There is sufficient information to allow replication of the research.\n\nIn the Results and Discussion part, the authors present and interpret the results of the modelling performed. This section is well organized.\n\nThe authors used the unit measurements according to the International Standards.\n\nThe figure and tables are numbered sequentially, and they are clearly labeled and positioned close to the relevant text. Titles of figure and tables are brief and informative.\n\nIn the Conclusions part the authors mentioned the major and specific conclusions of their research study. All the conclusions are justified and supported by the results obtained.\n\nThe abbreviations and nomenclature are used according to applicable international standards and rules.\n\nThe length of the manuscript is adequate.\n\nThe authors compared their results with other research findings.\n\nSignificant findings regarding implementation of one simple and straightforward multiple linear regression method to describe As(V) adsorption onto several coated and uncoated magnetite samples are provided by this research study. In my opinion, the work provides an advance towards the current knowledge.\n\nConsequently, I recommend the publication of this manuscript without modifications.\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": "237381",
"date": "28 Feb 2024",
"name": "Abdelazeem Eltaweil",
"expertise": [
"Reviewer Expertise Adsorption",
"environmental catalysis",
"MOFs",
"LDHs"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 the significance of heavy metal ions, particularly arsenic, in water pollution and focuses on adsorption as a water remediation method. The study models arsenate (As(V)) adsorption onto different magnetite samples using multiple linear regression for predictive analysis. The literature review highlights various predictive models used in adsorption studies. The methods section outlines the flow of the predictive model, input parameters, and the linear regression model's key points. The results demonstrate low absolute errors in predicting equilibrium adsorption capacity for different magnetite samples. The discussion emphasizes the simplicity and effectiveness of the linear regression model, suggesting its potential for further development and testing with diverse adsorption data. The conclusions affirm the satisfactory results and advocate for the use of existing models with sufficient experimental data for predictive modeling. Here are some major comments:\nRecognize the limitation of relying heavily on linearity in modeling; explore alternative approaches. Expand the dataset to enhance the model's applicability and reliability. Consider that the model's simplicity may limit its understanding of complex adsorption mechanisms. Provide a comprehensive discussion on the implications of error metrics; compare them with existing models. Validate the model's adaptability across diverse adsorbates. Explore the practical significance and real-world applications of the developed model. Discuss potential refinements for the model to contribute meaningfully to future research. few numbers of references have been used.\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?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1264
|
https://f1000research.com/articles/10-1263/v1
|
09 Dec 21
|
{
"type": "Brief Report",
"title": "Autism Spectrum Disorder and screen time during lockdown: an Italian study.",
"authors": [
"Maria Grazia Logrieco",
"Laura Casula",
"Giuseppe Niccolò Ciuffreda",
"Ilaria Nicolì",
"Maria Spinelli",
"Alberto Di Domenico",
"Francesca Lionetti",
"Roberta Novello",
"Giovanni Valeri",
"Mirco Fasolo",
"Stefano Vicari",
"Laura Casula",
"Giuseppe Niccolò Ciuffreda",
"Ilaria Nicolì",
"Maria Spinelli",
"Alberto Di Domenico",
"Francesca Lionetti",
"Roberta Novello",
"Giovanni Valeri",
"Mirco Fasolo",
"Stefano Vicari"
],
"abstract": "Background: Lockdown due to Covid-19 pandemic brought deep changes to the daily lives of children with Autism Spectrum Disorder (ASD), greatly increasing their amount of time spent at home. Methods: A cohort of 243 parents of children with ASD (2-15 years old) completed an original online survey regarding the child’s screen time and the modification of the ASD symptomatology during lockdown to investigate the relationship between them. Results: The data show that high solitary screen time is related with the worsening of ASD core symptoms. Conclusions: This study may help to increase awareness in the excessive use of screen in children with ASD during the lockdown, both during the pandemic as well as after it ends.",
"keywords": [
"Autism Spectrum Disorder",
"screen time",
"lockdown",
"children",
"parents",
"solitary screen time",
"Covid-19",
"survey"
],
"content": "Introduction\n\nThe lockdown imposed to contain the Covid-19 pandemic introduced strict restrictive measures to avoid the spread of the virus (Government, 2020). The adopted measures included a stay-at-home order and the closure of schools and educational facilities. Literature reported that during lockdown, parents of children faced serious difficulties in the organization of the children’s free time (Ozturk & Yalçin, 2021). This plight was even more challenging for families of children with developmental disabilities. One specific and wide subgroup of these families and children, are children with Autism Spectrum Disorder (ASD). The latest revision of DSM American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (APA, 2013), adopted the umbrella term Autism Spectrum Disorder with two features: difficulties in social communication and social interaction; and restricted and repetitive behavior, interests or activities. These two sets of symptoms have a wide range of severity levels, which may be different for each child with ASD (Lord et al., 2020). ASD symptomatology presented additional challenges for children to cope with during the COVID-19 pandemic, for instance the disruption of routines. Literature reported a worsening of the ASD core symptoms as an increase of behavioral problems, mannerisms and stereotypes, worsening in the area of sleep regulation, intensification of self and other-directed aggressive behaviors, increases in sensory motor agitation and restlessness (Di Renzo et al., 2020; Colizzi et al., 2020), and higher levels of anxiety and emotional dysregulation (Amorim et al., 2020). Furthermore, due to their children’s often difficult behavior, parents may have allowed more screen time (such as tablets, smartphones and television) during lockdown as a means of regulating their children (Thompson & Christakis, 2005), for its calming effect, and as a respite from the challenges posed by them (Nally et al., 2000). Literature shows that many children with ASD used electronic devices more often and for longer periods of the day, with it becoming an absorbent interest and that they found it difficult to switch from one activity to another (Istituto Superiore di Sanità [ISS], 2020). In fact, because of their deficits in impulse control and response inhibition, and because of their lower engagement in social and physical activities, children with ASD preferred screen use over other leisure activities, rendering them more prone to problematic screen use. However, no studies have focused on the relationship between the activities performed by children during lockdown (from March to May 2020) and any modification, either worsening or improvement, of ASD core symptoms. In this study we focus on a very common set of activities “screen time activities”. The aim of this brief report is to investigate the possible relationships between the amount of screen time and modification of the ASD core symptoms during lockdown, in children with ASD.\n\n\nMethods\n\nThe survey population composed of 243 parents of children with ASD between 2 and 15 years old, of both sexes (86% (n = 209) males). The child’s mean age was 7 years (SD = 3.3). The mothers’ mean age was 38.4 years (SD = 6.6) and fathers’ mean age was 42.4 years (SD = 7.5).\n\nIn respect to the child’s ASD diagnosis, 69 (28.4%) children presented a high symptoms severity, 108 (44.5%) medium and 66 (27.1%) low. 56 (23%) of the children had no language faculties, 46 (19%) produced single words, 92 (37.8%) produced short sentences, and 49 (20.2%) produced complex sentences. Lastly, 79 (32.5%) of children had a high cognitive functioning, 115 (47.3%) medium, and 49 (20.2%) low.\n\nParents of children with ASD filled out an anonymous online Qualtrics Survey (Qualtrics Survey Platform, RRID:SCR_016728), after reading and signing the written consent form and explicitly agreeing to take part to the study. The survey was shared via social media (autism related groups and pages on Facebook, and Whatsapp) for a limited time window (from May 15th to 30th, 2020). In cases where a parent had multiple children with ASD, the parent was asked to report on one child only and filled another survey for the other children. There was no monetary compensation for participating. The study was approved by the ethical committee of the Department of Neuroscience Imaging and Clinical Science of the University of Chieti-Pescara (Ethical approval number: DNISC2962) and was conducted according to the American Psychological Association guidelines in accordance with the 1964 Helsinki Declaration.\n\nFor the purposes of the study, the survey was reviewed and edited by a team of expert developmental psychologists, developmental neuropsychiatrists and statisticians. The survey consisted of three sections, each preceded by a small introduction:\n\nSociodemographic characteristics of the children\n\nIn the first section we asked parents information regarding their age and sex and about the age and the sex of the child.\n\nASD diagnosis\n\nThe second section concerned the child’s ASD diagnosis – specifically, parents reported the severity level of the autistic symptoms that the child was assigned when last seen by a Neuropsychiatrist. Diagnosis included ASD symptoms severity (high, medium and low), language competences (no language faculties, single words, short sentences, complex sentences) and cognitive functioning (high, medium and low).\n\nSurvey on the screen time of children with Autism Spectrum Disorder during lockdown\n\nThe third area consisted of an original questionnaire named “Survey on the screen time of children with Autism Spectrum Disorder during lockdown”. All the questions in this area referred to the past months (March-April-May, 2020). The instrument was created considering the existing literature and the daily issues experienced by the families during the lockdown.\n\nHere, the first set of questions were about the eventual ASD core symptoms modification during lockdown. Parents reported values on a 3-point Likert scale as improved (1) , same (2), worsened (3) about: language and communication, emotional regulation, social interaction, stereotypies, behavioral problems, restricted interests, and autonomies. A reliability analysis was carried out on these seven items. Cronbach’s alpha showed this part to reach acceptable reliability, α = 0.86.\n\nThe second set of questions collected information about the time spent by the child in different activities at home during lockdown. Parents were asked to rate how much time the child was spending with this activity as: never (1), short time (around 2 hours per day) (2) and a lot of time (more than 3 hours per day) (3). Activities were comprised of playing video-games, playing with friends online, using social networks, and watching television.\n\nThe data were analyzed with Pycharm version 2020.1 (PyCharm, RRID:SCR_018221), a software that uses the Python language. Descriptive and Spearman correlation statistics were computed on the original survey data. The variables expressed on a Likert scale were transformed into dichotomous variable in order to depict and highlight the effect of any improvements or worsen of child’s symptomatology, weakening the negative impact of a relatively low sample size on model accuracy; the time spent in the activities done during lockdown were reparametrized as a percentage of time spent in a specific activity over the total time spent in all activities.\n\n\nResults\n\nThe eventual modifications in the ASD symptoms during lockdown were considered. Looking at the data, more parents reported that language and communication competencies, emotional regulation and autonomies and social interaction improved during the lockdown, and stereotypies, behavioral problems, and restricted interests worsened (Table 1).\n\nThe data regarding activities suggested that children spent more time watching television (Never: N = 17, 7%; short time: N = 153, 63%; a lot of time: N = 73, 30%) and playing videogames (Never: N = 58, 23.9%; short time: N = 118, 48.6%; a lot of time: N= 67, 27.6%), than playing online with friends (missing = 18; Never: N = 171, 70.4%; short time: N = 51, 20.9%; a lot of time: N = 3, 1.2%) and using social networks (Never: N = 180, 74.1%; short time: N = 47, % 19.3; a lot of time: N = 16, 6.6%).\n\nFurthermore, we took into consideration the relationship between ASD symptoms modification and activities performed during lockdown. Table 2 shows the Spearman correlation coefficient between modification of ASD symptoms and the proportion of time spent in each single activity. The correlation between the variables suggested that more time spent watching TV, playing with videogames, and spending time on social networks was associated with a worsening of of ASD symptoms.\n\n\nDiscussion\n\nDuring lockdown, the closure of school and educational facilities, the loss of psychological and rehabilitation services, and the general stay-at-home orders, all led to more time spent at home, as well as daily spare time increasing considerably. Furthermore, any activities were more limited and mostly carried out either alone or with a parent. Children with ASD are highly attracted to screens and this kind of activity increased substantially during lockdown (Olive et al., 2020). The aim of his study was to investigate the relationship between the amount of screen time and the modification of the ASD symptoms during lockdown. Focusing on the ASD symptoms modification during lockdown our results showed a slight worsening of some core symptoms in the “restricted, repetitive patterns of behavior, interests, or activities” cluster. As previous research showed (i.e., Colizzi et al., 2020; Di Renzo et al., 2020), the lost support from school could have intensified the symptoms in these areas of ASD, and the increased worry of parents further exacerbated children's psychological well-being and increased their behavioral problems (Zhang et al., 2020). On the other hand, the improvements in the “social communication and social interaction area” may be explained because those skills acquired before the lockdown period, when supported by the parents, were not lost (Di Renzo et al., 2020). Indeed, attunement improved between parents and children, so children had more direct stimulation from more stable and even more emotionally positive reference.\n\nOur data show that children spent more time watching television and playing video-games than using social networks and playing online with friends. This evidence is confirmed in literature. In fact, children with ASD tend to have higher rate of solitary screen time, such as video game and television, than social interactive media (Mazurek et al., 2012). Considering the loss of school social interactions, the high rate of solitary use of social media appears to be an ulterior risk factor for the children wellbeing because makes them unavailable to learn through home social interactions, boosting an addiction to screens (Wetsby et al., 2020).\n\nThe present study shows a relation between the more time children spent with screen during lockdown, and the worsening of ASD core symptoms. The social withdrawal hypothesis proposes that increased screen time may limit social interactions with family members (Varni et al., 2011) which are crucial for language, communication, and socioemotional skills, heightening the difficulties in social communication and social interaction (Mazurek et al., 2012). Furthermore, high screen use leads to sleep disorders, emotional dysregulation, increases stress and anxiety and produces overstimulation (Wallenius et al., 2010) and ADHD-like behaviors (Ra et al., 2018). This can lead to an increase in behavioral problems and restricted and repetitive behaviors, interests or activities (Wetsby et al., 2020).\n\nHowever, the current study is not without limitations. This study relied on a parent’s evaluation of children’s ASD symptoms modification, so responses are potentially flawed due to social desirability. However, studies have found that parent concerns and reports accurately reflect the child’s ASD symptomatology (Ozonoff et al., 2009; Richards et al., 2016).\n\nIn the light of the profound changes that lockdown brought to the daily lives of children with ASD, the results of this study highlight the importance of considering the impact that prolonged screen time activities may have on the wellbeing of children. Considering that we live in a world surrounded by screens, that children with ASD are highly attracted to screens, and that we still live in a time of restrictions, it’s important to underline that high screen time represents a risk factor for the wellbeing of children with ASD. Increased awareness of the risk factors in this population in this unprecedented event is needed to prevent them in the short and long terms. Future research should deepen this argument enlarging the range of screen tools and ASD wellbeing topics. This study may help to increase attention of parents of children with ASD and health care providers and enable healthcare providers to coach parents in more suitable forms of play for children with ASD, both during the pandemic as well as after it ends.\n\n\nData availability statement\n\nDryad: Autism Spectrum Disorder and screen time during lockdown. https://doi.org/10.5061/dryad.r2280gbdd. (Logrieco, 2021).\n\nThis project contains the following underlying data:\n\n• Autism_Spectrum_Disorder_and_screentime_during_lockdown_copia.xlsx. Raw data file which includes the parents’ responses to the survey.\n\n• read_me_.docx. An explanatory document.\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\nAmerican Psychiatric Association: Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: APA; 2013.\n\nAmorim R, Catarino S, Miragaia P, et al.: The impactof COVID-19 on children with autism spectrum disorder. Impacto de la COVID 19 en niños contrastorno del espectro autista. Rev neurol. 2020; 71(8): 285. Publisher Full Text\n\nColizzi M, Sironi E, Antonini F, et al.: Psychosocial and behavioral impact of COVID-19 in autism spectrum disorder: an online parent survey. Brain Sci. 2020; 10(6): 341. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDi Renzo M, Di Castelbianco FB, Vanadia E, et al.: Parent-Reported Behavioural Changes in Children With Autism Spectrum DisorderDuring the COVID-19 Lockdown in Italy. Cont Edu. 2020; 1(1).\n\nGovernment: Italian Government: Measures to face the Coronavirus Covid-19.2020. Retrieved April 16th, 2020. Reference Source\n\nISS, O. N. A: Indicazioni ad interim per un appropriato sostegno delle persone nello spettro autistico nell’attuale scenario emergenziale SARS-CoV-2. Versione del. 2020; 30.\n\nLogrieco MGM: Autism Spectrum Disorder and screen time during lockdown. Dryad, Dataset. 2021. Publisher Full Text\n\nLord C, Brugha TS, Charman T, et al.: Autism spectrum disorder. Nat. Rev. Dis. Primers. 2020; 6(1): 1–23. Publisher Full Text\n\nMazurek MO, Shattuck PT, Wagner M, et al.: Prevalence and correlates of screen-based media use among youths with autism spectrum disorders. J. Autism Dev. Disord. 2012; 42(8): 1757–1767. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNally B, Houlton B, Ralph S: Researches in brief: The management of television and video by parents of children with autism. Autism. 2000; 4(3): 331–337. Publisher Full Text\n\nOlive L, Sciberras E, Berkowitz TS, et al.: Child and parent physical activity, sleep and screen time during COVID-19 compared to pre pandemic nationally representative data and associations with mental health.2020.\n\nOzonoff S, Young GS, Steinfeld MB, et al.: How early do parent concerns predict later autism diagnosis?. J. Dev. Behav. Pediatr: JDBP. 2009; 30(5): 367–375. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOzturk Eyimaya A, Yalçin Irmak A: Relationship Between Parenting Practices and Children's Screen Time During the COVID-19 Pandemic in Turkey. J. Pediatr. Nurs. 2021; 56: 24–29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRa CK, Cho J, Stone MD, et al.: Association of digital media use with subsequent symptoms of attention deficit/hyperactivity disorder among adolescents. JAMA. 2018; 320(3): 255–263. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRichards M, Mossey J, Robins DL: Parents’ concerns as they relate to their child’s development and later diagnosis of autism spectrum disorder. J. Dev. Behav. Pediatr: JDBP. 2016; 37(7): 532–540. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThompson DA, Christakis DA: The association between television viewing and irregular sleep schedules among children less than 3 years of age. Pediatrics. 2005; 116(4): 851–856. Publisher Full Text\n\nVarni JW, Limbers CA, Neighbors K, et al.: The PedsQL™ Infant Scales: feasibility, internal consistency reliability, and validity in healthy and ill infants. Qual Life Res. 2011; 20(1): 45–55. PubMed Abstract | Publisher Full Text\n\nWallenius M, Hirvonen A, Lindholm H, et al.: Salivary cortisol in relation to the use of Information and Communication Technology (ICT) in school-aged children. Psychology. 2010; 01(02): 88–95. Publisher Full Text\n\nWestby C: Screen Time and Children with Autism Spectrum Disorder. Folia Phoniatr. Logop. 2020; 1–8.\n\nZhang J, Shuai L, Yu H, et al.: Acute stress, behavioural symptoms and mood states among school-age children with attention deficit/hyperactive disorder during the COVID-19 outbreak. Asian J. Psychiatr. 2020; 51: 102077. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "102401",
"date": "16 Dec 2021",
"name": "Nagwa A. Meguid",
"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\nComments\nASD is a complex neurodevelopmental disorder characterized primarily by differences in social communication skills and the presence of restricted/repetitive behaviors, with a prevalence of 1 in 44. Screen time is typically associated with social isolation: it is now paradoxically enabling virtual social connections to mitigate the impact of physical and social distancing requirements.\nThe study is clearly defined and the introduction outlines the complexities and advantages of study, the aim of which was to investigate the relationship between the screen time and modification of the ASD symptoms during lockdown. They focused on ASD symptom modification during lockdown.\nResults showed a slight worsening of some core symptoms in the “restricted, repetitive patterns of behavior, interests, or activities” cluster. Results of this survey study revealed that children with ASD were less likely than those without to benefit from screen time to cope with social isolation, and screen time resulted in significantly more lost time on social interactions than the community sample, which may exacerbate difficulties in social domains.\nTables and figures are well presented, illustrated and adequate in number. Likewise, the Discussion is well organized and informative.\nRecommendations:\n1 - The survey was developed in consultation with parents of children with ASD and Parent Perceived Impact. Parents who are not actively engaged in screen time with their children may not be able to accurately account for their technology use. Authors are required to include parental attitudes if possible, otherwise the results are not definite.\n2 - Is there a difference between weekday and weekend screen time?\n3 - More details should be added to the survey to cover these areas: (1) the type of technology program used before and during the COVID-19 pandemic, and (2) the parent perceived impact of technology use on parent perceived quality of life and mental health In addition to the diagnostic, socio-demographic, and family characteristics of respondents. The inclusion of economic status and household income of the engaged families is recommended.\n4 - Authors are requested to discuss gender breakdowns in how boys and girls are spending time on each device or activity such as violent vs. non-violent video games.\n\n5 - On the other hand, we recommend to add that ASD group, as well as children who are not autistic, may have benefits of screen time during the COVID-19 pandemic for their social connectivity, education, and leisure time depending on the programs used.\nConclusion\nLess is known about screen time experiences of children and youth with autism spectrum disorder (ASD), who are at increased risk of adverse outcomes from screen time. Computer use is traditionally associated with a multitude of negative physical and mental health outcomes. Further critical examination of the predictors of screen time change and perceived impact to understand changes in screen time use and its impact on the well-being and quality of life of children with ASD is highly recommended.\nFinally, this is recommended for approval, subject to minor changes.\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? Partly",
"responses": [
{
"c_id": "10541",
"date": "17 Nov 2023",
"name": "Maria Grazia Logrieco",
"role": "Author Response",
"response": "1. Thank you for the suggestion. The study was conducted during the lockdown period, when the parents were spending most of the time at home with their children, and could observe them and report their behaviors. On the other hand, many other studies conducted during the lockdown or earlier, have found that parent concerns and reports accurately reflect the child’s ASD symptomatology (Olive et al., 2020; Ozonoff et al., 2009; Richards et al., 2016). 2. Thank you for the advice. Considering the time when the study was conducted, (March 2020-May 2020) the first lockdown, we did not investigate if there was any difference between the week and weekend time (eg. Spinelli et al., 2020; Nicolì et al., 2021). 3.Unfortunately, we did not asked about the type of technology program used before and during the COVID-19 pandemic, neither if the parent perceived impact of technology use on parent perceived quality of life and mental health in addition to the diagnostic, socio-demographic, and family characteristics of respondents. However, I attach here the Information regarding the families economic status: “Mothers’ mean age was 38.4 (SD = 6.6) and fathers’ mean age was 42.4 (SD = 7.5). The sample was equally distributed throughout the Italian peninsula. In particular, 70 participants (28.8 %) were living in the North area, 95 (39.1 %) in the Center, and 76 (31.3 %) in the South. Two hundred twenty-three (91.8 %) of the respondents were mothers. Considering the average family income, 27 (11.1 %) less than 1000 euro, 70 participants (28.8 %) declared to earn between 1000 and 1500 euro, 38 (15.6 %) declared to earn between 1500 and 2200, 70 participants (28.8 %) more than 2200 euro, and 38 (15.6 %) participants did not answer to the question.” 4. Thank you for the suggestion. Unfortunately, we did not investigate these topics. 5. Thank you for this suggestion. Besides the importance of avoiding the solitary screen time for children with ASD we wanted to point out that the prolonged screen time activities may have an impact on the wellbeing of children."
}
]
},
{
"id": "126662",
"date": "04 Apr 2022",
"name": "Fei-Yong Jia",
"expertise": [
"Reviewer Expertise screen time and childhood 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\nThis is a very interesting and important study concerning screen time modifying symptoms of children with autism spectrum disorder during lockdown due to the Covid-19 pandemic in Italy. 243 parents of children with ASD were enrolled in this online survey. The results of this study showed that high solitary screen time is related to the worsening of autistic symptoms. This study shows that we should pay more attention to avoiding or lessening the solitary screen time in ASD children in daily care during lockdown time.\nThe abbreviation of DSM in Line 5 of the introduction of the paragraph should be deleted.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1263
|
https://f1000research.com/articles/10-1259/v1
|
08 Dec 21
|
{
"type": "Opinion Article",
"title": "AXIN-AMPK signaling: Implications for healthy aging",
"authors": [
"Avijit Mallick",
"Bhagwati P. Gupta",
"Avijit Mallick"
],
"abstract": "The energy sensor AMP kinase (AMPK) and the master scaffolding protein, AXIN, are two major regulators of biological processes in metazoans. AXIN-dependent regulation of AMPK activation plays a crucial role in maintaining metabolic homeostasis during glucose-deprived and energy-stressed conditions. The two proteins are also required for muscle function. While studies have refined our knowledge of various cellular events that promote the formation of AXIN-AMPK complexes and the involvement of effector proteins, more work is needed to understand precisely how the pathway is regulated in response to various forms of stress. In this review, we discuss recent data on AXIN and AMPK interaction and its role in physiological changes leading to improved muscle health and an extension of lifespan. We argue that AXIN-AMPK signaling plays an essential role in maintaining muscle function and manipulating the pathway in a tissue-specific manner could delay muscle aging. Therefore, research on understanding the factors that regulate AXIN-AMPK signaling holds the potential for developing novel therapeutics to slow down or revert the age-associated decline in muscle function, thereby extending the healthspan of animals.",
"keywords": [
"Axin",
"AMPK",
"muscle",
"aging",
"C. elegans",
"LKB1",
"AAK-2",
"PRY-1"
],
"content": "Introduction\n\nWith aging, there is a decline in skeletal muscle mass and function. Aging muscle undergoes a shift in the balance between myogenic potential and fibrogenic activity that leads to reduced capacity of the muscle to repair and regenerate.1 Studies have shown that age-associated decline in muscle function is multifactorial and affected by genetic and environmental factors. While many genes have been identified that contribute to muscle development and function, their mechanisms of action are not well understood.\n\nThis review discusses a novel signaling network involving AXIN and AMP-activated protein kinase (AMPK) in maintaining muscle health that offers a new perspective on promoting healthy aging. Both these proteins are conserved in metazoans. AXIN is an established scaffolding protein that acts to integrate inputs from multiple signaling molecules, leading to the regulation of downstream effectors.2 AMPK plays a crucial role in sensing intracellular energy levels and keeping a balance between cellular metabolism and growth.3\n\n\nAXIN-AMPK signaling\n\nRecent findings from our lab and other published studies involving AXIN and its interacting partner AMPK provide a potential clue into the mechanism of muscle health maintenance. Work in the nematode C. elegans has revealed that the AXIN family member PRY-1 is necessary for animals’ normal motility and health, and its activated form promotes longevity by maintaining muscle mitochondrial homeostasis.4 A similar function was previously ascribed to the AMPK catalytic subunit homolog AAK-2.5,6 The genetic and biochemical experiments revealed that PRY-1 and AAK-2 work together, likely through protein-protein interaction, and PRY-1 is required for AAK-2-mediated beneficial effect on muscle health and lifespan (Figure 1). The interaction between PRY-1 and AAK-2 is not a unique phenomenon, as other AXIN family members also interact with AMPK in different biological contexts. For example, another C. elegans AXIN homolog AXL-1 forms a complex with AAK-2 following metformin treatment. Here, AXL-1 is necessary for metformin-mediated lysosomal localization and activation of AAK-2 in a VHA-3-LMTR-3-PAR-4 (v-ATPase-Ragulator-LKB1) complex dependent manner7 (Figure 2).\n\nGenetic and biochemical studies have shown that PRY-1/AXIN interacts with PAR-4/LKB1 and AAK-2/AMPK in muscles to promote AAK-2/AMPK phosphorylation. AAK-2 in turn activates DAF-16/FOXO cell non-autonomously in the intestine and promotes DAF-16/FOXO nuclear localization. Green colored P indicates activating phosphorylation.\n\nMetformin treatment induces formation of AXL-1/AXIN-based lysosomal VHA-3-LMTR-3-AXL-1/PAR-4-AAK-2 (v-ATPase-Ragulator-AXIN/LKB1-AMPK) complex that is required for AAK-2/AMPK activation. The effect of metformin is partially attained via inhibition of mTORC1, but other targets of the pathway remain unknown. Green colored P shows activating phosphorylation.\n\nThe Axin-containing complexes are also reported in mammalian systems. Following metformin treatment and glucose deprivation,8–10 the AXIN-based lysosomal pathway, consisting of v-ATPase-Ragulator complex (v-ATPase-Ragulator-AXIN/LKB1-AMPK), promotes AMPK phosphorylation by LKB1, leading to AMPK activation. In a separate study involving myotubes and mice gastrocnemius muscle tissue, exercise stimulated both AMPK and Rac1 while increasing the cellular levels of AXIN1. Accordingly, reducing the AXIN1 function blocked GTP loading of Rac1, AMPK activation, and glucose uptake in the exercising muscles.11 Additionally, it was shown that muscle-specific knockout (KO) of the AXIN1-binding Ragulator subunit LAMTOR1 completely abolished treadmill exercise-stimulated AMPK activation in gastrocnemius muscle.10 Together, these data demonstrate the crucial role of AXIN tethering in activating AMPK, which promotes muscle metabolism and benefits linked to exercise.\n\nInvestigations of cellular mechanisms underlying AXIN and AMPK interaction have revealed a regulatory relationship that depends on AMP levels12 (Figure 3). While low glucose triggered AMP-dependent activation of AMPK through the AXIN-based lysosomal pathway, a modest increase in AMP resulted in AXIN-dependent activation of both lysosomal and cytosolic AMPK. Finally, extreme nutrient starvation or high AMP concentrations caused phosphorylation of AMPK independently of AXIN function.12\n\nThe complex is formed following glucose deprivation, low to moderate increases in AMP levels, and metformin treatment. Once activated, AXIN-AMPK signaling promotes catabolism and inhibits anabolism by phosphorylating downstream targets that include ACC1, SREBP1c, Raptor and TSC2. Green and purple colored P indicate activating and inhibitory phosphorylation, respectively.\n\nIntriguingly, it was shown recently that skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) mice are phenotypically normal and exhibited no impairment of AMPK regulation or glucose uptake.13 Such a phenotype may be explained by redundancies between AXIN1 and its homolog AXIN2. Both proteins are expressed in skeletal muscles, and AXIN2 can functionally replace AXIN1 in regulating AMPK.12,14 Moreover, AXIN2, a negative regulator of WNT signaling, appears to be essential for myogenesis, as increased WNT signaling in aged skeletal muscle promoted fibrogenesis, thereby accelerating aging.15–17\n\nConsistent with the role of AXIN in AMPK activation and myogenesis, AMPK is shown to be crucial for regulating skeletal muscle development, growth, and degradation.18 In skeletal muscle, AMPK signaling has been linked to both acute and chronic exercise adaptations, in addition to a broad range of skeletal muscle disease states and ageing.19,20 Together these data support the growing evidence that both AXIN and AMPK and their signaling cascade are crucial to maintaining healthy muscles and slowing organismal deterioration with aging.\n\n\nDownstream effectors of AXIN-AMPK signaling\n\nStudies in mammalian models revealed that both metformin and glucose deprivation inhibit the mechanistic target of rapamycin complex 1 (mTORC1) activity, a master regulator of anabolic pathways.8,10 Both these treatments cause the mTORC1 components, RAPTOR and mTOR, to dissociate from the v-ATPase-Ragulator and facilitate the formation of the v-ATPase-Ragulator-AXIN/LKB1-AMPK complex. Similarly, research in C. elegans has demonstrated that the VHA-3-LMTR-3-AXL-1/PAR-4-AAK-2 complex negatively regulates phosphorylation of the mTORC1 target S6 kinase B1 (S6K) homolog RSKS-1.7 As the beneficial effects of AXIN-AMPK signaling in the C. elegans study were not directly attributed to mTORC1 inhibition, the authors suggested that the signaling cascade may utilize additional factors7 (Figure 2).\n\nThe downstream effectors of AXIN-AMPK have been reported in several other studies. Specifically, in a low glucose condition, the pathway phosphorylates proteins such as acetyl-CoA carboxylase (ACC1) and endoplasmic reticulum-localized sterol regulatory element-binding protein-1c (SREBP1c), thereby inhibiting fatty acid synthesis12 (Figure 3). Interestingly, in C. elegans, PRY-1 promotes transcription of SREBP1 homolog SBP-1 to regulate fatty acid synthesis4,21; however, the precise mechanism of this regulatory relationship is unknown. Another effector of PRY-1 appears to be the CREB-regulated transcriptional coactivator (CRTC) homolog.22 CRTC-1 is known to function downstream of AAK-2 and affects calcineurin-mediated lifespan and stress regulation in C. elegans.23,24 While AMPK and calcineurin signaling in mammalian systems regulate CRTCs in an antagonistic manner, the involvement of Axin in this regulatory network remains to be determined.25–28\n\nGiven that AMPK regulates many targets, it is expected that a subset may be co-regulated by AXIN. We recently reported that both pry-1 and aak-2 mutant transcriptomes significantly overlap with mutually up and downregulated genes. These common differentially expressed genes are associated with muscle structure development, muscle contraction, aging, and lipid metabolism. Moreover, we found that PRY-1-AAK-2 signaling functions in muscles leading to activation of AAK-2 in a cell-non-autonomous manner and phosphorylation and translocation of the FOXO transcription factor homolog DAF-16 into the intestinal cell nuclei4 (Figure 1). These results are supported by previous studies showing that activated DAF-16 is indispensable for muscle mitochondria homeostasis and lifespan extension. It is worth mentioning that FOXO3 is also phosphorylated by AMPK in the mammalian system; however, the involvement of AXIN in this process and the function of activated FOXO3 are unknown.29\n\nUnlike C. elegans, little is known about the role of AXIN and AMPK in regulating muscle health in another leading invertebrate model, namely the fruit fly D. melanogaster. Overexpression of D-axin in wing disc-associated myoblasts in larvae causes partial to complete loss of indirect flight muscles.30 However, the precise role of D-axin and the involvement of AMPK and TORC1 in adult muscles is unknown. In terms of other processes, it has been reported that a hypomorphic allele of D-axin alters the expression of metabolic genes and is hypersensitive to metabolic stress induced by fasting. Such a phenotype depends on TORC1 activity and involves increased ROS production.31\n\n\nGaps in our knowledge\n\nWhile much has been learned about Axin, AMPK, and their interactions, there are gaps in our understanding of the mechanisms regulating the complex formation, downstream effectors, and their role in maintaining muscle health. Some of the relevant questions are discussed below.\n\nThe existing data supports that AXIN function in the muscle is beneficial. AXIN2 is required for myogenesis and linked to muscle aging, whereas AXIN1 mediated signaling is necessary for glucose uptake in the exercising muscles.11,15,17 Both AXIN1 and AXIN2 are expressed in the skeletal muscle. Research in C. elegans hints that muscle-specific overexpression of pry-1 promotes mitochondrial network, muscle development, and muscle physiology.4 Whether such a role of Axin is conserved in higher eukaryotes is unknown.\n\nWhile AXIN1 and AXIN2 possess similar domains, they show differences in their regulation and expression pattern (subcellular localization and cell type-specific expression).14,32 Additionally, AXIN2 is required for muscle development. Interestingly, exercise-induced glucose uptake requires AXIN1 in skeletal muscles. While it remains to be seen whether AXIN2 plays a redundant role in this process and regulates AMPK, Li et al.13 reported no change in AMPK activation following AXIN1 imKO in the skeletal muscle. Furthermore, Zong et al.12 showed that AXIN2 could substitute AXIN1 in forming a complex between LKB1 and AMPK.\n\nIn C. elegans, PRY-1 and AXL-1 possess the characteristic domains for the AXIN family of proteins2 and negatively regulate WNT signaling.33,34 It has been shown that AXL-1 functions redundantly with PRY-1 to regulate the WNT effector protein BAR-1/β-catenin during the formation of the vulva and migration of Q neuroblast. However, both AXINs are functionally not equivalent and play roles independently to control specific processes. For example, PRY-1 is necessary for lipid metabolism, healthspan, lifespan, and seam cell development, whereas AXL-1 regulates excretory cell development.4,21,33–36 Recent experiments from our lab also highlight functional differences between the two Axin proteins. While PRY-1 and AXL-1 are necessary for metformin-induced lifespan extension,7 only PRY-1 is required for glucose deprivation mediated longevity in C. elegans (Mallick et al., unpublished). These same treatments, i.e., metformin and glucose deprivation, are known to extend the lifespan in an AAK-2-dependent manner.37,38 Overall, these studies demonstrate that AXIN homologs in every system have shared as well as unique functions. However, whether these proteins can redundantly activate AMPK remains to be investigated.\n\nRecent reports demonstrate that the lysosomal AXIN-AMPK signaling can be activated by glucose deprivation independently of AMP/ATP ratios. However, the medium-to-high elevation of AMP extends the activation of both cytosolic and lysosomal AMPK, which is also dependent on AXIN1.12 By contrast, very high AMP levels phosphorylate AMPK in a manner that does not involve AXIN1 and probably occurs via a conformational change in AMPK. Whether AXIN-dependent activation of AMPK also requires a similar change in AMPK conformation is unclear. Furthermore, it is unknown how glucose levels facilitate the complex formation and differential activation of AMPK by LKB1.\n\nSeveral other factors may also limit AXIN and AMPK mediated signaling. One of these is post-translational modification. AXIN activity is known to be regulated by phosphorylation.2,39,40 Another could be subcellular localization. While the AXIN-AMPK complex is localized to lysosomes and cytoplasm, the changes in their activities in response to external stimuli are poorly understood.10,12 Both factors are broadly expressed and in overlapping domains; however, whether their interactions are global or restricted to specific tissues remains to be determined. In this regard, it is worth mentioning that AMPK functions cell non-autonomously in C. elegans,24 and we have reported that the protein is needed in both muscles and intestine to mediate beneficial effects of constitutive expression of AXIN in muscles.4\n\nGiven that AMPK is involved in many different processes and regulates many downstream targets, one might expect that AXIN-AMPK interaction co-regulates a subset of the targets. In support of this, a recent paper suggests that AXIN-AMPK signaling phosphorylates targets that are different from ATP/AMP-dependent AMPK signaling.12 As mentioned above, our analysis of C. elegans pry-1 and aak-2 transcriptomes has revealed many overlapping genes that are differentially expressed. However, more work is needed to identify and validate common targets of AXIN-AMPK signaling that are involved in maintaining muscle health in different systems. Identification of such target genes could lead to a better understanding of molecular mechanisms underlying the signaling network and the development of diagnostic markers and therapeutic interventions to promote muscle health.\n\n\nNew research directions\n\nWe envisage several exciting research avenues involving AXIN-AMPK signaling. While substantial knowledge has been gained in terms of processes that each one participates in and mechanisms underlying their function, little is known how the interactions between the two proteins are regulated, leading to changes in the expression of target genes that carry out various roles. Below are some of the potential research directions to address the questions in the previous section.\n\nWhile it has been shown that the AXIN homologs in both C. elegans (PRY-1 and AXL-1) and mammalian systems (AXIN1 and AXIN2) can activate AMPK,4,7,9,12 the redundancies between the homologs and their tissue-specific interactions with AMPK are unknown. Moreover, the differences in lifespan and lipid metabolism phenotypes between the two AXIN mutants in C. elegans raise the question of functional equivalency regarding AMPK activation in physiological conditions. Future research along these lines should refine our understanding of AXIN-AMPK signaling and its conservation in eukaryotes.\n\nDepending on the context, signaling pathways may utilize different mechanisms to regulate their responses. In this regard, research in the following areas should improve our understanding of the regulatory mechanism of AXIN-AMPK signaling. First, whether a conformational change in AMPK following AXIN binding occurs similar to the AMP-dependent mechanism. Second, the role of post-translational modification of AXIN in activating AMPK. Third, identifying a specific region of the multidomain AXIN protein required for AMPK interaction that, in turn, may uncover potential competitors to modulate the signaling. And, finally, the discovery of factors affecting subcellular localizations of both AXIN and AMPK and, in turn, their interactions.\n\nOther modes of regulation of AXIN-AMPK signaling may include spatial and temporal changes in AXIN expression. AXIN is not only a negative regulator but also a downstream target of the WNT signaling.21,41 Consistent with this, PRY-1/AXIN is required for MOM-2/WNT mediated lifespan regulation,4 and MOM-2 is expressed in the body wall muscles of C. elegans. It remains to be explored whether AXIN function in muscles is regulated in a WNT-dependent manner in eukaryotes.\n\nResearch from our group has shown that overexpression of PRY-1/AXIN in C. elegans extends the lifespan and improves muscle health in older adults. Whether forced expression of mammalian AXIN in muscles may also promote the healthspan of animals by activating AXIN-AMPK signaling requires investigation. In line with this, expression analysis of AXIN1 and AXIN2 in old adults and patients with a muscle disease should prove valuable.\n\nAs mentioned above, AXIN and AMPK are crucial for muscle development and physiology. Furthermore, exercise promotes the activation of AMPK in an AXIN-dependent manner. Given that exercise promotes muscle health and delays aging,42–44 it is conceivable that AXIN and AMPK are involved in this process. More work is needed to understand the role of AXIN-AMPK signaling in exercise-mediated benefits.\n\n\nConclusion\n\nAXIN family of scaffolding proteins control a wide array of cellular processes by recruiting multiple factors and forming protein complexes. One of the interactors of AXIN is the well-known energy sensor AMPK. AMPK functions as a nexus between energy conservation and aging, and perturbations of its function lead to various age-related pathologies. AXIN-AMPK signaling promotes muscle health and delays age-associated deterioration. Future studies on the pathway, its interacting proteins, and tissue-specific effectors hold promise to uncover key candidates that may be targeted in the future to delay age-associated muscle degeneration and improve muscle health during aging.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "Acknowledgements\n\nAuthors thank Gupta lab members for discussions on the topic and feedback on the manuscript. Figures were created using BioRender.\n\n\nReferences\n\nWang Y, Wehling-Henricks M, Samengo G, et al.: Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide. Aging Cell. 2015; 14(4): 678–688. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMallick A, Taylor SKB, Ranawade A, et al.: Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans. J. Dev. Biol. 2019; 7(4): 1–23.\n\nHardie DG, Ross FA, Hawley SA: AMPK: A nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 2012; 13(4): 251–262. 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PubMed Abstract | Publisher Full Text\n\nKjøbsted R, Hingst JR, Fentz J, et al.: AMPK in skeletal muscle function and metabolism. FASEB J. 2018; 32(4): 1741–1777. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRanawade A, Mallick A, Gupta BP: PRY-1/Axin signaling regulates lipid metabolism in Caenorhabditis elegans. PLoS One. 2018; 13(11): e0206540. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMallick A, Taylor SKB, Mehta S, et al.: picd-1, a gene that encodes CABIN1 domain-containing protein, interacts with pry-1/Axin to regulate multiple processes in Caenorhabditis elegans. bioRxiv. 2021; 1–37.\n\nMair W, Morantte I, Rodrigues APC, et al.: Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB. Nature. 2011; 470(7334): 404–408. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurkewitz K, Morantte I, Weir HJM, et al.: Neuronal CRTC-1 Governs Systemic Mitochondrial Metabolism and Lifespan via a Catecholamine Signal. Cell. 2015; 160(5): 842–855. PubMed Abstract | Publisher Full Text | Free Full Text\n\nScreaton RA, Conkright MD, Katoh Y, et al.: The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell. 2004; 119(1): 61–74. PubMed Abstract | Publisher Full Text\n\nKoo SH, Flechner L, Qi L, et al.: The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature. 2005; 437(7062): 1109–1114. PubMed Abstract | Publisher Full Text\n\nKomiya T, Coxon A, Park Y, et al.: Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer. Oncogene. 2010; 29(11): 1672–1680. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang Y, Vera L, Fischer WH, et al.: The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature. 2009; 460(7254): 534–537. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGreer EL, Oskoui PR, Banko MR, et al.: The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor. J. Biol. Chem. 2007; 282(41): 30107–30119. Publisher Full Text\n\nBenchabane H, Xin N, Tian A, et al.: Jerky/Earthbound facilitates cell-specific Wnt/Wingless signalling by modulating β-catenin-TCF activity. EMBO J. 2011; 30(8): 1444–1458. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang T, Liao Y, Hsu FN, et al.: Hyperactivated Wnt Signaling Induces Synthetic Lethal Interaction with Rb Inactivation by Elevating TORC1 Activities. PLoS Genet. 2014; 10(5): e1004357. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThul PJ, Akesson L, Wiking M, et al.: A subcellular map of the human proteome. Science (80-). 2017; 356(6340). PubMed Abstract | Publisher Full Text\n\nOosterveen T, Coudreuse DYM, Yang PT, et al.: Two functionally distinct Axin-like proteins regulate canonical Wnt signaling in C. elegans. Dev. Biol. 2007; 308(2): 438–448. PubMed Abstract | Publisher Full Text\n\nKorswagen HC, DYM C, Betist MC, et al.: The Axin-like protein PRY-1 is a negative regulator of a canonical Wnt pathway in C. elegans. Genes Dev. 2002; 16(10): 1291–1302. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMallick A, Ranawade A, Gupta BP: Role of PRY-1/Axin in heterochronic miRNA-mediated seam cell development. BMC Dev. Biol. 2019; 19(1): 1–12.\n\nMallick A, Gupta BP: Vitellogenin-2 acts downstream of PRY-1/Axin to regulate lipids and lifespan in C. elegans. microPublication Biol. 2020; 1: 19–21.\n\nOnken B, Driscoll M: Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. elegans healthspan via AMPK, LKB1, and SKN-1. PLoS One. 2010; 5(1): e8758. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchulz TJ, Zarse K, Voigt A, et al.: Glucose Restriction Extends Caenorhabditis elegans Life Span by Inducing Mitochondrial Respiration and Increasing Oxidative Stress. Cell Metab. 2007; 6(4): 280–293. PubMed Abstract | Publisher Full Text\n\nTacchelly-Benites O, Wang Z, Yang E, et al.: Axin phosphorylation in both Wnt-off and Wnt-on states requires the tumor suppressor APC. PLoS Genet. 2018; 14(2): 1–24. Publisher Full Text\n\nWang Z, Tacchelly-Benites O, Yang E, et al.: Dual Roles for Membrane Association of Drosophila Axin in Wnt Signaling. PLoS Genet. 2016; 12(12): 1–26. Publisher Full Text\n\nJho E, Zhang T, Domon C, et al.: Wnt/β-Catenin/Tcf Signaling Induces the Transcription of Axin2, a Negative Regulator of the Signaling Pathway. Mol. Cell. Biol. 2002; 22(4): 1172–1183. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHartman JH, Smith LL, Gordon KL, et al.: Swimming Exercise and Transient Food Deprivation in Caenorhabditis elegans Promote Mitochondrial Maintenance and Protect Against Chemical-Induced Mitotoxicity. Sci. Rep. 2018; 8(1): 1–16.\n\nLaranjeiro R, Harinath G, Burke D, et al.: Single swim sessions in C. elegans induce key features of mammalian exercise. BMC Biol. 2017; 15(1): 1–17. Publisher Full Text\n\nLaranjeiro R, Harinath G, Hewitt JE, et al.: Swim exercise in Caenorhabditis elegans extends neuromuscular and gut healthspan, enhances learning ability, and protects against neurodegeneration. Proc. Natl. Acad. Sci. U. S. A. 2019; 116(47): 23829–23839. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "102289",
"date": "05 Jan 2022",
"name": "Jonathan S. Oakhill",
"expertise": [
"Reviewer Expertise Metabolic signaling pathways",
"structural biology",
"cell biology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors provide a largely balanced overview of current understanding regarding co-ordination between the energy sensor AMPK and well-defined scaffold protein AXIN1 to promote healthy aging, and succinctly outline knowledge gaps and future directions. A major question (for this protein biochemist at least) remains whether this occurs via direct interaction as the text and figures here suggest. Albeit an opinion piece, I think there is a degree of extrapolation and overstatement. For example, I could not find evidence in ref 7 to support the statement “...another C. elegans AXIN homolog AXL-1 forms a complex with AAK-2 following metformin treatment” on p3. Also AXIN2 redundancy has been demonstrated at the functional level, not structural, as stated on p6.\nThe AXIN1/AMPK complex was reported in 2013 but has not been independently verified as far as I’m aware. It is not a stretch to say the model has caused controversy in the field – mainly created by difficulty in replicating the primary co-IP and this should be given due accord. The authors published work using C. elegans notes that a physical interaction requires further examination.\nI suggest the article would benefit from clearly distinguishing ‘function’ from ‘interaction’. I also recommend elaboration on the nature of the molecular interaction between AMPK and AXIN1, for which biochemical data are reported (eg Zhang et al, 2013 Fig 5). Authors could comment on requirement for AMPK b-subunit myristoylation for formation of the axin/AMPK complex in vitro. The non-myristoylatable mutant b2-G2A failed to localise to lysosomes following glucose starvation. Likewise requirement for the AXIN1 region between residues 507-731, which is indispensable for stabilisation of the complex in vitro but is outside of conserved AXIN1/2 domains.\nPlease expand on what is known of the major AXIN regulatory post translational modifications.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Partly\n\nAre all factual statements correct and adequately supported by citations? Partly\n\nAre arguments sufficiently supported by evidence from the published literature? Partly\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "108092",
"date": "06 Jan 2022",
"name": "Anindya Ghosh Roy",
"expertise": [
"Reviewer Expertise Genetics",
"C elegans",
"neural circuit development",
"neuronal regeneration",
"aging"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 ‘Opinion article’ by Mallick and Gupta focusses on the in vivo function of AXIN-AMPK axis in muscle homeostasis and organismal health/aging. AMPK has long been known to regulate energy production in the context of change of ATP level due to stress, physical exercise etc. It has multiple functions and it is regulated by various means. The mode of its activation is different in response to differential levels of ATP depletion. Therefore figuring out the downstream effectors and biological effect in the context of differential levels of AMPK activation has been challenging.\nThere are various evidences in last few years that a scaffolding protein AXIN binds to AMPK and regulates the AMPK signaling positively. These evidences come from studying multiple model organisms including mice, flies and worms. The more recent finding from this group that AXIN and AMPK interaction plays an important role in delaying the muscle aging and organism level aging in C elegans model is very interesting (Mallick et al 2020). Moreover, the AMPK signaling helps the crosstalk between muscle and intestine to coordinate the aging process. Therefore, focusing on this topic to write this short review article is very timely and appropriate.\nI have a few suggestions on the organization of this article.\nFirst the authors should avoid referring to their article actively with phrases such as “study from our lab/group”. They may mention “recent study” instead.\n\nI suggest that they first discuss the in vivo findings on AXIN-AMKP signaling in other organisms such as mice and flies in muscle health, ATP homeostasis etc. They can have a sub-heading for this. Then they can bring a separate sub-titled section, which describes the findings using worm model focusing their recent findings. Essentially, I am suggesting that they break the section titled ‘AXIN-AMPK signaling’ in two parts as suggested above. This will allow them to discuss the key interesting hypothesis coming out from their work.\n\nOne point to highlight in the future direction/question is how AXIN-AMPK signaling in muscles regulates the intestinal regulation of DAF-16. They can have a sub-title on this. Please suggest a few possibilities.\n\nAnother point is to propose some research questions on how AXIN intersects between Wnt and AMPK signaling. What are the interesting questions in this direction that can be solved using the worm model?\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "102286",
"date": "17 Jan 2022",
"name": "Stefan Taubert",
"expertise": [
"Reviewer Expertise C. elegans",
"transcription",
"metabolism",
"stress response",
"longevity"
],
"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 review/opinion article considers the roles of the two AXIN type proteins in AMPK signaling, focusing on muscle function and primarily on research done in C. elegans. The article nevertheless balances well what is known from different species, and highlights several areas for future investigation. The article is well written and the figures are useful.\nThere are no major issues, as the discussion is balanced and inclusive of knowledge gained from various systems. It would have perhaps been useful to compare what is known about the two different AXIN proteins in a table (interacting proteins, expression, location, etc) to highlight differences in an easily accessible resource.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1259
|
https://f1000research.com/articles/10-1257/v1
|
08 Dec 21
|
{
"type": "Systematic Review",
"title": "Factor Xa inhibitor for venous thromboembolism management in patient with cancer: a systematic review and meta-analysis",
"authors": [
"Johanes Nugroho Eko Putranto",
"Ardyan Wardhana",
"Yoga Alfian Noor",
"Pirhot Lambok Marnala Yosua Siahaan",
"Makhyan Jibril Al Farabi",
"Ardyan Wardhana",
"Yoga Alfian Noor",
"Pirhot Lambok Marnala Yosua Siahaan",
"Makhyan Jibril Al Farabi"
],
"abstract": "Background: An earlier systematic review reported no differences in the incidence of recurrent venous thromboembolism and major bleeding between factor Xa inhibitors and standard anticoagulation. The present meta-analysis aimed to assess the effectiveness of factor Xa inhibitors for the management of venous thromboembolism (VTE), specifically in patients with cancer, as there were more randomized clinical trials (RCTs) available. Methods: The PubMed and Cochrane Library databases were systematically screened for all RCTs assessing factor Xa inhibitor efficacy for VTE management in cancer patients. Using RevMan 5.3, we performed a Mantel–Haenszel fixed-effects meta-analysis of the following outcomes: recurrent VTE, VTE events, and major bleeding rates. Results: We identified 11 studies involving 7,965 patients. Factor Xa inhibitors were superior in preventing VTE recurrence, compared to low-molecular-weight heparin (LMWH) (OR 0.60; 95% CI 0.45–0.80; P < 0.01) and vitamin K antagonists (VKA) (OR 0.51; 95% CI 0.33–0.78; P < 0.01). As prophylaxis, factor Xa inhibitors had a similar rate of VTE compared to VKAs (OR 1.08 [95% CI 0.31–3.77]; P = 0.90) and a lower rate compared to placebo (OR 0.54 [95% CI 0.35–0.81]; P < 0.01). Major bleeding rates were higher with factor Xa inhibitors than with LMWHs (OR 1.34 [95% CI 0.83–2.18]; P = 0.23), but significantly lower than VKAs (OR 0.71 [95% CI 0.55–0.92]; P < 0.01). Conclusions: Factor Xa inhibitors are effective for VTE management in patients with cancer; however, they are also associated with an increased bleeding risk compared to LMWH, but decreased when compared to VKA.",
"keywords": [
"bleeding",
"cancer",
"factor Xa inhibitor",
"oral anticoagulant",
"venous thromboembolism."
],
"content": "Introduction\n\nCancer patients are five times more likely to experience venous thromboembolism (VTE) than the general population.1 Second only to cancer itself, VTE is the second most common cause of mortality in cancer patients.2 According to previous clinical management recommendations, the typical VTE treatment in cancer patients involves the initial use of parenteral low-molecular-weight heparin (LMWH) followed by long-term use of oral vitamin K antagonists (VKA).3 However, recent recommendations proposed factor Xa inhibitors as one of the options of the main initial treatment for VTE.4\n\nFactor Xa inhibitors are preferred over LMWH and VKA because they conveniently do not require injections every day compared to LMWH, their more predictable effects, lack of monitoring or frequent repeat doses, and fewer drug interactions compared to VKA.5 An earlier systematic review reported differences between factor Xa inhibitors and standard anticoagulation drugs in the incidence of recurrent VTE and major bleeding.6 Based on this research, the present meta-analysis aims to evaluate the effectiveness of factor Xa inhibitors for the management of venous thromboembolism, particularly in patients with cancer.\n\nEthical approval for this research was obtained from the Dr. Soetomo General Hospital Surabaya Ethical Committee in Health Research (1964/KEPK/IV/2020).\n\nUMIN Clinical Trial Registry (UMIN ID 000040346).\n\n\nMethods\n\nWe adopted the Preferred Reporting Items for Reviews and Meta-Analyses guidelines for analysis reporting.7 Any RCTs that studied VTE rates or major bleeding, as primary or secondary outcomes, in cancer patients who received an oral factor Xa inhibitor were included. Phase II trials, trials with an antiplatelet control group, and trials using an anticoagulant as VTE post-procedure prophylaxis were excluded.\n\nWe conducted a systematic search using the PubMed and Cochrane Library databases on April 24, 2020, after gaining approval from the Institutional Review Board. As for the title, abstract, and medical subject heading, we used search terms like “cancer,” “factor Xa inhibitor,” “oral anticoagulant,” “venous thromboembolism,” “apixaban,” “rivaroxaban,” “edoxaban,” “prophylaxis,” “bleeding,” “thromboembolism,” “thromboprophylaxis,” “randomized,” and “rct.”\n\nWe screened more studies by looking at the references in the included articles. Two investigators independently selected studies, with disagreements resolved through discussion and a third investigator's opinion. Thereafter, for each report, two investigators independently extracted the following information: authors, year of publication, trial name, cancer status, sample size, dose and duration of anticoagulation, duration of patient follow-up, and outcomes for the two treatment groups where available.\n\nWe determined four comparison groups: (1) factor Xa inhibitor versus LMWH as treatment for VTE; (2) factor Xa inhibitor versus VKA as treatment for VTE; (3) factor Xa inhibitor versus placebo as prophylaxis for VTE; (4) factor Xa inhibitor versus VKA as prophylaxis for VTE. The outcomes of our meta-analysis were recurrent VTE or new VTE event rates and incidence of major bleeding. VTE events were confirmed by leg vein ultrasound scanning, D-dimer testing, or both; alternatively, clinically overt pulmonary embolism was confirmed by imaging. Major bleeding was defined as in Schulman et al.8\n\nThe Cochrane Collaboration Risk of Bias Tool was used by two independent investigators to assess the methodological quality of included studies, and the GRADE approach was employed to grade each outcome.9,10 Any disputes were settled through discussion with a third investigator. We calculated odds ratios (ORs) for all outcomes at the longest follow-up period and used Review Manager (RevMan v5.3 2014) to apply the Mantel−Haenszel fixed-effects method. We conducted a modified intention-to-treat analysis including patients who had received ≥ 1 medication dose. We planned to a conduct sensitivity analysis by removing studies likely to be biased. The I2 statistic was used to assess statistical heterogeneity between studies. If the heterogeneity was > 50%, we applied a random-effects model for analysis.11\n\n\nResults\n\nThe search identified 202 citations in PubMed and 41 in the Cochrane Library, among which 43 were duplicates (Figure 1). We found 22 more studies of which we evaluated the full text. Four studies were post-procedure prophylaxis trials, three lacked a control, two were phase II trials, and two were extensions of included trials, so 11 were omitted. As a result, we could include 11 studies in our analysis.12–22\n\nTable 1 lists the characteristics of the included studies. There were four trials on apixaban, four on rivaroxaban, and three on edoxaban. The study size ranged from 300 to 1,170 patients. Five studies were subgroup analyses of patients with cancer from larger primary trials.12–16 We pooled their data only from the subgroup of patients with cancer, not all study population. One study was a pooled analysis of the subgroup of patients with cancer in “sister” trials.17 Four trials13,18–20 compared factor Xa inhibitors with LMWH, and three12,14,17 compared factor Xa inhibitors with VKA as a VTE treatment. Two trials15,16 compared factor Xa inhibitors with placebo and two21,22 compared factor Xa inhibitors with VKA as prophylaxis of VTE. We included one trial that investigated two doses of edoxaban for VTE prophylaxis, where the outcomes of both groups were combined and analyzed as one intervention group.16\n\nThe risk of bias across domains is presented in Figure 2. In most studies, the randomization process, adherence to the intervention, assessment, missing outcome results, and reporting were deemed adequate. In four trials, participants were blinded. The percentage of patients not followed up ranged from 0.2% to 5.6%. All trials reported the results from modified intention-to-treat analysis.\n\nThe quality of evidence for each outcome analyzed using the GRADE approach is presented in Table 2. We did not downgrade from the risk of bias, inconsistency, indirectness, and imprecision aspect of all outcomes, because of a low risk of bias, no substantial heterogeneity, a large enough sample size, and narrow confidence interval (CI). We downgraded one level for the major bleeding outcome because the funnel plot of major bleeding outcome suggested publication bias (Figure 3).\n\nSeven studies involving 4,771 patients reported VTE recurrence (Table 2). Recurrence occurred in 4.9% (117/2,399) of patients allocated to factor Xa inhibitors, 9.1% (132/1,445) allocated to LMWHs, and 6.9% (64/927) of those allocated to VKAs. In comparison (Figure 4), the reduction of the risk of VTE recurrence with factor Xa inhibitors compared to LMWH was acceptable (four trials; OR 0.60; 95% CI 0.45–0.80; P < 0.01), without substantial heterogeneity (I2 = 26%; P = 0.26). VTE recurrence rates were lower in patients treated with factor Xa inhibitors compared to patients treated using VKAs (three trials; OR 0.51; 95% CI 0.33–0.78; P < 0.01), without substantial heterogeneity (I2 = 0%; P = 0.37).\n\nThree studies, including 2,056 patients, reported the incidence of new VTE after anticoagulant prophylaxis. The factor Xa inhibitor group had a 4.1% (42/1,021) VTE occurrence rate, while the VKA and placebo groups each had 1.45% (5/355) and 9.6% (65/680), respectively. According to the meta-analysis shown in Figure 5, there were similar VTE incidences in the factor Xa inhibitor and the VKA groups (one trial; OR = 1.08 [95% CI, 0.31–3.77]; P = 0.90); however, the heterogeneity analysis could not be applied. The estimated effect of factor Xa inhibitors on VTE incidence compared to placebo showed a statistically significant reduction (two trials; OR = 0.54 [95% CI, 0.35–0.81]; P < 0.01), without substantial heterogeneity (I2 = 31%; P = 0.23).\n\nEleven studies, including 7,965 patients, reported major bleeding (Table 2). Major bleeding occurred in 5.5% (231/4,178) of patients allocated to factor Xa inhibitors, 3.6% (52/1445) to LMWHs, 8.1% (134/1,662) to VKAs and 1.3% (9/680) to placebo. According to the meta-analysis shown in Figure 6, the acceptable increase of risk cannot be confirmed from the description of major bleeding with factor Xa inhibitors compared to LMWH, as based on an OR of 1.34 (95% CI, 0.83–2.18) with a P = 0.23, which is not statistically significant. However, factor Xa inhibitors significantly reduced the risk of major bleeding compared to VKAs (five trials; OR = 0.71 [95% CI, 0.55–0.92]; P = 0.009), without substantial heterogeneity (I2 = 0%; P = 0.72). The risk of major bleeding was higher with factor Xa inhibitors versus placebo (two trials; OR = 1.98 [95% CI, 0.88–4.44]; P = 0.10) but not statistically significant, without substantial heterogeneity (I2 = 0%; P = 0.96).\n\n\nDiscussion\n\nThe aim of this meta-analysis was to determine the efficacy and safety of factor Xa inhibitors for VTE treatment in cancer patients. Recurrence was 4.9%, 9.1%, and 6.9 % for the factor Xa inhibitor, LMWH, and VKA groups, respectively. All were lower than the findings of a retrospective cohort study which reported an incidence of 13.1%, 17.6%, and 17.9%, respectively.23 Our review of four studies involving over 4,771 patients found that factor Xa inhibitors were associated with a lower risk of VTE recurrence when compared to LMWH, and even lower when compared to VKA. This result was consistent with a recent meta-analysis which combined data from RCTs and retrospective cohort studies.24\n\nAnother finding in our meta-analysis in terms of safety profiles was that factor Xa inhibitors were associated with an increased risk of bleeding when compared to LMWH, but a lower risk when compared to VKA. This result is in line with the findings of other systematic reviews.24–26 However, another meta-analysis found a significantly higher incidence of bleeding (two trials, OR= 2.72 [95% CI: 1.05–7.01]; P= 0.039) with factor Xa inhibitors, relative to LMWH.27 Importantly, the bleeding outcome in comparison to LMWH was the result of pooled data from nonspecific cancer patients. The results of the analysis of major bleeding in comparison to LMWH were mainly influenced by those of the HOKUSAI VTE Cancer trial and the recent CARAVAGGIO trial.28,29 Both had different results: the former showed significantly higher bleeding in the edoxaban group while the second showed similar major bleeding events between groups.\n\nOur meta-analysis also provided information about the efficacy of factor Xa inhibitors as prophylaxis, which suggested that, compared to placebo, it can significantly reduce VTE incidence. According to a recent clinical practice guideline, high-risk cancer outpatients can receive thromboprophylaxis with a factor Xa inhibitor or LMWH, in the absence of major risk factors for bleeding.30 The high cost and the pain of daily LMWH injections was avoided with the factor Xa inhibitor regimen.\n\nWith respect to factor Xa inhibitors and LMWH, the inclusion of the CARAVAGGIO trial, with highly rigorous evidence, increased the accuracy of the estimated outcomes. There are a number of limitations to the current meta-analysis: the majority of the data corresponded to subgroup or post-hoc analyses. Further, the following variables were not controlled for: cancer stage, type of cancer, follow-up period. While most of the included studies evaluated patients for six months, the optimal duration of anticoagulation treatment was not evaluated to achieve an agreement. Finally, despite our systematic electronic database search and our investigation of the references in the included studies, we may have missed relevant studies.\n\n\nConclusion\n\nFactor Xa inhibitors are effective for VTE management in patients with cancer; however, they are also associated with an increased bleeding risk compared to LMWH, but decreased when compared to VKA.\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\nFigshare: PRISMA checklist for ‘Factor Xa inhibitor for venous thromboembolism management in Patients with cancer: a systematic review and meta-analysis’. https://doi.org/10.6084/m9.figshare.16590086.v331\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nThis work was performed as part of Johanes Nugroho employment at the Department of Cardiology and Vascular Medicine, Universitas Airlangga/Dr. Soetomo General Hospital, East Java, Indonesia. The authors also would like to thank Enago (www.enago.com) for the English language review and this work was supported by the Indonesian Endowment Fund for Education (Lembaga Pengelola Dana Pendidikan).\n\n\nReferences\n\nElyamany G, Alzahrani AM, Bukhary E: Cancer-associated thrombosis: an overview. Clin Med Insights Oncol. 2014; 8: 129–137. PubMed Abstract | Publisher Full Text\n\nKhorana AA, Francis CW, Culakova E, et al.: Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J. Thromb. Haemost. 2007; 5: 632–634. PubMed Abstract | Publisher Full Text\n\nKearon C, Akl EA, Comerota AJ, et al.: Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141: e419S–e496S. Publisher Full Text\n\nLyman GH, Carrier M, Ay C, et al.: American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv. 2021; 5(4): 927–974. PubMed Abstract | Publisher Full Text\n\nFox BD, Kahn SR, Langleben D, et al.: Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ. 2012; 345: e7498. PubMed Abstract | Publisher Full Text\n\nRobertson L, Kesteven P, McCaslin JE: Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of pulmonary embolism. Cochrane Database Syst. Rev. 2015; 2016(Issue 12): Art. No.: CD010957. Publisher Full Text\n\nMoher D, Liberati A, Tetzlaff J, et al.: The PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Open Med. 2009; 3: 123–130.\n\nSchulman S, Kearon C: Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J. Thromb. Haemost. 2005; 3: 692–694. PubMed Abstract | Publisher 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 Aug 28; 366: l4898. Publisher Full Text\n\nRyan R, Hill S: How to GRADE the quality of the evidence Version 3.0. Cochrane Consumers and Communication Group; 2018 Dec [cited 2019 July 13]; [about 25 p.]. Reference Source\n\nHiggins JPT, Green S: Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011 [cited 2019 July 10]. Reference Source\n\nRaskob GE, van Es N , Segers A, et al.: Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol. 2016; 3: e379–e387. PubMed Abstract | Publisher Full Text\n\nRaskob GE, van Es N , Verhamme P, et al.: on behalf of the Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N. Engl. J. Med. 2018; 378(7): 615–624. Publisher Full Text\n\nAgnelli G, Buller HR, Cohen A, et al.: Oral apixaban for the treatment of venous thromboembolism in cancer patients: Results from the AMPLIFY trial. J. Thromb. Haemost. 2015; 13(12): 2187–2191. PubMed Abstract | Publisher Full Text\n\nChen ST, Hellkamp AS, Becker RC, et al.: Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF. Eur Heart J Qual Care Clin Outcomes. 2019; 5(2): 145–152. PubMed Abstract | Publisher Full Text\n\nFanola CL, Ruff CT, Murphy SA, et al.: Efficacy and safety of edoxaban in patients with active malignancy and atrial fibrillation: analysis of the ENGAGE AF - TIMI 48 trial. J Am Heart Assoc. 2018; 7(16): e008987. PubMed Abstract | Publisher Full Text\n\nPrins MH, Lensing AW, Bauersachs R, et al.: Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013; 11(1): 21. PubMed Abstract | Publisher Full Text\n\nAgnelli G, Becattini C, Meyer G, et al.: Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med. 2020; 382: 1599–1607. Publisher Full Text\n\nYoung AM, Marshall A, Thirlwall J, et al.: Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: Results of a randomized trial (SELECT-D). J Clin Oncol. 2018; 36(20): 2017–2023. PubMed Abstract | Publisher Full Text\n\nMcBane RD 2nd, Wysokinski WE, Le-Rademacher JG, et al.: Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Blood. 2020; 18(2): 411–421.\n\nKhorana AA, Soff GA, Kakkar AK, et al.: Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med. 2019; 380: 720–728. PubMed Abstract | Publisher Full Text\n\nCarrier M, Abou-Nassar K, Mallick R, et al.Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med. 2019; 380: 711–19. Publisher Full Text PubMed Abstract |\n\nStreiff MB, Mccrae K, Yannicelli D, et al.: Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol. 2018; 93(5): 664–671. PubMed Abstract | Publisher Full Text\n\nYang M, Li J, Sun R, et al.: Comparison between direct factor Xa inhibitors and low-molecular-weight heparin for efficacy and safety in the treatment of cancer-associated venous thromboembolism: A meta-analysis. J Can Res Ther. 2019; 15: 1541–1546. PubMed Abstract | Publisher Full Text\n\nFuentes HE, McBane RD 2nd, Wysokinski WE, et al.: Direct Oral Factor Xa Inhibitors for the Treatment of Acute Cancer-Associated Venous Thromboembolism: A Systematic Review and Network Meta-analysis. Mayo Clin Proc. 2019; 94(12): 2444–2454. PubMed Abstract | Publisher Full Text\n\nLi A, Garcia DA, Lyman GH, et al.: Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res. 2019; 173: 158–163. PubMed Abstract | Publisher Full Text\n\nBrunetti ND, Gesuete E, De Gennaro L, et al.: Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: A meta-analysis study. Int J Cardiol. 2017; 230: 214–221. PubMed Abstract | Publisher Full Text\n\nHokusai VTE Cancer Investigators: Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med. 2018; 378: 673–674. Publisher Full Text\n\nCaravaggio Investigators: Apixaban for the Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020; 382: 1599–1607. Publisher Full Text\n\nKey NS, Khorana AA, Kuderer NM, et al.: Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020; 38: 496–520. PubMed Abstract | Publisher Full Text\n\nAl Farabi, Jibril M: PRISMA XA Checklist and Diagram. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "102373",
"date": "28 Jan 2022",
"name": "Suko Adiarto",
"expertise": [
"Reviewer Expertise Cardiovascular Medicine and 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\nThe reviewer, while appreciating the authors' objective, namely to provide a meta-analysis of recent studies using factor Xa inhibitors, low-molecular-weight heparin (LMWH), and vitamin K antagonists (VKA) in patients with venous thromboembolism (VTE) and cancer, intends to submit some general and specific observations:\nThe topic is an extremely important one, and the authors of this paper by accessing multiple data sources have a unique opportunity to produce a clinically important paper.\n\nIn results section, the authors acknowledge that all patients of interest had cancer, thus, what is of particular interest to the clinicians is while acknowledging the factor X inhibitors work, which factor X and at what dose was the most effective and or the safest, so that the clinicians can make an important decision regarding patient management. Also, the type of cancer in the included studies need to be specified.\n\nIn result section, the authors make an important statement that the factor Xa inhibitors are more effective than low molecular wave heparin or vitamin K antagonists. This is an important point, however the clinician requires more specific information.\n\nMoreover, among the bibliographic entries only some of the meta-analytical sector studies already present in the literature are reported.\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": "102367",
"date": "28 Jan 2022",
"name": "Irene Terrenato",
"expertise": [
"Reviewer Expertise cancer",
"biostatistics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this study authors conducted a systematic review and a meta-analysis to explore the effectiveness of Factor Xa inhibitors compared to standard anticoagulation treatments for the management of venous thromboembolism (VTE) in patients with cancer. The study is well conducted and the methods section is complete and detailed. All the statistical analysis were properly applied and the conclusions are adequately supported by the results presented in the paper. This reviewer recognizes the value of the manuscript however minor revisions are needed to improve the paper.\nIn particular:\nAbstract: The major bleeding result should be re-written according to the text of the paper. The comparison between Factor Xa inhibitors and LMWH is not statistically significant therefore authors cannot comment and generalize it as if it were.\n\nTable 2: Please make all labels in the table more readable: - Add “Xa inhibitors” in the first column for each comparison for each outcome. - Add “p-value” instead of “P”. - Add “ I2 (p-value)” instead “I2 (P)”\n\nFigure 4,5, and 6: In the titles, add the labels to each panel for each comparison.\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/10-1257
|
https://f1000research.com/articles/10-1255/v1
|
07 Dec 21
|
{
"type": "Method Article",
"title": "Slinker: Visualising novel splicing events in RNA-Seq data",
"authors": [
"Breon Schmidt",
"Marek Cmero",
"Paul Ekert",
"Nadia Davidson",
"Alicia Oshlack",
"Breon Schmidt",
"Marek Cmero",
"Paul Ekert",
"Nadia Davidson"
],
"abstract": "Visualisation of the transcriptome relative to a reference genome is fraught with sparsity. This is due to RNA sequencing (RNA-Seq) reads being predominantly mapped to exons that account for just under 3% of the human genome. Recently, we have used exon-only references, superTranscripts, to improve visualisation of aligned RNA-Seq data through the omission of supposedly unexpressed regions such as introns. However, variation within these regions can lead to novel splicing events that may drive a pathogenic phenotype. In these cases, the loss of information in only retaining annotated exons presents significant drawbacks. Here we present Slinker, a bioinformatics pipeline written in Python and Bpipe that uses a data-driven approach to assemble sample-specific superTranscripts. At its core, Slinker uses Stringtie2 to assemble transcripts with any sequence across any gene. This assembly is merged with reference transcripts, converted to a superTranscript, of which rich visualisations are made through Plotly with associated annotation and coverage information. Slinker was validated on five novel splicing events of rare disease samples from a cohort of primary muscular disorders. In addition, Slinker was shown to be effective in visualising deletion events within transcriptomes of tumour samples in the important leukemia gene, IKZF1. Slinker offers a succinct visualisation of RNA-Seq alignments across typically sparse regions and is freely available on Github.",
"keywords": [
"RNA-Seq",
"Visualisation",
"Novel Splicing Events",
"superTranscripts",
"bioinformatics"
],
"content": "Introduction\n\nGenomic variants often carry through to the transcriptome. Through these events, gene products can be inhibited, upregulated, or modified, which disrupts typical function. Understanding how a genomic variant has altered transcription can offer insights into causal mechanisms for pathogenesis or potential targets for therapeutic intervention.1,2 DNA variants can be identified through genome sequencing and transcriptional disruption can be measured by RNA sequencing (RNA-Seq). In addition, RNA-Seq data can be used to detect an assortment of variants such as single nucleotide polymorphisms (SNPs), deletions or insertions, and altered splicing.2–6 It is common practice to visualise any novel events relative to control samples with tools such as the Integrative Genomics Viewer (IGV).7 This process involves aligning sequencing reads to a reference genome. However, when visualising RNA-Seq data, the size of introns are typically significantly larger than the exons that harbour most of the aligned reads.8,9 As a consequence, these visualisations are sparse. The intronic regions with low coverage offer little information, yet significantly reduce the interpretability of the transcribed regions.\n\nIn an effort to provide succinct representations of RNA-Seq data, we previously developed the concept of superTranscripts.10 A superTranscript is the flattened collection of transcripts within a gene and includes only the concatenated sequence of its exons. Subsequently, alignment to a superTranscript reference mostly resolves the sparsity problem through elimination of low-information intronic regions. This concept was further extended in our previous work with the release of Clinker, which uses superTranscripts to visualise fusion genes.11 In the Clinker pipeline, the pre-generated superTranscripts of genes identified as belonging to a fusion are combined to form a new reference. The sequencing reads are then mapped to this with the splice-aware alignment tool, STAR.12 Any splice junctions spanning the two genes in the superTranscripts are indicative of a fusion breakpoint. Although this method offers succinct representations of fusion events, it is not applicable to other types of events that can produce novel structures in transcripts. Specifically, in both the rare disease and cancer context, it is important to visualise any events that might occur within the excised intronic regions, or those that add sequences to the reference transcripts upstream or downstream of annotated exons.\n\nTo address these requirements in the visualisation of novel transcripts, we present Slinker, a superTranscript generation and visualisation method. Slinker builds on the concept of visualisation using superTranscripts, but uses genome-guided assembly rather than predefined annotation to incorporate the novel transcribed regions of interest into a reference. Through this, Slinker retains novel transcribed regions outside of annotated exons, that can be described as: novel exons, retained introns, skipped exons, truncated exons, and extended exons (Figure 1).\n\nCompared to the reference annotation: retained introns are defined by the inclusion of regions between exons, up to and including the exon boundary. Novel exons are defined by the inclusion of regions between exons, not including the exon boundaries. Skipped exons are defined by the existence of a splice junction in the case that starts and ends at known exon boundaries, but does not exist within the controls. Truncated exons occur when an exon in the case does not extend to the annotated exon boundary. Conversely, an extended exon is where an assembled exon within the case exceeds an annotated exon boundary.\n\nThese events can be an important consequence of genomic variants and may be associated with a disease phenotype. To demonstrate the utility of Slinker, we applied it to rare disease variants, discovered with the aid of RNA-Seq in genes associated with primary muscle disorders in skeletal muscle2 and events detected in childhood leukemia.6,13 We determined that Slinker offers a succinct and complementary method to visualise and explore RNA-Seq data. Slinker is a Bpipe pipeline publicly available via Github (Extended data).\n\n\nMethods\n\nSlinker is a pipeline that is used to visualise novel gene events using RNA-Seq. The main steps in the pipeline are outlined in Figure 2. Slinker requires multiple inputs: a gene name, aligned RNA-Seq reads (for the case and each control), a genomic sequence reference, and a transcriptome reference annotation. A custom annotation can also be supplied. These must be provided in GTF format with the naming conventions for the attributes reflecting those used within Ensembl annotations.14 Upon completion, a PNG file containing a static image of the visualisation and an interactive HTML version are generated and saved to a user-defined destination.\n\nReference transcripts are first filtered by Transcript Support Level (TSL) as indicated in the reference annotation. The TSL is a tag included within Ensembl annotation that informs on the size and quality of evidence supporting the existence of the associated transcript. These transcripts, along with the input BAM files, are used to perform genome-guided assembly and output the predicted transcripts for each control and the case sample. The merged result of these assemblies is then flattened, exons concatenated, and oriented in the transcriptionally forwards direction to create the genome-guided superTranscripts. The reads previously mapped to the user-supplied gene are extracted from each input BAM and then re-aligned to this new reference. Finally, the coverage from each alignment, splice junctions, and transcript annotation are combined into both interactive and static visualisations upon completion of the pipeline.\n\nThe first step in the Slinker pipeline is to filter the gene transcripts to be visualised by the level of support in the Ensembl annotation. Specifically, all transcripts that either have a Transcript Support Level of 1 or are lacking this information are retained, the rest are filtered out. This ensures that only the best-supported transcripts are included in the assembly. The next step uses Samtools (v1.13) to extract all the reads aligned to the genomic region that the user-supplied gene defines in each input BAM. From each of these reduced BAM files, Stringtie2 (v2.1.7) performs genome-guided assembly using either the supplied annotation or the hg19 or hg38 references packaged with Slinker.15 The output of Stringtie2 is a GTF file for each BAM that contains all potential reference and novel transcripts existing within that sample. The transcripts are further filtered by the Stringtie2 coverage estimate, removing any novel transcripts that do not meet the defined threshold (default, c = 1). These transcripts are then merged into a single GTF file. The reason for generating transcripts for both the case and controls is so that deletion events in the case are exposed. Next, we flatten these transcripts into a single linear representation, with concatenated exons, and then visually orient the strand left-to-right, creating a data-driven superTranscript.\n\nA reference is then created from the generated superTranscript through gffread (v0.9.9) and STAR’s (v2.7.3a) genomeGenerate mode.12,16 The reads extracted from each input BAM that overlap the gene of interest are then aligned to this new reference using STAR in alignReads mode, specifically with all splice junction score penalties set to 0. Assembled transcripts are then annotated according to the new superTranscript coordinates. Finally, a custom plotting package using the Python library, Plotly (v4.0 and above), is used to generate both a static image and interactive HTML output. These plots contain coverage and splice junction tracks for the test sample and controls with the superTranscript annotations included for context. Slinker automatically detects and highlights novel splicing events in the gene of interest. These events are discovered through comparisons between the reference and novel transcripts and highlighted according to the novel event’s proximity to known exon boundaries, or whether an exon has been skipped. For instance, retained introns are defined by the inclusion of the region between exons in a gene, including the exon boundary. Novel exons are defined by the inclusion of regions between exons, not including the exon boundaries. Skipped exons are defined by the existence of a splice junction in the studied case that starts and ends at known exon boundaries, but does not exist within the controls. Truncated exons occur when an exon does not extend to the annotated exon boundary in the case. Conversely, an extended exon is where an assembled exon within the case exceeds an annotated exon boundary.\n\nSlinker can be executed through a single command line option, where the inputs and outputs of each particular stage of the pipeline are handled by Bpipe.17 However, users who do not wish to use Bpipe may also run each step manually. The core dependencies of Slinker are the STAR aligner, Stringtie2, Plotly (v4 and above), gffread, and Samtools.12,15,16,18,19 Runtime for a single gene is under 10 minutes with 20gb of memory and four cores allocated, with a control and case sample containing approximately 125 and 275 million reads, respectively.\n\n\nResults\n\nIn order to demonstrate the utility of Slinker for visualising transcriptional variants that are associated with rare disease, we applied it to muscle biopsy samples obtained from Cummings et al.2 Of these, four were selected for visualisation based on the existence of relevant novel splicing events in disease related genes (Table 1). These events were found to have consensus between Cummings et al.2 and the variant caller, MINTIE.6 Three skeletal muscle controls were selected from the Genotype-Tissue Expression (GTEx) consortium that were also used as controls within Cummings et al.2,20 The selected samples were then aligned to hg38 with the STAR aligner in 2-pass mode, of which the resulting BAM files were inputted into the Slinker pipeline.12\n\nThe GTEX samples were used as controls for the COL6A1, POMGNT1, RYR1, and NEB genes. The B-ALL20_7 and B-ALL9_4 samples were validated through Multiplex-ligation dependent probe amplification (MLPA) to not contain IKZF1 deletions and were used as controls against samples that were validated to have DEL4-7, DEL2-7, and DEL4-8.\n\nFigure 3 demonstrates Slinker’s superTranscript visualisation for the RYR1 gene, which has 105 exons across 154kb of the genome. This was compared to the visualisation of the same region using a refined IGV sashimi plot. Log coverage settings were enabled in both Slinker and IGV. Slinker clearly revealed the novel event of a truncated exon in exon 25, which was far less obvious in the genomic view that included the unnecessary splice junctions and alignment sparsity.\n\nA. Slinker visualisations can show coverage (log scale) across the entire gene including events such as truncated exons (purple shading with adjacent drop in coverage), in a single, compact visualisation. Such a visualisation is desirable as users can consider the event in the greater context of the gene's expression. B. Integrative Genomics Viewer (IGV) Sashimi plot including the same case, controls, and transcripts as in A but not in the superTranscript format. Case is shown in purple and the controls in teal. The truncated exon is highlighted with the purple vertical line.\n\nNext, we demonstrated Slinker’s ability to visualise a range of novel events involving both added and deleted sequences in transcripts, each confirmed through MINTIE. Figure 4A depicts two novel splicing events in POMGNT1 found within a single case sample, and is highlighted through a comparison with the three GTEX controls (Table 1). In this case, we could see a retained intron in the genome-guided assembly (highlighted in yellow) and an exon-skipping event (highlighted in purple) in exon 7. Applying Slinker to the COL6A1 gene in another sample clearly revealed the novel exon as reported by Cummings et al.2 (Figure 4B). Furthermore, a truncated exon is shown in the RYR1 gene (Figure 3A) and an extended exon is shown within the NEB gene (Figure 5).\n\nIn this case, the TSL filter was not applied and a reference with all transcripts was passed through to Slinker. This was due to the large number of transcripts of NEB, which were assembled by Stringtie and masked the interesting event. This demonstrates the utility of being able to pass through custom annotations which may be more suitable to the visualisation at hand.\n\nFinally, we applied Slinker to three childhood B-Cell Acute Lymphoblastic Leukemia samples obtained from the Royal Children’s Hospital (RCH), that harboured various IKZF1 deletions; these were validated in DNA using a multiplex-ligation-dependent probe amplification (MLPA) assay (Table 1). Figure 6A depicts an exon 4-7 deletion within one such case compared to two other leukemia samples in the RCH cohort. These two samples were chosen due to their high IKZF1 expression relative to other samples within the cohort, but did not contain a deletion either. In addition to the automatic highlighting denoting a SE event, a clear drop in expression across exons 4 and 7 can be seen in the case relative to the control samples. The 2-7 deletion event (Figure 6B) was also clearly highlighted as a SE event. However, this was not true for the 4-8 deletion sample as no splice junctions existed and the deletion included the final exon (Figure 6C). However, the drop in coverage between the case and controls in this succinct form demonstrates the utility of Slinker for providing a visual comparison between any samples. An interesting aspect of the 4-7 IKZF1 deletion was the assembly of multiple transcripts containing the deletion event (Figure 6B). This demonstrates that Slinker may help provide more information for deletion events over exclusive alignment to predefined superTranscripts.\n\nA. An exon 4-7 deletion in IKZF1. A clear dip in coverage in the case compared to the controls can be seen within the purple highlighted region. Slinker was run using only a single transcript (ENST00000331349), which was representative of the canonical. The highlighted novel exon was annotated in a transcript that is within the greater reference. Transcripts were filtered using the minimum coverage parameter to include all assemblies with the known deletion event. Coverage was normalised by total reads in IKZF1. B. A 2-7 deletion in IKZF1. A clear dip in coverage in the case in comparison to the controls can be seen within the purple highlighted region. In this figure, Slinker was run using only a single transcript (ENST00000331349) which was representative of the canonical. Coverage was normalised by total reads in IKZF1. C. A 4-8 deletion in IKZF1. This comparison demonstrates a slight change in coverage post exon 3 to the end of the transcript in the case. This is representative of the deletion event known to have occurred. Coverage was normalised by total reads in IKZF1.\n\n\nDiscussion\n\nDNA mutations can be causal drivers of disease.2,6 While genomic sequencing is becoming more commonly used to diagnose genetic diseases, there are still many cases where the variants cannot be directly identified as disease-causing, and are therefore called variants of unknown significance. Mutations with the potential to impact splicing are of particular interest. One way to assess the effect of a variant is to investigate the resulting transcript using RNA sequencing and compare these transcripts to a set of controls. While there are several approaches proposed for this purpose, the visualisation of this data can be improved.2,21,22 Here we address this issue with Slinker, which was built on the superTranscript visualisation framework. One of the fundamental advantages of the superTranscript method is the removal of the visualisation sparsity due to uninformative intronic information. However, novel splicing events can retain an intronic sequence, and it is therefore necessary to first determine which sequences are transcribed in the sample. Slinker utilizes the Stringtie2 data-driven method for assembling the transcripts in the sample which is then combined with reference transcripts to capture all potentially expressed sequences.\n\nDue to the large insertion of sequences relative to the superTranscript, retained introns and novel exons were expected to be the simplest events to visualise with Slinker. This is reflected in Figure 4A and 4B. The same is true for exon skipping, where the existence of a splice junction at annotated exon boundaries in the case versus lack thereof in the control was clear (Figure 4A). However, truncated and extended exons appeared to be less obvious in Slinker given the relatively small amount of sequence which were removed/added (Figures 3A and 5). Nevertheless, the bespoke superTranscripts, in conjunction with the highlighting and comparisons with controls could reveal these types of events in the static visualisation even in the largest of genes (Figure 3A). In addition, Slinker generates an interactive plot so that the user can simply zoom in on these regions to better understand the event whilst also zooming out to appreciate the greater context if required.\n\nThough Slinker was developed to highlight novel splicing events in rare diseases, it can also be used to visualise cancer transcripts. Slinker was applied to three B-Cell Acute Lymphoblastic Leukemia (B-ALL) cases harbouring 4-7, 4-8, and 2-7 IKZF1 deletions. Deletions within this gene are a known risk factor in aggressive forms of this cancer and are used to monitor disease progression.13 In each of these examples, a clear deletion event could be seen through either the presence of skipped exons or the relative drop in coverage when compared to the controls (Figure 6). However, generally, cancer is a genetically complex disease and consequently a genetic visualisation is also challenging.23 Nevertheless, these results demonstrate that Slinker can be an appropriate choice for providing a succinct visualisation of this complexity and may be applicable to a broader set of diseases.\n\nFurther work may involve improving this aspect of the software, including highlighting other novel events, such as inversions and duplications. However, this is limited by the assembler’s capacity to retrieve an accurate assembly, including the variant, and for a superTranscript to be an appropriate visual representation.6\n\n\nConclusion\n\nSlinker is a bespoke superTranscript generation and visualisation tool with a demonstrated ability to succinctly present novel splicing events in RNA-Seq data. Its key advantage consists in removing redundant information without manual intervention, leaving room for more useful information, such as the expression across the entire gene.\n\nWe have produced a tool that has been validated on a number of known novel splice variants and is publicly available from Github (https://github.com/Oshlack/Slinker).\n\n\nData availability\n\nEuropean Genome-Phenome Archive: The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia, https://identifiers.org/ega.study:EGAS0000100421220 This study contains the paediatric B-ALL samples (B-ALL18_4, B-ALL19_11, B-ALL7_8, B-ALL8_1, and B-ALL9_4).\n\nNCBI dbGaP: Genetics of Inherited Muscle Disease, https://identifiers.org/dbgap:phs000655.v3.p1\n\nNCBI dbGaP: Common Fund (CF) Genotype-Tissue Expression Project (GTEx), https://identifiers.org/dbgap:phs000424.v6.p1\n\nAnalysis code available from: https://github.com/Oshlack/Slinker\n\nArchived code as at time of publication: https://doi.org/10.5281/zenodo.5719747\n\nLicense: MIT\n\n\nCompeting interests\n\nNo competing interests were disclosed.",
"appendix": "Acknowledgements\n\n\n\n• Tumour samples and coded data were supplied by the Children’s Cancer Centre Tissue Bank at the Murdoch Children’s Research Institute and The Royal Children’s Hospital. Establishment and running of the Children’s Cancer Centre Tissue Bank is made possible through generous support by Cancer In Kids @ RCH, The Royal Children’s Hospital Foundation and the Murdoch Children’s Research Institute.\n\n\nReferences\n\nByron SA, Van Keuren-Jensen KR, Engelthaler DM, et al.: Translating RNA sequencing into clinical diagnostics: opportunities and challenges. Nat. Rev. Genet. 2016 May; 17(5): 257–271. PubMed Abstract | Publisher Full Text\n\nCummings BB, Marshall JL, Tukiainen T, et al.: Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci. Transl. Med. 2017 Apr 19; 9(386) PubMed Abstract | Publisher Full Text\n\nKim D, Pertea G, Trapnell C, et al.: TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013 Apr 25; 14(4): R36. Publisher Full Text\n\nVan der Auwera GA, O’Connor BD: Genomics in the Cloud: Using Docker, GATK, and WDL in Terra. O’Reilly Media, Inc.; 2020; 496.\n\nMortazavi A, Williams BA, McCue K, et al.: Mapping and quantifying mammalian transcriptomes by RNA-Seq. Nat. Methods. 2008 Jul; 5(7): 621–628. PubMed Abstract | Publisher Full Text\n\nCmero M, Schmidt B, Majewski IJ, et al.: MINTIE: identifying novel structural and splice variants in transcriptomes using RNA-seq data. Cold Spring Harbor Laboratory; 2020 [cited 2020 Nov 30]; 2020.06.03.131532. Publisher Full Text\n\nRobinson JT, Thorvaldsdóttir H, Winckler W, et al.: Integrative genomics viewer. Nat. Biotechnol. 2011 Jan 1; 29(1): 24–26. PubMed Abstract | Publisher Full Text\n\nVenter JC, Adams MD, Myers EW, et al.: The sequence of the human genome. Science. 2001 Feb 16; 291(5507): 1304–1351. Publisher Full Text\n\nENCODE Project Consortium: An integrated encyclopedia of DNA elements in the human genome. Nature. 2012 Sep 6; 489(7414): 57–74. PubMed Abstract | Publisher Full Text\n\nDavidson NM, Hawkins ADK, Oshlack A: SuperTranscripts: a data driven reference for analysis and visualisation of transcriptomes. Genome Biol. 2017 Aug 4; 18(1): 148. PubMed Abstract | Publisher Full Text\n\nSchmidt BM, Davidson NM, Hawkins ADK, et al.: Clinker: visualizing fusion genes detected in RNA-seq data. Gigascience. 2018 Jul 1; 7(7). PubMed Abstract | Publisher Full Text\n\nDobin A, Davis CA, Schlesinger F, et al.: STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013 Jan 1; 29(1): 15–21. PubMed Abstract | Publisher Full Text\n\nBrown LM, Lonsdale A, Zhu A, et al.: The application of RNA sequencing for the diagnosis and genomic classification of pediatric acute lymphoblastic leukemia. Blood Adv. 2020 Mar 10; 4(5): 930–942. PubMed Abstract | Publisher Full Text\n\nHowe KL, Achuthan P, Allen J, et al.: Ensembl 2021. Nucleic Acids Res. 2021 Jan 8; 49(D1): D884–D891. PubMed Abstract | Publisher Full Text\n\nKovaka S, Zimin AV, Pertea GM, et al.: Transcriptome assembly from long-read RNA-seq alignments with StringTie2. Genome Biol. 2019 Dec 16; 20(1): 278. PubMed Abstract | Publisher Full Text\n\nPertea G, Pertea M: GFF Utilities: GffRead and GffCompare. F1000Res. 2020; 9: 304. Publisher Full Text\n\nSadedin SP, Pope B, Oshlack A: Bpipe: a tool for running and managing bioinformatics pipelines. Bioinformatics. 2012 Jun 1; 28(11): 1525–1526. PubMed Abstract | Publisher Full Text\n\nCollaborative data science. Montréal, QC: Plotly Technologies Inc; 2015.\n\nLi H, Handsaker B, Wysoker A, et al.: The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009 Aug 15; 25(16): 2078–2079. PubMed Abstract | Publisher Full Text\n\nCarithers LJ, Ardlie K, Barcus M, et al.: A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Biopreserv Biobank. 2015 Oct; 13(5): 311–319. PubMed Abstract | Publisher Full Text\n\nYépez VA, Mertes C, Müller MF, et al.: Detection of aberrant gene expression events in RNA sequencing data. Nat. Protoc. 2021 Feb; 16(2): 1276–1296. PubMed Abstract | Publisher Full Text\n\nUlirsch JC, Verboon JM, Kazerounian S, et al.: The Genetic Landscape of Diamond-Blackfan Anemia. Am. J. Hum. Genet. 2019 Feb 7; 104(2): 356. PubMed Abstract | Publisher Full Text\n\nGreaves M, Maley CC: Clonal evolution in cancer. Nature. 2012 Jan 18; 481(7381): 306–313. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "118437",
"date": "05 Jan 2022",
"name": "George Wiggins",
"expertise": [
"Reviewer Expertise Cancer genetics",
"RNA-sequencing",
"bioinformatics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have developed a novel method (Slinker) to visualize RNA isoforms that improves interpretation. The method requires condensing the genomic region to view only the sequence that is supported by RNA-sequencing reads.\nIn my opinion Slinker does address the need in visualizing RNA isoforms that are assembled from RNA-sequencing data. A limitation that should be discussed is the reliance on StringTie2 for transcript assemble. RNA isoform discovery is a growing field, in which Slinker would offer great use, if adaptable to the development of new tools (e.g. FLAIR, bambu).\nMinor comments are listed below:\n\nI have assumed long and short-read sequencing can be visualized equally? If not, this needs to be highlighted as a limitation in the discussion.\n\nIn the discussion, the authors highlight how RNA species can help determine the pathogenicity of a given variants. For interpretation of RNA splicing events, it is important to determine whether splicing shift the coding frame. Is this possible to implement? This is not a requirement for indexing but a suggested improvement to Slinker.\n\nAll figures are presented well but could be improved with increased font sizes. Additionally, is it possible to provide an HTML version of the one plot in the supplementary information or in the github repo?\nFigure3A has purple shading at the 5` end of the gene that I assume is not relevant, this should be removed for clarity.\n\nPlease provide definitions for acronyms used in plots, e.g. superTranscript panels have TE, NE, TF etc.\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": []
},
{
"id": "102214",
"date": "07 Jan 2022",
"name": "Stephen Montgomery",
"expertise": [
"Reviewer Expertise Computational biology",
"transcriptomics",
"human genetics"
],
"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\nSchmidt et al provide a pipeline for visualizing novel splicing events in RNA-seq data. The key limitations with existing approaches that they have identified are that sparsity of mapped RNA-seq reads to the genome making visualization of novel events harder to detect and further, that existing approaches are mainly guided by existing/known gene annotations. The combined approach appears useful however there are a number of minor weaknesses.\nIn practice, novel products/events are first found statistically and then visualized. It appears that the authors are suggesting that this is mostly done first by manual inspection and Slinker makes it easier to find them. From the examples provided with Slinker or with IGV it would be very difficult to eyeball the differences without considerable experience. In fact, even the authors in the figures have to highlight the critical regions so the readers know what to look at. I am not entirely sure the problem they are describing is that large or they have sufficiently solved it.\n\nOverall, I think the clearly described pipeline in combination with the visualizations provides more utility and impact. I would be interested in knowing how dependent the pipeline is on the specific tools or is it compatible with specific conventional file formats and the user can change the underlying components as desired. Can the genome build be easily changed?\n\nI think Figure 1 would benefit from an example of the corresponding superTranscripts. It wasn't immediately clear to me how a Skipped Exon would be conveniently visualized compared to the retained intron in Figure 2. Overall, some better documentation on how to visualize specific events as the practical examples were hard to read and very small.\n\nThe examples (Fig 3, 4, 5) have abundant text that is nearly unreadable. I am a bit concerned that the output of Slinker is hard to convert into publication quality figures. Does it output as vector graphics for Illustrator/Inkscape if someone was making a multi-panel figure?\n\nIn some of the figures there appear to be other events but they are not highlighted. It would be interesting for the authors to comment on that. For instance in Figure 3 exon 69-70.\n\nThe number of controls compared to is pretty small. In practice, it may be useful to compare to 100s or 1000s of controls to find an aberrant event. Is this possible? Figure 4 focused on 3 GTEx control samples only.\n\nWith the splice junction penalty score set to 0, are there many more false positives than true events? How many events would visually look interesting in other randomly selected comparisons of a couple samples between genes? Does setting this score influence the recovery of the known disease event examples?\n\nIn the discussion, 1st para, the word mutation and variant is used interchangeably. I would recommend being more precise here.\n\nYou don't have to cite it. But you might find our splicePlot tool interesting too. It was designed for sQTL but one can summarize data across lots of samples. However, not with the flexibility you have here since it only focused on junctions that one previously prioritized/found interesting. https://doi.org/10.1093/bioinformatics/btt733\n\nOverall, nice work. The paper was well-written. I hope the tool provides some help for people looking to explore novel junctions.\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": []
},
{
"id": "118438",
"date": "03 Feb 2022",
"name": "Amy Huei-Yi Lee",
"expertise": [
"Reviewer Expertise Systems immunology",
"multi-omics integration",
"neonatal sepsis",
"host-pathogen interactions"
],
"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\nVisualizing RNA-Seq data using the reference genome via a tool like Integrative Genomics Viewer is challenged by the sparsity of transcriptome data, as RNA-Seq reads predominately map to exons. This impedes our abilities to detect SNPs, deletions/insertions and altered splicing events using RNA-Seq reads, and the associative impact on expression levels of the impacted gene. Schmidt et al. extend the concept of superTranscripts, which is a concatenated sequence of all the exons with a gene, with genome-guided assembly to allow visualization of novel exons, retained introns, skipped exons, truncated exons and extended exons. The manuscript is very well written with clear, detailed figures (especially the beautiful schematic of the workflow as shown in Figure 2). This is definitely a tool that I am looking forward to using in my own work.\nI only have two minor comments:\nThe colors used in Fig 1 need to be explained in the legends – and the green exons/red introns should probably be different colors to make it colorblind friendly.\n\nThe comparison of case and control requires coverage/sequencing depth to help with detection of some of the novel splice events (as shown in Fig 3 – 6). What happens when the sequencing depth between case and control are drastically different?\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": []
}
] | 1
|
https://f1000research.com/articles/10-1255
|
https://f1000research.com/articles/10-14/v1
|
11 Jan 21
|
{
"type": "Research Article",
"title": "Enhancement of pyocyanin production by subinhibitory concentration of royal jelly in Pseudomonas aeruginosa",
"authors": [
"Dina Auliya Amly",
"Puspita Hajardhini",
"Alma Linggar Jonarta",
"Heribertus Dedy Kusuma Yulianto",
"Heni Susilowati",
"Dina Auliya Amly",
"Puspita Hajardhini",
"Alma Linggar Jonarta",
"Heribertus Dedy Kusuma Yulianto"
],
"abstract": "Background: Pseudomonas aeruginosa, a multidrug resistant Gram-negative bacterium, produces pyocyanin, a virulence factor associated with antibiotic tolerance. High concentrations of royal jelly have an antibacterial effect, which may have the potential to overcome antibacterial resistance. However, in some cases, antibiotic tolerance can occur due to prolonged stress of low-dose antibacterial agents. This study aimed to investigate the effect of subinhibitory concentrations of royal jelly on bacterial growth and pyocyanin production of P. aeruginosa. Methods: Pseudomonas aeruginosa ATCC® 10145™ and clinical isolates were cultured in BHI media for 18 hours followed by optical density measurements at 600 nm wavelength to determine minimum inhibitory concentration (MIC). After 36 hours of incubation, pyocyanin production was observed by measuring the absorbance at 690 nm. Pyocyanin concentrations were calculated using extinction coefficient 4310 M-1cm-1. Results: Results of the MIC tests of both strains were 25%. The highest production of pyocyanin was observed in the subinhibitory concentration group 6.25%, which gradually decreased along with the decrease of royal jelly concentration. Results of one-way ANOVA tests differed significantly in pyocyanin production of the two strains between the royal jelly groups. Tukey HSD test showed concentrations of 12.5%, 6.25%, and 3.125% significantly increased pyocyanin production of ATCC® 10145™, and the concentrations of 12.5% and 6.25% significantly increased production of the clinical isolates. Conclusions: This study concluded royal jelly concentrations of 25% or above could inhibit bacterial growth; however, only the concentrations of 12.5% and 6.25% could increase pyocyanin production in P. aeruginosa, both in ATCC® 10145™ and clinical isolates. In conclusion, it is advisable to determine the appropriate concentration of royal jelly to obtain beneficial virulence inhibiting activity.",
"keywords": [
"royal jelly",
"antibacterial effect",
"Pseudomonas aeruginosa",
"pyocyanin"
],
"content": "Introduction\n\nPseudomonas aeruginosa (P. aeruginosa) is one of the Gram-negative bacilli bacteria which causes nosocomial infections that can be fatal, especially in immunocompromised patients1–3. These bacteria are often found in the dental unit waterlines which allows the transmission of these bacteria into the oral cavity4. As an opportunist pathogen, P. aeruginosa is also frequently involved in oral infections, such as necrotizing ulcerative gingivitis, periodontitis, and mandibular osteomyelitis5–7. Although the mechanism is not clear yet, its presence in the oral cavity has been shown to result in systemic infections, such as nosocomial pneumonia8.\n\nBased on the reports from several clinical cases, the infection caused by P. aeruginosa bacteria can be fatal. Treatment of P. aeruginosa infection is sometimes ineffective, which is closely related to the number of virulence factors possessed by the bacteria9. The bacterial cell surface components and some secretory products are important virulence factors of P. aeruginosa, one of which is pyocyanin10. Pyocyanin is a cytotoxic pigment from the Phenazine group of compounds that can facilitate biofilm development, cause pro-inflammatory effects, and result in host cell death11.\n\nThe resistance of P. aeruginosa to various spectrums of antibiotics creates difficulties in handling the infection it causes12. It has been reported recently that the administration of antibiotics below the minimum inhibitory concentration (MIC) can cause specific bacterial responses, such as an increase in pyocyanin production in P. aeruginosa. PAO1 and P14 are the attempts by the bacteria to survive under antibiotic stress13. This certainly motivates researchers to further analyze the infection they cause, and find the appropriate antibiotic concentration or dose to overcome the problem.\n\nRoyal jelly is a natural bee product that has the potential to be developed to overcome antibiotic resistance. Royal jelly has anti-inflammatory, antibacterial, and antioxidant effects14. Royal jelly proteins, such as Jelleine, major royal jelly protein-1 (MRJP1), and royalicin are known to have antibacterial effects against P. aeruginosa. Major royal jelly protein-1 and Jelleine can interfere with the permeability of the outer membrane of the cell, causing the loss of vital contents of bacterial cells, which in turn causes cell death. Cationic antimicrobial peptides, such as royalicin, are known to also interfere with cell membrane permeability in various Gram-positive and Gram-negative bacteria, such as P. aeruginosa15–17. Results of previous studies have shown that royal jelly can inhibit the growth of P. aeruginosa. In this study, royal jelly showed inhibition of the growth of P. aeruginosa ATCC® 27853™18. In addition, it has also been known that royal jelly in various concentrations can inhibit the nonspecific attachment of P. aeruginosa ATCC® 27853™19, but so far, the effect of the subinhibitory concentration of royal jelly against these bacteria is unknown. Furthermore, as pyocyanin is an indicator of the pathogenicity of P. aeruginosa strains, the aim of this study was to determine the effect of subinhibitory royal jelly concentration on pyocyanin production in representative strains of a high level pyocyanin-producer P. aeruginosa ATCC® 10145™ and clinical isolates.\n\n\nMethods\n\nThis in vitro laboratory experimental research was done at the Integrated Research Laboratory of the Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta. All research procedures have been approved by the Ethics Committee of the Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta (No. 00393/KKEP/ FKG-UGM/EC/2020).\n\nThe royal jelly used in this study was obtained from Nusukan, Surakarta, Central Java, Indonesia. This product is produced from Apis mellifera bees that have been identified previously19. Royal jelly 5.5 grams was dissolved in 10 ml of cold phosphate buffered saline (PBS), then homogenized using a magnetic stirrer (24 hours, 4°C). The royal jelly solution was centrifuged (12,000 g, 45 minutes, 4°C), then the supernatant was filtered using 0.45 µm millipore to produce 55% royal jelly. Furthermore, royal jelly was stored at a temperature of 4–8°C20.\n\nPseudomonas aeruginosa ATCC® 10145™ (Thermo Scientific) was obtained from the Integrated Research Laboratory of the Faculty of Dentistry, Universitas Gadjah Mada. A clinical isolate of P. aeruginosa derived from patient sputum was obtained from the Laboratory of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada. Both of these strains were each inoculated in Luria Bertani broth and incubated at 37°C for 24 hours. After that, the culture was centrifuged at 3000 rpm for 15 minutes and then resuspended using 0.98% NaCl to obtain a bacterial concentration equivalent to 1.5 × 105 CFU/ml.\n\nA sterile 55% w/v royal jelly solution was diluted in brain heart infusion (BHI; Himedia Laboratories) broth to obtain a concentration of 50% and then serial dilution was performed in 96 well microplates. A total of 5 µl of the P. aeruginosa ATCC® 10145™ suspension or clinical isolate bacteria (1.5 × 105 CFU/ml) was inoculated in all groups, except the groups that had been determined as blanks (blanko). The culture was then incubated at 37°C for 18 hours. After that, the microplate was scanned using the Spark® Multimode Microplate Reader (Tecan trading AG) to measure optical density (OD) using a 600 nm wavelength. The percentage of bacterial viability inhibition was determined based on the OD value of the treatment group against the control.\n\nRoyal jelly solution was diluted into sterile BHI broth to get the concentration of 12.5%, 6.25%, 3.125%, 1.56%, 0.78%, 0.39%, 0.19%, and 0.098% w/v. Both strains of P. aeruginosa were cultured on BHI broth containing various concentrations of royal jelly as treatment and BHI broth only as a blank (blanko). The cultures were incubated at 37°C for 36 hours, then the pyocyanin production of each strain was observed visually, which appeared green in the culture supernatant. The pyocyanin concentration was further quantified using previously published methods21. Briefly, after 36 hours of incubation, the culture supernatant was transferred to a sterile tube and centrifuged at a rate of 10,000 g for 30 minutes. The supernatant was filtered using a 0.45 µm Millipore filter and transferred to 96 new well microplates. The absorbance value of the supernatant containing pyocyanin was measured at a wavelength of 690 nm, then the pyocyanin concentration was calculated using the following equation21.\n\nConcentration of pyocyanin = A690 nm (A690 nm of sample - A690 nm of blank) / ε * d\n\nε = extinction coefficient (pyocyanin at A690 nm = 4310 M-1cm-1)\n\nd = path length (0.23 cm for 96 well microplate)\n\nThe data in this study were presented as the percentage of bacterial viability and pyocyanin concentration in the P. aeruginosa culture supernatant. All data were tested for normality using the Shapiro-Wilk and the Levene Test for homogeneity using SPSS Statistic v20. Furthermore, one-way ANOVA and Games-Howell parametric analysis were performed for bacterial cell viability data; and parametric one-way ANOVA followed by Tukey HSD on pyocyanin concentration data.\n\n\nResults\n\nThe antibacterial activity of royal jelly against the two strains of P. aeruginosa is shown in Figure 1. Data on the percentage of bacterial growth inhibition shows normal distribution data (p>0.05), but has a non-homogeneous variant (p<0.05). One-way ANOVA showed a significant difference in the percentage of growth inhibition in P. aeruginosa ATCC® 10145™ (p = 0.000) and P. aeruginosa clinical isolate (p = 0.000) between royal jelly treatment groups and negative control. In this study, it was proven that royal jelly can inhibit the viability of both P. aeruginosa strains starting from a concentration of 25%. The results of the multi-comparison analysis showed that there was no significant difference between the concentrations of 25% and 50% and significant differences were identified between the concentrations of 25% and 50% with 12.5% to 0.098% in both strains. It can be concluded that the MIC for both strains is 25%.\n\nBacterial cultures were incubated with varying concentrations of royal jelly for 18 hours at 37°C. Royal jelly 50% and 25% inhibit bacterial growth. The difference is based on the results of the Games-Howell analysis at the significance value (*) p <0.05. ATCC® 10145™ (a) strain; clinical isolate (b).\n\nPyocyanin was identified as green in culture supernatant P. aeruginosa ATCC®10145™ and clinical isolate. After 36 hours of incubation, pyocyanin production was increased in the stimulated culture group with subinhibitory concentrations below 25%. The intensity of green color in the culture medium increased with the increase in the concentration of royal jelly (Figure 2). The change in the color intensity of the culture supernatant was consistent with the results of the pyocyanin concentration measurement.\n\nP. aeruginosa bacteria (1.5 × 105 CFU/well) ATCC® 10145™ (a); clinical isolate (b). Royal jelly 12.5% (A); 6.25% (B); 3,125% (C); 1.56% (D); 0.78% (E); 0.39% (F); 0.19% (G); 0.098% (H); 0% (I); No treatment (J).\n\nPyocyanin concentration data in each royal jelly treatment group and negative control were the results of experiments on triplicate cultures. Figure 3 shows the average pyocyanin concentration for each group. The highest average pyocyanin concentration was identified in P. aeruginosa ATCC® 10145™ induced by royal jelly with a concentration of 6.25%, which was 23.59 μM, while the lowest mean was identified in clinical isolates of P. aeruginosa without exposure to royal jelly, which was 0.7 μM. The pyocyanin concentration of P. aeruginosa ATCC® 10145™ was seen to be higher than clinical isolate in the same concentration in all treatment groups.\n\nPyocyanin production increased due to exposure to sub-inhibitory royal jelly concentrations of 6.25% and decreased at lower royal jelly concentrations. The difference was based on the results of the Tukey-HSD analysis at the significance value (*) p <0.05. ATCC® 10145™ (a) strain; (b) clinical isolate.\n\nPyocyanin concentration data both on ATCC® 10145™ and clinical isolate in all groups were normally distributed (p>0.05) and homogeneous (p>0.05). There was a significant difference in the concentration of pyocyanin ATCC® 10145™ (p = 0.000) and clinical isolate (p = 0.000) between the treatment groups. The results of multiple comparison analysis of Tukey-HSD on P. aeruginosa cultures of ATCC® 10145™ showed a significant difference between the royal jelly groups with concentrations of 0% with 12.5%, 6.25%, and 3.125%. In addition, a significant difference in pyocyanin concentrations in clinical isolate was found between the 0% royal jelly group with 12.5% and 6.25%.\n\n\nDiscussion\n\nThe antibacterial effect of royal jelly has been widely reported by previous researchers15–17. The ability of royal jelly to inhibit the growth of P. aeruginosa is thought to be related to the variety and concentration of its antibacterial protein. Royal jelly components that have been identified as having antibacterial activity are major royal jelly protein-1 (MRJP-1), Jelleine I–III, royalicin, and 10-hydroxy-2-decenoic (10-HDA)15,17,22.\n\nThis study showed that royal jelly concentrations of 25% and 50% had antibacterial activity against P. aeruginosa ATCC® 10145™ and clinical isolate. The results of this observation are different from previous studies that showed P. aeruginosa growth could be inhibited at concentrations >50%18. This difference is thought to be closely related to differences in geographical location, botanical origin, climate, and storage conditions of royal jelly, which affect the antibacterial component of royal jelly23. Previous studies have shown that royal jelly originating from different geographic and botanical locations affects the quantity of 10-HDA. Royal jelly originating from tropical climates is reported to contain lower concentrations of 10-HDA than cold climates23. The higher temperature and longer storage time also resulted in a significant reduction in the quantity of MRJP124. However, the bacterial strains studied probably also had an effect, as previously reported there was a variable response between clinical isolates and standard bacteria18,19.\n\nPyocyanin is an indicator of the pathogenicity of P. aeruginosa. To our knowledge, this study report is the first to demonstrate a dualism effect of royal jelly on P. aeruginosa. The subinhibitory concentration of royal jelly amplify the effect of an autoinducer. It was able to increase the production of pyocyanin in ATCC® 10145™ and clinical isolates to protect and maintain their survival13. The pyocyanin concentration in the ATCC® 10145™ strain appeared to be significantly higher than the clinical isolates. This observation is in accordance with previous studies that found the ATCC® 10145™ strain produced more pyocyanin than the clinical isolate strains from active ulcerative keratitis patients25. The presence of phzM and phzS genes was thought to affect the concentration of pyocyanin produced26. This was proven by previous studies that the phzM and phzS gene expression of multidrug resistance (MDR) clinical isolate P. aeruginosa was lower leading to less pyocyanin production than non-MDR isolates and PAO1 strains27. Some clinical isolates were also reported not to have the genes so that these bacteria cannot produce pyocyanin26. Other research results also showed that the pyocyanin concentration of ATCC® 10145™ strains is higher than that of PAO1 and PA14 strains after incubation for 60 hours28. It is estimated that ATCC® 10145™ is one of the strong pyocyanin producing strains. However, other virulence factors possessed by this strain were lower than the clinical isolate strains so that they were considered less virulent25.\n\nVarious virulence factors, including pyocyanin are generally associated with the quorum sensing mechanism29. Quorum sensing refers to the communication process between microbial cells using autoinducer molecules30. One of the autoinducer molecules that plays an important role in the regulation of pyocyanin production is the pseudomonas quinolone signal (PQS). Mutation of the PQS gene results in reduced pyocyanin production31. When bacterial cells are exposed to exogenic stress, such as an antibacterial agent that can threaten their survival, the bacteria immediately respond to the stimulus by inducing the production of PQS which is responsible for activating various genes involved in the production of virulence factors, including pyocyanin29,32. Although the effect of royal jelly subinhibitor concentration on this autoinducer molecule is not yet known, several studies have reported that the increase in pyocyanin production is closely related to the effect of subinhibitor antibiotics that increase PQS gene expression33. It is thought that this is the cause of increased pyocyanin production at subinhibitory concentrations.\n\nThe increase in pyocyanin production in P. aeruginosa bacteria will have implications for the mechanism of bacterial attachment and biofilm formation. Apart from its production, which is closely related to the quorum sensing mechanism, pyocyanin is also a signaling factor in the quorum sensing process itself. This was identified from the results of research on P. aeruginosa PAO1 and PA1434. In addition, the increase in pyocyanin is likely to have an impact on the activity of bacteria to produce extracellular DNA (eDNA). Extracellular DNA is an important part of extracellular polymeric substance (EPS) which is the main component of the biofilm matrix. The increase in EPS production is very beneficial for the bacterial attachment process and subsequently the formation of biofilms. Pyocyanin can induce eDNA production in low level pyocyanin-producer strains, PAO1 and pyocyanin-deficient strains, PA14. In this study, it was proven that pyocyanin caused an increase in the production and release of eDNA, which is the main component in forming and stabilizing bacterial biofilms35.\n\nThe increase in pyocyanin production induced by subinhibitory royal jelly concentrations in P. aeruginosa ATCC® 10145™ and clinical isolates in this study is an interesting phenomenon. Although, subinhibitory royal jelly concentrations were not effective in inhibiting the growth of these bacteria, on the other hand, they increased production of pyocyanin virulence factors. This has inspired the alleged biphasic nature of royal jelly which has antibacterial potential, but at different exposure concentrations, it can induce the production of P. aeruginosa bacteria virulence factors. This phenomenon leads us to think that researchers, as well as medical practitioners, should be careful in determining the concentration of royal jelly for its antibacterial research purposes or its therapeutic potential. This of course requires further research on the mechanisms associated with bacterial response to subinhibitory concentrations of royal jelly.\n\n\nConclusions\n\nRoyal jelly at a concentration of 25% was only able to inhibit the growth of P. aeruginosa bacteria, but at subinhibitory concentrations it could increase pyocyanin production in P. aeruginosa strain ATCC® 10145™ and clinical isolate. Based on the results of this study, we suggest selecting the appropriate dose or concentration for the purpose of inhibiting the growth and production of P. aeruginosa virulence factors.\n\n\nData availability\n\nFigshare: Pseudomonas aeruginosa pyocyanin, https://doi.org/10.6084/m9.figshare.13247429.v136.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nResearchers appreciate the help of Bunga Artika as a laboratory assistant who helped in this research.\n\n\nReferences\n\nCorrin B, Nicholson AG: Pathology of the Lungs. 3rd ed. London: Churchill Livingstone. Elsevier. 2011; 177. Publisher Full Text\n\nMigiyama Y, Yanagihara K, Kaku N, et al.: Pseudomonas aeruginosa bacteremia among immunocompetent and immunocompromised patients: relation to initial antibiotic therapy and survival. Jpn J Infect Dis. 2016; 69(2): 91–96. PubMed Abstract | Publisher Full Text\n\nWolska K, Kot B, Jakubczak A: Phenotypic and genotypic diversity of Pseudomonas aeruginosa strains isolated from hospitals in Siedlce (Poland). Braz J Microbil. 2012; 43(1): 274–282. PubMed Abstract | Free Full Text\n\nOuellet MM, Leduc A, Nadeau C, et al.: Pseudomonas aeruginosa isolates from dental unit waterlines can be divided in two distinct groups, including one displaying phenotypes similar to isolates from cystic fibrosis patients. Front Microbiol. 2015; 5: 802. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJandial A, Mishra K, Panda A, et al.: Necrotising ulcerative gingivitis: a rare manifestation of Pseudomonas infection. Indian J Hematol Blood Transfus. 2018; 34(3): 578–580. PubMed Abstract | Publisher Full Text | Free Full Text\n\nColombo APV, Magalhaes C, Hartenbach FAR, et al.: Periodontal disease associated biofilm : a reservoir for pathogens of medical importance. Microb Pathog. 2016; 94: 27–34. PubMed Abstract | Publisher Full Text\n\nPappalardo S, Tanteri L, Brutto D, et al.: Mandibular osteomyelitis due to Pseudomonas aeruginosa. Case report. Minerva Stomatol. 2008; 57(6): 323–329. PubMed Abstract\n\nCaldas R, Boisrame S: Upper aero-digestive contamination by Pseudomonas aeruginosa and implications in Cystic Fibrosis. J Cyst Fibros. 2015; 14(1): 6–15. PubMed Abstract | Publisher Full Text\n\nMacin S, Akarca M, Sener B, et al.: Comparison of virulence factors and antibiotic resistance of Pseudomonas aeruginosa strains isolated from patients with and without cystic fibrosis. Rev Rom Med Lab. 2017; 25(4): 327–334. Publisher Full Text\n\nKhalifa ABH, Moissenet D, Thien HV, et al.: Virulence factor in Pseudomonas aeruginosa: mechanisms and modes of regulation. Ann Biol Clin (paris). 2011; 69(4): 393–403. PubMed Abstract | Publisher Full Text\n\nHall S, McDermott C, Anoopkumar-Dukie S, et al.: Cellular effects of pyocyanin, a secreted virulence factor of Pseudomonas aeruginosa. Toxins (Basel). 2016; 8(8): 236. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNguyen L, Garcia J, Gruenberg K, et al.: Multidrug-resistant Pseudomonas infections: hard to treat, but hope on the horizon? Curr Infect Dis Rep. 2018; 20(8): 23. PubMed Abstract | Publisher Full Text\n\nZhu K, Chen S, Sysoeva TA, et al.: Universal antibiotic tolerance arising from antibiotic-triggered accumulation of pyocyanin in Pseudomonas aeruginosa. PLoS Biol. 2019; 17(12): e3000573. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFratini F, Cilia G, Mancini S, et al.: Royal jelly: an ancient remedy with remarkable antibacterial properties. Microbiol Res. 2016; 192: 130–141. PubMed Abstract | Publisher Full Text\n\nBrudzynski K, Sjaarda C, Lannigan R: MRJP1- containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates. Front Microbiol. 2015; 6: 711. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFontana R, Mendes MA, De Souza BM, et al.: Jelleines: a family of antimicrobial peptides from the royal jelly of honeybees (Apis mellifera). Peptides. 2004; 25(6): 919–928. PubMed Abstract | Publisher Full Text\n\nBilikova K, Huang SC, Lin IP, et al.: Structure and antimicrobial activity relationship of royalisin, an antimicrobial peptide from royal jelly of Apis mellifera. Peptides. 2015; 68: 190–196. PubMed Abstract | Publisher Full Text\n\nBoukraa L: Additive activity of royal jelly and honey against Pseudomonas aeruginosa. Altern Med Rev. 2008; 13(4): 330–333. PubMed Abstract\n\nHartono SK, Haniastuti T, Susilowati H, et al.: The effect of in vitro royal jelly provision on adhesion of Pseudomonas aeruginosa. Maj Kedokt Gigi Indones. 2019; 1(1): 1-5. Publisher Full Text\n\nSusilowati H, Murakami K, Yumoto H, et al.: Royal jelly inhibits Pseudomonas aeruginosa adherence and reduces excessive inflammatory responses in human epithelial cells. Biomed Res Int. 2017; 2017: 3191752. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrice-Whelan A, Dietrich LEP, Newman DK: Pyocyanin alters redox homeostasis and carbon flux through central metabolic pathways in Pseudomonas aeruginosa PA14. J Bacteriol. 2007; 189(17): 6372–6381. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHan B, Fang Y, Feng M: In-depth phosphoproteomic analysis of royal jelly derived from western and eastern honeybee species. J Proteome Res. 2014; 13(12): 5928–5943. PubMed Abstract | Publisher Full Text\n\nWei WT, Hu YQ, Zheng HQ, et al.: Geographical influences on content of 10-hydroxy-trans-2-decenoic acid in royal jelly in China. J Econ Entomol. 2013; 106(5): 1958–1963. PubMed Abstract | Publisher Full Text\n\nLi JK, Feng M, Zhang L, et al.: Proteomics analysis of major royal jelly protein changes under different storage conditions. J Proteome Res. 2008; 7(8): 3339–3353. PubMed Abstract | Publisher Full Text\n\nSewell A, Dunmire J, Wehmann M, et al.: Proteomic analysis of keratitis-associated Pseudomonas aeruginosa. Mol Vis. 2014; 20: 1182–1191. PubMed Abstract | Free Full Text\n\nSamad A, Ahmed T, Rahim A, et al.: Antimicrobial susceptibility patterns of clinical isolates of Pseudomonas aeruginosa isolated from patients of respiratory tract infections in a Tertiary Care Hospital, Peshawar. Pak J Med Sci. 2017; 33(3): 670–674. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFuse K, Fujimura S, Kikuchi T, et al.: Reduction of virulence factor pyocyanin production in multidrug-resistant Pseudomonas aeruginosa. J Infect Chemother. 2013; 19(1): 82–88. PubMed Abstract | Publisher Full Text\n\nRada B, Lekstrom K, Damian S, et al.: The Pseudomonas toxin pyocyanin inhibits the dual oxidase- based antimicrobial system as it imposes oxidative stress on airway epithelial cells. J Immunol. 2008; 181(7): 4883–4893. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLin J, Cheng J, Wang Y, et al.: The Pseudomonas Quinolone signal (PQS): not just for quorum sensing anymore. Front Cell Infect Microbiol. 2018; 8: 230. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang W, Li C: Exploiting quorum sensing interfering strategies in gram-negative bacteria for the enhancement of environmental applications. Front Microbiol. 2016; 6: 1535. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBala A, Kumar L, Chhibber S, et al.: Augmentation of virulence related traits of pqs mutants by Pseudomonas quinolone signal through membrane vesicles. J Basic Microbiol. 2014; 55(5): 566–578. PubMed Abstract | Publisher Full Text\n\nBru J, Rawson B, Trinh C, et al.: PQS produced by the Pseudomonas aeruginosa stress response repels swarms away from bacteriophage and antibiotics. J Bacteriol. 2019; 201(23): e00383–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCummins J, Reen FJ, Baysse C, et al.: Subinhibitor concentrations of the cationic antimicrobial peptide colistin induce the pseudomonas quinolone signal in Pseudomonas aeruginosa. Microbiology(Reading). 2009; 155(Pt 9): 2826–2837. PubMed Abstract | Publisher Full Text\n\nDietrich LE, Price-Whelan A, Petersen A, et al.: The penazine pyocyanin is a terminal signalling factor in the quorum sensing network of Pseudomonas aeruginosa. Mol Microbiol. 2006; 61(5): 1308–1321. PubMed Abstract | Publisher Full Text\n\nDas T, Manefield M: Pyocyanin promotes extracellular DNA release in Pseudomonas aeruginosa. PLoS One. 2012; 7(10): e46718. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSusilowati H, Amly DA, Yulianto HDK, et al.: Pseudomonas aeruginosa pyocyanin. figshare. Figure. 2020. http://www.doi.org/10.6084/m9.figshare.13247429.v1"
}
|
[
{
"id": "77076",
"date": "01 Feb 2021",
"name": "Ariadna A. Djais",
"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 examined royal jelly and Apis mellifera bees as a base ingredient. These ingredients are antibacterial with pycocyanin as a pigment by the bacterium Psedomonas aeroginosa. The P. aeroginosa was selected because these bacteria are known as multidrug-resistant bacterium. This research is interesting and specific. In this study, the data was analyzed as an indicator of the difference in the contrast of the green pigment color, which was carried out by measuring at a wavelength of 690 nm.\nIn my opinion, this research needs to add more information regarding the methods chapters:\nIt is necessary to add information about the stage of royal jelly making as the test material.\n\nIt is necessary to add information about the bacterium identification technique which used by the researcher when confirming clinical isolates as P. aeroginosa.\n\nNumber of replication of independent experiment conducted by the researcher.\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": "6363",
"date": "13 Jul 2021",
"name": "Heni Susilowati",
"role": "Author Response",
"response": "Thank you for providing a review and suggestions for improving our manuscript. Below are our revisions to the manuscript according to the review comments. 1. Response to comments 1: We explain the stages of preparing royal jelly on the manuscript, written in the Methods section (page 3) as follows: Royal jelly used in this study was obtained from Nusukan, Surakarta, Central Java, Indonesia and harvested in May-October 2019. This product was obtained from the beekeeper Apis mellifera who lives in the randu trees (Ceiba pentandra) and sono wood (Dalbergia latifolia). Apis mellifera bee species have been identified through previous research19. Royal jelly 5.5 grams was dissolved in 10 ml of cold phosphate buffered saline (PBS), then homogenized using a magnetic stirrer (24 hours, 4oC). The royal jelly solution was centrifuged (12,000 g, 45 minutes, 4°C), then the supernatant is taken and checked the pH. The results of pH measurements with a pH meter showed a pH of 3.79. Furthermore, the supernatant was filtered using 0.45 µm Millipore to produce 55% royal jelly. 2. Response to comment 2: We write an explanation of how to identify bacteria in the Methods section (page 3), which is as follows: Identification of the clinical isolate was carried out using API 2ONE (bioMérieux, Inc). 3. Response to comment 3: Each experiment was carried out with 6 replications. We write the revision on page 3 of the Methods section, on bacterial viability tests and pyocyanin detection."
},
{
"c_id": "6788",
"date": "09 Jul 2021",
"name": "Heni Susilowati",
"role": "Author Response",
"response": "Thank you for providing a review and suggestions for improving our manuscript. Below are our revisions to the manuscript according to the review comments. 1. The response to comment 1 We explain the stages of preparing royal jelly on the manuscript, written in line 2-6 of paragraph 2 of the Methods section as follows: Royal jelly used in this study was obtained from Nusukan, Surakarta, Central Java, Indonesia and harvested in May-October 2019. This product was obtained from the beekeeper Apis mellifera who lives in the randu trees (Ceiba pentandra) and sono wood (Dalbergia latifolia). Apis mellifera bee species have been identified through previous research (Hartono et al., 2019). Royal jelly 5.5 grams was dissolved in 10 ml of cold phosphate buffered saline (PBS), then homogenized using a magnetic stirrer (24 hours, 4oC). The royal jelly solution was centrifuged (12,000 g, 45 minutes, 4°C), then the supernatant was taken and checked for the pH. The results of pH measurements using a pH meter showed a pH of 3.79. Furthermore, the supernatant was filtered using 0.45 µm Millipore to produce 55% royal jelly. 2. The response to comment 2 We have written an explanation of how to identify bacteria in line 5 of paragraph 3 the Methods section, which is as follows: Identification of the clinical isolate was carried out using API 2ONE (BioMérieux, Inc). 3. Response to comment 3 The bacterial viability assay experiment was carried out in quadruplicate, meanwhile, the pyocyanin experiments were performed in triplicate. We write the revision in the last line of related paragraphs in the Methods section."
}
]
},
{
"id": "77077",
"date": "04 Feb 2021",
"name": "Theerthankar Das",
"expertise": [
"Reviewer Expertise Biofilms",
"antimicrobial agents"
],
"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 intention of this study is good and to enlighten the antibacterial and anti-virulence effect of royal jelly in P. aeruginosa.\nTo be more conclusive this study needs more work:\nIts better to use chloroform-HCl (standard and more popular) assay to quantify pyocyanin yield - its more rigorous than just taking absorbance at 690nm of pyocyanin (broad peak).\n\nBiofilm (Crystal violet for biomass quantification) study needs to be done to ensure impact of royal jelly/pyocyanin on biofilm development.\n\nConfocal microscopy will be of great help to show biofilm architecture.\n\nSpecific comments:\nWhy solubilized royal jelly is centrifuged and supernatant is only taken? What happens with pellets (are there any pellets found after centrifugation?). If yes - then how can we know that supernatant has all royal jelly?\n\nAt 25% royal jelly we see only 60% growth inhibition for both bacterial strains. Its not MIC - you can call it LC50 (lethal dose to reduce at least 50% growth). MIC is when there is zero or 1-2% growth only.\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": "6769",
"date": "13 Jul 2021",
"name": "Heni Susilowati",
"role": "Author Response",
"response": "We thank you for the thorough and careful review of our manuscript. We apologize for our delay in revisions due to the various obstacles we face regarding the availability of laboratory facilities and access during the Covid-19 pandemic. The following are our responses to the suggestions and specific comments. The response to comment 1 (quantification of pyocyanin) We measured the concentration of pyocyanin contained in the culture supernatant of P. aeruginosa. This condition is in accordance with the previous research conducted by Price-Whelan et al. (2007). Indeed, we only measured the absorbance value of the supernatant filtrate of the bacterial culture at a wavelength of 690 nm, but the pyocyanin concentration was then known by calculations using a formula published by previous researchers (Price-Whelan et al, 2007). The constant value of 4310 M -1cm -1 for the absorbance at 690 nm has been determined based on the research of Dietrich et al. 2006. Since our experimental conditions match the experimental conditions in both studies, both of which are published in outstanding journals, we feel it is sufficient to refer to their methods. The response to comment 2 (Biofilm [Crystal violet for biomass quantification] study) We have conducted additional experiments to detect the association between pyocyanin production in bacteria exposed to royal jelly and biofilm formation using the static microtiter plate biofilm assay (crystal violet staining) method. To analyze the relationship between pyocyanin production and biofilm mass production, we have used P. aeruginosa ATCC 10145 as this strain is more responsive in producing pyocyanin when compared to the clinical isolate strains we previously use. The results showed that the detectable biofilm mass significantly increased in bacterial cultures exposed to 12.5% royal jelly extract. Meanwhile, cultures treated with 25% royal jelly did not show any biofilm formation. The 6.25% royal jelly extract and the lower concentrations induced biofilm mass formation but at a lower quantity than 12.5% royal jelly. This evidence suggests a relationship between royal jelly concentration, pyocyanin production, and biofilm mass formation. The subinhibitory concentration (12.5%, 6.23%) of the royal jelly extract induced more pyocyanin production and biofilm mass formation rather than the higher concentrations. Related changes were in the Methods, Results, and Conclusion of the Abstract, paragraph 6 of the Methods, paragraph 5 of Results, Figure 4, and line 5 of paragraph 6 on the Discussion section in the manuscript. The response to comment 3 (microscopy of biofilm architecture) In order to complement the data regarding the effect of royal jelly on the mass formation of biofilms, we have carried out observations of the microscopic architecture of P. aeruginosa ATCC 10145 biofilms using scanning electron microscopy, since we could not access the confocal microscopy method at our university. We chose secondary electron (SE) mode rather than a backscattered electron (BSE) to investigate biofilm in a three-dimensional perspective. The results of observations on representative samples showed that in the culture exposed to 25% royal jelly extract there was no biofilm mass deposition, while the group exposed to 12.5% royal jelly showed a larger density of biofilm than the 6.25% royal jelly group. Chlorhexidine 0.2% control showed total inhibition of biofilm mass formation. Methods, results, discussion, and related references have been added to the manuscript on Methods, Results, and Conclusion in the Abstract, paragraph 7 of the Methods section, paragraph 6-7 of the Results section, and line 5 in paragraph 6 of the Discussion section. Specific comments: 1. Why solubilized royal jelly is centrifuged and supernatant is only taken? Answer: The extraction method using phosphate buffer saline (Hu et al, 2019) was chosen in order to dissolve major royal jelly protein 1 (MRJP1), the active components that are antibacterial or anti-adhesion. It is known that MRJP1 is a hydrosoluble protein dissolved in PBS, which is higher in supernatants than in pellets (Gismondi et al., 2017). What happens with pellets (are there any pellets found after centrifugation?). If yes - then how can we know that supernatant has all royal jelly? After centrifugation, there were indeed pellets, and it has been found that the pellets contain more liposoluble proteins than supernatants. To ensure that the compounds contained in the PBS royal jelly extract supernatant, further research is needed; However, from the research of Furusawa et al. (2016), it was found that MRJP1 was contained in the supernatant of PBS royal jelly extract in quite a large amount, reaching 27.6%. The active components that are antibacterial or anti-adhesion in the supernatant of royal jelly extract in this study cannot be explained with certainty, but the royal jelly used in this study was thought to mainly contain MRJP1. We add this explanation to paragraph 2 of the Discussion section. Additional sources of literature have been written in the reference list numbers 37, 38, and 39. 2. At 25% royal jelly, we see only 60% growth inhibition for both bacterial strains. It is not MIC - you can call it LC50 (lethal dose to reduce at least 50% growth). MIC is when there is zero or 1-2% growth only. Answer: We agree with the reviewer's comments regarding the MIC score. In clinical isolates, 25% royal jelly extract caused 60% death in the bacterial population; meanwhile, in the standard strain (P. aeruginosa ATCC 10145), this concentration caused growth inhibition of 85%. We have revised the first sentence in Methods of Abstract and two last sentences in the Results section."
},
{
"c_id": "6787",
"date": "09 Jul 2021",
"name": "Heni Susilowati",
"role": "Author Response",
"response": "We thank you for the thorough and careful review of our manuscript. The following are our responses to the suggestions and specific comments. The response to comment 1 (quantification of pyocyanin) We measured the concentration of pyocyanin contained in the culture supernatant of P. aeruginosa. This condition is in accordance with the previous research conducted by Price-Whelan et al. (2007). Indeed, we only measured the absorbance value of the supernatant filtrate of the bacterial culture at a wavelength of 690 nm, but the pyocyanin concentration was then known by calculations using a formula published by previous researchers (Price-Whelan et al, 2007). The constant value of 4310 M -1cm -1 for the absorbance at 690 nm has been determined based on the research of Dietrich et al. 2006. Since our experimental conditions match the experimental conditions in both studies, both of which are published in outstanding journals, we feel it is sufficient to refer to their methods. The response to comment 2 (Biofilm [Crystal violet for biomass quantification] study) We have conducted additional experiments to detect the association between pyocyanin production in bacteria exposed to royal jelly and biofilm formation using the static microtiter plate biofilm assay (crystal violet staining) method. To analyze the relationship between pyocyanin production and biofilm mass production, we have used P. aeruginosa ATCC 10145 as this strain is more responsive in producing pyocyanin when compared to the clinical isolate strains we previously use. The results showed that the detectable biofilm mass significantly increased in bacterial cultures exposed to 12.5% royal jelly extract. Meanwhile, cultures treated with 25% royal jelly did not show any biofilm formation. The 6.25% royal jelly extract and the lower concentrations induced biofilm mass formation but at a lower quantity than 12.5% royal jelly. This evidence suggests a relationship between royal jelly concentration, pyocyanin production, and biofilm mass formation. The subinhibitory concentration (12.5%, 6.23%) of the royal jelly extract induced more pyocyanin production and biofilm mass formation rather than the higher concentrations. Related changes were in the Methods, Results, and Conclusion of the Abstract, paragraph 6 of the Methods, paragraph 5 of Results, Figure 4, and line 5 of paragraph 6 on the Discussion section in the manuscript. The response to comment 3 (microscopy of biofilm architecture) In order to complement the data regarding the effect of royal jelly on the mass formation of biofilms, we have carried out observations of the microscopic architecture of P. aeruginosa ATCC 10145 biofilms using scanning electron microscopy, since we could not access the confocal microscopy method at our university. We chose secondary electron (SE) mode rather than a backscattered electron (BSE) to investigate biofilm in a three-dimensional perspective. The results of observations on representative samples showed that in the culture exposed to 25% royal jelly extract there was no biofilm mass deposition, while the group exposed to 12.5% royal jelly showed a larger density of biofilm than the 6.25% royal jelly group. Chlorhexidine 0.2% control showed total inhibition of biofilm mass formation. Methods, results, discussion, and related references have been added to the manuscript on Methods, Results, and Conclusion in the Abstract, paragraph 7 of the Methods section, paragraph 6-7 of the Results section, and line 5 in paragraph 6 of the Discussion section. Specific comments a. Why solubilized royal jelly is centrifuged and supernatant is only taken? Answer: The extraction method using phosphate buffer saline (Hu et al, 2019) was chosen in order to dissolve major royal jelly protein 1 (MRJP1), the active components that are antibacterial or anti-adhesion. It is known that MRJP1 is a hydrosoluble protein dissolved in PBS, which is higher in supernatants than in pellets (Gismondi et al., 2017). What happens with pellets (are there any pellets found after centrifugation?). If yes - then how can we know that supernatant has all royal jelly? Answer: After centrifugation, there were indeed pellets, and it has been found that the pellets contain more liposoluble proteins than supernatants. To ensure that the compounds contained in the PBS royal jelly extract supernatant, further research is needed; However, from the research of Furusawa et al. (2016), it was found that MRJP1 was contained in the supernatant of PBS royal jelly extract in quite a large amount, reaching 27.6%. The active components that are antibacterial or anti-adhesion in the supernatant of royal jelly extract in this study cannot be explained with certainty, but the royal jelly used in this study was thought to mainly contain MRJP1. We add this explanation to paragraph 2 of the Discussion section. Additional sources of literature have been written in the reference list numbers 37, 38, and 39. b. At 25% royal jelly, we see only 60% growth inhibition for both bacterial strains. It is not MIC - you can call it LC50 (lethal dose to reduce at least 50% growth). MIC is when there is zero or 1-2% growth only. Answer: We agree with the reviewer's comments regarding the MIC score. In clinical isolates, 25% royal jelly extract caused 60% death in the bacterial population; meanwhile, in the standard strain (P. aeruginosa ATCC 10145), this concentration caused growth inhibition of 85%. We have revised the first sentence in Methods of Abstract and two last sentences in the Results section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-14
|
https://f1000research.com/articles/10-1253/v1
|
07 Dec 21
|
{
"type": "Research Article",
"title": "An informational sociobiological explanation of the constitution of the human body",
"authors": [
"Jeel Moya-Salazar",
"Libertad Contreras-Pulache",
"Nelly Lam-Figueroa",
"Hans Contreras-Pulache",
"Libertad Contreras-Pulache",
"Nelly Lam-Figueroa"
],
"abstract": "Background: Pedro Ortiz (1933-2011), in the latest four decades of his life, developed the Informational Sociobiological Theory (IST) in a university teaching context that became the foundation of post-grade studies in neuroscience in Peru. The IST looks for a totality explanation of the phenomena of the universe proposes an explanation of the constitution of the human body. In what consist this explanation of the configuration of the human body? Methods: A bibliographical qualitative study was conducted starting from primary documental sources. It was considered among the sources, all related to the editorial project Books of Social Psychobiologic (elaborated by Ortiz during the first decade of this age). The results have been presented across a conceptual analysis, narrative and graphic, oriented to expose Ortiz’ ideas in relation to the human body’s morphology. Results: The structural architecture of the human body, and in particular in one person; shows five levels of complexity which begins in cells, the intercellular matrix, the neural system, the paleocortical psyche, and neocortical psyche. In this involve explanation, the organs of the body are essentially tissue systems, and are integrated (subsumed) at the neural level (which informationally goes through the plexuses, ganglia, and subcortical nuclei). The two levels of superior complexity to the neural system, are the space of the psychic activity, unconscious and conscious, which is suprastructurally to all bodily structures. Ortiz is settled on a different monism: that guides us to imagine and think that all psychic activity is suprastructural to the body. Conclusions: There is an original explanation of the human body within the IST. This informational morphology dialogues with the knowledge of biology, neurology, anatomy, physiology, embryology, and histology, and is proposed as a structuring element in all the conceptual architecture that represents the IST.",
"keywords": [
"Information",
"Theory",
"Peru",
"Neocortex",
"Paleocortex",
"neuroscience."
],
"content": "Introduction\n\nWhen Pedro Ortiz Cabanillas (1933-2011), in the early 1960s at the Universidad Nacional Mayor de San Marcos (UNMSM), began to plant the seeds that five decades later he called “Informational Sociobiology Theory” (IST), he did it from the position of a physician, specialized in the human nervous system, interested in having a total explanation of the universe.1,2 This huge pretension parents the IST with a sort of “philosophy of nature”, or a “scientific macro-theory”. Then, the formulations of the IST constitute a kind of philosophical and programmatic matrix from which different scientific explanations can germinate. In this work, we are going to focus on the IST’s explanations about the constitution of the human body, and consider this question: How does IST explain the constitution of the human body?\n\nFollowing a biographical route, we know that by late 1993 and early 1994, Ortiz conceived an informational systematic approach. From the development of his own definition of “information”, Ortiz elaborated an epistemic framework that coherently explained the entire extension of nature: the universe (the cosmos), on one side, the planet Earth, and in it, on the other side, living beings (informational systems). Living beings are material systems organized by information.3 On this road, Ortiz proposed a new qualitative definition of “information” which served as basis for the IST since 1994.4\n\nIn IST, the information is an attribute of the matter (not a part of the human communication); and information is a material structure that organizes all the living beings.5,6 In the middle of 1990s, this definition of information crowned almost four decades of clinical experience, academic exploration and teaching. Additionally, a systematic research program (called IST) was opened, which Ortiz conducted between 1994 and 2011. For an organic and critical oncoming of the IST’s approaches, Ortiz implemented at the beginning of this century the neuroscience postgraduate program in Peru (whether at a diplomate, master and doctorate level) at the UNMSM, which, after almost two decades, is currently the only postgraduate program in neuroscience that is valid in Peru.7\n\nAs a part of this research program, Ortiz published the following books: “The system of personality” (1994), where he exposes a basic and schematical totality of the IST; “Introduction to Clinical Medicine 1” (1996); in this book, he exposes the synthesis and the method to realize a general medical exam; “The development of the personality” (1997), where he sketches out the first links between the IST and education; “The conscious level of the memory” (1998), where Ortiz explains a hypothesis regarding the role of the memory as an attribute of the life; “Introduction to Clinical Medicine 3” (1999), explanations and sustentations to realize an integral neurological exam; “Language and Self-expression” (2002); developing the sociobiological explanation of the language and the vision of the brain as a semiotic system; “Book 1 of Socio Psychobiological” (2004), also called “Introduction to a Human Psychobiology”; “Book 6 of Socio Psychobiological” (2004), called “the Conscious level of the Self-activity”; “Introduction to Clinical Medicine 2” (2006), where Ortiz exposes the sustentations and the method to realize an integral psychological exam; “Social Ethics” (2007), exposition of the proximity of the IST to explain the freedom, justice and solidarity; “Education and development of personality” (2008), where he elaborates on an education-focused proposal”; second edition of “Introduction to Clinical Medicine 2” (2009); second edition of “Book 1 of Socio Psychobiological” (2010); and, finally, a collection of papers written between 1984 and 2011 called “The Informational Explanation” (2011).3,8–21\n\nOrtiz wrote three books about clinical methods titled: “Introduction to Clinical Medicine”, volumes 1, 3, and 2 (following the order of publication): “The Essential Clinical Examination”; “The Integral Neurological Examination”; “The Integral Psychological Examination”. The first one gives guidelines on conducting the clinical medical exam (Ortiz 1996), the second one applies to the realization of the psychological exam (Ortiz 2006, 2009), and the third one focuses on the integral neurological exam (Ortiz 1999).8,10,14,17\n\nThis shows that the exploration of the human body has always been one of Ortiz’s main interests. In all these documents, the traditional procedures for exploring the human body are fully redefined, especially in the exploration of neuropsychological aspects.\n\nThe effort that Ortiz made to enter into the territory of psychology and neurology is astonishing, creating his own definitions for concepts that are used traditionally such as: consciousness, attention, anxiety, personality, intelligence, temperament, cognitive, affective, volitional, motivation, conduct, unconsciousness, etc.\n\nFor example, he does not refer to the “mind” in any moment (the word “mind”, in plain, does not exist in a sociobiological informational dictionary). Ortiz explored the limits of an explanation of the human body’s constitution in the editorial project “Books of Social Psychology” (BSP). Ortiz started the BSP in the late 1990s as a part of a collection of materials for teaching purposes, but developed them through the first decade of the 21st century. In the BSP, Ortiz proposed applying the IST to understand the complex configuration of the human body. This is what Ortiz called “informational sociobiology”.22 The BSP were written for working critically in the classes that Ortiz gave (for example, in the postgraduate neurosciences program at the UNMSM the courses have the same titles as the BSP).\n\nThey are not a summary manual like a monograph or narrative review of prior knowledge; the originality of the BSP is that they represent the work in progress where Ortiz developed his own conception in terms of cellular biology, histology, embryology, anatomy, physiology, neurology, psychology, and sociology (but in an original, particular, and different form: the IST). Initially there were three BSP, but after more than ten years of work, and at the end of the first decade of the 21st century, Ortiz structured them into seven books. In his lifetime, Ortiz published just Book 1 and Book 6 (both in 2004, and a second edition of the first one in 2010).12,13 After his death, Books 2, 3, 4, 5 and 7 remained unfinished and unpublished. Working versions of all the BSP were published, posthumously, in 2017.23–25 We aimed to review the totality of these seven BSP and to explore how, sociobiological informationally, the constitution of the human body is explained.\n\n\nMethods\n\nThis is a qualitative and hermeneutic study, with a focus on the informational sociobiological theory, that takes as an epistemic mark all the concepts exposed in the BSP and explicitly highlights those explanations relating to the constitution of the human body.\n\nIn Peru, since 1961, Pedro Ortiz Cabanillas developed an academic trajectory, a life dedicated, entirely and integrally, to the teaching, research and systematic development of his IST, a denomination that was assumed by himself in the end of his life. Pedro Ortiz died in 2011.\n\nAfter his death, all of his academic documents (published books and papers, and documents not published) and the hard disc of his personal computer were included as part of the “Pedro Ortiz-Archive” (PO-A). This archive includes physical documents (handwritten, typewritten, or computer printed), produced between 1940 and 2011, and digital documents (presentations and text documents), most of them produced after 2000. The PO-A also includes a series of scattered papers, notes, carts, work notes, study files, drafts, and other academic materials. In 2012, one of the authors (HCP) founded the “Centro de Documentación e Investigación Pedro Ortiz Cabanillas” (CDI-POC). The PO-A is under the care and administration of CDI-POC in Lima, Peru. After almost a decade of work there are some tangible results such as:\n\ni. The posthumous publication of more than 10 unedited books: “The scientific explanation of the human” (Ortiz, 2013); the second edition of “The system of the personality” with series of documentary annexes (Ortiz, 2016), the seven constituent books of the BSP (Ortiz, 2017, Socio Psychobiological 3 tomes); “Language and Self-expression” (second edition, 2019) and “The conscious level of the memory” (second edition, 2019), “The current problems of education and neuroscience” (Ortiz, 2019), and “Clinical Neuroscience” (Ortiz, 2019).22–30\n\nii. The compilation of his short-dispersed oeuvre written between 1984 and 2011 called “Informational explanation” (10 articles in 2011; 49 in the second edition in 2019)19,31; iii. the publication of one biography32; and iv. the digital opening of the PO-A, together with the support of the UNMSM, through a website planned to be completed in 2025, the digitization of the entire academic works of Pedro Ortiz Cabanillas.\n\nShortly after its opening, the CDI-POC started developing a research program explicitly oriented around the IST. This academic production has explored, in abundance, the cinema phenomena from an informational interpretation.33–36 Additionally, there has been realized a series of argumentative revisions in favor of: i. acknowledging the value of Ortiz’s academic oeuvre4; ii. revealing the presence of Ortiz in the framework of the history of Peruvian neurology7; iii. establishing the dialogue between the IST and the “unsolved problems of neuroscience”37; iv. updating the IST in light of studies in computational neuroscience and neuroimaging38; v. applying the model of the nervous system of the IST to explain the behavior of a character in a contemporary literary work39; and vi. what we want in this research, describing the informational sociobiological explanation of the constitution of the human body.\n\nRecently, the CDI-POC has established, in union with Research Group in Applied Neurosciences “Neuron” (of the Medicine faculty of UNMSM), a space of digital teaching, called “Informational Sociobiological Studies Seminary”. The purpose of this Seminary is to promote the systematic reading of Ortiz’s oeuvres, preparing all those interested in deepening the line of thought that Ortiz devised and designed. The inaugural edition of the Seminary took five months (January to May 2021) and included an entire reading of Book 1 of Social Psychology “Introduction to a Psychobiology of Man”, published by Ortiz in 2010 (on the cusp of his intellectual development), and the entire material of the sessions is duly digitized on YouTube.\n\nIn relation to the reading approach (the theory approach), which this research follows according to the Ortiz oeuvres, it is important to note that there are two approaches developed to explain this phenomenon. The first was developed in 1995, as a commentary to “The system of personality” (1994), the first book of Ortiz.3 In this document, Maria Luisa Rivara de Tuesta affirms that, while Ortiz develops his theory, he is constantly playing the role of an “existential phenomenologist philosopher”; in particular, this commentary links Ortiz’s explanation of the human body and the approximation to the same phenomenon (the nature of the body) by the notion expounded by the French philosopher Maurice Merleau-Ponty.\n\nThe second approach was proposed by Diego Llontop (considering the Ortiz oeuvres: “The system of personality”, 1994; “Development of personality”, 1997; “The conscious level of the memory” 1998; “Language and self-expression”, 2002; and the Book 1 of Social Psychology “Introduction to a Psychobiology of a Man”, 2004), under a tripartite approach: Hegel (thesis), Mark (antithesis) and Ortiz (synthesis), where Llontop highlighted the material and universal conditions that are expressed in the IST.3,5,9,11,12\n\nThus, Ortiz is characterized by these two conceptual approaches: as a phenomenologist on one side and as a dialethic materialist on the other side. In both, it is evident that Ortiz formulates the human body explanation’s (in the middles of different concepts) without any theory nor idea about dualism (for example: mind-brain, soul-body, psychology-neurology, sociology-psychology, etc.).\n\nThe difference between these two approaches and this research is that we propose a new interpretation. Our approach is founded on a theoretical position that is not looking to put Ortiz in the traditional role of a philosopher, but that tries to use a more philosophical approach to interpret his works (based on the documentation and research of his academic oeuvres). We call this method “informational sociobiological hermeneutics”. This proposal is supported thanks to editorial, research and teaching works that have been taken place over the course of a decade.\n\nFor the conceptual framework, we have considered the seven published “Books of Social Psychobiology”. There are the following versions of the Books (with the year that Ortiz last worked on the book): Book 1 (2004, 2010), Book 2 (2009), Book 3 (2009), Book 4 (2010), Book 5 (2009), Book 6 (2010) and Book 7 (2006).12,13,23–25 In addition, the authors consulted all the PO-A’s digitals documents of the editorial project “Books of Social Psychobiology” (the Books). All the materials related to the editorial project have been checked, in order to verify that there does not exist other Book versions that haven’t been considered previously. Once the Books have been selected, we conducted a slow and careful reading of them in order to delimit the concepts of the theory in general and then establish the integration of them into one interpretive matrix (or total conceptual model). This integration of the theories that Ortiz proposes in the BSP have been carried out following the general interpretative scheme of the IST that Ortiz summarized, in his academic testament, by the form of “five fundamental laws”22:\n\n1. The universe is ordered in a matter of reflection processes, both entropic or decomposition (whereby it tends to a lesser order) as negentropic or composition (whereby it tends to higher order).\n\n2. The living beings constitute a material system not just organized, but organized based on various kinds of information.\n\n3. The society is the only living supra-individual system that has been organized based on an extra-individual information class that is social by nature.\n\n4. The men are the only living beings that must incorporate this kind of information that organizes the society where they are born and develop, to form their conscious.\n\n5. The conscious activity determines the transformation of the human individuals to social individuals, i.e., in personalities.\n\nThe total concept model that is displayed in Figure 1, presents concepts mentioned more frequently in the BSP as bigger than those mentioned less frequently. The blue lines that attach concepts serve to establish the narrative mechanisms that are used within the informational sociobiological explanation. Once the model is established (the informational sociobiological interpretive matrix), we chose only the concepts that make reference to the constitution of the human body, such as at the cellular level, the organs, the systems, the human nervous system, the morphophysiology of the human body, in general, and in particular, the morphophysiology of the brain. The concepts not chosen (because they don’t explicitly work in the human body’s constitution) were: the organization of matter, the nature of universe, the philosophical aspects of information, the history of neurosciences, the explanation of living beings (from bacteria to psychism), the evolution of hominids, the birth of humanity, the history of society (from its archaic, ancient and modern periods), the aspects of personal development, the conscious psychic information, the memory, the speech and the language, and some specific psychological aspects. In this way, in this revision are included concepts that have a relationship with the description of the structural activity (constitution) of a person (in line with the scope that the histological, anatomical and physiological examination could offer). In the total concept model shown in Figure 1, we have highlighted in red the concepts that are included in this present research.\n\nThe narrative revision is presented like an informational sociobiological explanation, based on the concepts of the IST. In addition, there are some schematic figures (graphics) that make visually explicit the dynamic flow of the interaction of the concepts in the delimited epistemic framework. Both the narrative revision and the schematic graphics have been realized with the vision to clarify, with a pedagogic affaire, keeping in mind an uninitiated reader in the statements of the IST.\n\n\nResults\n\nThe original names of the Books have denoted, since the beginning, a programmatic claim. Thereby, the titles: “Introduction to a Human’s Social Psychobiology” (Book 1), “The Cell Level of the Personal Activity” (Book 2), “The Tissue Level of the Personal Activity” (Book 3), “The Neural Level of the Personal Activity” (Book 4), “The Unconscious Psychic Level of the Personal Activity” (Book 5), “The Conscious Psychic Level of the Personal Activity” (Book 6), and “Develop of the Personal Psychic Activity” (Book 7).23–25 In the PO-A, it is found that there are three files in which Ortiz managed his documents related with the Books. These three files, or dispositions, are organized differently, as seen in Figure 2. Disposition 1 and Disposition 2 contain texts documents (and different versions of the Books). Disposition 3 contains images, photographs and conceptual schemes that Ortiz drew up by himself; in the files of Disposition 3, there are no text documents, all the content is essentially images. Beyond the differences between these three dispositions presented, one fact is true: it is possible that, according to Ortiz, there were twelve Books in total. In that case, in addition to the seven Books mentioned above, there would have been: Book 8: “PBS Talk”; Book 9: “PBS Memory”; Book 10: “PBS Clinical Neuroscience”; Book 11: “PBS Education”; and, Book 12: “PBS Ethic” (the names in quotation marks are the names that Ortiz himself gave them, and “PBS” was the acronym that Ortiz used to designate “Social Psychobiology”).\n\nTo start, Ortiz defined the society in systematic and informational terms, not like the integration of people but like a supra-individual structure (and material) that involves the people since before their birth. This societal system that involves people is established by all the people that have been creating and accumulating along its history. In this sense, the historical development of society started 70,000 years ago, the moment that the hominization (the course since the hominid to human) progressed to socialization (the passing of the human to person, it means: social being).\n\nIn line with all the Books, it is argued that there exists just one society and that the only living beings that are “social” are those that have grown and developed in “society” (or alternatively, because the only one who has a society is one which involves him). From this interpretative paradigm, one is not social because one lives in a group, but because one lives in society. The living beings (the bees, the ants, the elephants, and others) constitute “multi-individual” groupings; they are not social, because social is being in society, and society is “supra-individual”. This society and the persons that are involved constitute a single amalgam that is, at the end, a new form of life (the latest and most complete form of developed life on earth, as a part, or region, of the universe). With this understanding, from the beginning, it’s clear the intention of the Books is to position an explanation that integrates universe, earth, life, society and people. This can be seen in Figure 3, where the configuration of the human body results in a system of five levels of complexity; not linear but enveloping, where each system that emerges subsumes the preceding levels (the tissue organizational level subsumes the cellular organizational level; the neural organizational level subsumes the tissue organizational level; the unconscious psychic level subsumes the neural organizational level; and finally, the conscious psychic level subsumes the unconscious level). In this way, the human body is energized by determinations that go from the simple to the complex (which in the Books is called epigenetic determination) and from the complex to the simple (which in the Books is called kinetic determination).\n\nSpeaking and moving, for example, are the result of kinetic manifestations, while smelling and looking put in motion a series of epigenetic processes. Every person, as complex architecture, is enveloped by society (which is a part of the material universe) and that is the base of the highest level of complexity. This means that the level of the conscious psychic organization (neocortical, or simply: consciousness) is not conditio sine qua non but conditio per quam of the existence of the society (that, informationally, is the most complex living system ever established on earth).\n\nFor the Books, each level of organization of life (cellular, tissue, neural, unconscious psychic and conscious psychic) corresponds to a type of information. For the level of cellular organization is the genetic information (also known as DNA); for the tissue level, the metabolic information (the extracellular matrix); for the neural level, the neural information (the subcortical nerve networks, that are: the reticular networks, -the plexuses-, ganglion networks -the autonomic nervous system-, and nuclear networks -the medulla and the subcortical brain-); for the unconscious psychic level, the information is the paleocortex (that, specifically, is defined as the paralimbic cortex and the heterotypic cerebral cortex); and for the conscious psychic level, the information is the neocortex (that, specifically, is defined as the association cerebral cortex: anterior temporal, orbitofrontal, parietotemporal-occipital, medial prefrontal and dorsolateral prefrontal). Note that an essential feature in the proposal of the Books is that at no moment does it make reference to the information as a message or content that is processed in the brain, but rather that the information is the brain (as long as material structure). On the other hand, the paleocortex and neocortex definitions are specific and original to the Book’s proposal. As seen in Figure 4, the organic systems of the human body can be divided into two systems, the visceral systems and the somatic systems. Within the visceral systems are the endocrine, digestive, respiratory, cardiovascular, urinary and reproductive systems; while within the somatic systems are the immune, muscular skeletal, osteoarticular, fascial and dermal systems. These organic systems, at most, manage to reach two levels of complexity (cellular and tissue) and are shrouded, subsumed, for the neural organization level (in its visceral and somatic divisions, respectively). The visceral neural system includes the ganglion of the autonomic nervous system, and to a series of subcortical nuclei grouped in the spinal cord and subcortical brain, especially located in the medial regions (for example: medial nuclei of the thalamus, nuclei of the hypothalamus, and tonsil nuclei, among others), while the somatic neural system includes essentially nuclei in the spinal cord and subcortical brain, specially located in the lateral regions (for example: lateral nuclei of the thalamus and nuclei of the base, among others). The nuclei of the visceral neural system constitute the “visceral neural axis” (and, in effect, there would be two axes, left and right) while the nuclei of the somatic neural system constitute the “somatic neural axis” (also two axes, left and right).\n\nAs one knows from any text in neuroanatomy, the neural axes cross from one side to the other side of the body, integrating both hemi bodies into a single synthetic reality (this cross of the neural axes is not shown in Figure 4, but is important nonetheless). In the same way, when Ortiz says “conscious” (neocortical) and “unconscious” (paleocortical), these terms have been understood within the same informational explanation that is presented in the Books and not with the view of traditional definitions that have long been established in psychology, neurology or psychiatry. For Ortiz, the IST, and in the Books in particular, the conscious is not the capacity of the people to realize something, and the unconscious is not the Freudian unconscious, but rather it is all much simpler: the unconscious is the paleocortex, and conscious is the neocortex.\n\nFinally, and as Figure 5 exposes, the IST can explain the configuration of human body, and its morphology, as seen from these two perspectives. From the outside to the inside (lower section of Figure 4), it means: if one as an observer is located in the universe and in society and goes to the human body from the cellular, tissue, neural, unconscious and conscious levels (epigenetically, knowing that each level of complexity kinetically determines the preceding levels). In this perspective, as demonstrated in the lower section of Figure 5, the maximum level of the human body complexity (neocortex) is found in the “innermost” circle of the human body. However, as the upper section of Figure 5 demonstrates, if an observer is located at the interior of himself, from this perspective, the previous “innermost” is not entirely exact, so there is not an “inside place”. Instead, the maximum level of complexity of the human body (neocortex) does, in reality, involve all the preceding levels of complexity. In this sense, the conscious activity would be an emergent and enveloping activated structure to all concrete reality of the human body. In simple words: our thoughts, our feelings, all our memories (when we remember them) are not in the brain but in all the constitution of the human body. Like that, the morphology that the Books propose is not the sum of different parts of corporeality, but the integration of these different parts into an enveloping system of complexity, determined from the bottom up (epigenetically) and from top down (kinetically) at five levels of structured organization (genetic, tissue, neural, psychic and social information).\n\n\nDiscussion\n\nIn light of these results, it’s clear that the academic effort of Pedro Ortiz Cabanillas in creating the IST includes an original explanation of the human body constitution. Depending on this explanation, the human body is constituted as a concatenation of envelope systems, that go from the cells (first level of complexity) to the neocortical brain (fifth level of complexity), and is organized from an epigenetic determination (from cells to neocortex) and from a kinetic determination (from neocortex to cells).\n\nTraditionally, the constitution of the human body is explained as follows: the cells are grouped in tissues, tissues grouped in organs, and organs grouped in systems; and within the systems, there is the nervous system which involves, by definition, all the rest of organs and systems.40–43 In this way (which is not fully explained), all the systems of the body are integrated in just one individual; and therefore to this individual there are properties and characteristics that are not applicable to their parts. This supposes that the nervous system is behind the integration of all corporal systems that constitutes a single human individual, but it is unclear how this nervous system reaches such an amazing feat. In addition, the neocortex is generally described, in the traditional sciences, as referring to almost the entire human cerebral cortex.44,45 In contrast, the IST is positioned as an alternative explanation. In the IST, for example, the neocortex makes explicit reference to brain areas of association; similarly, the heterotopic cortex can be considered a neocortex for the traditional vision but not for the informational explanation developed by Ortiz (that instead defines it as paleocortex).\n\nOrtiz’s explanation allows us to consider what science poses as the human body, weighting all the scientific explanations with the purpose of avoiding scientific excesses or, worse, positions and hypotheses with no evidence. This can play an important role in the current morphology discussion about what is the better evidence to help understand the human body.46,47 Perhaps one of the most subtle aspects, potentially applicable to the informational explanation, is its consideration as a matrix that interprets or explains, in other forms, the actual scientific knowledge. For example, it recognizes that cadaver dissection plays an important role in the training of a doctor,48–51 hence in a complementary way we can note that the informational explanation of the human body reinforces the passage from comprehension of the corpse to the living human being (patient), above all the neuropsychological limits. This complementary nature of the informational morphology with the traditional morphology would redound to the students’ understandings, especially in contexts of the search for effective pedagogies that integrate the ways of teaching52 and the contents, i.e., the conceptual architecture.\n\nRegarding the suggestions that these Books could be twelve, and not seven, it remains pending the detail and clarification according to the purposes followed by those who enter into informational studies. Ten years after his death, Pedro Ortiz’s ideas begin to germinate, expanding horizons and perspectives.\n\nThe limitations of this research can be grouped into:\n\ni. Methodological, by the nature of the qualitative approach (without precedents in the study of Ortiz’s oeuvre), and informational sociobiological hermeneutical (an original method that is proposed, for the first time, in this work); so, this research does not have a pre-existing specific background that explores its topic of interest. Clearly, this is one of the aspects more urgent in the development of the informationals sociobiological studies: to create a critical mass of knowledge, dialogist and opening, that allows discussions about the directions of developing of the IST.53\n\nii. At time of writing, Ortiz’s oeuvre is only known by a small academic group; this is as limiting as it is an opportunity, as the evidence of the birth of a different conceptual paradigm requires additional research and testing, so this provides future researchers a direction but has little research thus far.\n\niii. One of our main limitations was the selection of concepts and the organization of them to capture the place that our research topic inhabits in the IST. Figure 1 shows a method to understand the IST and its total comprehension of the phenomena that has been helpful for the conceptual mapping of the structure of the human body.\n\n\nConclusions\n\nWe demonstrate that the IST, developed by Pedro Ortiz, is a feasible theory to use when talking about an original and alternative way to explain the organization and constitution of the human body; an “informational morphology” which creates dialogue between the knowledges of the biology, neurology, anatomy, physiology, embryology, histology, and others. This “own conception” of the configuration of the human body is entirely dependent of the knowledges of the IST, and his comprehension makes sense only within the IST. This means that the informational morphology cannot be explained except throughout the definitions and concepts of the IST. Ortiz dedicated more than the last decade of his life to writing the Books, and shows the radical structuring importance of the “informational explanation of the human body” within the framework of the architecture of thought that is the IST. In synthesis: there is an original explanation of the constitution of the human body, and the Informational Sociobiological Theory makes it intelligible (that is, seen with logos and not with eyes).\n\n\nData availability\n\nThe Books considered in the theorical framework are duly published by the editorial funds of the Universidad de Ciencias y Humanidades and the Universidad Nacional Mayor de San Marcos in Peru. They are currently available only in their original language (Spanish), and can be found in the references. The global presentation of the IST to the non-Spanish reader is one of the pending commands that should be resolved in the present decade. All of Ortiz’s remaining materials are part of the PO-A, and they are carefully overseen by the CDI-POC. To access all this documentary heritage for research purposes, you can submit a request through www.pedroortizcabanillas.com.",
"appendix": "References\n\nLa Teoría OP: Sociobiológica de Pedro Ortiz. Ortiz P. El Sistema de la Personalidad. Contreras-Pulache H, editor. Lima: Fondo editorial de la Universidad de Ciencias y Humanidades; 2da edición. 2016; pp. 389–396.\n\nContreras-Pulache H, Moya-Salazar J: In Memoriam: Pedro Ortiz Cabanillas (1933-2011). Pan J Neurop. 2019; 13(2): 187–188.\n\nOrtiz P: El Sistema de la Personalidad. Lima: Orión. 1994.\n\nContreras-Pulache H, Espinoza-Lecca E, Sevillano-Jimenez J: Apuntes sobre la evolución histórica de la obra de Pedro Ortiz Cabanillas y su Teoría Sociobiológica Informacional. Rev. Peru. Med. Exp. Salud Publica. 2018; 35(4): 699–706. PubMed Abstract | Publisher Full Text\n\nOrtiz P: La formación de la personalidad. Apuntes de interés pedagógico. Lima: Dimaso Editores; 1997.\n\nOrtiz P: El nivel consciente de la memoria: Una hipótesis de trabajo. Lima: Fondo Editorial de la Universidad de Lima; 1998.\n\nContreras-Pulache H, Espinoza-Lecca E, Moya-Salazar J: Aproximación biográfica a Pedro Ortiz Cabanillas (1933-2011) y su Teoría Sociobiológica Informacional en el contexto de la neurología científica peruana. Int. J. Morphol. 2019; 37(4): 1316–1324. Publisher Full Text\n\nOrtiz P: Introducción a la Medicina Clínica. Volumen 1. El examen clínico esencial. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 1996.\n\nOrtiz P: El nivel consciente de la memoria. Una hipótesis de trabajo. Lima: Fondo Editorial de la Universidad de Lima; 1998.\n\nOrtiz P: Introducción a la Medicina Clínica. Volumen 3. El examen neurológico integral. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 1999.\n\nOrtiz P: Lenguaje y habla personal. El cerebro humano como sistema semiótico. Lima: Fondo Editorial Universidad Nacional Mayor de San Marcos; 2002.\n\nOrtiz P: Cuadernos de Psicobiología Social 1. Introducción a una Psicobiologíca del Hombre. Lima: Fondo Editorial Universidad Nacional Mayor de San Marcos; 2004.\n\nOrtiz P: Cuadernos de Psicobiología Social 6. El nivel consciente de la actividad personal. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 2004.\n\nOrtiz P: Introducción a la Medicina Clínica. Volumen 2. El examen psicológico integral. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 2006.\n\nOrtiz P: Ética social. Para el desarrollo moral de las instituciones educacionales y de salud. Lima: Fondo Editorial de la de la Universidad Nacional Mayor de San Marco; 2007.\n\nOrtiz P: Educación y formación de la personalidad. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2008.\n\nOrtiz P: Introducción a la Medicina Clínica 2. El examen psicológico integral. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 2ed.2009.\n\nOrtiz P: Cuadernos de Psicobiología Social 1. Introducción a una Psicobiologíca del Hombre. Lima: Fondo Editorial Universidad Nacional Mayor de San Marcos; 2th2010.\n\nOrtiz P: La explicación Informacional (tomo 1). Lima (PE): Centro de Investigación Anastomosis; 1ed.2011.\n\nOrtiz P: La explicación Informacional (tomo 2). Lima (PE): Centro de Investigación Anastomosis; 1ed.2011.\n\nOrtiz P: La explicación Informacional (tomo 3). Lima (PE): Centro de Investigación Anastomosis; 1ed.2011.\n\nOrtiz P: El Sistema de la Personalidad. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2ª2016.\n\nOrtiz P: Psicobiología Social (tomo 1). Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 1ed.2017.\n\nOrtiz P: Psicobiología Social (tomo 2). Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 1ed.2017.\n\nOrtiz P: Psicobiología Social (tomo 3). Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 1ed.2017.\n\nOrtiz P: La explicación científica del Hombre. Lima: Fondo Editorial Lumbreras; 1st2013.\n\nOrtiz P: Lenguaje y Habla Personal. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2ª2019.\n\nOrtiz P: El Nivel Consciente de la Memoria. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2ª2019.\n\nOrtiz P: Los Problemas Actuales de la Educación y la Neurociencia. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2ª2019.\n\nOrtiz P: Neurociencia Clínica. Lima: Fondo Editorial de la Universidad Nacional Mayor de San Marcos; 1ª2019.\n\nOrtiz P: La explicación Informacional (libro-cd). Lima: Centro de Documentación e Investigación Pedro Ortiz Cabanillas; 2ed.2019.\n\nContreras PH: Festina Lente. Presencia de Pedro Ortiz Cabanillas. Lima: Fondo Editorial de la Universidad de Ciencias y Humanidades; 2021.\n\nContreras-Pulache H, Joya AIQ, Moya-Maldonado DS, et al.: An informational interpretation of the Aveyron’s wild child: L'enfant sauvage (1970). J. Med. Mov. 2019; 13(4): 221–230.\n\nContreras-Pulache H, Gomez-Saenz L, Soriano-Abal A, et al.: Coco (2019): An informational approach on life after death. J. Med. Mov. 2020; 16(3): 175–183.\n\nMoya-Salazar J, Cañari B, Gomez-Saenz L, et al.: Film Therapeutics: a possibility of assistance. J. Med. Mov. 2021; 17(2): 139–148.\n\nMoya-Salazar J, Contreras-Pulache H, Cañari B: An informational neurobiological explanation purposes of the poetry of notes on blindness (2016). J. Med. Mov. 2021; 17(3): 63–71.\n\nContreras-Pulache H, Hernandez-Yepez P, Chicoma-Flores KJ: The neuroscience of the future: What do we want?. eNeurobiologia. 2020; 11(27).\n\nContreras-Pulache H: Repetir Neurociencia. Revista Vuela Pluma. 2020; 9.\n\nContreras-Pulache H, Moya-Salazar J: Para hablar con el hocico: el experimento mental de John Berger. Pan. J. Neurops. 2019; 13(2): 182–185.\n\nDrake R, Vogl AW, Mitchell AWM: Gray's Anatomy for Students: With Student Consult Online Access. Amsterdam: Elsevier; 4th2019.\n\nNetter FR: Atlas of human anatomy. Amsterdam: Elsevier; 7th2019.\n\nRouvière H, Delmas V, Delmas A: Anatomía Humana Descriptiva, topográfica y funcional. Tomo 1. Cabeza y cuello. Paris: Elsevier Masson; 11th2005.\n\nTestut L: Tratado de Anatomía Humana. Barcelona: Salvat; 34th1981.\n\nMarín-Padilla M: Evolución de la estructura de la neocorteza del mamífero: nueva teoría citoarquitectónica. Rev. Neurol. 2011; 33(9): 843–853. Publisher Full Text\n\nPimienta HJ: La corteza cerebral más allá de la corteza. Rev. Col. Psiq. 2004; 33(1): S58–S75. 2004.\n\nSuazo GI, Manterola DC: What is Published in Human Morphology? Types of Designs and Levels of Evidence. Int. J. Morphol. 2010; 28(2): 461–470.\n\nSuazo GI: Evidence Based Morphology; Quo Vadis?. Int. J. Morphol. 2013; 31(4): 1524–1525. Publisher Full Text\n\nAziz MA, McKenzie JC, Wilson JS, et al.: The human cadaver in the age of biomedical informatics. Anat. Rec. 2002; 269(1): 20–32. PubMed Abstract | Publisher Full Text\n\nCoulehan JL, Williams PC, Landis D, et al.: The first patient: Reflections and stories about the anatomy cadaver. Teach. Learn. Med. 1995; 7(1): 61–66. Publisher Full Text\n\nInzunza HO: Competencias Generales en Medicina, Rol de la Anatomía. Int. J. Morphol. 2008; 26(2): 243–246. Publisher Full Text\n\nOlder J: Anatomy: a must for teaching the next generation. Surgeon. 2004; 2(2): 79–90. PubMed Abstract | Publisher Full Text\n\nLibin L, Xiaotong M, Wujin C, et al.: Análisis del Efecto de la Enseñanza de Morfología Humana Normal con un Modelo de Enseñanza Mixta y Evaluación Formativa en China. Int. J. Morphol. 2019; 37(3): 1085–1088.\n\nMoya-Salazar J, Contreras-Pulache H, Espinoza-Lecca E: Reader response: Characteristics of graduating US allopathic medical students pursuing a career in neurology. Neurology. 2020; 94(17): 761.2–761.76762. Publisher Full Text"
}
|
[
{
"id": "142556",
"date": "12 Sep 2022",
"name": "Stefano Zago",
"expertise": [
"Reviewer Expertise Clinical Neuropsychology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 paper focusing on a theory which aims to explain the dynamics of the human body at what looks like a philosophical, rather than strictly scientific, level. I propose that the Authors should make this point clear in the manuscript. Indeed, it looks like they refer to a conception of the human brain which is quite “old-fashioned”. They should state this within the limitations. Moreover, the manuscript should undergo proofreading by an English native speaker, since there are some phrasings that can be significantly improved.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1253
|
https://f1000research.com/articles/10-652/v1
|
26 Jul 21
|
{
"type": "Research Article",
"title": "Current situation of vaccine injury compensation program and a future perspective in light of COVID-19 and emerging viral diseases",
"authors": [
"Tommie Crum",
"Kirsten Mooney",
"Birendra R. Tiwari",
"Tommie Crum",
"Kirsten Mooney"
],
"abstract": "Background: Vaccines have had a great impact on disease prevention and mortality reduction. Very rarely, vaccines also can result in serious adverse effects. In consideration of this fact, vaccine injury compensation programs have been implemented in many countries to compensate a vaccinee for associated adverse effects. The existing vaccine injury compensation system addresses routine immunization schemes. However, there are rising concerns about the compensation for adverse effects caused by new vaccines such as those developed for coronavirus disease 2019 (COVID-19). The objective of this article is to review the existing vaccine injury compensation programs in different countries. The review also highlights the necessity to include all upcoming new vaccines for COVID-19 and other emerging viral diseases in the compensation schemes. Methods: Published articles relating to vaccine compensation injury programs, vaccines, injuries, disabilities, illnesses, and deaths resulting from vaccination were searched in data bases. Through a careful review of the abstracts, 25 relevant articles were selected for analysis. Results: We identified 27 countries on four continents with vaccine injury compensation schemes: 17 countries in Europe, 7 countries in Asia, the United States, a Canadian Province and New Zealand. No programs were identified in Africa and in South America. Program design, funding, and eligibility for compensation vary vastly between countries. We identified 17 countries operating well-established vaccine injury compensation programs. However, minimal information is available on numerous other countries. Conclusion: We have identified 27 countries operating vaccine injury compensation programs. In Canada, Quebec is the only province with a scheme; however, discussions are ongoing in Canada for nationwide implementation in light of COVID 19. Study limitations include limited scientific material, which hindered our research. Additional data concerning payout for each type of injury and the number of claimants related to a specific vaccine injury worldwide could provide a more comprehensive analysis.",
"keywords": [
"Vaccine",
"Vaccine Injury Compensation Programs",
"Immunization",
"COVID-19 vaccines",
"emerging viral diseases"
],
"content": "Introduction\n\nVaccines have been used for years to induce herd immunity and confer resistance to disease. Vaccines have had a great impact on health, economics and social welfare.1 Second only to safe drinking water, vaccinations have improved on mortality reduction and are the most cost-effective health intervention.2 Normally vaccines are licensed after years of safety testing processes. Initial vaccine testing is carried out on animal models and subsequent testing employs thousands of human participants. Multiple stage clinical trials assure that vaccines do not confer serious injury to most people.3 However, likewise any medication, their side effects do pose a risk. The main components of vaccines are microbial antigens as active immunizing agents. Depending on the type of vaccine, the immunizing agent can be a microbial product such as a toxoid, microbial proteins, capsular components and whole live attenuated or killed organisms. In addition, vaccines are produced with a number of other substances such as aluminum hydroxide, mineral oils, gelatin, polyethylene glycol and antibiotics. These substances function as an adjuvant, stabilizer or preservative in the vaccine. Furthermore, vaccines may be contaminated with the residue of cell cultures if the organisms of interest were propagated in cell lines for antigen production. Therefore, in rare cases vaccines have shown to pose the possibility of causing mild to serious hypersensitivity reactions in individuals allergic to any of the constituents of the vaccine.4 These rare adverse events can result in anaphylaxis, brachial neuritis, encephalopathy, thrombocytopenia, skin rashes, arthritis, Guillain-Barre syndrome, bowel intussusceptions and narcolepsy.5,6\n\nGermany was the first country to initiate a vaccine injury compensation program (VICP) in 1961 when the Supreme Court judged in favor of a vaccinee who was injured by the administration of a smallpox vaccine. The VICP was designed to be a no-fault claim system and were instituted as an alternative to the traditional civil law system for resolving vaccine injury claims. In a no-fault claim system, the claimant must prove the vaccination to be the cause of injury rather than the injury being at medical fault.7,8 Although, originally the VICP aimed to mainly compensate vaccinees who sustained an injury, the VICP plays several roles in today’s society. The expanded role of the current VICP includes maintaining adequate supplies of vaccines at a reasonable cost, to protect physicians from liability, and to encourage pharmaceuticals companies to develop new vaccines.9\n\nConsiderable amounts of compensation have been provided for vaccine injuries in various countries through their respective programs since the inception of VICPs. For example, the United States of America’s (USA) vaccine compensation program has awarded compensation to more than 6,276 families and individuals totaling to $4.7 billion since its inception in 1986.10\n\nVICPs are increasingly relevant in the present global situation given the current coronavirus 2019 (COVID-19) pandemic and the need to rapidly establish public trust in immunization. The world has been continually facing serious public health threats with several emerging and reemerging infectious diseases.11 The COVID-19 pandemic, caused by a novel virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), that began in December 2019 from Wuhan City, Hubei Province of China12,13 is the most terrible scourge of humanity in over a century. A search of ongoing vaccines platforms for COVID-19 in ClinicalTrials.gov reveals approximately 223 candidate vaccines under development in different stages, 11 of them have reached to phase III clinical trials. Two candidate mRNA vaccines (developed by Pfizer/BioNTech, and Moderna) and two recombinant vaccines developed by Oxford-AstraZeneca and Johnson & Johnson have received emergency use authorization from the World Health Organization (WHO) and the Governments of several countries including USA, United Kingdom (UK), United Arab Emirates (UAE), European Union (EU) and India. In addition, CoronaVac of Sinopharm is an inactivated version of the SARS-CoV-2 has been authorized in China. Sputnik V, an adenovirus vector vaccine has been authorized in Russia. Vaccination is already in progress worldwide and as of June 16, 2021 over 2 billion and 777 million vaccine doses have been administered (covid19.who.int). An enormous number of vaccine injury events are expected as vaccinations continue in the days ahead. In light of these circumstances, all of the COVID-19 vaccines which received the emergency use authorization have to be included in a compensation scheme. The new updated scheme should be well defined and equitable so that it can include other new vaccines which are under developmental stages targeting emerging and re-emerging viral diseases.14\n\nThe objective of this article is to identify the current status of VICPs in multiple countries operating a VICP, reporting specific vaccines that are covered, and identifying funding sources for their compensation program. This article will also highlight the need of vaccine injury compensation programs in light of the current COVID-19 pandemic and many other emerging diseases.\n\n\nMethods\n\nWe started developing a conceptual framework about vaccine injury compensation after discussion among the authors in April 2019; soon after, a literature search was run. We kept on searching and the last literature search was carried out on 16 June 2021. Based on the objectives, inclusion and exclusion criteria were set. We included countries with no-fault VICPs and peer-reviewed articles were reviewed regarding the VICPs as well as gray literature (law, guidelines, reports, and bulletins). We excluded publications of vaccine clinical trial-related injuries and compensations due to faulty medical practices. The main database searched was MEDLINE (PubMed interface) using medical subject heading (MeSH) terms for relevant literatures. Additionally, relevant gray literature was retrieved by Google searching. Articles published from January 1979 to April 2021 were searched. Several relevant keywords and phrases such as ‘vaccine injury compensation program’, ‘no-fault compensations system’, ‘vaccine adverse effects’, ‘disabilities’, and ‘illnesses’ were used in the search string while searching through Google. Variables such as countries with VICPs, payout amount, funding source were used for the extraction of data. Since this is a qualitative, non-meta-analysis review, data were extracted manually and findings are presented in summary tables. Funding sources for injury compensation and operation of the VICP in different countries were identified from country specific literature searching. All three authors were involved in the review process independently, and the final selection was made with collective discussion among the authors.\n\n\nResults\n\nA total of 123 articles were retrieved by MEDLINE and another 26 were retrieved from Google searches. After assessing the articles, 25 articles were selected based on inclusion criteria for analysis in this study (Figure 1).\n\n\nCurrent global situations of VICPs\n\nThroughout researching VICPs we identified 27 countries (Table 1) having VICPs on four continents. No VICP was identified in Africa or South America. Most of the developed countries have instituted and implemented adroitly rounded and evolving vaccine injury compensation programs. However, minimal information is available from several other countries.15-17\n\n\nEvaluation of VICPs by country\n\nDenmark – Denmark’s VICP was first established in 1972. The most frequent vaccines that occur in compensation litigation in Denmark include pertussis, diphtheria, tetanus, polio and tuberculosis. The minimum financial compensation is $60 USD equivalent with the average payout of $100,000 USD equivalent. Denmark’s program is funded through central taxation and social security revenues. The Danish Patient Insurance Association is the governing body that confirms any injuries and awards any specific compensation. In Denmark, coverage is provided for the following: loss of earnings or loss of work capacity, permanent injury, pain and suffering, as well as health expenses relating to treatment. In case of death, compensation can also provide death benefits for dependent family members and for the coverage of funeral expenses. The standard of proof in Denmark requires more than 51% likelihood that the injury is associated with the vaccine. The people of Denmark enjoy overall satisfaction with their VICP.18,19\n\nFinland – Finland’s VICP was first established in 1984. Finland maintains a cooperative that vaccine manufacturers are required to join to be covered in the case of litigation against them for vaccine injury compensation. Litigation against a vaccine manufacturer can include compensation for pain and suffering, permanent disability, cosmetic injuries, scars and narcolepsy. Finland only requires a 50% standard of proof to approve compensation. Finland boasts a high award rate for compensation programs at 50% of all filed claims receiving an award. Finland awards approximately $992,000 USD equivalent annually to claimants. Finland’s program is funded through the pharmaceutical injury insurance program.20\n\nNorway – Norway’s VICP was first established in 1995 and funded by the pharmaceutical association. The average yearly monetary payout provided by the Norwegian’s VICP for vaccination related injuries is $1.1 Million USD equivalent. Norwegians file less than 100 claims per year for vaccine related injuries. The Pharmaceutical Association reports a 40% success rate for a claim that is filed to receive compensation. In Norway, a 51% chance that the injury is caused by the vaccine in question is required for compensation to be rewarded.21\n\nSweden – Sweden’s VICP was first established in 1978. Sweden provides approximately $105,000 USD equivalent per approved claim to no-fault injury claimants with a success rate of 35%. The pharmaceutical industry and Government insurance both provide financial coverage for compensation payouts. In Sweden, a proposed vaccine injury victim needs only to provide probable cause to file a petition. Approximately 626 claims are filed each year for vaccine injuries in Sweden.22,23\n\nSwitzerland – Switzerland’s VICP was first established in 1970. Switzerland provides compensation for vaccine injuries related to mandatory or officially recommended vaccines and all pathologies subsequent to vaccinations excluding self-harm. There program is funded through Cantons Federal Subsidies. Individual cantons are responsible for developing their own procedures to implement federal vaccine compensation laws. A canton may deny compensation for a vaccine injury if compensation has been provided from another source. Cantons receive a federal subsidy for up to 25% up their operating expenses. The cantons in Switzerland are comparable to the states in the United States of America.24\n\nGermany – Germany’s VICP was first established in 1961. Germany’s VICP covers mandatory and recommended vaccinations which vary year by year. Coverage is awarded for not only death benefits but survivor benefits as well. Also included is compensation in the form of social assistance for health wellbeing and economic consequences of injuries. Germany’s VICP is funded through general revenue of the Länder (State Government). Germany’s program set the precedent for VICP establishments by becoming the first program in operation in 1961.25,26\n\nFrance – France’s VICP was first established in 1963. France’s VICP covers state required and mandatory vaccines. The program is administered through the Ministry of Solidarity and Health. Eligible claims include injuries only directly attributable to the vaccine. France states that the standard of proof must be convincing and clear evidence presented within 4 years post vaccine injury. Types of awards provided for compensation through France’s VICP include non-economic losses, pensions, disability, funeral and medical expenses. Financial loss of support for dependents of vaccine injury victims is also available through France’s program. France’s VICP is funded through the National Treasury. In France, an administrative tribunal makes choices pertaining to vaccine injury compensations. France averages approximately 39 vaccine injury claims per year.26\n\nUnited Kingdom – United Kingdom’s VICP was first established in 1978. The United Kingdom’s VICP is called the Vaccine Damages Payment Scheme (VDPS) which was created under the Vaccine Damages Payment Act in 1979. The VDPS is directed under the Department of Work and Pensions (Responsible for accessing claims for damages) as well as the Department of Health (Responsible for policy). The United Kingdom provides compensation for injuries resulting from the administration of recommended childhood vaccines and for adults who have been vaccinated with influenza, diphtheria, tetanus, influenza, poliomyelitis, measles, rubella, tuberculosis, and smallpox. Armed forces vaccinations are also covered under the adult vaccine compensation program. A unique aspect of the United Kingdom’s VICP is that any person making a fraudulent claim is liable for a $1,285 USD equivalent fine. The United Kingdom’s VICP is funded through the National Treasury. The United Kingdom’s compensation program pays out an average of $2 million USD equivalent per year to approved claimants. Filing must occur within 6 years post injury. The maximum award paid out per approved claim is $155,000 USD equivalent.26,27\n\nItaly – Italy’s VICP was first established in 1992. Italy covers vaccine injuries through their VICP for compensation of state recommended vaccines including diphtheria, tetanus, polio, hepatitis B, measles, mumps, rubella (MMR), human papilloma virus (HPV),rotavirus, and pertussis. Claimants can seek compensation including benefits for medical expenses, death benefits, Kawasaki disease, Henoch Schonlein Purpura, allergic reactions, thrombocytopenia, and hemolytic anemia. The VICP in Italy is funded through the Ministry of Health of the Italian Government.28\n\nSouth Korea – Korea’s VICP was first established in 1994. Korea covers vaccine injuries resulting from vaccination with diphtheria, pertussis, tetanus (DtaP), MMR, Bacille Calmette Guerin (BCG), Japanese encephalitis, Korean hemorrhagic fever, and influenza. Korea’s program is based on the WHO causality assessment criteria. The Korean National Vaccine Injury Compensation Program (KNVICP) provides compensation for victims of vaccine injury. Almost 68% of vaccine injury claims are successfully compensated in Korea. Korea requires that a claimant has spent more than $300 USD equivalent on medical expenses.29,30\n\nChina – China’s VICP was first established in 1988. In China, the oral polio, measles, hepatitis B vaccine (HBV) and meningococcal polysaccharide vaccine (MPV) vaccines are all covered for compensation injuries limited to death and disability only. The average pay out per approved claimant is $10,400 USD equivalent. Funding per payout compensation is provided by the government and the vaccine manufacturer. China’s complicated and laborious process of filing for vaccine compensation includes a three-stage process which results in a very timely and expensive process for claimants. Epidemiological studies are required to prove that the vaccine in question resulted in the injury sustained. Public protest has occurred on numerous occasions due to the masses being profoundly disappointed in the system of vaccine injury adjudication in China.31\n\nJapan – Japan’s VICP was first established in 1970. Japan provides compensation for diphtheria, poliomyelitis, measles, mumps, rubella, Japanese B encephalitis, tetanus, tuberculosis and smallpox vaccine (class I). Influenza vaccine (class II). Compensations include health care benefits, medical allowances, funeral, death, disability, and injury coverage. Compensation amount is paid either through the Health Service Bureau or through the Pharmaceutical and Food Safety Bureau (PFSB). Japan has established a set amount per pay out, if the injury has an undisputed correlation with the vaccine. The maximum awarded compensation is $1 Million USD equivalent. Due to the stringent requirements for filing and limitations placed upon claimants, very few cases are advanced into the court system. The resulting vaccine award rate per claim is 80%.32\n\nTaiwan – Taiwan’s VICP, the Vaccine Injury Compensation Program Working Group (VICPWG), was first established in 1988. BCG, influenza and MMR are all covered through Taiwan’s VICP. The MMR vaccine makes up 33% of the payouts and the BCG vaccine is the most compensated vaccine. Injuries that receive compensation in Taiwan include physical and mental effects, serious injuries and death. These guidelines are similar to the World Health Organization’s recommendations for vaccine injury compensation programs, 98 vaccine injury compensation claims are paid out on average per year in Taiwan. This equates to a 40% success rate per claimant. Taiwan set the maximum payout amount for each injury at $200,000 USD equivalent. They provide compensation for physical and mental impairments at $165,000 USD equivalent per occurrence and for serious illness provides $33,000 USD equivalent. Mild adverse reactions receive a payment of only $6,500 USD equivalent per approved claim. In Taiwan, the Government provides funding for the VICPWG through a $0.05 USD equivalent tax on each vaccine dose that is purchased.33,34\n\nCanada – Canada’s VICP was first established in 1985. Canada maintains the position as the only country in the world to operate a VICP within their country that is not accessible toall citizens of the country. Currently, Quebec is the only province in Canada that provides vaccine compensation. Quebec develops, maintains, and funds their own vaccine compensation injury program for the citizens; in the event of a vaccine injury the remaining citizens of Canada are not eligible for participation in the program. In the province of Quebec, a citizen who is injured by administration of a vaccination must provide unequivocal proof of permanent impairment to be eligible to receive compensation for a vaccine injury. Their program has awarded an average of $4.4 Million USD equivalent through the Provincial Ministry of Health and Social Services. Vaccines that are covered are numerous and change regularly.35,36 According to the recent news, Canada announced a nationwide vaccine compensation injury program specifically designed to encourage confidence in COVID-19 vaccinations (ctvnews.ca). This program will be operated separately from Quebec’s program and will only include coverage for the COVID-19 vaccinations. Minimal information has been released at this point, as it is still in its development.\n\nNew Zealand – New Zealand’s VICP was first established in 1974. New Zealand maintains a no-fault program with significant relative ease of approval of compensation due to a claimant’s lack of need to prove negligence by medical professionals. Vaccine injuries are uniquely identified as medical injuries by New Zealand’s VICP. New Zealand is able to maintain their VICP cost at an acceptable level through the program being intertwined with social and employment resources. New Zealand provides buy in opportunities for physicians, no legal fees for compensation seekers and caps on monetary compensation for claimants. New Zealand’s VICP requires a notification of injury within 12 months post injury and only permanent disability is covered for vaccine injury compensation. The average individual payout is $2,850 USD equivalent per claim, government funding supplement vaccine injury compensation programs in New Zealand.37\n\nUnited State of America (USA) – The USA’s VICP program was first established in 1988. In the USA recommended childhood vaccines and adult influenza vaccine recovered under the National VICP. Compensable injuries vary per vaccine. For DTaP, MMR, and HBV, injuries including anaphylaxis, brachial neuritis, arthritis and thrombocytopenic purpura are compensated. For all covered vaccines both permanent disability and death are compensated. In the USA, a 3-year filing deadline is implemented. The government maintains a vaccine injury table and follows it for proof of causality for their standard of proof. Off table claims do occur and special groups of the VICP are assigned to handle all off table claims and adjudication. These claimants are required to provide undeniably high levels of epidemiological evidence for their claim. These claimants usually require legal representation to handle the immensity of their claims. Covered compensation would include medical bills, lost wages, future care costs, attorney’s fees, death and non-economic losses. The USA levies a tax on every vaccine dose that is distributed to cover the cost of the program. The USA provides a vaccine court to adjunct claims. However, ultimately 80% of cases are negotiated and settled out of court. The USA’s VICP has an average of 643 claims per year with 34% of those claims receiving compensation. Approximately, $4.7 billion dollars has been paid out to vaccine injury victims through the vaccine courts in the USA to date.38-41\n\n\nFuture perspective of VICPs in light of COVID-19 and other emerging diseases\n\nAlthough, enormous strides have been made in the areas of compensating families affected by vaccine injuries, the world’s governments have concurred that improvements in these programs should continue to be developed. Development and expansion of vaccine injury compensation programs would continue to encourage responsible medicine as well as thoughtful humanitarianism worldwide. The existing no-fault vaccine-injury compensation schemes in 27 countries are for routine immunizations; however, these systems are not always well defined to cover the losses or damages of vaccine administration during pandemic crises. The presently ongoing COVID-19 pandemic devastation urges today’s society to redefine and employ the VICPs in an urgent manner. An improved VICP would ensure a competent and productive program to match the needs of today’s ever evolving world situation and to provide safe and equitable access to vaccines. It is likely that over a billion doses of COVID-19 vaccines will be administered worldwide by the end of 2021.The recently launched COVID-19 mRNA vaccines were developed by using a very new platform. This technology utilizes the mRNA complexed with cationic lipid nanoparticles, cholesterol and polyethylene glycol.42 Emergency use authorization has been granted because of the urgent need. Therefore, phase III clinical trials of these vaccines had a limited sample size and duration. Some serious vaccine related adverse effects can be expected after the administration of new vaccine for the first time in humans.43 Severe adverse reactions including anaphylaxis and blood clotting disorders have been reported after administration of COVID-19 vaccines.44,45 In addition to COVID-19, presently, there are several ongoing emerging and reemerging viral diseases pandemic in nature and several candidate vaccines platforms are in the pipelines to respond these diseases.46 As more vaccines are made available for human use, more vaccine injury events can be expected. Considering the current situations, there are suggestions for the revision of the existing vaccine injury compensation system.47 A few already practicing mechanisms can be adapted, such as the World Health Organization (WHO) insurance system for vaccines during a public health emergency initiative COVID-19 Vaccines Global Access (COVAX). The COVAX authority can be used to promote improvements in regional or national compensation system for member countries. One example of a possible improvement is for all programs to add a nominal per-dose tax to the manufacturer.47\n\n\nConclusion\n\nVICPs are established on the principle of no-fault claims. This principle states that the adverse effects are not related to an individual’s fault or a vaccine manufacturer’s misdeed; they are inevitable consequence of medical interventions. There is no standard definition for causation. Eligibility criteria for compensation are often based on WHO guidelines or the specific country’s operating principles and decisions. The lowest vaccine injury payout was identified in New Zealand and the highest was identified in Norway. The USA’s program is the costliest due to its legal based structure. The VICPs process also supports supply of vaccines, maintains the cost, and protects physicians from liability. Compensation programs have increasingly restored public confidence in the safety of vaccinations and their modifications to adjust to current world issues. Additional studies as new information is available may provide comprehensive data on individual countries enhancing our overall research. Additional data concerning payout for each type of injury and number of claimants of all VICPs worldwide could also provide a more comprehensive analysis. Further research would be advantageous in respect to other countries currently having minimal information about VICPs. Billions of people are expected to receive new vaccines for COVID-19 by the end of 2021; there are valid and founded concerns to initiate VICP modifications worldwide to accommodate the changing situation. VICPs must be redefined to include several upcoming vaccine platforms for emergency uses targeting emerging and reemerging diseases.\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\nRodrigues Charlene MC, Plotkin Stanley A: Impact of Vaccines; Health, Economic and Social Perspectives. Frontiers in Microbiology. 2020; (11): 1526. PubMed Abstract | Publisher Full Text | Free Full Text\n\nState of the world’s vaccines and immunization.3rd ed. Geneva: World Health Organization; 2009. Publication: Bulletin of the World Health Organization; Type: Policy & Practice, Article ID: BLT.10.081901. Reference Source\n\nArtaud C, Kara L, Launay O: Vaccine Development: From Preclinical Studies to Phase 1/2 Clinical Trials. Methods Mol Biol. 2019; 2013: 165–176. PubMed Abstract | Publisher Full Text\n\nKocourkova A, Honegr J, Kuca K, et al.: Vaccine Ingredients: Components that Influence Vaccine Efficacy. Mini Rev Med Chem. 2017; 17(5): 451–466. PubMed Abstract | Publisher Full Text\n\nStratton KR, Howe CJ, Johnston RB: Adverse Events Associated With Childhood Vaccines Other Than Pertussis and Rubella: Summary of a Report From the Institute of Medicine. JAMA. 1994; 271(20): 1602–1605. PubMed Abstract\n\nChung EH: Vaccine allergies. Clin Exp Vaccine Res. 2014 Jan; 3(1): 50–57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLooker C, Kelly H: No-fault compensation following adverse events attributed to vaccination: a review of international programmes. Bull World Health Organ. 2011; 89(5): 371–378. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nAttwell K, Drislane S, Leask J: Mandatory vaccination and no fault vaccine injury compensation schemes: An identification of country-level policies. Vaccine. 2019 May 9; 37(21): 2843–2848. PubMed Abstract | Publisher Full Text\n\nHealth Resource Service Administration: About the National Vaccine Injury Compensation Program.Reference Source\n\nNational Vaccine Injury Compensation Program Monthly Statistics Report.2020. Reference Source\n\nMorens D, Folkers G, Fauci A: The challenge of emerging and re-emerging infectious diseases. Nature. 2004; 430: 242–249. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu F, Zhao S, Yu B, et al.: A new coronavirus associated with human respiratory disease in China. Nature. 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhou P, Yang X, Wang X, et al.: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrovato M, Sartorius R, D’Apice L, et al.: Viral Emerging Diseases: Challenges in Developing Vaccination Strategies. Front Immunol. 2020; 11(2130). PubMed Abstract | Publisher Full Text | Free Full Text\n\nMungwira RG, Guillard C, Saldaña A, et al.: Global landscape analysis of no-fault compensation programmes for vaccine injuries: A review and survey of implementing countries. PLoS ONE. 2020; 15(5). PubMed Abstract | Publisher Full Text | Free Full Text\n\nA review of the Expanded Program on Immunization (EPI) in the African Region 1998.Harare: WHO; January 2018. Reference Source\n\nGlobal Advisory Committee on Vaccine Safety.December 2018; WHO. Reference Source\n\nThe Danish Liability for Damages Act.Copenhagen: Patient forsikringen; 2010. Reference Source\n\nKeane M, Moloney T, Lee C, et al.: Vaccine Injury Redress Programmes. An Evidence Review . March 2019. Reference Source\n\nFinnish Pharmaceutical Insurance Pool: Helsinki . Finnish Pharmaceutical Insurance Pool; 2011. Reference Source\n\nLegislative Landscape Review: Legislative Approaches to Immunization Across the European Region. Sabin Vaccine Institute. December 2018. Reference Source\n\nCooper JK: Sweden’s no-fault patient-injury insurance. N Engl J Med. 1976 Jun 3; 294(23): 1268–1270. PubMed Abstract | Publisher Full Text\n\nCohen ED, Korper SP: Swedish No-Fault Patient Compensation Program - Provisions and Preliminary Findings. Insurance Law Journal. 1976; (637), pp. 70–80. Reference Source\n\nSwiss federal Council: National Vaccination Strategy – Short Version. Article number: 316.522.eng. FOPH publication number: 2017-OEG-06. 2020. Reference Source\n\nProtection against infection act (Infektionsschutzgesetz - IfSG), 1045. Berlin: Federal Law Gazette . 20 July 2000: 2000. Reference Source\n\nAppendix E: Vaccine-Injury Compensation in Other Countries.Reference Source\n\nThe Regulatory Reform (Vaccine Damage Payments Act 1979) Order 2002, Statutory Instrument 2002 no. 1592.London: Office of Public Sector Information; 2002. Reference Source\n\nComandé G: Medical law in Italy . Nov 2013. Reference Source\n\nKim JS, Jo DS, Go U, et al.: National vaccine injury compensation program in Korea: A 12- year experience. Pediatrics. 2008; 121(S2): S165. Reference Source\n\nJo DS, Kim JS: Perspectives on vaccine injury compensation program in Korea: pediatricians’ view. Clin Exp Vaccine Res. 2013; 2(1): 53–57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFei L, Peng Z: No-fault compensation for adverse events following immunization: A review of Chinese law and practice. Med Law Rev . 2017; 25(1): 99–114. PubMed Abstract | Publisher Full Text\n\nIhara T: The National Vaccine Injury Compensation Program in Japan. Nihon Rinsho. 2011 Sep; 69(9): 1645–1650. PubMed Abstract\n\nYu-Ling C, Song-En H, An-Hua C, et al.: A comparison of vaccine injury compensation scheme in Germany, Finland and Taiwan. Taiwan Epidemiology Bulletin. 2015; 31(18): pp.159–164. Reference Source\n\nWang P-C: Updates on Vaccine Injury Compensation Program in Taiwan and program evaluation. Epidemiology Bulletin. 2015; 31(18): 149–158. Reference Source\n\nKutlesa NJ: Creating a sustainable immunization system in Canada - the case for a vaccine-related injury compensation scheme. Health Law J. 2004; 12: 201–242. PubMed Abstract\n\nVaccine Injury Compensation Program: Government of Quebec.2019. Reference Source\n\nDavis P, Lay-Yee R, Fitzjohn J, et al.: Compensation for medical injury in New Zealand: Does “no-fault” increase the level of claims making and reduce social and clinical selectivity? J Health Polit Policy Law. 2002; 27(5): 833–854. PubMed Abstract | Publisher Full Text\n\nHensen R: Inoculated against recovery: a comparative analysis of vaccine-injury compensation in the United States and Great Britain. Tulsa J Comparative International Law. 2007-2008; 15: 61. Reference Source\n\nEvans G, Cook K: The National Vaccine Injury Compensation Program.American Academy of Pediatrics; 2011. Reference Source\n\nVaccine Injury Compensation Data, official website of the U.S. Health Resources & Services Administration.2019. Reference Source\n\nHealth Resources and Services Administration (HRSA), HHS: National vaccine injury compensation program: calculation of average cost of a health insurance policy. Final rule. Fed Regist. 2007 Jul 5; 72(128): 36610–36612. PubMed Abstract\n\nPardi N, Hogan M, Porter F, et al.: mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov. 2018; 17, 261–279. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWood N, Macartney K, Leask J, et al.: Australia needs a vaccine injury compensation scheme: Upcoming COVID-19 vaccines make its introduction urgent. Aust J Gen Pract. 2020 Sep 9; 49. PubMed Abstract | Publisher Full Text\n\nCDC COVID-19 Response Team; Food and Drug Administration: Allergic reactions including anaphylaxis after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine: United States, December 14–23, 2020. MMWR Morb Mortal Wkly Rep. 2021 Jan 15; 70(2): 46–51. Reference Source\n\nNews Explainer: COVID vaccines and blood clots: five key questions.16 April 2021. Reference Source\n\nWagner JL: New vaccine in the pipeline 2020. Pharmacy times. 2020-08-28. Reference Source\n\nSam Halabi JD, Andrew Heinrich JD, Omer SB, et al.: No-Fault Compensation for Vaccine Injury — The Other Side of Equitable Access to Covid-19 Vaccines. N Engl J Med. 2020; 383: e125. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "93932",
"date": "08 Oct 2021",
"name": "Lal B. Rawal",
"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\nOverall, this research work has a great public health importance and thanks to the authors for such great works. Followings are some of my observations and comments/ feedback. I hope these will help authors to improve the quality of the paper.\nAbstract:\nAbstract, results: Please clearly state the information relating to continents and countries, where the studies were conducted.\n\nHow did authors assess/ determine the well-established program in 17 countries? It's unclear. I invite authors to clearly state these.\n\nAbstract: The conclusions in the abstract sub-section do not align with the findings presented above. I invite authors to reframe it. Perhaps like: We conclude that the vaccine injury prevention and compensation programs are available limited number of countries across four continents - mostly in Europe. Lack of standard approach and scope of injury prevention and compensation programs across the countries exists. Some important limitations include: 'Therefore, additional data...'\n\nBody of the manuscript,\n\nPage 3, methods section:\nThe methods section needs standard/ more academic way of presenting the work, perhaps like: Using a standard framework to review the literature, we searched key online databases for relevant literature published till 16 June 2021.\n\nDid you use a review framework like PRISMA or STROBE guidelines? If so, you could then include it here.\n\nPage 4, methods, para 1: The dates of literature search and reviewed mentioned in the page 4 para 1 is inconsistent with the ones noted in page 3, last para. These dates need maintaining consistency.\n\nI have added some minor observations in the manuscript. Please find the manuscript with my edits/ comments attached here.\n\nPage 4, results section: Authors have noted 25 articles, but the programs have been available in 27 countries. If this is correct, I would invite authors to clearly state these details.\n\nPage 8, conclusion section: This conclusion section needs re framing. Please see the comments/ provided in the Abstract section. I invite authors to reframe it with developing conclusions based on the findings presented above, followed by some specific and doable recommendations.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7500",
"date": "13 Dec 2021",
"name": "Birendra Tiwari",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for your time and valuable comments. I have revised the manuscript addressing your comments and suggestions. The clarifications of few of your queries have been mentioned below. Abstract, Results: Please clearly state the information relating to continents and countries, where the studies were conducted. Response: Given on the table 1 and 2, because of the word limit in the abstract we could not mention all the countries and continents here. Authors have noted 25 articles, but the programs have been available in 27 countries. If this is correct, I would invite authors to clearly state these details. Response: Few records have included the VICP of 2 or more countries. For example, the reference 26 provide the information of 3 countries (Germany, France and United Kingdom)"
}
]
},
{
"id": "90430",
"date": "19 Oct 2021",
"name": "Keshab Parajuli",
"expertise": [
"Reviewer Expertise Microbiology 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 review article entitled “Current situation of vaccine injury compensation program and a future perspective in light of covid-19 and emerging viral diseases” is well written and has included very relevant information regarding the objectives.\n\nSince there are a lot of ambiguities regarding no-fault compensation schemes, this article provides comprehensive details for future researchers. I found sufficient details in the methods and appropriately interpreted.\n\nConclusions are drawn appropriately supporting and representing the whole article in a glance.\nI approve this review for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-652
|
https://f1000research.com/articles/10-177/v1
|
04 Mar 21
|
{
"type": "Research Article",
"title": "Perception on online teaching and learning among health sciences students in higher education institutions during the COVID-19 lockdown – ways to improve teaching and learning in Saudi colleges and universities",
"authors": [
"Khalid Aziz Ansari",
"Faraz A. Farooqi",
"Soban Qadir Khan",
"Muhanad Alhareky",
"Ma. Abigail C. Trinidad",
"Taha Abidi",
"Muzaheed M",
"Khalid Aziz Ansari",
"Soban Qadir Khan",
"Muhanad Alhareky",
"Ma. Abigail C. Trinidad",
"Taha Abidi",
"Muzaheed M"
],
"abstract": "Background: Online learning or E-learning are approaches to broadcasting teaching by the means of internet technology and software applications. Kingdom of Saudi Arabia is likewise embarking on the rapid growth in online education. The purpose of this study is to investigate the student’s perceptions regarding online teaching and learning during COVID 19. Methods: An online computer-based cross-sectional study was conducted between May and June 2020. A pre-validated questionnaire was used and administrated to health sciences students studying at Dammam Universities through online software QuestionPro. Results: Out of total 281, 68% of the participants were females (n=188) while 31.9% (n=88) were male students with an average age of 23.1(4.5) years. Overall, 176 (62%) of the students expressed their satisfaction with online learning. Conclusion: Findings will help academicians to identify strengths, areas of improvement, and encourage faculty to think deeply to restructure course learning objectives, teaching techniques to engage students and improve learning process.",
"keywords": [
"COVID-19",
"E-learning",
"Traditional learning",
"Student’s Perceptions"
],
"content": "Introduction\n\nIn order to control the ongoing worsening situation of the spread of Coronavirus1 amongst their residents, most countries declared a full or partial lockdown within their territories.2 Various education ministries across the globe also took abrupt measures to minimize face-to-face contact among students and staff and advised higher education institutions to transform all academic teaching online. Therefore, all face-to-face academic activities were put on hold in the middle of the semester; and in order not to disrupt the provision of lectures in academic institutions such as colleges and universities, all academic activities were shifted towards virtual teaching. The virtual online educational system became a necessity and is now becoming popular as a normal teaching practice in various countries for the undefined future.\n\nOnline learning is a teaching method administered by means of the internet and software applications.3 The rapid spread of this technique resulted in various universities actively targeting students worldwide to encourage them to attain an education online to save money.4–6 The Kingdom of Saudi Arabia (KSA) is likewise embarking on the rapid growth in online education.\n\nKSA is enhancing its educational goals and actively contributing to international educational changes to meet the challenges of future generations.7–8 KSA has established several online universities such as Online Islamic University (2010) and The Saudi Electronic University (SEU) (2011). Citizens living far away from the main campuses and cities have to travel and live away from their families therefore online education will help them to stay in their hometown and still fulfill their educational desires.10 In the KSA, there have been many attempts to blend online education with the traditional education system. However, no conclusive data is available on the students’ and faculty's perception towards online learning. In addition, the faculty's competencies to adopt computer-based teaching make this method of teaching and learning more challenging.11\n\nOn the 2nd March 2020, KSA announced its first patient infected by Coronavirus. As a result, on 8th March 2020, KSA suspended all schooling, including universities and other educational institutes, until further notice as an effort to control the virus outbreak.12 In compliance with the KSA’s Ministry of Education’s ordinance regarding the suspension of educational activities, Imam Abdulrahman Bin Faisal University (IAU) and other universities within the region ceased all on-going events, hence, lectures and clinical sessions, and laboratories started to facilitate its students through virtual, online channels such as ZOOM and Microsoft’s Teams application.\n\nPrevious research has shown that the acceptance of online learning was deemed to be increasing amongst those students who have experienced it because students understand it as a more flexible way to learn that is less time consuming and allows students to learn in the comfort of their home.13 Although there is evidence which suggests that the students are also missing the interpersonal environment which is only present in traditional learning when they meet teachers face-to-face. This research also demonstrates that they have to be more independent learners as there is limited tutor availability.14,15 The situation we are currently facing concerning the pandemic and forced conversion to online learning for many institutions has created the need for further research into the student experience to ensure the quality of education has not been compromised. The objective of this research was to explore students’ perception of the implementation of online teaching and learning support. We identify the strengths and areas of improvements in online teaching and learning in higher education institutions in KSA. The aim is to gain a more rounded and detailed understanding of students' experiences of remote learning and the support they have received from their institutions during the COVID 19 lockdown, their satisfaction with the provided facilities as well as their continued engagement with online learning. Moreover, the findings from our study provide academicians the opportunity to further enhance the quality of pre-COVID-19 traditional face-to-face teaching methods as we look to retain the benefits from better understanding the virtual learning environment. In addition, identifying the strengths and weaknesses could lead to improvements for e-learning based on students' insights into their learning experiences.\n\n\nMethods\n\nA cross-sectional online-based study was conducted from May 2020 to June 2020 wherein a pre-validated questionnaire was generated through QuestionPro (advanced version). This questionnaire was sent via an online survey to all students of universities (IAU and SEU) in KSA. All students enrolled in the academic year 2019-2020 were eligible to participate in this study. Students’ email IDs were taken from the registrar’s office of the academic institutions to communicate details of the study to students. Students’ participation was voluntary, and a statement was incorporated in the survey form for participants to give their consent before they started the survey.\n\nThe selection of student participants for the survey was done by purposive sampling. The selection process was designed to maximize the representation of diversity of the participants in terms of subject specialties (Dentistry, Medicine, Public Health), gender, and age to portray the wide spectrum of student backgrounds from the different colleges and universities in KSA. For the students to participate and to be included in the study they had to be currently enrolled in a KSA college or university and belonging to any specified discipline.\n\nMoreover, consent to participate was given by the completion of the survey. A total of 350 students commenced the survey and 20% of them left the survey incomplete (did not reach the main questions). Therefore 281(80%) students who completed the survey were included in the final analysis of the study.\n\nAs this study involves human subjects, ethical approval is required under the bylaws of the Helsinki declaration. The institutional review board (IRB) in Imam Abdulrahman Bin Faisal University (IAU) is accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP), which operates under the laws and regulations for human research in Saudi Arabia. For this study, the ethical approval was applied through the IAU Converis Management System, which is an electronic system that allows and facilitates research applications for members of IAU. The ethical approval for the study was obtained from the Institutional Review Board (IRB) at IAU (EA-202051).\n\nThe questionnaire was extracted and modified from a previously published study on distance-based education.16 Modified questionnaires were pilot tested on 20 students belonging to both institutes (10 from each, traditional (IAU) vs online (SEU)) for reliability and validity. The questionnaire was divided into three sections, Demographic Information (consisting of 11 questions), Teaching and Learning Process (consisting of 9 questions with a forced 4-point Likert scale response), and Students Technical Support (consisting of 7 questions with 4-point Likert scale response). Cronbach alpha value for the Teaching and Learning section was obtained as 0.69, and for technical support, it was 0.76, which indicated acceptable internal consistency. Section 1 of the questionnaire covered the demographical characteristics of participants such as age, gender, institution’s name, department, Grade Point Average (GPA), parents’ education, and profession. Section 2 was based on the participants’ experience with the online learning responses amid COVID-19 and Section 3 consists of statements about technical support provided to the students in the case of any issue arising during lectures or examinations. There were two additional open-ended questions included to ask students about their future preferences and suggestions to further improve the quality of online learning.\n\nStatistical Package of Social Sciences (SPSS version 23) was used for data entry and analysis. For descriptive statistics, frequency distribution, percentages, averages, standard deviation, and bar graphs were created. For inferential statistics, two independent samples t-test was used to compare average scores with the questions that had two categories. Chi-square/Fisher's Exact Test was used for comparing variables with two or more categories. To handle the missing values, we assign discreet values (codes) during analysis in SPSS. The level of significance was set as 0.05 level of significance.\n\n\nResults\n\nThe number of students who participated in the study and completed the survey forms was 281. The average age was 23.1±4.5 years. About 68% of the participants were females (n = 188) while 32% (n = 88) were males. The distribution of students according to their institution and their academic level is presented in Table 1. There were 128 (45.6%) students who stated that they had a separate study room, 136 (48.4%) replied that they did not have a separate study room and 17 (6%) did not reply to the question. Analysis of the questions related to parents' qualifications revealed that the fathers were more qualified than the mothers. Table 1 also shows the qualification levels of the parents.\n\nThe questionnaire had nine questions which were asked to assess the students' satisfaction with the online teaching and learning process. It was found that students were very satisfied with the faculty’s prompt response in a variety of ways (mean score 3.03): their commitment in delivering lectures in terms of punctuality, preparation (mean score 3) and with providing online materials which helped them to better understand the course or topics (mean score 2.93) (Table 2). Statistical significance was tested by comparing the response scores with demographic variables. Fathers’ education was found to have a statistically significant relation with questions “faculty is fully committed to the deliver lectures” and “faculty communication and provided online material” (p = 0.04 and 0.018, respectively). Mothers’ education had a significant association with the questions “faculty supported and responded quickly” and “during online lectures, faculty give break or extra time” (p = 0.042 and 0.026, respectively). In terms of the learning environment, the students who had a separate study room had significantly higher average scores for each question except for question 4 (“Feedback to student assignments is provided helpfully”) (p = 0.12). Similarly, students’ study year level had a significant association with their responses to statements “Faculty is promptly responding (Q1)”, “Faculty is fully committed (Q2)” and “Faculty supported(Q3)” (p = 0.035, 0.018, and 0.009, respectively). Specifically, senior students (final year students) showed higher satisfaction than junior students (foundation year, year 1 or 2 students).\n\nEvaluation of questions about students’ satisfaction towards the technical support provided during the teaching process is presented in Table 3. Demographic questions were analyzed with questions tabulated in the table “How do you rate the IT services” and the question “Was the lecture time provided to cover the specific topic enough” were found to correlate with the students’ study year (p = 0.033) which showed a significant increase in averages due to increasing in academic level. Question 5 (“Was the lecture time provided to cover the specific topic enough”) also had a significant association with fathers' and mothers' education levels (p = 0.036 and 0.035, respectively). The question \"do you have a separate study room?\" had a significant relationship with the questions “how do you rate the internet connection”, “how do you rate the IT services” and “overall, I am satisfied with the e-learning”. Those who had separate study rooms had a significantly high average score compared to their counterparts (p = 0.019, 0.002, and <0.001, respectively). Overall, the students were in agreement (62%) that they are satisfied overall with the e-learning process.\n\nEvaluation of students’ responses about what an instructor can do differently to help them learn, showed that \"provide feedback instantly\" and \"make course-related stuff handier/more mobile base\" were the options with the highest responses (Figure 1). Furthermore, 163 (63.2%) had agreed that they would recommend E-learning in the future while 95 (36.8%) had disagreed that they would recommend this for future use. The most common reason for recommending E-learning in the future was students feeling more comfortable (Figure 2). Conversely, the stress of using the online system was the most common reason for not recommending E-learning in the future (Figure 3).\n\nStudents’ type of institution (online vs traditional) was analyzed with the question “would you recommend this e-learning in the future”. The comparison was provided that a significantly high proportion of students (87.3%) who belonged to E-learning institutions had agreed that they would recommend E-learning in the future compared to 57.6% of traditional institution students (p = 0.0001). Furthermore, the institution type was analyzed with questions relating to technical support provided during lectures, and average scores and p-values were tabulated in Table 4. We found four questions where the difference between the satisfaction of students belonging to traditional institutes was signficantly different than those belonging to blended online institutes (SEU). Selfguided instruction, duration of lecture time and overall satisfaction was scored high by the students of e-learning institutes (p-values = 0.001, 0.047, 0.0001 respectively).\n\n* Statistically significant with 0.05 level of significance.\n\n\nDiscussion\n\nOnline learning has revolutionized teaching and learning in higher education institutions during the recent pandemic.17 Most internationally ranked university students are far more confident in terms of asynchronous learning opportunities through the instructional use of e-mail, chat rooms, bulletin boards, online lectures through Blackboard Ultra or Zoom as well as online assessments.18–19 The technologies are transforming education from the perspectives of learners, instructors, IT managers, and administrators. Therefore, examining perceptions of learners’ experiences is a widely used strategy, which often influences behavior.20 It is important to study students’ perceptions of online course quality for institutions, administrators, faculty, and students themselves in order for the online learning environment to be successful.\n\nAlthough virtual teaching is not very popular or common among many Saudi institutions, the COVID-19 pandemic presents an extraordinary situation worldwide, which became even worse from time to time during the end of the academic year where there were a lot of uncertainties regarding the teaching of course material, course completion, examination, and assessments. The present study aims to evaluate health sciences students' perceptions about online learning in Saudi higher education, which replaced traditional face-to-face teaching due to the COVID-19 pandemic across the globe.\n\nIn the present study, Saudi students’ responses highlighted areas of good practice and areas for further development and/or improvement. The areas of good practice found in this study were the faculty’s prompt responses to students’ queries related to teaching material and/or assessments, faculty commitments and preparation to provide online lectures, and maintaining contact with students’ during the lockdown crisis. However, students were not satisfied with the course design which suggests that there is a need to modify each course teaching, learning, and assessment methodology that was originally designed to be delivered face-to-face. However, since extensive online teaching was introduced without any prior notice to students and planning from the teaching staff, this was an expected finding. Every institution needed to be well prepared to design the module specification more flexibly and make adjustments in such a way that students adapt to both face-to-face and online teaching, learning, and assessment changes without any stress which may influence performance in their courses.\n\nThe areas of further development that respondents mentioned were delayed feedback from the faculty and a lack of group work or team-based learning.21 However, there were innate challenges with the implementation of this with differing class sizes, accessibility, disability issues, and facilities. It also warrants some adjustments in the learning outcomes but may raise issues where time is constrained. Therefore, continuous informal feedback (talking to students or their tutors), students' written feedback (module feedback surveys) or critically reviewing their performance in course assessments and through direct feedback are more beneficial tools and key to education to enhance learning development.\n\nIn the present study, parents’ education is also found to be a significant confounder for students’ satisfaction, which may suggest that educated parents may tend to be more concerned and provide more support to facilitate their children’s education. This is consistent with a previous study that stated that parenting behavior influences children’s education.22 Our study found that those who have a separate study room are more in favor of online teaching.22 The home study environment is believed to have a positive influence on students’ learning13 - and the present study suggested that students who have a spare room for their studies are more satisfied with their learning experience.\n\nIt could be deemed that the responses provided to several of the questions/statements indicated that the students were positively disposed towards some aspects of online learning: namely, communication and faculty provided online material which helped students to understand the topics and contributed to their satisfaction with the technical support provided to them during lectures or examinations. Additionally, 19% found it is more comfortable and 18% thought that online teaching was less time consuming. Conversely, 17% found it took more time to study while more than 50% agreed that they would recommend it in the future but with some concerns (e.g. more complicated, stressful, internet problem in the area or cannot learn this way).\n\nTechnical support provided during exams and lectures was also appreciated by the students. The overall satisfaction with online teaching demonstrated by students was 68%, indicating their agreement towards the continuation of E-learning. Providing feedback instantly, open discussion sessions, and improving availability of resources were the highest-rated questions (21%, 21%, 20% respectively).\n\nThis study also explored students’ opinions on how the faculty performed differently to support students' learning and >60% of the population suggested an effective learning environment, regular assessment activities, and instant feedback would be beneficial to monitor students' learning which is in line with the findings of a previous study.23 Moreover, technology-enhanced learning may make it easier for students to follow their course content electronically at their own pace.24 Various studies highlighted technology-enhanced learning and teaching as a significant revolution in all educational settings. Literature also suggests smartphones as a new paradigm in higher education for overcoming obstacles25 and educational providers may also consider using apps such as Menti, Kahoot, Formative, Socrative, and Turning Point to assess learning of larger groups. The most unique benefit is that there are many ways through which learning can be more effective thus further enhance the quality of online teaching practice in higher education.\n\nFurthermore, the study highlighted some factors pertaining to why participants may favor virtual learning. More than 50% of participants stated that it is more comfortable, time-saving, provides time for students to do self-study, and of course since the lectures are recorded students can review them as many times as desired to get a better understanding, thus improving students’ engagement. This does however raise the question of how actively all students are engaging in the online sessions. Meeting and communication tools such as Collaborate, Zoom, and Microsoft Teams have features to promote active learning through audience participation, offering the possibility of enhancing engagement through student participation. However, it has been suggested that involvement in an online learning session is not necessarily the same as engagement, and the more vocal students are often those who are only engaging in learning at a surface level.26 Students who have a lower profile may well still be learning and benefitting from the experience27, even if not contributing to the group activity. Emphasizing participation and rewarding this behavior does not recognize differences in learning processes, where students may be exhibiting a choice to learn in silence.28 Many students prefer to remain anonymous, preserving their privacy and perceived safety, and find their silence empowering.29 Furthermore, enforced participation can lead to disengagement.30 Encouraging rather than rewarding anonymous participation may, therefore, improve engagement. However, it does beg the question of whether or not students should be judged on their level of engagement and participation and whether participation in these online sessions is a sensible way to assess if they are helping the students achieve the learning outcomes for the session. Among those who chose ‘not recommended’ (36%), they found online teaching ‘stressful’ (20%), ‘complicated’ (15%) and ‘cannot learn this way’ (14%) was the highest rated response, and therefore it is essential to identify factors of stress that negatively influence the students’ learning which may guide the faculty to make certain modifications to make this mode of learning less stressful and more interesting for students.\n\nOverall, the method of using a questionnaire in this study was successful in exploring students' perceptions of their learning experience. It also explored their opinion about the most effective way to maximize their learning. Based on the findings, the results guided us to consider the modification of a range of areas related to students’ learning, including assessment and feedback mechanism, approaches to teaching, and improving students’ engagement and professional development, which would enhance the learning experience and cater for the diversity of students within the program.\n\nThis is a small study but will feed into the curriculum development of the different courses across a range of programs. There is a growing appreciation that a student’s attitude can have an impact on a student’s achievement, thus consideration of incorporating these findings when designing a curriculum will be highly beneficial.\n\nFurthermore, this study will also benefit the students who are stakeholders in higher education institutions and who are considered to be one of the vital contributors to this educational inquiry. It is hoped that this study will benefit the students who participated as their institutions make changes to courses. The findings from this exploration of students’ attitudes can support the development of a positive online learning experience, as well as guide the faculty members in designing their course specifications and program curricula to best utilize the virtual learning environment and systems. It has shown that if students and faculty members are treated not simply as stakeholders but as partners, teaching and learning strategies will be enhanced further in relation to online education.31\n\n\nStudy limitations\n\nThere are vast limitations to this study. The number of participants was around 20% less than expected. This may be due to multiple factors including the more stressful and unprecedented situation students are experiencing during the pandemic. The questionnaire was kept short and took no longer than 5 minutes to complete. We know the students surveyed were in the last phase of the final examination and all other educational activities were concluded so it was more difficult to reach them.\n\nAnother limitation is related to the questionnaire used in this study. Although questionnaires and interviews are normally deemed to provide qualitative information, the use of a Likert-scale would allow the conversion of questionnaire data to numerical data.32–34 This scale is often a 5-point ordinal scale that respondents use to rate the degree to which they agree or disagree with a statement on a symmetric agree-disagree scale. This allows responses to be ranked, but strictly speaking, the distances between the different responses is not measurable or necessarily equal. Nevertheless, this is a technique frequently used in educational research to provide quantifiable data.35\n\nThe use of closed questions in the present study questionnaire that were incorporated in this inquiry is generally considered an effective and efficient technique. However, such questions could have risked being suggestive, allowing for misconceptions and missing crucial, pertinent, facts that the respondent would like to convey.36\n\nMoreover, the questionnaire used in this study was in the English language and therefore may be considered as one of the most important limitations as the participants’ native language is Arabic. They may, therefore, respond more accurately if the questionnaire was in the Arabic language or a bilingual version to ease the comprehension of the respondents.\n\nOverall, the majority of the students, 176 (62%), were satisfied with the online learning process which gave the same perception as presented by a recent study in Poland among medical students.37 We have learnt from this study that if it were to be conducted again, some modifications would need to be performed in the research design and tools to make this study more conclusive. For instance, collecting data from all students across the different programs in Saudi Arabia or to include faculty and other teaching staff to enhance the quality of online teaching and learning.\n\nThe findings also emphasize the role of faculty on influencing students’ experience by effective communication which also has greater impact on students’ learning.38 This also suggests that increasing the use of technology and faculty training will improve their teaching practice using technology.38 However, this needs a careful evaluation to identify areas of improvement in teaching, to have a positive effect on educational outcomes. In addition, further studies are needed to explore how the quantity and quality of technology use affect student learning outcomes over time and what type of technology may be more popular among students as well as faculty.39\n\nFurthermore, long term data may also guide higher education institutions to make informed judgments on faculty’s strengths and concerns about using technological tools for teaching.\n\n\nConclusion\n\nThe findings were intended to inform teaching practice and guide the faculty and staff to develop a mechanism that allows the students to share their learning experiences. Analyzing students’ perception across most of the health sciences programs in Saudi higher education institutions will provide evidence to support the faculties which are looking to increase students’ satisfaction and enhance the quality of the learning experience, which in turn should intensify students’ engagement.40 Sixty two (62%) percent of students were found to be satisfied with the e-learning process. Incorporating suitable survey practices will also guide the faculties to regularly review and modify the curriculum design and make both the module specifications and the teaching methods more learner or student-centered.41\n\nThe compelling trend towards the utilization of electronic resources in the field of education and the development in technology is appealing and challenging. One way to help improve and develop students’ intuitive minds in this modernized technological environment is by utilizing electronic resources to actively indulge students to facilitate effective teaching and learning processes through E-learning.42\n\nOverall, this study has helped researchers and faculties to identify strengths and also areas of improvement in the E-learning process, including encouraging faculties to think deeply into the restructuring of course learning objectives and teaching techniques to engage students and improve the wider learning process. Thus, the findings of this study can serve as a tool for others to develop programs that facilitate the advancement of E-learning into an effective mode of teaching and learning to enhance the range of methods of educational delivery in Saudi Arabia. Particularly in response to the present situation of the so-called “new normal” that is being caused by COVID-19 pandemic.\n\n\nData availability\n\nHarvard Dataverse V2: Perception on Online Teaching and Learning Among Health Sciences Students in Higher Education Institutions during the COVID-19 Lockdown – Ways to Improve Teaching and Learning in Saudi Colleges and Universities, https://doi.org/10.7910/DVN/3KJGBD V2; License CC0.43\n\nThis project contains the following extended data:\n\nFarooqi, Faraz (2021), “Perception on Online Teaching and Learning Among Health Sciences Students in Higher Education Institutions during the COVID-19 Lockdown – Ways to Improve Teaching and Learning in Saudi Colleges and Universities”, Mendeley Data, V1, https://dx.doi.org/10.17632/r9vkdj8pw6.1.44",
"appendix": "References\n\nCucinotta D, Vanelli M: WHO declares COVID-19 a pandemic. Acta bio-medica: Atenei Parmensis 2020 Mar 19; 91(1): 157–60. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: WHO Director-General's opening remarks at the media briefing on COVID-19-11 March 2020 Transcript.2020Reference Source [Last accessed November 25, 2020]\n\nVolery T, Lord D: Critical success factors in online education. Int. J. Educ. Manage 2000; 14(5): 216–223. Publisher Full Text\n\nNguyen T: The effectiveness of online learning: Beyond no significant difference and future horizons. MERLOT J Online Learn Teaching 2005; 11(2): 309–319.\n\nMay SC: A Comparative Analysis of Student Success and Perceptions of Engagement between Face-to-Face and Online College Courses. EdD Lindenwood University; 2019.\n\nIllieva T/Sofia University VEDAMO E-Learning Is Easy Available.Reference Source [Accessed: 22 June, 2020]\n\nAsiry MA: Dental students’ perceptions of an online learning. Saudi Dent J 2017; 29(4): 167–170. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAl-Asmari AM, Rabb Khan MS: E-learning in Saudi Arabia: Past, present and future. Near and Middle Eastern J Res Educ 2014; 18(2014): 2. Publisher Full Text\n\nAbedalla RW, Pinchot JL, Samrgandi N, et al.: Saudi Students’ Perceptions of Online Education versus On-ground Education in Saudi Arabia. In: Proceedings of the Information Systems Educators Conference ISSN 2014; (Vol. 2167, p. 1435).\n\nAlkhalaf S, Nguyen A, Drew S: Assessing eLearning Systems in the Kingdom of Saudi Arabia’s Higher Education Sector. In: International Conference on Intelligent Network and Computing (ICINC 2010) 2010.\n\nAlebaikan RA: Perceptions of blended learning in Saudi universities (Doctoral dissertation, University of Exeter).2010.Reference Source [last accessed on: July 15, 2020]\n\nSaudi Arabia closes schools over coronavirus concerns: Arab New Updated on March 9, 2020.Reference Source [last accessed on: July 15, 2020]\n\nHouse L, Weldon RN, Wysocki AF: Student perceptions of online distance education in undergraduate agricultural economic programs. J Agri Appl Econ 2007; 39(1379-2016-113002): 275–84. Publisher Full Text\n\nUry G, Ury C: Online, On-ground: What’s the difference. In The 21 st. Annual Conference on Distance Teaching and Learning 2005.Reference Source\n\nGeyer C: Distance Learning-Advantages and Disadvantages of Take-home Hardware. Vienna University of Technology .Reference Source [last accessed on: July 15, 2020]\n\nInstitute of Higher Education Policy: Quality on the line: benchmarks for success in Internet-base distance education.Washington, DC: Institute for Higher Education Accreditation; Retrieved October 4, 2003. Reference Source\n\nAnkuran D: Impact of Digital Social Media on Indian Higher Education: Alternative Approaches of Online Learning during COVID-19 Pandemic Crisis. Int J Sci Res Pub , 2020; 10(5): 604–611. Publisher Full Text\n\nLynch R: The relationship between academic self-regulation and online distance education.University of Southern California; 2003. Publisher Full Text\n\nBandura A: Self-efficacy: the exercise of control. New York: W. H. Freeman and Company; 1997.\n\nJurczyk J, Benson SN, Savery JR: Measuring student perceptions in web-based courses: A standards-based approach. Online Journal of Distance Learning Administration 2004; 7(4): n4.\n\nO’Neill G, McMahon T: Student-centred learning: What does it mean for students and lecturers.2005.\n\nLi Z, Qiu Z: How does family background affect children’s educational achievement? Evidence from Contemporary China. The Journal of Chinese Sociology 2018 Dec 1; 5(1): 13. Publisher Full Text\n\nGonzález A: Turning a traditional teaching setting into a feedback-rich environment. International Journal of Educational Technology in Higher Education. 2018 1; 15(1): 32. Publisher Full Text\n\nShih JL, Hwang GJ, Chu YC, et al.: An investigation-based learning model for using digital libraries to support mobile learning activities. The Electronic Library 2011 Aug 9. Publisher Full Text\n\nAlwraikat M: Smartphones as a new paradigm in higher education overcoming obstacles. International Journal of Interactive Mobile Technologies 2017; 11(4), 114–135. Publisher Full Text\n\nMarton F, Säljö R: On qualitative differences in learning: I—Outcome and process. British journal of educational psychology 1976 Feb; 46(1): 4–11. Publisher Full Text\n\nBeaudoin MF: Learning or lurking?: Tracking the “invisible” online student. The internet and higher education 2002 Jun 1; 5(2): 147–55.\n\nGulati S: Compulsory participation in online discussions: is this constructivism or normalisation of learning?. Innovations in education and teaching international 2008 May 1; 45(2): 183–92. Publisher Full Text\n\nKelly GA: A brief introduction to personal construct theory. Perspectives in personal construct theory 1970; 1: 29. Publisher Full Text\n\nBrookfield SD: Understanding and facilitating adult learning. Milton Keynes: Open University Press; 1986.\n\nHealey M: Students as partners in learning and teaching in higher education. In: Workshop Presented at University College Cork 2014 Feb 4; (Vol. 12, p. 15).\n\nJamieson S: Likert scales: How to (ab) use them?. Med Educ 2004; 38(12): 1217–8. PubMed Abstract | Publisher Full Text\n\nLikert R: A technique for the measurement of attitudes. Archives of Psychology 193222(140): pp. 55.\n\nAli S, Alam BF, Farooqi F, et al.: Knowledge and Attitude toward COVID-19: A Cross-Sectional Study from Pakistan. Euro J Dent 2020 Dec 7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSullivan GM, Artino Jr AR: Analyzing and interpreting data from Likert-type scales. J Grad Med Educ 2013 Dec; 5(4): 541–2. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAkuratiya DA, Meddage DN: Students’ Perception of Online Learning during COVID-19 Pandemic: A Survey Study of IT Students. Tablet 57(48): 23.\n\nMcColl E, Jacoby A, Thomas L, et al.: Design and use of questionnaires: a review of best practice applicable to surveys of health service staff and patients. Health Technol Assess 2001; 5(31), pp. 1–256. PubMed Abstract | Publisher Full Text\n\nAbedini M, Abassi A, Mortazavi F, et al.: The Effective factors on the communication between students and faculty members from student's prospective in Birjand University of medical sciences. Procedia-Social and Behavioral Sciences 2013 Jul 4; 83: 94–8. Publisher Full Text\n\nLei J, Zhao Y: One-to-one computing: What does it bring to schools?. Journal of Educational Computing Research 2008 Sep; 39(2): 97–122. Publisher Full Text\n\nJones IS, Blankenship D: Learning styles, online courses, gender, and academic achievement of Hispanic students in higher education. Research in Higher Education Journal 2018; 35.\n\nClaxton CS, Murrell PH: Learning Styles: Implications for Improving Educational Practices. ASHE-ERIC Higher Education Report No. 4, 1987.1 Dupont Circle, Suite 630, Washington, DC 20036: Association for the Study of Higher Education; 1987.\n\nFarooq I, Ali S, Moheet IA, et al.: COVID-19 outbreak, disruption of dental education, and the role of teledentistry. Pak J Med Sci 2020; 36(7): 1726–1731. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFarooqi F: Perception on Online Teaching and Learning Among Health Sciences Students in Higher Education Institutions during the COVID-19 Lockdown – Ways to Improve Teaching and Learning in Saudi Colleges and Universities. Harvard Dataverse, V2, UNF:6:zXPr8Ma5Apphg+IXa5IZfA== [fileUNF], doi: 10.7910/DVN/3KJGBD. 2020. Publisher Full Text\n\nFarooqi F: Perception on Online Teaching and Learning Among Health Sciences Students in Higher Education Institutions during the COVID-19 Lockdown – Ways to Improve Teaching and Learning in Saudi Colleges and Universities Mendeley Data, V1, doi: 10.17632/r9vkdj8pw6.1. 2021. Publisher Full Text"
}
|
[
{
"id": "80947",
"date": "05 Mar 2021",
"name": "Muhammad Naveed Anwar",
"expertise": [
"Reviewer Expertise Data mining",
"data analysis",
"data science",
"big data",
"statistical analysis",
"online teaching and learning",
"online businesses",
"digital businesses."
],
"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 an interesting piece of work especially in the current scenario. It is good to see that the survey questionnaire and data for this study is accessible to other researchers for further work.\n\nThe title of paper mentions “Perception on online teaching and learning among Health Sciences Students...” but this research work does not discuss it. It can be removed from the title and from the text if it is not discussed.\n\nIt would be good to have chi-squared values but they are not provided.\n\nThe “Results” heading on the very first page needs +/-4.5 only 4.5 is not clear.\n\nThis paper needs proof reading.\n\nThere are some very small paragraphs; they need to be joined with other paragraphs or extended.\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": "6542",
"date": "07 Dec 2021",
"name": "Faraz Farooqi",
"role": "Author Response",
"response": "Dear Dr. Naveed, Thank you for your valuable suggestion to improve the study. We have modified the article as per your comments. Kindly note that p-values are mentioned within the text now and health sciences students is now mentioned as well. Thank you again for your time as well. Best regards."
}
]
},
{
"id": "80945",
"date": "11 Mar 2021",
"name": "Imran Alam Moheet",
"expertise": [
"Reviewer Expertise Dental Education",
"Tertiary education",
"Dental materials",
"biomaterials"
],
"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 authors have done a great job. It is a very important topic under the current circumstances.\n\nThe references need to be proofread again as all of them are not in the same format.\n\nThe conclusion is a bit long, The first two paragraphs of the conclusion seem to be part of the discussion; if possible rephrase or move it to the discussion.\n\nReferences should not be used in the conclusion unless the journal allows it.\n\nThe reason for referencing the article by Farooq et al. (20201) is that it contains relevant information regarding e-learning during covid-19 and it is very current (2020) and the authors should use it as a reference in their discussion instead of articles that are a decade old.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "6543",
"date": "07 Dec 2021",
"name": "Faraz Farooqi",
"role": "Author Response",
"response": "Dear Dr. Imran, Thank you for your time and efforts to review this article. The mentioned reference is already cited on position 42 in the discussion. Other valuable suggestions were also incorporated in the text. Thank you and best regards."
}
]
}
] | 1
|
https://f1000research.com/articles/10-177
|
https://f1000research.com/articles/10-1251/v1
|
07 Dec 21
|
{
"type": "Research Article",
"title": "Globalization and life lost due to tuberculosis: evidence from a multi-country study",
"authors": [
"Shyamkumar Sriram",
"Muayad Albadrani",
"Muayad Albadrani"
],
"abstract": "Background: Tuberculosis affects around 30% of the population of the world. Tuberculosis causes an increase in early mortality and thus has the potential to increase the number of years of life lost. Globalization directly or indirectly by affecting the factors that increase the susceptibility for tuberculosis infection has the potential to increase the spread and mortality due to tuberculosis. This study assessed the causal link between globalization and the years of life lost due to tuberculosis. Methods: Data from the Demographic and Health Survey (DHS) and World Bank for 2004 and 2005 were used for a number of covariates and possible mediators. Data from the Institute of Health Metrics and Evaluation (IHME) were used for the outcome variable and important globalization indicators. The primary health outcome that was studied is tuberculosis and the measure that was used to quantify tuberculosis mortality is the years of life lost (YLL). Path analysis was used. Results: The main independent variables of economic and social integration were not statistically significant. For every unit increase in the proportion of people that were using treated drinking water, there was a -0.0002 decrease in the YLL due to tuberculosis. For every unit increase in the proportion of people with earth floor, there was a 0.0002 units increase in YLL due to tuberculosis. For every unit increase in the proportion of people living using clean fuel, there was a 0.0004 decrease in the YLL due to tuberculosis. Conclusions: Social and economic globalization have no effect on the years of life lost due to tuberculosis, highlighting that globalization actually does not contribute to tuberculosis mortality. However, improving other important determinants such as sanitation, providing safe drinking water and clean households will reduce the mortality due to tuberculosis, highlighting the need to invest in them.",
"keywords": [
"Globalization",
"tuberculosis",
"Years of Life Lost",
"mortality"
],
"content": "Background\n\nTuberculosis (TB) is a disease that is caused by the bacteria, Mycobacterium tuberculosis. Tuberculosis affects around 30% of the population of the world.1 Incidence of tuberculosis is around nine million new cases every year.1 Studies globally show that tuberculosis causes an increase in early mortality and thus has the potential to increase the number of years of life lost. Annual mortality due to tuberculosis is around one and half million.1 The transmission of the disease is predominantly airborne in most of the cases and exposure to the disease agent is needed for any person to develop the infection or the disease.2 However, there are many individual, household and environmental factors that increase the susceptibility of the individual to develop the infection.3 Globally, the disease which had been controlled over the past two decades has shown to be reemerging in a number of countries, especially in the developing world.4–6 Globalization, specifically the negative effects and externalities of globalization have shown to increase the spread of a number of infectious diseases. Some studies have explored the effect of globalization on tuberculosis spread and found that globalization increases the spread of tuberculosis, especially in countries with poverty and poor health systems.7 Evidence also shows that globalization has also been found to have a negative effect on poverty specifically by increasing poverty for certain underprivileged sections of the population.8 Some of the factors which increase the susceptibility of an individual to develop tuberculosis such as living in over-crowded houses, having poor sanitation facilities, poor housing conditions, and the consumption of unsafe water are all directly related to the availability of household resources and poverty.7,9 Thus, globalization, by directly or indirectly affecting the factors that increase the susceptibility for tuberculosis infection, has the potential to increase the spread and mortality due to tuberculosis and in turn increasing the number of years of life lost.\n\nThere are many aspects and components of globalization. There is a constant movement of people across the globe (social globalization) and the flow of capital across countries (economic globalization).10 Both social and economic components of globalization have the potential to increase the spread of tuberculosis either directly by increased movement and contact of people or by causing changes in the economy which affects the factors that increase the susceptibility to develop tuberculosis. Evidence shows that in some populations globalization increased their economic conditions, while in others globalization reduced their economic status leading to an increase in poverty, unemployment, and unsanitary living conditions.11,12 There is only scarce literature linking globalization and tuberculosis.2,3,13–15 Current available literature on globalization and tuberculosis is able to only correlate the increase in globalization over the past decade and the increase in burden of tuberculosis in specific countries of the world. These studies failed to prove conclusively that globalization by itself leads to changes in the spread of tuberculosis, although some patterns were observed. Also, the studies on globalization are more prone to confounding because of many unforeseen factors. Currently evidence on the effect of globalization on the mortality and years of life lost due to tuberculosis is lacking. This study aims to address this gap in literature through the empirical use of secondary data that is available from several international agencies to quantify and assess the causal link between globalization and the years of life lost due to tuberculosis.\n\n\nMethods\n\nThe secondary datasets used in this study are available in the public domain after all individual level identification variables were removed. It was not possible to identify the residence of any of the households as well. Therefore, ethical approval was not required for the study.\n\nNot applicable\n\nThis study examined the population globally representing 40 countries from every continent and every WHO region in the world. The specific age-group that was studied is the age group of 15 years and above. The primary health outcome that was studied is tuberculosis and the measure that was used to quantify tuberculosis mortality was the years of life lost (YLL). YLL for TB for 2010 was used in the study. Tuberculosis has an incubation period of a few months to about two years from exposure to the development of disease. The independent variables was studied for 2005. This five year gap not only provided the time for the disease to develop from exposure but also the period when there was a shift in the independent variables and the impact of those variables on the population health outcome, TB.\n\nThe DHS Program STATcompiler was used to extract the data from the DHS and World Bank. Data on the proportion of households with poor household sanitation, open defecation, safe drinking water, smoking cigarettes, literacy, type of cooking fuel, BCG vaccination, overcrowding, and unclean floors were obtained from the Demographic and Health Survey (DHS) for years 2004 and 2005. Data on the Poverty headcount and GNI per capita were obtained from the World Bank for the years 2004 and 2005. Data were assessed for a number of covariates and possible mediators. Data from the Institute of Health Metrics and Evaluation (IHME) were used for the outcome variable (Years of Life Lost due to Tuberculosis) and important globalization indicators (Economic globalization index and Social globalization index) for the year 2010 were used. The time-period for tuberculosis development varies. Tuberculosis has an incubation period of a few months to about two years from exposure to the development of disease. The effect of the key independent variable and other variables on the development of tuberculosis can be studied only if they are examined for at least three to five years before 2010 (the year when tuberculosis outcome is studied).\n\nThe key dependent variable was the Years of Life Lost (YLL) due to tuberculosis in 40 countries. The main independent variables included the variables of globalization index namely the variable for economic integration and social integration. The possible mediators included the variables for sanitation, clean drinking water, indoor air pollution (clean cooking fuel), and over-crowding.\n\nDescriptive analysis was be used to describe the trends in the data. Path analysis was used to study both the effect of the various independent variables on the outcome variable and also to study the effect of the globalization index variables (economic and social integration) on the mediator variables. Path analysis helped in understanding the directed dependencies among the different variables. Statistical software STATA (version 17) was be used for the data analysis.\n\n\nResults\n\nThe average overall proportion of population having improved household sanitation facility was 49.10% as shown in Table 1. Table 2 shows the descriptive statistics by country. In Jordan (99.6%), the highest proportion of population had improved sanitation facility while Madagascar (4.2%) had the lowest sanitation facility. The average overall proportion of people living in households treating drinking water was 66.77%. Egypt (95.5%) had the highest proportion of population living in households that were treating drinking water. The average overall proportion of people using clean fuel for cooking was 25.44%. The proportion varied from 99.9% in Jordan to none of the population having clean cooking fuel in Sierra Leone. The average overall proportion of population in households with seven or more persons sleeping per room was 2.50%. India had the highest proportion of overcrowding in houses, while Indonesia had the lowest overcrowding among the list of selected countries. The average overall proportion of people living in houses with earth/sand floors was 37.70%. Niger around 87.2% of the houses having sand floors, while Jordan had only 0.1% of the houses with sand floors. The average years of life lost due to tuberculosis was 0.0323 years with Indonesia facing the highest years of life lost due to TB, while counties like Guyana, Kenya, Peru facing the lowest years of life lost due to TB. The average economic integration score was 2.97. Uganda (4.92) had the highest economic integration, while Haiti (0.34) had the lowest economic integration. The average social integration score was 1.09. Uganda (6.90) had the highest social integration, while Nepal (0.03) had the lowest social integration.\n\nA path analysis model with an OLS regression component was used to study the effect of the main independent variables of globalization (economic and social globalization) and other covariates and potential mediating variables on the outcome variable of years of life lost due to tuberculosis. The results of the regression analysis are shown in Table 3. The main independent variables of economic and social integration were not statistically significant showing that they have no significant effect on the years of life lost (YLL) due to tuberculosis. Other possible mediator variables such as proportion of population having improved household sanitation facility did not have any statistically significant effect on the YLL due to tuberculosis. The variables of proportion of people living in households treating drinking water, the variable proportion of people using clean fuel for cooking and the proportion of people living in houses with earth/sand floors were statistically significant. For every unit increase in the proportion of people living in households that were using treated drinking water, there was a −0.0002 decrease in the YLL due to tuberculosis. For every unit increase in the proportion of people living in houses with earth or sand floor, there was 0.0002 units increase in the YLL due to tuberculosis. For every unit increase in the proportion of people living using clean fuel for cooking, there was a 0.0004 decrease in the YLL due to tuberculosis. The results of the path regression analysis show that economic integration had a positive impact on sanitation and a negative effect on water treatment and the proportion of households with sand floors. Social integration on the other hand seemed to have a negative impact on sanitation, while having a positive effect on the proportion of households that were treating water.\n\n\nDiscussion\n\nThe results of the study show that there is no effect of social and economic globalization on the years of life lost due to tuberculosis. Literature shows that there are no other studies that have explored this specific relationship of globalization in the context of years of life lost due to tuberculosis. However, there are other studies which have explored similar relationships between globalization and other diseases and outcome measures.10 For example, a study analyzed the effect of social and economic globalization on obesity and overweight and concluded that the different components of globalization increased the propensity of the individual to become overweight, especially among women.10 However, in this research, no such relationships could be established in the context of globalization and tuberculosis. This study shows that sanitary conditions in the household are not statistically associated with the years of life lost due to tuberculosis. However, other studies have shown that living in a household with good sanitary conditions not only decreased the propensity of developing tuberculosis but also reduced the mortality due to tuberculosis.9,16,17 This research also shows that people who are living in households that are consuming treated drinking water had lower years of life lost due to tuberculosis. This is consistent with findings in literature which show that households that consume boiled and treated safe drinking water had lower risk of developing tuberculosis and also associated lower mortality due to tuberculosis.16,18–20 The people who live in houses that have dusty environment with earth or sand floors have been found to have higher mortality due to tuberculosis and thus higher years of lost. This aligns with the findings from literature which show that living in an unclean and dusty environment increases the susceptibility of developing tuberculosis and also increasing the progression and severity of the disease leading to increased mortality.16,21 Houses with dirty floors and dust serve as a vehicle for transmission for tuberculosis, especially if the patient removes saliva or phlegm on the floor of the house. In addition, evidence shows that there is a higher probability of reactivation of tuberculosis infection among individuals who live in insanitary and unclean household conditions.22 Indoor air pollution has shown to be an important predisposing and enabling factor for tuberculosis.23,24 Usage of unclean cooking fuel which is rampant in developing countries is one of the important causes globally for indoor air pollution.25,26 This study also supports this finding. Households that use clean cooking fuel has been found to have lower years of life lost due to tuberculosis compared to households that used unclean fuel for cooking. This study shows that economic integration has a positive effect on sanitation. There is no specific literature which relates economic globalization with sanitation however some evidence shows that globalization increases household wealth in some populations, and this is directly proportional to increased levels of sanitation.15 The negative relationship between economic globalization and poor access to safe drinking water could not be supported by any evidence from literature. In this study, social integration has a negative impact on household sanitation. Although no specific evidence linking social globalization and household sanitation could be found, some evidence from literature show that globalization has the potential to push certain groups of the population into poverty which reduces their financial capacity to maintain proper hygiene and sanitation in the household.8,11,12,27–30\n\n\nConclusions\n\nThis study provides vital analysis into the different aspects of globalization and their effect on tuberculosis spread in many countries across different continents. This will help in global policy making regarding infectious disease spread. Social and economic globalization have no effect on the years of life lost due to tuberculosis, highlighting that globalization actually does not contribute to tuberculosis mortality. This will help in clearing the common myth that globalization is one of the main reasons for tuberculosis spread across national borders. However, improving other important determinants such as sanitation, providing safe drinking water and clean households will reduce the mortality due to tuberculosis, highlighting the need to invest in them. In conclusion this research could not find any relationship between globalization and the years of life lost due to tuberculosis. More research is needed to understand the mechanism in which social and economic globalization influence tuberculosis specifically the years of life lost due to tuberculosis.\n\nThe main strengths of this study include the use of secondary data from multiple international agencies which have a reliable and robust method of data collection and adequate data quality control mechanisms in place. The study also considers the adequate time lag between the independent variables (exposures) and the health outcome to develop. The main limitations of this study also arise from the use of secondary data. Any study that uses secondary data suffers from this limitation, i.e., the study becomes limited by the data collected and survey methodology used. The contents and the questions asked in the survey limits the extent of our research questions to fit the data that is available for analysis. Also, cross-sectional data has been used for the study and thus no follow-up over time has been done. This cross-sectional nature of the data creates an important limitation that it allows to study only the association and not actual causation of mortality due to tuberculosis because of globalization to be established. Cross-sectional data cannot infer causal association mainly because temporality is not known and thus cannot assess the change in outcomes over time. The limitations of the model include the use of path regression analysis. Although the OLS component of the path regression model can be used to establish association between the outcome variable and the various independent variables, but path analysis is not a causality test so the causal associations of the potential mediating variables cannot be ascertained.31\n\n\nData availability\n\nThe DHS Program STATcompiler was used to extract the data from the DHS and World Bank. Data on the proportion of households with poor household sanitation, open defecation, safe drinking water, smoking cigarettes, literacy, type of cooking fuel, BCG vaccination, overcrowding, and unclean floors were obtained from the Demographic and Health Survey (DHS) for years 2004 and 2005. Access to the dataset requires registration and is granted only for legitimate research purposes. A guide for how to apply for dataset access is available at: https://dhsprogram.com/data/Access-Instructions.cfm. Data on the Poverty headcount and GNI per capita were obtained from the World Bank for the years 2004 and 2005. World Bank data is available for open access. Poverty headcount data is available at: https://data.worldbank.org/indicator/SI.POV.DDAY and GNI per capita is available at: https://data.worldbank.org/indicator/NY.GNP.PCAP.CD. Data from the Institute of Health Metrics and Evaluation (IHME) were used for the outcome variable (Years of Life Lost due to Tuberculosis) and important globalization indicators (Economic integration and integration) for the year 2010 was used. Data can be obtained from the IHME website: http://www.healthdata.org/.",
"appendix": "References\n\nWorld Health Organization: Global Tuberculosis Report 2020. Accessed on 15 May 2021. Reference Source\n\nSelgelid MJ: Ethics, Tuberculosis and Globalization. Public Health Ethics. 2008; 1(1): 10–20. Publisher Full Text\n\nFanning EA: Globalization of tuberculosis. CMAJ. 1998; 158(5): 611–612. PubMed Abstract\n\nPorter JD, McAdam KP: The re-emergence of tuberculosis. Annu. Rev. Public Health. 1994; 15: 303–323. Publisher Full Text\n\nBorgdorff MW, van Soolingen D : The re-emergence of tuberculosis: what have we learnt from molecular epidemiology?. Clin. Microbiol. Infect. 2013; 19(10): 889–901. PubMed Abstract | Publisher Full Text\n\nBrennan PJ: Tuberculosis in the context of emerging and reemerging diseases. FEMS Immunol. Med. Microbiol. 1997; 18(4): 263–269. PubMed Abstract | Publisher Full Text\n\nMarais BJ, Hesseling AC, Cotton MF: Poverty and tuberculosis: is it truly a simple inverse linear correlation?. Eur. Respir. J. 2009; 33(4): 943–944. PubMed Abstract | Publisher Full Text\n\nRahim HL, Abidin ZZ, Ping SD, et al.: Globalization and its Effect on World Poverty and Inequality. Global Journal of Management and Business. 2014; 1(2): 8–13.\n\nSingh SK, Kashyap GC, Puri P: Potential effect of household environment on prevalence of tuberculosis in India: evidence from the recent round of a cross-sectional survey. BMC Pulm. Med. 2018; 18(1): 66. PubMed Abstract | Publisher Full Text\n\nGoryakin Y, Lobstein T, James WPT, et al.: The impact of economic, political and social globalization on overweight and obesity in the 56 low and middle income countries. Soc. Sci. Med. 1982; 133(133): 67–76. Publisher Full Text\n\nWade RH: Is Globalization Reducing Poverty and Inequality?. World Dev. 2004; 32(4): 567–589. Publisher Full Text\n\nBasu K: Globalization, poverty, and inequality: What is the relationship? What can be done?. World Dev. 2006; 34(8): 1361–1373. Publisher Full Text\n\nSaleh J-E: Globalization and the Spread of Multi-Drug Resistant Tuberculosis. Journal of Health, Medicine and Nursing. 2015; 18: 20–24.\n\nGirardi E, Sañé Schepisi M, Goletti D, et al.: The global dynamics of diabetes and tuberculosis: the impact of migration and policy implications. Int. J. Infect. Dis. 2017; 56: 45–53. PubMed Abstract | Publisher Full Text\n\nLabonté R, Mohindra K, Schrecker T: The Growing Impact of Globalization for Health and Public Health Practice. Annu. Rev. Public Health. 2011; 32(1): 263–283. Publisher Full Text\n\nCardoso BA, Fonseca FO, Moraes AHAN, et al.: Environmental aspects related to tuberculosis and intestinal parasites in a low-income community of the Brazilian Amazon. Rev. Inst. Med. Trop. Sao Paulo. 2017; 59: e57-e. Publisher Full Text\n\nWorld Health Organization: Global tuberculosis report 2016. Geneva: WHO; 2016.\n\nClasen T, Pruss-Ustun A, Mathers CD, et al.: Estimating the impact of unsafe water, sanitation and hygiene on the global burden of disease: evolving and alternative methods. Tropical Med. Int. Health. 2014; 19(8): 884–893. PubMed Abstract | Publisher Full Text\n\nGreenberg AE, Kupka E: Tuberculosis Transmission by Waste Waters: A Review. Sewage Ind. Waste. 1957; 29(5): 524–537.\n\nVaerewijck MJM, Huys G, Palomino JC, et al.: Mycobacteria in drinking water distribution systems: ecology and significance for human health. FEMS Microbiol. Rev. 2005; 29(5): 911–934. PubMed Abstract | Publisher Full Text\n\nAditama W, Sitepu F, Saputra R: Relationship between Physical Condition of House Environment and the Incidence of Pulmonary Tuberculosis, Aceh, Indonesia.2019; 227.\n\nCardona P-J: Reactivation or reinfection in adult tuberculosis: Is that the question?. International Journal of Mycobacteriology. 2016; 5(4): 400–407. PubMed Abstract | Publisher Full Text\n\nPatel V, Foster A, Salem A, et al.: Long-term exposure to indoor air pollution and risk of tuberculosis. Indoor Air. 2021; 31(3): 628–638. PubMed Abstract | Publisher Full Text\n\nSchweitzer MD, Patel V, Mirsaeidi M, et al.: Does Indoor Air Pollution Enhance the Risk of Tuberculosis Infection? B63 LATENT TUBERCULOSIS INFECTION AND EPIDEMIOLOGY OF TUBERCULOSIS DISEASE. American Thoracic Society International Conference Abstracts: American Thoracic Society. 2017; p. A3983-A.\n\nFaizan MA, Thakur R: Association Between Solid Cooking Fuels and Respiratory Disease Across Socio-Demographic Groups in India.2019; 9(23): 190911.\n\nBates MN, Pope K, Sijali TR, et al.: Household fuel use and pulmonary tuberculosis in western Nepal: A case-control study. Environ. Res. 2019; 168: 193–205. PubMed Abstract | Publisher Full Text\n\nNjuguna J: Progress in sanitation among poor households in Kenya: evidence from demographic and health surveys. BMC Public Health. 2019; 19(1): 135. PubMed Abstract | Publisher Full Text\n\nDehury B, Mohanty SK: Multidimensional poverty, household environment and short-term morbidity in India. Genus. 2017; 73(1): 3. PubMed Abstract | Publisher Full Text\n\nMariwah S, Amo-Adjei J, Anima P: What has poverty got to do with it? Analysis of household access to improved sanitation in Ghana. Journal of Water, Sanitation and Hygiene for Development. 2017; 7(1): 129–139. Publisher Full Text\n\nGizaw Z, Addisu A: Evidence of Households’ Water, Sanitation, and Hygiene (WASH) Performance Improvement Following a WASH Education Program in Rural Dembiya, Northwest Ethiopia. Environ. Health Insights. 2020; 14: 117863022090310. Publisher Full Text\n\nHeise DR: Problems in Path Analysis and Causal Inference. Sociol. Methodol. 1969; 1: 38–73. Publisher Full Text"
}
|
[
{
"id": "102228",
"date": "14 Jan 2022",
"name": "Setya Haksama",
"expertise": [
"Reviewer Expertise Health Policy",
"Administration",
"and Disaster"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. All variables should be written clearly and systematically, first the independent variables should be described, then the dependent variables should be described.\n2. Resources of data from World Bank was too old.\n3. No data was obtained from 40 countries measured in relation to this research, there should be a ranking for each country that can indicate which countries have good scores and which countries have low scores.\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": [
{
"c_id": "7707",
"date": "17 Jan 2022",
"name": "Shyamkumar Sriram",
"role": "Author Response",
"response": "Multiple data sources from multiple agencies were used. Data from the World Bank for specific years was used to match the data availability from other agencies. Data could not be obtained for the specific years for some of the countries. So they were not used for the research. Different variables have been adequately described in the paper."
}
]
},
{
"id": "119876",
"date": "17 Jan 2022",
"name": "Mohamed Adil AA",
"expertise": [
"Reviewer Expertise Infectious Diseases",
"Biotechnology",
"Disease Transmission Dynamics"
],
"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 highlights important areas in the arena of globalization and the spread of infectious diseases.\nThe article particularly looks into data from a number of countries globally, thus increasing the validity and reliability of the study across continents and also globally.\n\nCould this study be replicated by using longitudinal data to establish causality and stronger inferences?\nDo the path regression results provide more robust results than OLS analysis?\nWhat was the main logic in choosing only a specific set of covariates and not all the possible covariates for tuberculosis?\n\nThis a good study and will help in addressing many lacunae in the area of global health research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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": "119880",
"date": "18 Jan 2022",
"name": "Arutselvi Devarajan",
"expertise": [
"Reviewer Expertise Interaction of Tuberculosis and Diabetes",
"Health Systems Research",
"Diabetic epidemiology",
"Pscyhosocial 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\nThis paper explored an important aspect of the public health issue of TB and its association with globalization.\nI have some suggestions for the authors:\nThe nature of data was cited as the reason for not being able to completely explain the causal link, I suggest the authors mention only association (as the data may exhibit some correlation but not causation) instead of the \"causal link\" in the objective.\n\nAlthough the current introduction is good, it would be better if there are more indirect indicators or covariates that affect tuberculosis incidence.\n\nThe methods section is good and elaborate. The aspects of globalization - economic and social, and other aspects of globalization could also be considered in this research or for future research.\n\nThe main outcome variable is Years of Life Lost due to tuberculosis. It would be much better if disability-adjusted life years could have been used in future papers to expand this research.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-1251
|
https://f1000research.com/articles/10-796/v1
|
12 Aug 21
|
{
"type": "Research Article",
"title": "Future land use change simulations for the Lepelle River Basin using Cellular Automata Markov model with Land Change Modeller-generated transition areas",
"authors": [
"Darlington Chineye Ikegwuoha",
"Harold Louw Weepener",
"Megersa Olumana Dinka",
"Harold Louw Weepener",
"Megersa Olumana Dinka"
],
"abstract": "Background: Land cover/land cover (LULC) change is one of the major contributors to global environmental and climate variations. The ability to predict future LULC is crucial for environmental engineers, civil engineers, urban designers, and natural resources managers for planning activities. Methods: TerrSet Geospatial Monitoring and Modelling System and ArcGIS Pro 2.8 were used to process LULC data for the region of the Lepelle River Basin (LRB) of South Africa. Driver variables such as population density, slope, elevation as well as the Euclidean distances of cities, roads, highways, railroads, parks and restricted areas, towns to the LRB in combination with LULC data were analysed using the Land Change Modeller (LCM) and Cellular-Automata Markov (CAM) model. Results: The results reveal an array of losses (-) and gains (+) for certain LULC classes in the LRB by the year 2040: natural vegetation (+8.5%), plantations (+3.5%), water bodies (-31.6%), bare ground (-8.8%), cultivated land (-29.3%), built-up areas (+10.6%) and mines (+14.4%). Conclusions: The results point to the conversion of land uses from natural to anthropogenic by 2040. These changes also highlight how the potential losses associated with resources such as water that will negatively impact society and ecosystem functioning in the LRB by exacerbating water scarcity driven by climate change. This modelling study provides a decision support system for the establishment of sustainable land resource utilization policies in the LRB.",
"keywords": [
"CA-Markov",
"future land use/land cover",
"Lepelle River Basin",
"land change modeller."
],
"content": "Introduction\n\nSocioeconomic activities together with related human population increase and general increase in urbanization, elucidated by the rate of expansion of cities globally, result in unimaginable land use/land cover (LULC) changes. The United Nations projects that the world will grow by 10% (from 7.7 billion in 2019 to 8.5 billion in 2030), to 26% by 2050 (9.8 billion), resulting in 10.9 billion by the end of the 21st century (42% increase)1. These increases are expected to be concentrated in nine specific countries, namely India, Pakistan, Egypt, Ethiopia, Nigeria, the Democratic Republic of Congo, Tanzania, Indonesia and the United States of America.1 More strikingly, the human population of India is projected to overtake China by 2027. Thus, human population growth in both urban and rural areas is one of the major reasons for rapid changes in LULC. Various natural types of land cover are being converted to urban residential areas and other human uses.1,2 Land conversion from its original use into another land use type is known as LULC change, which is a consequence of complex interactions between human activity and the physical environment.2\n\nAdvances in geospatial modelling have made it possible to simulate of land use change (LUC) at spatial scales. A method commonly used in simulation of LUC is based on cellular automata theory and the GIS framework found in TerrSet Clark labs 18.31.3 In recent times, the establishment of simulation models to monitor and simulate the changes in land cover has attracted local and global interest. Generally, most simulation approaches are duo-stepped: the first is the number of predictions, and the second is the simulation of the spatial patterns of the future. Attempts to incorporate LULC drivers with spatial patterns are very complex processes; hence they are few.\n\nLand use activities have a direct correlation with global warming via modifications to the ecosystem by, biodiversity, and biological degradation processes which ultimately impacts and contributes to climate change. For instance, at medium confidence level, research showed that agriculture, forestry and other land use forms accounted for around “13% of CO2, 44% of methane (CH4), and 82% of nitrous oxide (N2O) emissions from human activities globally during 2007-2016, representing 23% (12.0 +/- 3.0 GtCO2e yr-1) of total net anthropogenic emissions of GHGs21”.4\n\nThese changes lead to landscape alterations and negatively affect natural land surfaces. The loss of biodiversity, higher emission of greenhouse gases, degradation of soils and global climate change can be directly traced to negative LULC trends.5 It is therefore very important to understand the dynamics of LULC in terms of the causes, consequences, and sequence.6 In the last two decades, several models (such as analytical equation-based models, statistical models, evolutionary models, cellular models, Markov models, hybrid models, expert system models and multi-agent models) have attempted to analyse and predict future LULC with varying degrees of success.2,7 Within Africa, a few studies have used the Markov chain model (e.g.8,9) while only a handful in the environmental discipline (such as Kamusoko et al. 2009; Mashapa et al. 2021) have used the Cellular Automata-Markov (CAM) approach. This study also uses the CAM model. Both the Cellular Automata (CA) and Markov model have great advantages in the study of LUCs, albeit both have respective disadvantages (see Hasan et al. 2020). The Markov chain model has been widely used to determine LUCs, however, the traditional Markov chain model has slight difficulty in predicting the spatial pattern of LUCs. The CA model, with powerful spatial computing capabilities, simulates spatial variation of systems more effectively.2,13\n\nThe CA–Markov model provides a robust approach for the spatial and temporal modelling of LUCs because the Markov model outputs and GIS-based Land Change Modeller (LCM) results can be incorporated effectively.2 The CA–Markov model incorporates the benefits from the time series inherent in the multi-layer perceptron (MLP) neural networks training parameters and spatial predictions of the CA theory.3 In this study, the LULC of the Lepelle River Basin (LRB) is analysed using the GIS-based CAM module in Idrisi Clarks Lab 18.31 version.\n\n\nMethods\n\nThe LRB, formerly known as the Olifants River Basin, is one of Southern Africa’s most important catchments. Geographically, this river basin is in the north-eastern corner of South Africa and southern Mozambique bounded between coordinates 23°46′24.0″ S to 26°33′40″ S and 28°19′28.5″ E to 31°57′25.5″ E (Figure 1). The Lepelle River is approximately 770 km long and, with its tributaries, drains 54,570 km2 which is an area equivalent to the size of Slovakia or Croatia.14 Its waters irrigate farming across the western section of the Mpumalanga Province in South Africa and supply water to several coal-operated power stations in the area. The river also flows through the Limpopo Province’s platinum belt and supplies water to several mines. It then flows through the Drakensberg mountains and down the escarpment to irrigate farms in the “Lowveld” (situated in Mpumalanga Province of South Africa) and brings life to the Kruger National Park.14 Finally, it joins the Limpopo River in Mozambique, before flowing into the Indian Ocean south of Xai-Xai. This makes the river critical to the economies of both South Africa and Mozambique.15 The 30 dams along its course also provide water to three provinces during times of drought and approximately ten million people rely on this water.16\n\nFor this study, data already processed by the South African National Biodiversity Institute (SANBI) for 1990 and 2013-2014 were used for calibration, while the South African National Land-Cover (SANLC) datasets for 2018 were used for validation because of its superiority to the conventional supervised/unsupervised methods. This superiority arises from the fact that landscape mapping and consequently change detection in natural landscapes, such as woodland, grassland and shrublands etc. are typically more challenging; since these landscape features typically do not have ‘hard’ boundaries, but rather gradients, within which a class boundary must be defined. In addition, this challenge is often compounded as a result of inter-annual seasonal differences, and associated differences in interpretable spectral/spatial image characteristics. So, the SANLC 2018 data is better than the old conventional SANBI one because it has improved spatial, spectral and temporal capabilities such as being able to provide 20m resolution imagery compared to the 30m imagery from the old one.17 The models and algorithms used to generate the SANLC 2018 dataset are based on those used in the production of the SANLC 1990 and SANLC 2013-14 datasets, but were modified and adapted to suit the enhanced spatial, spectral and temporal characteristics of 20m resolution Sentinel 2 satellite imagery.17\n\n1990 and 2013-2014 datasets\n\nSANBI produced the 1990 and 2013/2014 dataset using the LANDSAT Thematic mapper 5 for the whole of South Africa. The production of the 1990 and 2013-14 SANLC datasets quantified landscape changes through a 25-year period with good spatial scale and detail.18 This process of generating the 1990 and 2013-14 SANLC dataset was possible because both datasets used equivalent image data and mapping procedures. Both datasets were analogous with detail, scale, and consistency of information and content.17 Both national land-cover (LC) datasets used semi-automated spectral modelling techniques to generate the basic LC components. These basic LC components form the basis upon which the more detailed final LULC data were deducted and classified. These quasi-automated LC mapping techniques offer a more efficient alternative to conventional classification techniques.17 Unlike the analyst-assisted pixel-based classifiers techniques, these automated techniques allow for rapid production of standardised, yet informative LC classifications. This facilitated the necessary standardised references from which landscape changes could be derived and quantified.17\n\n2018 dataset\n\nThe new SANLC 2018 dataset was generated from 20-meter multi-seasonal Sentinel 2 satellite imagery.17 The imagery adopted describes the full temporal range of available imagery acquired by Sentinel 2 spanning 01 January 2018 to 31 December 2018. The SANLC 2018 dataset relied heavily on the Oct 2020 gazetted land-cover classification standard (SANS 19144-2) having 73 classes of information and is analogous to the previous 1990 and 2013-14 SANLC datasets.19 The 1990 and 2013-14 South African National Land-Cover datasets which were used for the CAM, as the earlier and latter image, were both generated from 30 meter resolution collected from Landsat Thematic Mapper TM 5 imagery, as this was the best option available at that time of production, with regards to free-to-access, medium resolution imagery.17 The timely launch of Sentinel-2A in late 2015, and subsequently Sentinel-2B in early 2017, has resulted in it becoming accepted as the de-facto medium resolution imagery of choice for current and ongoing landscape mapping and classification in South Africa.17\n\nThe SANLC 2018 dataset which evolved from SANBI was generated solely using European Space Agencies (ESA) free-to-access Sentinel-2 satellite imagery, acquired during the period 1 January – 31 December 2018. Sentinel-2 imagery was chosen over Landsat 5 as the preferred source of imagery due to its improved spatial, spectral, and temporal capabilities, compared to Landsat.17 Sentinel 2A and 2B satellites are collectively able to provide 20-meter resolution imagery, containing 12 spectral bands, every five days, anywhere across the globe. This has enabled a full seasonal profile of image acquisitions to be used in the 2018 land-cover modelling procedures; as it has been possible to acquire as a minimum, at least one but often more cloud free image coverages per month, over all locations within South Africa, which is not possible with Landsat due to the significantly lower 16-day update cycle. Thompson17 indicates that the same Sentinel 2 only image content approach will be continued in all future SANLC datasets generated using the same modelling and production procedures in the production of the new SANLC 2018 dataset finalised and made publicly available on 1st October 2019 from https://egis.environment.gov.za/data_egis/data_download/current. It is worth noting that no effort was made to perpetrate the errors from the old dataset in the new data set.17 Also, the difference between this data sets are quite minute when compared individually\n\nImage processing and data analysis\n\nAccording to Thompson17 the generation of automated land-cover data in the new, Sentinel 2 based procedure involves two separate, but sequential processing steps. Firstly, fully automated image modelling procedures known as “New Development and Expansion Insights” (NDEI) hosted in the GEOTERRA Image spatial modelling software were used to generate what is referred to as the “spectrally-defined” base LC characteristics. These characteristics are the primary ‘building blocks’ which are used to describe the entire landscape in terms of primary cover characteristics such as woody vegetation, grasslands, bare or water-dominated surfaces etc. No attempt was made at this stage to define additional detail such as whether the tree cover was a natural forest, or a managed forest plantation etc.\n\nThe conversion of these primary ‘base’ land-cover classes into more detailed sub-classes, such as natural versus man-planted forest, occurred during the second step. In the second step, ancillary spatial datasets, referred to as ‘geographical masks’, available in ArcGIS were used to convert the base land-cover classes into more detailed sub-classes. The geographical masks define specific, pre-determined areas-of-interest within the South African landscape, within which the primary, spectrally defined base classes were de-constructed into more specific land-cover and/or land-use sub-classes. In each case, a specific set of modification rules which could be either multiplication, division, null set etc rule hosted in the Map algebra tool of ArcGIS were used to either amalgamate, sub-divide or re-allocate the primary, base-level class (es) to the required sub-class detail. The primary rationale behind the use of these geographical masks was to facilitate the delineation of sub-classes that could not be achieved using spectral data alone. This is because spectral data only describe the broad categories of the full landscape extent. Since many unrelated sub-classes can often share similar spectral characteristics (e.g., river water versus water-in-pans, or coastal dunes and sand-roads) the masks were needed.\n\nAutomated LC mapping models and associated procedures were used in the production of the SANLC 2018 dataset.17 These utilise both cloud-based image archives and cloud-based geo-data computing capabilities. However, the final compilation and merging of the different land-cover and land-use information components (i.e., water, mining extent, forest plantations etc), were completed in a conventional desktop environment. GEOTERRA Proprietary software’s automated modelling capabilities were employed in these desktop environments.17 This design was used so that the entire workflow could eventually be migrated to cloud-based technologies and become a fully automated process to allow the SA Government to generate comparable South African National Land-Cover datasets in the future. This process (termed “CALC” for Computer Automated Land-Cover”), is projected to enhance the generation of a new, updated SANLC 2020 dataset in early 2021 due to its ability to easily detect boundaries and/or unique (image) spectral characteristics.\n\nThe models and algorithms used to generate the SANLC 2018 dataset are based on those used in the production of the SANLC 1990 and SANLC 2013-14 datasets but have been modified and adapted to suit the enhanced spatial, spectral, and temporal characteristics of 20m resolution Sentinel 2 imagery, as opposed to the 30-meter resolution Landsat imagery previously used. The overall concept and approach to land-cover and land-use modelling is, however, essentially the same as that used in the production of the previous SANLC 1990 and SANLC 2013/14 datasets. However, the LULC classes obtained from the SANLC (47-class categories) were still too many and would have resulted in too much computation by the CA-Markov model, hence, they were reclassified into seven main classification types, as defined in Table 1, using ArcGIS Pro 2.8. QGIS can also be used to generate the results as a free alternative to ArcGis Pro.\n\nGeneral requirements in the detection and prediction of LULC studies are measures of accuracy and validation of the classification model. The SANLC 2018 map accuracy was determined on a reduced 47 categories rather than the full 73 × class mapping legend.17 This simplified map accuracy legend was developed to exclude any potential sources of error resulting from temporary differences between the date of reference data acquisition and image-generated land-cover content, such as clear-felled plantation stands. In addition, certain levels of sub-class detail, such as the dominant vegetation type associated with different residential areas, was generalised into a more broadly representative ‘Built-up’ class.17\n\nAccording to Thompson (2019) the reference points for the SANLC 2018 map accuracy assessment are captured and spatially located primarily from the 2018 Sentinel 2 20m resolution digital image tiles. Where necessary, additional visual reference was made to high resolution Google Earth imagery and associated Street View @ ground photography.17 The overall map accuracy for the SANLC 2018 land-cover dataset of South Africa, calculated on the 47-x class accuracy legend is 90.14%, with a mean class accuracy of 89.63%, and 90% confidence limits of 89.65 – 90.62 %. A kappa index of 89.91 was achieved”.17\n\nLULC change modelling\n\nLULC change was analysed using Land Change Modeler (LCM) in the TerrSet (AKA IDRISI) software, which is a stepwise empirically-driven model which follows three broad steps of 1) Change analysis, 2) Transition potential computation and 3) Change prediction to generate future land cover map.3,20\n\nThe transition potential of each LULC class was used by the LCM model to generate transition areas for the LULC classes for 2018. These areas are then used by CAM as input areas for generating the 2018 LULC map by making use of the Transition suitability map. It was originally developed to manage biodiversity influences, and to analyse and forecast LULC changes.12,20 This model is based on the Artificial Neural Network (ANN), Markov Chain matrices, and transition suitability maps, generated by training with MLP or logistic regression.3 This model attempts to predict the LULC changes from the thematic raster images having the same number of classes, same extent (same rows and columns), same resolution, and same sequential order.12,21 QGIS can be used as a free alternative to TerrSet to generate the results.\n\nCA-Markov model\n\nMarkov chain analysis is a very useful tool for estimating Probability Distribution Functions (PDFs) of potential outcomes and has been applied widely to land cover change modelling.22 It assumes that the probability of a system being in a certain state at a certain time can be determined if its state at a previous time is known if rates of change through the calibration period will remain constant throughout the simulation period. Through a process of cross-tabulation of land cover areas Markov chain sequence estimates the amount of land cover change that will occur to the future date.3 The main approach of the Markov chain, which is a component of the CAM, is the generation of transition areas and a probability transfer matrix for the prediction of future land use/cover change trends. The Markov chain model can be summarized as timelines T0T1T2andTnwhere the current timeline is Ti which can be transformed to a future point in time Tj by the transition probabilities Pij. Therefore, timeline Ti+1 in the system can be computed by the former timeline Ti in the Markov chain using equation (1) below.\n\nWhere P = Probability matrix in the Markov model\n\nLow and high probabilities are bounded by 0 and 1, respectively.\n\nThe Cellular Automata (CA) model is a bottom-up dynamic model that integrates the spatiotemporal dimension and thus incorporates direction. Importantly, CAM simulates the space-time complexity even though space–time and state are discrete.23,24 This allows for a more accurate demonstration and simulation of the spatial and dynamic processes in LULC. The CAM model mainly contains cells, cell space, neighbours, rules, and time. The neighbours are identified by the filter of the CA model. The closer the distance between the central cell and its neighbour, the greater the weight factor. This agrees with Tobler’s first law of geography, which says that all things are related but nearer things are more related than distant things.25\n\nThe CAM model is a mixture between cellular automata and Markov chain nested within the TerrSet Geospatial Monitoring and Modelling System (TGMMS). The TGMMS model processes raster data such as ‘geotiff’ format data processed in ArcGIS Pro in the TerrSet Clark lab software module. The transition areas of the Markov chain model are normally used as inputs for the CA model.26 However, the transition areas file generated alongside a probability matrix in the LCM module is more suitable as an input for the CA-Markov than the conventional transition areas from Markov chain model. This can be attributed to the MLP machine learning process executed by LCM forced against the driving factors. To determine these, the LCM utilises the TerrSet’s Markov module at the time a prediction is run. According to Eastman (2016). Markov calculates using the earlier and latter images how much land will be expected to transition from the latter image to the prediction date based on transition potentials into the future.\n\nAn important aspect of any modelling or prediction is the validity or confidence level of the prediction. Kappa statistics is one of the validation tools embedded in the Idrisi module alongside the CA-Markov model. Kappa statistics provide a quantitative measure of the goodness of fit or the best value between the predicted model and the observed maps, revised for precision by possibility in the form of Kno (overall accuracy), KLocation (kappa for grid cell level location), KLocation strata (kappa location strata), and Kstandard (kappa standard). The Kappa values are bounded by 1 and -1, where positive values show, by chance, rare greater improved agreement, and negative values indicate a lack of or bad agreement.12 Kappa values are categorised as poor (< 0.40), fair to good (0.40-0.75), and excellent (> 0.75).12\n\nThe CAM model also considers suitability of LUCs and the effect of natural, societal, and economic factors about LUCs. Based on previous research by Faichia et al. (2020) and the recent trend towards LUC (Hasan et al. 2020), this paper analysed the LUCs for the LRB in South Africa. This was based on the quantity of LUC characteristics of the structure and spatial pattern as the primary research content. The CAM model combined with GIS was selected to capture the complex dynamics of the study area. The Markov model is better suited for long-term forecasts, effectively simulating the spatial pattern of LUCs, with great science and practice. The norm when using CAM is to input the transition areas file generated by the Markovian transition estimator found within the Markov Chain module, however, the transition area file generated by the LCM can also be used in place of that from the Markovian estimator. This was done as certain studies12,27,28 have documented that MLP is much more efficient for calculating multiple transition potentials for shorter time periods with areas experiencing less landscape changes.29,30 Even though TerrSet’s Multi-objective Land Allocation (MOLA) helps to resolve conflicting factors when using the multi-criteria evaluation (MCE), the choice of which driver variable to include for a particular land category transition analysis is purely based on expert judgement. But with LCM, the MLP trains the driver factors and determines which to include into the computation for the transition potentials. To successfully simulate scenarios in CAM, a few things must be considered such as windowing, working directories and space available in disc. These factors must be considered, else frequent errors will occur leading to unexpected termination of the simulation. Windowing in TerrSet Clarks Lab is a way of fine-tuning the extent of a spatial image such that the number or rows and columns are the same. The working directory for any simulation in TerrSet Clarks Lab must be specified to avoid error due to missing data. Lastly, the space available should be preferably 100GB or more.\n\nLULC future scenarios\n\nLCM generates two predictors of future land cover namely soft prediction and hard prediction. Soft prediction, denoted by the potential to transition map, is a continuous mapping of vulnerability to change.3 It is computed by combining all the transition potentials to estimate the propensity to which the areas have the most favourable conditions to precipitate change. The soft predictor reveals the probability of a cell to experience land cover change. However, it does not provide an indication as to what the new land cover will be. Conversely, the hard prediction procedure is based on the MOLA module which negotiates a suitable compromise by optimizing the suitability of lands for each objective given the assigned weights matrix.3 Land allocation conflicts are resolved by allocating cells to the land cover class with the highest weighted transition potential, based on a rule of minimum distance to ideal point by assigning the weighted ranks described by Houet and Hubert-Moy (2006). Finally, the transition probability matrix generated from the Markov chain analysis informs how much land is allocated to a class for in the future. However, the transition areas generated by the LCM module were then captured as inputs into the CAM model. Figure 2 summarises the procedure for LCM/CAM.\n\nThe following procedures were executed to successfully run the LCM model: ArcMap Pro 2.8 was used to extract the 1990, 2013/14 and 2017/18 national LULC raster maps using parts of Limpopo, Mpumalanga, and Gauteng Province as the mask dataset. The maps were then reclassified in the classification types described in Table 1. The objective of reclassification into the seven classes (i.e. no data, natural vegetation, plantations, water bodies, bare land, cultivated land, built-up areas and mine sites) was to simplify the LULC classes and decrease processing time in the modelling. Once the data was obtained, the explanatory variables such as population density maps and restricted area maps e.g., parks were also produced. The reclassify tool in ArcGIS Pro 2.8 was used to reclassify the land cover into seven classes. This tool allows the user to assign new values to each existing pixel value in a raster image. The values can be allocated as ranges or individual values. The Euclidean Distance tool in ArcGIS Pro 2.8 calculates, for each pixel value, the Euclidean distance to the closest feature (road, town, park, railroad etc.). The distances are measured as the shortest line between the pixel and feature. The units are in the projection units of the raster (meters in this case). Figure 3 shows the derived driving factors for change in land use in the LRB.\n\nThe Transition Potentials tab in the LCM module cannot be accessed without first completing and saving the results in the change analysis step. In the change analysis step land cover maps having the same land use classifications of the area in question for two different years (1990 and 2013) were inputted into the model. The model computed the gains and losses between the years for each land use category. Once the gains and losses were computed one could now proceed to the transition potential tab. In the transition potential tab, transitions between the two land cover maps were divided into a set of sub-models where each sub-model was identified with the set of driver or explanatory variables in Figure 3 below. Transition potential maps for each transition were computed as an expression of time-specific potential for change in the form of a 7 × 7 matrix because. The 7 × 7 matrix is simply because the land use map was reclassified into seven land use categories as defined in Table 1 above.3 The Fuzzy facility within the MCE wizard which is also linked to the LCM transformed the driver variables into a standard between one and zero while the Cramer’s V assisted to explore the potential power of each of the driver/explanatory variables. Five dynamic variables (distance to rail, distance to towns, distance to city, distance to roads and population density) and four static variables (Elevation, slope, distance to highway and distance to parks) were added to the model either as static or dynamic components. Static variables are those aspects of basic suitability for the transition under consideration and do not change over time.3 Dynamic variables are drivers such as proximity to existing development or infrastructure which change overtime and are recalculated during a prediction. In LCM each transition was considered and computed as a separate sub-model by default, however, with MLP, multiple transitions can be grouped into a single sub-model if it is considered that they all result from the same underlying driving forces. Only MLP can be used to model multiple transitions in one sub-model.3\n\nAll map layers needed to run the LCM are imported in Idrisi from ArcMap. These maps are all raster images. The importation into Idrisi was done by using the import tool in Idrisi by choosing the government-data-provider format. Transition sub-models were created for the individual land use variables to compute the individual transition potential of a land class to another land class. These sub-models are created using the transition sub-model builder hosted within the LCM module by inputting the relevant driver variables which are most likely to precipitate change from one land use category to the other for instance from natural vegetation to Plantation driver variables such as to towns, population density can be used. This driver variables can be either static such as distance to towns or dynamic such as population density. To know which driver variable may be relevant, the Cramer’s V is used to test the explanatory strength of each variable in relation to the land use category. Generally, variables with Cramer’s V of up to 0.15 are useful while those with up to 0.4 are quite excellent. The transition sub-models were used to train the MLP neural network in order to produce an accurate transition potential value.\n\nThe land use data for 1990 was used as the earlier image while 2013/2014 was used as input for the latter image in LCM. A first prediction for 2018 was simulated using CAM but with LCM generated transition areas. The 2017/2018 data from SANLC was used to validate the model by running the KAPPA statistics. Other data such as Euclidean proximities which include distance to road, distance to railroad, distance to city, distance to highway, aspect, elevation, slope percent, population density and distance to parks (restricted areas) were used as explanatory driver variables. The driver variable weather static or dynamic which will influence the change in LULC was determined using Cramer’s-V in the LCM module.\n\nA transition suitability map was generated in the MCE sub-model using the Analytical Hierarchy Process (AHP) which is a method of organising and analysing complex problems by breaking them down into smaller problems in conjunction with MOLA to compute the suitability maps.32 These maps show the extent to which land use categories are able to transition into other land use categories. Maps for the seven classes were generated and merged into a 7-suit map using the collection editor tool. The MCE was fed fuzzy reclassified driving factors and constraints shown in Figure 3 above. The driving factor maps were produced using ArcGIS Pro 2.8 as stated earlier to indicate the shortest distance to the pixel and feature.\n\n\nResults\n\nA varying number of changes have occurred across the classes of land uses in the LRB between 1990, 2017/2018, and 2040. The charts for the gains and losses for the seven land uses categories are shown in Figure 4. The gains and losses between 1990-2013 show a slower conversion between land use categories compared to the changes between 2013 and 2018 while for 2017-2040 only vegetation category saw great changes.\n\nLosses are negative while gains are positive.\n\nTable 2 below shows the transition areas for 2018 which was used as an input parameter for the CAM model simulation. Table 2 is a table 7 × 7 matrix of area categories generated as potentials of LULC to change from one category state to the other e.g., Bare to Plantations is zero meaning no land is allocated for change between these categories from 2013-2018.\n\nThe KAPPA statistics for the cross-validation between the observed 2018 and simulated 2018 is seen in Figure 5. An excellent agreement was achieved with Kno= 0.9469 (Overall kappa). Kstandard= 0.9216, Klocation= 0.9415 and Klocation strata= 0.9415.\n\nTable 3 shows a summary of the percentage differences between the observed and simulated LULC areas for the years 2017/2018 and 2040. The percentage areas are well within the acceptable levels. The highest difference is +25.4% for 2018 (water) and +31.6% for 2040 (water), which is probably due to some slight error in reflection/refraction angle of water during digitization.33 All other percentage differences are minimal.\n\nFrom the prediction results more mines will sprout in the LRB by a further 124.5 km2, natural vegetation, and built-up areas will also increase by 3233.1 km2 and 285.3 km2, respectively. Lastly, plantations are projected to increase slightly by 19.1 km2.\n\nOnce validation was achieved, a predication of future LULC was carried out by first creating transition areas for 2040 and then predicting the 2040 LULC using CAM. The resulting map for 2040 LULC is shown in Figure 6, alongside the 1990, 2013 and 2018 LULC maps. In Figure 6, the 2017 class B represents the 2018 data by Thompson.17\n\nThe legends shown in Figure 6 above show which parts of the LRB comprises which land use category. The legend in Figure 6 have been shortened to accommodate the names in the figure but the full names and their aliases are as follows: Vegetation for Natural vegetation, Plantations for Plantations, Water for Water bodies, Bare for Bare land, Cultivated for Cultivated land, Built-up for Built-up areas, and Mines for Mine sites. One can see the changes in land use categories from 1990 to 2040 and the magnitude of these changes have been captured in Figure 4 above.\n\n\nDiscussion\n\nThe Lepelle River Basin has always been a mining area and hence it is often seen as the ‘powerhouse’ of South Africa. Eskom has nine major coal-fired facilities in the catchment. A percentage of the coal for these power generators comes from parts of the LRB as well.34 The diverse population groups living in the LRB and along the river in Mozambique all rely on the resources and services that the complex ecosystem in the LRB provides. The life-giving, livelihood-sustaining natural resources of the LRB and its associated ecological services are under threat. Unchecked pollution, inappropriate land resource use, weak and poorly enforced policies and regulations, and poor protection of habitats and biodiversity are degrading the LRB at an alarming rate. Factors such as mining of heavy metals, inappropriate land management, urban sprawl and unsustainable use of natural resources all affect the level of resources and services the ecosystem can provide.\n\nIt is therefore important to be able to predict for planning purposes the LULC for the future LRB. Hence the prediction for 2040 was carried out based on the assumption that the rate of change in the catchment will follow the same pattern in history into the next 18 years. Vegetation and built-up areas are projected to increase as seen in the result section. These increases in vegetation could be due to used up abandoned mines and lands rendered unusable due to mining activities as well as less cultivation. Water bodies in the region are projected to dwindle by 420.6 km2 while bare land and cultivated land areas are also on the decrease by 74 km2 and 3175.1 km2, respectively. These could be because of several factors such as increasing population, increasing mining activities and conversion of bare lands to built-up areas, which consequently is on the rise as well as the increase in the area being mined.\n\n\nConclusion\n\nThis study employed the 2018 LULC classes data derived using spectrally based modelling from Sentinel-2 spectral image as well as the SA 1990 and 2013/2014 data. These spectrally defined land-cover classes utilise time-dependent spectral differences exhibited by different landscape surfaces throughout the typical seasonal cycle. This utilisation is achieved by making full use of the multi-acquisition date image datasets into the modelling procedures, so that seasonal changes such as vegetation (or water) cover permanency and/or frequency of occurrence can be determined and leveraged. The overall accuracy for the data was 90.14%, with a mean class accuracy of 89.63%, and 90% confidence limits of 89.65– 90.62 %. A kappa index of 89.91 was achieved for the land classification. Also, a CAM was used to simulate the 2018 LULC for the LRB using the transition areas for 2018 generated by the LCM from machine learning process of MLP ANN. This simulation was carried out as a validation process since the observed 2017/2018 LULC were available. The overall validation Kappa (0.9469) was excellent. After the validation was achieved LULC for 2040 was successfully predicted using the same CAM. From the 2040 simulation, it is seen that built-up areas as well as areas being mined and under plantation will increase slightly while natural vegetation increases quite considerably due to used up abandoned mines less cultivation, perhaps due to inhabitants taking on mining jobs and other formal jobs than farming. The result reveals an array of losses and gains for certain LULC classes in the LRB by 2040: natural vegetation (gain 8.5%), plantations (gain 3.5%), water bodies (loss 31.6%), bare ground (loss 8.8%), cultivated land (loss 29.3%), built-up areas (gain 10.6%) and mines (gain 14.4%). These results indicate the conversion of land use from natural to anthropogenic use by 2040. These changes flag concerning losses associated with ecosystem resources such as water which will destructively impact human wellbeing in the LRB and other areas of the country by exacerbating water scarcity alongside climate change. The model was validated and serves as an appropriate decision support system for the establishment of sustainable land resource utilization policies and an early warning system for negative LULC change detection in the LRB.\n\n\nData availability\n\nSouth African National Biodiversity Institute (SANBI) 1990 and 2013-2014 datasets, and the South African National Land-Cover (SANLC) 2018 dataset are freely available from the GIS Data Downloads website from the Department of Forestry, Fisheries and the Environment (DFFE), Republic of South Africa: https://egis.environment.gov.za/data_egis/data_download/current. This is because the SANBI data formerly found on http://biodiversityadvisor.sanbi.org/online-biodiversity-data/ were migrated to the DFFE website.",
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}
|
[
{
"id": "95934",
"date": "05 Oct 2021",
"name": "Pieter van der Zaag",
"expertise": [
"Reviewer Expertise water resources management"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of the paper is nowhere explicitly formulated (at least I could not find it). A large part of the paper reports on findings done by some other body (e.g. the conclusion section reads the following two sentences, which refer to the SANLC2018 map made by Thompson (2019) [ref. 17]: “The overall accuracy for the data was 90.14%, with a mean class accuracy of 89.63%, and 90% confidence limits of 89.65– 90.62 %. A kappa index of 89.91 was achieved for the land classification” (which is a literal repeat of the same sentences written on page 5 in the section “data sets”). Such a sentence implicitly suggests that these results were based on work done by the authors of this paper, which, as I understand it, is not the case.\nThe paper does not explain before the Results section how the 2040 land use map was constructed. What I infer from the paper is the following: based on the observed land use change between the years 1990, 2013 and 2017/2018 as established by Thompson (2019) [ref. 17], the authors of this paper trained a model and used it to project a new land use map of 2040. This new map has a few surprising shifts in trends (2017/18 to 2040), compared to the preceding period (2013 to 2017/18):\nCultivated land: Whereas from 2013 to 2017/2018 the net change in total area of cultivated land increased significantly, between 2017/2018 and 2040 it sharply decreases\n\nWater: Whereas from 2013 to 2017/2018 the net change in total area of water increased, between 2017/2018 and 2040 it decreases\n\nVegetation: Whereas from 2013 to 2017/2018 the net change in total area with vegetation decreased, between 2017/2018 and 2040 it sharply increases.\nThe authors did not discuss these findings and do not explain in any serious manner why these land use trends (as modelled) changed so fundamentally.\nRemains the question: have the modelled changes of future LULC any real value, or are they just an artefact of the LCM, and are the authors just feeding a computer model (which was built by others) with some data (which they also got from others)?\nIf my previous observation is correct, this is not worth indexing.\nThe “Discussion” section (p.13) contains some sentences that were not investigated, and thus are in my view out of place (namely the following sentences: “Unchecked pollution, inappropriate land resource use, weak and poorly enforced policies and regulations, and poor protection of habitats and biodiversity are degrading the LRB at an alarming rate. Factors such as mining of heavy metals, inappropriate land management, urban sprawl and unsustainable use of natural resources all affect the level of resources and services the ecosystem can provide.”) These sentences may be factually correct, but they have not been related to the old and new land uses. In the last part of the discussion section (on p.14) a relation is mentioned, e.g. the “dwindling water bodies”, but these were erroneous, according to the 7th paragraph of page 11. So, this is highly confusing (and the comment no p. 11 is based on a wrong interpretation of the data presented in Table 3).\nThe last sentence of the “Conclusion” section (p.14-15) I found confusing. The authors claim that the validated model “serves as an appropriate decision support system for the establishment of sustainable land resources utilization policies …” If this were true, the authors have to (a) show that indeed this model is informing and influencing policy decisions, and (b) demonstrate that this indeed led to adequate results. They have done neither.\nBelow I list detailed comments.\nIn all, I find the paper very thin in contributing original data. The modelling results have not been critically discussed. I therefore do not see merit for indexing it in a science journal.\nSome detailed comments:\np.1: Second sentence in the conclusions section of the abstract is grammatically incorrect\n\np.3: It is stated in the 1st paragraph that “the world will grow by 10%”. Do you mean: the world’s population?\n\np.3, 3rd paragraph: it is stated or suggested that land use activities have a direct correlation with global warming and that this all contributes to climate change. So this suggest that there are no land use activities that have a negative (and carbon-absorbing) impact on climate change. This is obviously incorrect.\n\np.3, 4th paragraph, 1st sentence: this is a problematic sentence. Which changes are meant here? Land use changes or climate change or both?\n\np.4-6; The entire section “Data sets” (p.4 and 5) and the subsection “Data analysis and interpretation; image processing and data analysis” (p.5-p.7) reports work done by others than the authors of this paper. Correct?\n\np.9, 2nd paragraph: somewhere there is a word “because.” At the end of a sentence.\n\np.12, Figure 4: does this Figure contain data that the authors did not generate themselves? If so, the source of the data should be explicitly acknowledged.\n\np.12, Table 2: First, does this Table contain data that the authors did not generate themselves? If so, the source of the data should be explicitly acknowledged. Second, is the title of the table correct? I think it is not, as it refers to a transition, but it doesn’t make explicit which transition it concerns. Third, add units: what do these numbers represent?\n\np.13, Figure 5: we do not need a screenshot of a computer programme to report a few indicators, which are reported in the text on p.11, 6th paragraph\n\np.13, Table 3: First, we need to clarify who produced which data that are presented in this table. For me this was not clear, and this needs to be clarified, and those data produced by some other body need to be acknowledged explicitly. Second, we need units for each column with numbers. Third, the “Area difference” reported in columns 4 and 5 is fundamentally different from the “Area difference’ reported in columns 7 and 8. The former serves as a kind of validation; they report the difference in observed (column 2) and modelled (column 3) areas for the period 2017/18 and 2018. The latter reports the change in land use between the land use observed in 2017/18 (column 2) and the modelled land use in 2040 (column 6). Fourth, the signs of these “area difference” was confusing to me; positive means, in the former case, that the simulated/modelled land use in 2018 was smaller than the observed land use in 2017/18; positive means, in the latter case, that the simulated/modelled land use in 2040 was smaller than the observed land use in 2017/18. Rather counterintuitive.\n\np.14: In the “Conclusion” section: “bare ground (loss 8.8%)” should read: “bare ground (loss 18.8%)”\n\np.15-17: The “References” list contains references that are incomplete (e.g. #16 and #19 do not mention the source).\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? Yes\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "7278",
"date": "06 Oct 2021",
"name": "Darlington Chineye Ikegwuoha",
"role": "Author Response",
"response": "I disagree with some of the comments of the reviewer. This is because the purpose of this study was not to generate historical LULC data for the LRB. The target of the study was thus to: Calibrate the model i.e., generate data from the model that will be very close to the one generated by (Thompson. M.2019 Ref 17). Hence the data by Thompson was used as the reference data (observed data). To generate future data for the year 2040 based on the successful calibration of the model following the methods as specified in the topic of the journal article."
}
]
}
] | 1
|
https://f1000research.com/articles/10-796
|
https://f1000research.com/articles/10-1244/v1
|
06 Dec 21
|
{
"type": "Systematic Review",
"title": "Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review",
"authors": [
"Ponco Birowo",
"Isaac Ardianson Deswanto",
"Widi Atmoko",
"Nur Rasyid",
"Isaac Ardianson Deswanto",
"Widi Atmoko",
"Nur Rasyid"
],
"abstract": "Background: Infertility has been a significantly growing problem worldwide, affecting approximately 10-15% of couples within reproductive age. Among the many causes of male infertility, Y-chromosome microdeletion is considered one of the most frequent genetic causes. Thus, this systematic review was constructed to determine the prevalence of Y-chromosome microdeletion and the population variations in the different types of Y-chromosome microdeletions. Methods: We searched the PubMed, Scielo, and Science Direct databases to obtain articles that addressed the frequency of Y-chromosome microdeletion and male infertility. We identified 14 articles that originated from China, India, Iran, Brazil, Indonesia, North America, South Korea, and Slovakia, and the vital information collected included the year of publication, authors, number of patients with different types of Y-chromosome microdeletions, and the proportion of microdeletion in the major affected sub-regions of the Y-chromosome. Results: In this review, we attempted to highlight the variation in the frequency of Y-chromosome microdeletion in different geographical populations. The highest and lowest frequencies of Y-chromosome microdeletion were found in Indonesian (23.94%) and Slovakian (3.5%) populations, respectively. Conclusion: In conclusion, Y-chromosome microdeletion was undeniably found to be one of the leading genetic causes of male infertility. Azoospermic factor c (AZFc) microdeletion was the most frequent type of Y-chromosome microdeletion, typically presenting in patients with various clinical manifestations that ranged from oligozoospermia to azoospermia and exhibiting the highest chance for sperm retrieval. This review will undoubtedly help clinicians in providing a more accurate consultation to their patients and determining the success rates of assisted reproductive technology.",
"keywords": [
"microdeletion",
"Y chromosome",
"azoospermia",
"oligozoospermia",
"male infertility"
],
"content": "Introduction\n\nInfertility has been a major growing problem worldwide, affecting approximately 10-15% of couples within reproductive age; approximately 30-50% of these cases are attributable to male factors.1 Among the many causes of male infertility, Y-chromosome microdeletion is considered one of the most frequent genetic causes.2 The Y-chromosome, consisting of a short arm (Yp) and a long arm (Yq), has been long known as one of the sex-determining chromosomes. Y-chromosome microdeletions are interstitial deletions that occur in the azoospermic factor (AZF) region in the Yq. Microdeletions affect testis development, consequently leading to the manifestation of azoospermia or oligozoospermia in the affected patients.3,4 Clinically, there are three important non-overlapping regions in the AZF gene, including the azoospermia factor a (AZFa), azoospermia factor b (AZFb), and azoospermia factor c (AZFc), and they correspond to five microdeletion patterns, AZFa, AZFb, AZFc, AZFbc, and AZFabc.4\n\nY-chromosome microdeletion testing is considered an essential part of infertility evaluation of severely oligozoospermic or azoospermic men. This is especially true for couples who are considering using assisted reproductive technology [(ART - in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)].5,6 However, Y-chromosome microdeletion analysis is not a common practice in various infertility centers despite its acknowledged benefits. This is attributable to the cost imposed on the patients and the limited coverage of this examination by most existing health insurance companies.7 One other possible reason for this variation in Y-chromosome microdeletion testing is the differing frequencies of Y-chromosome microdeletions in different geographical areas. Smaller studies from various countries have shown that the frequency of Y-chromosome microdeletion ranges from 1-14%.8 This indicates that the cost-effectiveness and necessity of this particular test are deteriorated in regions where Y-chromosome microdeletions are relatively less frequent.\n\nTherefore, this review was conducted to gather the most recent clinical evidences that document the prevalence of and population variation in Y-chromosome microdeletions; we attempted to highlight the variation in the prevalence of Y-chromosome microdeletion in different geographical populations.\n\n\nMethods\n\nSearch strategy and selection criteria\n\nThis systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines.9 A comprehensive literature search of three different databases (PubMed, Scielo, and Science Directs) was performed using the following keywords: “Y-Chromosome” OR “Y-chromosome” AND “microdeletion,” AND “male infertility”. The keywords were the same for all databases. The search was limited to studies published within the last 10 years. The articles included in this review were selected based on the following predetermined inclusion criteria: (1) articles written in English, (2) articles that addressed the frequency of Y-chromosome microdeletion and male infertility, and (3) original studies with readily available full-text articles. On the other hand, the exclusion criteria included: (1) other type of articles including letters to the editor, reviews, and editorials; (2) articles that included patients with chromosomal abnormalities; and (3) articles that included patients who had undergone radiotherapy and chemotherapy. Duplicated manuscripts obtained from more than one database were counted as only one article.\n\nInitial screening from titles and abstracts of the articles was done independently by two investigators (PB and IAD). The full texts of potentially relevant articles, or articles where no decision could be made from the abstract, were then reviewed. If there was any disagreement, the decision was made through discussion with other investigators (NR and WD). This search strategy yielded 141 results from the three above-mentioned databases, and three duplicated articles were automatically omitted. The abstracts of the remaining articles were screened to select the articles that were relevant to this review. As a result, 112 articles were excluded, leaving 26 articles for further investigation and evaluation of the full-text article. Finally, 12 studies were excluded, and 14 studies were found to be eligible for this review. The search strategy performed in this review is summarized in Figure 1.\n\nThe quality of each study was assessed using a tool developed by Hoy et al.10 to assess the risk of bias in prevalence studies. 10 domains were assessed based on internal and external validity of the studies: representativeness of the data, sampling methods, sample selection, likelihood of non-response bias, data collection, case definitions used, reliability and validity of the instruments, similarity of mode of data collection, length of prevalence period, and reliability of the calculations. Each domain was given a score of one (yes) or zero (no). Studies were classified as having low risk, moderate risk and high risk of bias if the overall score were >8, 6-8, and ≤5 respectively.\n\nThe data from the selected articles were then extracted independently by two authors (PB, IAS) using a standardized data extraction form that included the year of publication, authors, the number of patients with different types of Y-chromosome microdeletions, and the proportion of microdeletion in the major affected sub-regions of the Y-chromosome. Any discrepancy on the data extracted were solved by discussion and reference to the original article to meet the consensus.\n\n\nResults\n\nThe search strategy yielded 138 manuscripts from the three databases after omitting the duplicated articles, as previously mentioned. After a careful and thorough review of the titles, abstracts, and the main manuscripts, 14 articles were found to be eligible for this review; see flowchart.26 From these 14 articles, five manuscripts originated from China, two each from India and Iran, and one each from Brazil, Indonesia, North America, South Korea, and Slovakia. All the important data of these 14 articles were concisely summarized, as shown in Table 1. From the risk of bias assessment, no study was found to have higher risk of bias. 8 of 14 studies included have an intermediate risk of bias whereas the rest have a low risk of bias. Quality of assessment results are also summarized in Table 1.\n\nAZFa, azoospermia factor a; AZFb, azoospermia factor b; AZFc, azoospermia factor c.\n\nVariation in the frequency of Y-chromosome microdeletion in different geographical populations was observed. The highest and lowest frequencies of Y-chromosome microdeletion were found in Indonesian (23.94%) and Slovakian (3.5%) populations, respectively. AZFc microdeletions were identified as the most common Y-chromosome microdeletions, exhibiting the highest chance for sperm retrieval. The rates of Y-chromosome microdeletions, along with the percentages of the affected sub-regions of the Y-chromosome, in each country were listed and summarized in this review, as shown in Figure 2.\n\nThe figure is under the terms of the Creative Commons Zero “No rights reserved” data waiver. AZFa, azoospermia factor a; AZFb, azoospermia factor b; AZFc, azoospermia factor c.\n\n\nDiscussion\n\nApproximately 10-15% of couples within reproductive age worldwide face infertility problems. Male infertility contributes to approximately 30-50% of these cases.1 Y-chromosomal microdeletion is ranked second, after Klinefelter Syndrome, in the most common genetic causes of male infertility.6 Y-chromosome microdeletion affects testicular development greatly, phenotypically manifesting as azoospermia or oligozoospermia.4 The frequency of Y-chromosome microdeletion found in this review ranged from 1.7% to 23.9%. The high variability of Y-chromosome microdeletion among the different studies in this review mainly depended on the number of samples recruited in each study and the manner in which the samples were recruited. One study by Birowo P et al. in Indonesia reported the frequency of Y-chromosome microdeletion to be approximately 23.9% (17 out of 71 patients with non-obstructive azoospermia or severe oligozoospermia). Another study conducted by Saliminejad et al. in Iran showed that only 1.7% (2 out of 125) male infertility patients showed complete AZFc deletion. These two patients presented with non-obstructive azoospermia, while all other patients included in the oligozoospermia group in this particular study did not present with Y-chromosome microdeletions at all.16 Discrepancy in the frequency of Y-chromosome microdeletion was also observed in another study conducted by Totonchi et al. in a different institution in Iran. According to the results of this study, approximately 5.06% (185 out of 3654) infertile patients, enrolled from 2005 to 2011, were diagnosed with Y-chromosome microdeletion and a majority of the patients (74.96%) showed azoospermia.19 This discrepancy in Y-chromosome microdeletions was also observed among the studies conducted in different regions of China. For instance, Liu et al. conducted a retrospective study in southwestern China and found that 12.87% (185 out of 1274) infertile patients were diagnosed with Y-chromosome microdeletion.11 Another comparably large study conducted by Dai et al. in northeastern China reported the frequency of Y-chromosome microdeletion to be 4.8% (58 out of 1200 patients). This clearly showed that variation in the frequency of Y-chromosome microdeletion was observed in not only different countries, but also different regions of a particular country.\n\nA 10-year cohort study conducted by Stahl et al. in North America showed that AZFc Y-chromosome microdeletions harbor the most common type of Y-chromosome microdeletions [78 out of 149 patients (52.3%)]. Patients diagnosed with this particular type of Y-chromosome microdeletion presented with various sperm concentration-related clinical manifestations ranging from oligozoospermia (3.8%) to severe oligozoospermia (32.1%) and azoospermia (64.2%). The other patients, who were mainly included in the azoospermia group [54 out of 55 patients (98.1%)], were diagnosed with other types of Y-chromosome microdeletions, including AZFa, AZFb, AZFbc, and complete Yq deletions.4 This finding that AZFc Y-chromosome microdeletions are the most commonly diagnosed Y-chromosome microdeletions with incidence ranging from 46.6% to 100% was concurrent with the findings of other studies conducted in Brazil, China, India, Iran, and Korea.11–13,22–24 However, one study conducted by Birowo et al. in Indonesia reported AZFa Y-chromosome microdeletions (64.7%), instead of AZFc Y-chromosome microdeletions, to be the most frequent type of deletion. The high prevalence of partial AZFa microdeletion (absent sY84, present sY86) could be attributed to the larger proportion of azoospermic patients recruited in this study (only 2 out of 17 patients presented with severe oligozoospermia). Additionally, it could be explained by the possibility of a single-nucleotide polymorphism (SNP), increasing the false positive results of AZFa microdeletions. This SNP, which is common in the Chinese ethnic group, includes a single-nucleotide conversion of T to G in the target sequence of the reverse sY84 primer (rs72609647). It can only be determined by sequencing the sY84 locus.13,25\n\nY-chromosome microdeletion is one of the leading genetic causes of male infertility, greatly affecting testicular development.5 Birowo P et al. analyzed the testicular histology of two patients with partial AZFa deletion, one with AZFb deletion, and one with DBY gene exon 2 deletion. The testicular histology of the patient with AZFb deletion showed maturation arrest at the primary spermatocyte stage in all tubules, while that of the patient with DBY gene exon 2 deletion showed Sertoli cell only (SCO) syndrome. The testicular histology of the two patients with partial AZFa deletion indicated divergent spermatogenesis activity among the tubules. All four patients typically presented with azoospermia.13 Y-chromosome microdeletion evaluation also provides a deeper insight into the possibility of success of utilizing ART.4,11,24 In general, AZFc deletion typically presents with various sperm concentration-related clinical manifestations ranging from oligozoospermia to azoospermia. Stahl et al. successfully exhibited a sperm retrieval rate as high as 71.4% in azoospermic patients with AZFc deletion by microTESE. However, no successful sperm retrieval was observed in the AZFa, AZFb, AZFbc, and AZFabc (Yq) deletion groups. Additionally, Liu et al. demonstrated that almost half (45.1%) the patients with AZFc deletion developed oligozoospermia, consequently indicating that a high sperm retrieval rate in these patients can be achieved by self-ejaculation instead of invasive surgical procedures. Furthermore, in terms of hormonal levels, younger oligozoospermic patients (21-30 years) with AZFc deletion typically exhibited higher testosterone and estradiol and lower follicle-stimulating hormone and luteinizing hormone expression levels.11 This information allowed us to make an important finding that patients diagnosed with AZFc deletion showed higher chances of sperm retrieval for IVF/ICSI.\n\n\nConclusion\n\nIn conclusion, Y-chromosome microdeletion was undeniably found to be one of the leading genetic causes of male infertility. Y-chromosome microdeletion screening, although costly, may be potentially useful in geographical regions where high frequency of Y-chromosome microdeletion is exhibited. In this systematic review, the highest and lowest frequencies of Y-chromosome microdeletion were found in Indonesia (23.94%), despite the possibility of false positive results due to the SNP, and Slovakia (3.5%), respectively. One of the limitations of this review was the discrepancy in the number of samples recruited in each of the included studies, possibly affecting the variation in the overall rates of Y-chromosome microdeletions. Nevertheless, almost all the studies included in this systematic review showed that AZFc microdeletion was the most frequent type of Y-chromosome microdeletion, typically presenting with various clinical manifestations that ranged from oligozoospermia to azoospermia and exhibiting the highest chance for sperm retrieval. This review will certainly help clinicians in providing a more accurate consultation to their patients and determining the success rates of ART.\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 and flow diagram for ‘Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: A systematic review’, https://doi.org/10.17605/OSF.IO/RVUW7.26\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\nAkin H, Onay H, Turker E, et al.: Primary male infertility in Izmir/Turkey: a cytogenetic and molecular study of 187 infertile Turkish patients. J. Assist. Reprod. Genet. 2011; 28(5): 419–423. PubMed Abstract | Publisher Full Text\n\nDe Kretser DM, Baker HW: Infertility in men: recent advances and continuing controversies. J. Clin. Endocrinol. Metab. 1999; 84(10): 3443–3450. PubMed Abstract\n\nElfateh F, Rulin D, Xin Y, et al.: Prevalence and patterns of y chromosome microdeletion in infertile men with azoospermia and oligozoospermia in northeast China. Iran J. Reprod. Med. 2014; 12(6): 383–388. PubMed Abstract\n\nStahl PJ, Masson P, Mielnik A, et al.: A decade of experience emphasizes that testing for Y microdeletions is essential in American men with azoospermia and severe oligozoospermia. Fertil. Steril. 2010; 94(5): 1753–1756. PubMed Abstract | Publisher Full Text\n\nSimoni M, Bakker E, Krausz C: EAA/EMQN best practice guidelines for molecular diagnosis of y-chromosomal microdeletions. State of the art 2004. Int. J. Androl. 2004; 27(4): 240–249. PubMed Abstract | Publisher Full Text\n\nKrausz C, Hoefsloot L, Simoni M, et al.: EAA/EMQN best practice guidelines for molecular diagnosis of Y-chromosomal microdeletions. State-Of-The-Art 2013. Andrology. 2014; 2(1): 5–19. PubMed Abstract | Publisher Full Text\n\nAknin-seifer IE, Lejeune H, Touraine RL, et al.: Y chromosome microdeletion screening in infertile men in France: A survey of French practice based on 88 IVF centres. Hum. Reprod. 2004; 19(4): 788–793. PubMed Abstract | Publisher Full Text\n\nFerlin A, Arredi B, Speltra E, et al.: Molecular and clinical characterization of Y chromosome microdeletions in infertile men: A 10-year experience in Italy. J. Clin. Endocrinol. Metab. 2007; 92(3): 762–770. 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 Jul 21; 6(7): e1000097. PubMed Abstract | Publisher Full Text\n\nHoy D, Brooks P, Woolf A, et al.: Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement. J. Clin. Epidemiol. 2012 Sep; 65(9): 934–939. Publisher Full Text\n\nLiu T, Song YX, Jiang YM: Early detection of Y chromosome microdeletions in infertile men is helpful to guide clinical reproductive treatments in southwest of China. Medicine (Baltimore). 2019; 98(5): e14350. PubMed Abstract | Publisher Full Text\n\nde Sousa Filho EP , Christofolini DM, Barbosa CP, et al.: Y chromosome microdeletions and varicocele as aetiological factors of male infertility: a cross-sectional study. Andrologia. 2018; 50(3): 1–5. Publisher Full Text\n\nBirowo P, Putra DE, Dewi M, et al.: Y-chromosomal microdeletion in idiopathic azoospermic and severe oligozoospermic Indonesian men. Acta Med. Indones. 2017; 49(1): 17–23. PubMed Abstract\n\nZhu XB, Gong YH, He J, et al.: Multicentre study of Y chromosome microdeletions in 1,808 Chinese infertile males using multiplex and real-time polymerase chain reaction. Andrologia. 2017; 49(5): 1–7. Publisher Full Text\n\nLiu XG, Hu HY, Guo YH, et al.: Correlation between Y chromosome microdeletion and male infertility. Genet. Mol. Res. 2016; 15(2): 1–8. Publisher Full Text\n\nDai RL, Hou Y, Li FB, et al.: Varicocele and male infertility in northeast China: Y chromosome microdeletion as an underlying cause. Genet. Mol. Res. 2015; 14(2): 6583–6590. PubMed Abstract | Publisher Full Text\n\nSen S, Pasi AR, Dada R, et al.: Y chromosome microdeletions in infertile men: prevalence, phenotypes and screening markers for the Indian population. J. Assist. Reprod. Genet. 2013; 30(3): 413–422. PubMed Abstract | Publisher Full Text\n\nSaliminejad K, Sadeghi MR, Kamali K, et al.: Discrepancy in the frequency of Y chromosome microdeletions among Iranian infertile men with azoospermia and severe oligozoospermia. Genet. Test. Mol. Biomarkers. 2012; 16(8): 931–934. PubMed Abstract | Publisher Full Text\n\nTotonchi M, Meybodi AM, Boroujeni PB, et al.: Clinical data for 185 infertile Iranian men with Y-chromosome microdeletion. J. Assist. Reprod. Genet. 2012; 29(8): 847–853. PubMed Abstract | Publisher Full Text\n\nKim MJ, Choi HW, Park SY, et al.: Molecular and cytogenetic studies of 101 infertile men with microdeletions of Y chromosome in 1,306 infertile Korean men. J. Assist. Reprod. Genet. 2012; 29(6): 539–546. PubMed Abstract | Publisher Full Text\n\nFu L, Xiong DK, Ding XP, et al.: Genetic screening for chromosomal abnormalities and Y chromosome microdeletions in Chinese infertile men. J. Assist. Reprod. Genet. 2012; 29(6): 521–527. PubMed Abstract | Publisher Full Text\n\nBehulova R, Varga I, Strhakova L, et al.: Incidence of microdeletions in the AZF region of the Y chromosome in Slovak patients with azoospermia. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2011; 155(1): 33–38. Publisher Full Text\n\nPandey LK, Pandey S, Gupta J, et al.: Loss of the AZFc region due to a human Y-chromosome microdeletion in infertile male patients. Genet. Mol. Res. 2010; 9(2): 1267–1273. PubMed Abstract | Publisher Full Text\n\nLiu XY, Wang RX, Fu Y, et al.: Outcomes of intracytoplasmic sperm injection in oligozoospermic men with Y chromosome AZFb or AZFc microdeletions. Andrologia. 2017; 49(1): 1–6. Publisher Full Text\n\nWu Q, Chen GW, Yan TF, et al.: Prevalent false positives of azoospermia factor a (AZFa) microdeletions caused by single-nucleotide polymorphism rs72609647 in the sY84 screening of male infertility. Asian J. Androl. 2011; 13(6): 877–880. PubMed Abstract | Publisher Full Text\n\nBirowo P, Deswanto IA, Atmoko W, et al.: Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: A systematic review.2020, November 4. Publisher Full Text"
}
|
[
{
"id": "102128",
"date": "14 Dec 2021",
"name": "Doddy Moesbadianto Soebadi",
"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 authors have clearly stated the rationale and the objectives of the study, i.e. to gather the most recent clinical evidence that document the prevalence of and population variation in Y-chromosome microdeletion; and the variation in different geographical populations. The authors adhered to the PRISMA reporting guidelines, the inclusion criteria, as well as the information sources, search strategies, data collection, quality assessment, and outcomes are also clearly outlined. The conclusion drawn was adequately supported by the data; also the limitations of this review. This systematic review will have a great impact on the practice of male infertility treatment.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": []
},
{
"id": "309872",
"date": "16 Aug 2024",
"name": "Yankai Xia",
"expertise": [
"Reviewer Expertise Environmental exposure and reproductive 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\nGeneral comment Y-chromosome microdeletion is considered one of the most frequent genetic causes of male infertility. This review was conducted to gather the most recent clinical evidences that document the prevalence of and population variation in Y-chromosome microdeletions to highlight the variation in the prevalence of Y-chromosome microdeletion in different geographical populations, Which provides guidance on Y-chromosome microdeletion testing to some extent. However, due to its some limitations and limited innovation, the contribution of this manuscript for the field is limited. Major comments: 1. The study attempted to explore variation in the prevalence of Y-chromosome microdeletion in different geographical populations, but this research only involved 14 articles with five manuscripts originated from China, two each from India and Iran, and one each from Brazil, Indonesia, North America, South Korea, and Slovakia. The authors observed large differences in the frequency of Y chromosome microdeletions in different regions of the same country, but the number of samples recruited from some country such as Indonesia, Brazil and Slovakia was not large and the source was single, the representativity of the samples is to be considered. 2. It is necessary to assess the comparability between the study populations from different articles, which can be done by considering factors such as the means of detecting Y-chromosome microdeletion and the proportion of the distribution of azoospermia, severe azoospermia and oligozoospermia among the recruited male infertility patients. 3. In the conclusion part, the author declared that Y-chromosome microdeletion is the “leading cause” of male infertility, however, the data reported could not support the conclusion. Is there any statistical analysis to help readers better understand the results? Since the data of manuscript were largely extracted from hospitalized patients, how is the prevalence in the general population? Is there selection bias existed? Minor comments: 1. The manuscript lacks an analysis of the research status of Y-chromosome microdeletion at home and abroad, and we suggest supplementing it to clarify the necessity of the research. 2. Figure 1 should be uploaded with higher resolution. Also, standardized PRISMA flow chart is recommended. 3. For the rates, can author provide estimates with 95% confidential interval? 4. The publication bias should be evaluated. 5. For the risk of bias assessment, please provide more details in the results part. 6. Please clarify the study design of included publication.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Partly\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly",
"responses": []
},
{
"id": "309870",
"date": "20 Aug 2024",
"name": "Özlem Okutman",
"expertise": [
"Reviewer Expertise reproductive genetics"
],
"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 entitles “Population variation in Y-chromosome microdeletion and its role in the evaluation of male infertility management: a systematic review » summarizes the literature results of Y microdeletion frequencies in different geographical populations for a 10 years period. Although authors claim that it is a systematic review, unfortunately I believe this is not a systematic review but rather a very limited review of the last 10 years Y microdeletion publications. The authors do not mention why they limited their study to 10 years. If there is no systematic review before, it should cover all years from the identification of Y microdeletions in infertile men. If not, it should begin from the last systematic review’s data extraction date. They don’t give MeSH words combination which is essential for systematic reviews to control outcomes of data extraction. The keywords they mentioned are far too limited even with correct combination.\n\nHaving no European-based paper is not surprising though Y chromosome microdeletion in azoospermia and severe oligozoospermia has been pre-request in routine for long time. Although the title mentions the role of Y microdeletion in the evaluation of male infertility management ,authors did not make this evaluation.\nI believe their data extraction method is limited and non-producible. I believe academic validity of the article is so low. I don’t agree about the acceptance.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? No\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Partly\n\nIf this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1244
|
https://f1000research.com/articles/10-1243/v1
|
06 Dec 21
|
{
"type": "Research Article",
"title": "Reducing the Complexity of Casual Representation in Bayesian Belief Network",
"authors": [
"Yit Yin Wee",
"Shing Chiang Tan",
"KuokKwee Wee",
"Shing Chiang Tan",
"KuokKwee Wee"
],
"abstract": "Background: Bayesian Belief Network (BBN) is a well-established causal framework that is widely adopted in various domains and has a proven track record of success in research and application areas. However, BBN has weaknesses in causal knowledge elicitation and representation. The representation of the joint probability distribution in the Conditional Probability Table (CPT) has increased the complexity and difficulty for the user either in comprehending the causal knowledge or using it as a front-end modelling tool.\n\nMethods: This study aims to propose a simplified version of the BBN ─ Bayesian causal model, which can represent the BBN intuitively and proposes an inference method based on the simplified version of BBN. The CPT in the BBN is replaced with the causal weight in the range of[-1,+1] to indicate the causal influence between the nodes. In addition, an inferential algorithm is proposed to compute and propagate the influence in the causal model. Results: A case study is used to validate the proposed inferential algorithm. The results show that a Bayesian causal model is able to predict and diagnose the increment and decrement as in BBN.\n\nConclusions: The Bayesian causal model that serves as a simplified version of BBN has shown its advantages in modelling and representation, especially from the knowledge engineering perspective.",
"keywords": [
"Bayesian Belief Network",
"Causal Model",
"Causal representation"
],
"content": "Introduction\n\nKnowledge representation in a graphical model eases the knowledge organization and information understanding process. Causal frameworks such as Cognitive Map (CM),1 Fuzzy Cognitive Map (FCM),2 and Bayesian Belief Network (BBN),3 use graphical models to represent domain knowledge and have been widely adopted in various domains in the past few decades.4 BBN is a graphical model that used nodes to represent domain variables and links to represent the causal relationship among the nodes. However, the causal strengths of the causal relationship are represented in a tabular format. The complexity of the representation is increased with the growth of the size of conditional probability tables in BBN. The size of the CPT in BBN is growth in exponential proportion to the number of variables and the number of discrete states for each variable. Although high precision of inference outcome can be provided in BBN, such precision is often not needed or not necessary to the purpose of application. Moreover, elicitation of conditional probabilities from domain experts during the BBN modelling process is an unnatural and tedious job. BBN lacks intuitiveness in terms of representation and suffers from complexity problems in inference.5\n\nThis paper introduces a simplified BBN, namely the Bayesian causal model. A Bayesian causal model improves the representation of BBN by replacing the CPT with a single numeric value that is attached to the causal link. Moreover, a new inferential algorithm is proposed to propagate the influence in the Bayesian causal model. The proposed causal framework shows its advantages in modelling and representation, especially from the knowledge engineering perspective. Incremental updates in the model can be done easily because no reconstruction of the causal model is needed when a component is added/removed. To show the validity of the Bayesian causal model, a procedure to represent a Bayesian causal model as a BBN and comparison of the inference outcome in the Bayesian causal model corresponds to a specific probability in the Bayesian network are carried out in this study.\n\n\nMethods\n\nThe Bayesian causal model is formally defined in this section. Figure 1 shows the representation of the causal influence between nodes in the Bayesian causal mode.\n\nInstead of CPT, causal strength between the nodes is represented as a single value in the range of [−1, +1]. −1 represents the decrease of 100% of the probability value and +1 denotes the increase of 100% of the probability value. The initial probability of each node is pre-determined as 0.5.\n\nThe propagation steps of the newly available evidence in the Bayesian causal model are as follows.\n\nInfluence Propagation steps\n\n1. Start from either one of the nodes with evidence\n\n2. Calculate the change in the evidence node\n\na. The change of evidence increase/decrease can obtain by (Probability in evidence node – 0.5)/0.5\n\n3. Propagate the evidence AGAINST the arc.\n\na. Causal weight = causal weight/no. of cause node\n\nb. Influence = the change of evidence increase/decrease * (causal weight/no. of cause node)\n\n4. Continue to propagate until further propagation is impossible.\n\n5. Back to the node with completed causal influence from all effect nodes. Calculate the total influence.\n\na. Total backward influence = sum of causal influence from all effect node\n\n6. Start propagating the influence FOLLOW the arc\n\na. The influence from the cause node needs to exclude the previous backward influence from this effect node to the cause node.\n\nb. Total forward influence = sum of causal influence from all cause nodes\n\n7. Once the node obtains complete backward and forward influence,\n\na. Total influence = total backward influence + total forward influence\n\n8. Back to 4.\n\n9. Stop when all nodes obtain the total causal influence.\n\n10. Calculate the posterior probability of each node\n\na. Posterior probability = total causal influence * 0.5 + initial probability.\n\n11. Start from the other node with evidence.\n\n12. Continue steps 2-9.\n\n13. Calculate the posterior probability of each node\n\na. If total causal influence is positive\n\nPosterior probability = total causal influence * (1 − posterior probability) + posterior probability.\n\nb. If total causal influence is negative\n\nPosterior probability = total causal influence * posterior probability + posterior probability\n\nThe proposed inference algorithm for Bayesian causal model is implemented using C++ programming language and Code::Blocks 20.03.\n\n\nResults\n\nAn example of a sprinkler is used to demonstrate and validate the inference method in the Bayesian causal model. Table 1 illustrates the description of nodes in the causal model. There are a total of five nodes and five links in the causal model. The Bayesian causal model of sprinkler example is constructed as shown in Figure 2. Then, the Bayesian causal model is encoded into a BBN as shown in Figure 3. To validate the inference algorithm in Bayesian causal model, reasoning processes are performed in the Bayesian causal model and the BBN that are constructed earlier. The probabilities of any two nodes in the causal models are increased to 1 to observe the changes of probability in other nodes. The reasoning outcomes of both casual models are then recorded and compared as shown in Table 2.\n\nAccording to the inference results shown in Table 2, the Bayesian causal model has shown its ability to predict and diagnose as in BBN because the reasoning outcome of both causal models are not differed too much.\n\n\nConclusions\n\nIn this paper, a new causal model ─ the Bayesian causal model is introduced and defined. The causal strength in the Bayesian causal model is represented by a numeric value from −1 to +1. Whereas the value in each node is interpreted as probabilities. The semantics of the variables and influences are defined in this study. Moreover, the computation of the propagated influence from a node to another one in the causal model is proposed. The Bayesian causal model has provided an intuitive and simple graphical representation of causal knowledge. The representation of the causal strength with a single value in the Bayesian causal model has overcome the complexity of representation in BBN. Moreover, the construction of a Bayesian causal model from domain experts is less laborious and the user could easily understand the causal knowledge from the Bayesian causal model.\n\n\nData availibility\n\nAll data underlying the results are available as part of the article and no additional source data are required.\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe author(s) declared that no grants were involved in supporting this work.",
"appendix": "Acknowledgements\n\nThis research work was supported by Multimedia University, Malaysia.\n\n\nReferences\n\nAxelrod R: Structure of decision: the cognitive maps of political elites. Princeton, NJ: Princeton University Press; 1976.\n\nKosko B: Fuzzy Cognitive Maps. Int. J. Man-Machine Studies. 1986; 24(1): 65–75. Publisher Full Text\n\nPearl J: Fusion, Propagation, and Structuring in Belief Networks. Artif. Intell. 1986; 29(3): 241–288. Publisher Full Text\n\nSedki K, De Beaufort LB: Cognitive Maps and Bayesian Networks for Knowledge Representation and Reasoning. IEEE 24th International Conference on Tools with Artificial Intelligence. 2012; 1035–1040.\n\nCooper GF: The computational complexity of probabilistic inference using Bayesian belief networks. Artif. Intell. 1990; 42(2-3): 393–405. Publisher Full Text"
}
|
[
{
"id": "136326",
"date": "18 May 2022",
"name": "Bukhoree Sahoh",
"expertise": [
"Reviewer Expertise Explainable Artificial Intelligence",
"Causality",
"Complex Event Processing",
"Causal Machine Learning",
"Causal Inference"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this article, the authors propose a Bayesian causal model based on Bayesian Belief Network and claim it provides an intuitive and simple graphical representation of causal knowledge. The authors concluded that the representation of the causal strength with a single value in the Bayesian causal model had overcome the complexity of representation in BBN.\nI carefully read and consider the details, and my concerns have appeared below:\nThe paper representations are not scientific, and the authors did not explain the problem statements or research contributions in the introduction. The authors did not detail the background knowledge about BBN and related works, how recent approaches are not good enough and why the paper is proposed. The authors introduced Influence Propagation steps but did not well-explain why it is needed. The methodology must be represented in a systematic diagram of how one node changes the belief of the other. The single value in the range of [−1, +1] was not explained how and why they are more special than traditional CPT. The results show nothing relevant to the title Reducing the Complexity of Casual Representation in Bayesian Belief Network. The authors did not discuss how they converged to the problems they had to solve. They did not develop what the number and edge mean. For example, how results explained the issues, \"the Conditional Probability Table (CPT) has increased the complexity and difficulty for the user,\" as the authors wrote in the abstract. The authors did not describe the meaning of edges in Figure 2, such as S points to G labelled by +0.9, so what is the semantic meaning of +0.9, and how it is relevant to the problem. The authors did not show the results as they claim in the abstract \"the complexity and difficulty for the user either in comprehending the causal knowledge\" and how this article overcomes that concern. Moreover, the authors did not show how the \"Bayesian causal model is able to predict and diagnose the increment and decrement as in BBN\". The prediction at least must be represented by a comparison between the predictive performances of the proposed approach and the traditional one. The conclusions have no information concerning current limitations and future works. For example, the authors did not explain what the proposed approach could do and what it could not deal with in recent versions that need more future research contributions. The author must show their expertise in what kinds of techniques, methods, and solutions may be used in the future to solve the current limitations. The references are so poor that the well-known research papers in the present were not researched carefully. For example, the references were published in 1986, 1986, 1990, and 2012. What are the considerations for recent research in 2020, 2021, or 2022?\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": "157866",
"date": "23 Jan 2023",
"name": "Marek J. Druzdzel",
"expertise": [
"Reviewer Expertise Bayesian networks",
"probabilistic modeling",
"causality",
"causal discovery"
],
"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 proposes a simplification of the Bayesian networks formalism which, according to the authors, makes it easier to construct Bayesian networks/causal graphs and makes them easier to understand.\nThe authors seem to be unaware of the existing work on qualitative Bayesian networks (Wellman, Henrion, Druzdzel, van der Gaag), order of magnitude networks (Goldszmidt), CAST formalism (KC Chang), and canonical probabilistic models such as Noisy-OR, Noisy-AND, Noisy-MAX, Noisy-MIN, etc., that allow for specifying the strength of influence of each individual link in a Bayesian network. It is unclear to me how the proposed simplification improves on the existing models, formalisms, and algorithms. QGeNIe software of BayesFusion, available free of charge for academic research and teaching, implements a simplification of Bayesian networks and does it correctly, i.e., according to the rules of probability.\nFinally, if the authors demonstrate that the proposed formalism offers advantages over the existing formalisms, they should discuss the effect of the proposed simplification on accuracy of inference. Causal connections can be rather complex and this is reflected in the need for tables that specify precisely the impact of combinations of causes on the effect. Separating influences gets rid of all synergies between causes and will lead to simplified, sometimes incorrect inferences. This is OK but it is important to discuss cases where the proposed simplification will be inadequate.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-1243
|
https://f1000research.com/articles/10-428/v1
|
28 May 21
|
{
"type": "Research Article",
"title": "Local attributable burden disease to PM2.5 ambient air pollution in Medellín, Colombia, 2010–2016",
"authors": [
"Hugo Grisales-Romero",
"Juan Gabriel Piñeros-Jiménez",
"Emmanuel Nieto",
"Sandra Porras-Cataño",
"Nora Montealegre",
"Difariney González",
"Dorian Ospina",
"Juan Gabriel Piñeros-Jiménez",
"Emmanuel Nieto",
"Sandra Porras-Cataño",
"Nora Montealegre",
"Difariney González",
"Dorian Ospina"
],
"abstract": "Background: Exposure to 2.5-micron diameter air pollutants (PM2.5) has been associated with an increased risk of illness and death worldwide; however, in Latin American health impacts assessment of this risk factor is scarce. Medellín is one of the most polluted cities in the region, with a population growth rate that is twice as high as that of other Colombian cities, which implies a growing population at risk. Methods: A descriptive study of the disease burden was carried out using the city as the unit of observation. Health events were selected based on epidemiologic evidence and the availability of the population attributable fraction associated with PM2.5. The mortality records were taken from the module of deceased of the Single Registry of Affiliates of the Health System; the morbidity records were taken from the Individual Health Services Registries. For the estimation of the burden of disease, the current Global Burden of Disease guidelines were followed. Results: Attributable disability-adjusted life years to exposure to ambient PM2.5 pollution (DALYsPM2.5) constituted 13.8% of total burden of the city. Males showed the greatest loss of DALYsPM2.5 due to acute events, while in women the greatest loss was due to chronic events. Ischemic heart disease, chronic diseases of the lower respiratory tract, and influenza and pneumonia were the events that contributed the most to DALYsPM2.5. 71.4% of the DALYsPM2.5 corresponded to mortality, mainly in the population over 65 years of age. Regarding attributable morbidity, acute events were more prevalent in both sexes, especially due to respiratory diseases Conclusion: Premature death among the elderly population has the greatest weight on burden of disease attributable to ambient PM2.5 pollution, mainly due to respiratory and cardiovascular diseases, without significant differences according to gender.",
"keywords": [
"Disability Adjusted Life Years",
"Population Attributable Fraction",
"air pollution",
"attributable burden",
"Colombian population"
],
"content": "Introduction\n\nAir pollution is one of the main concerns surrounding public health worldwide due to its impacts on human health and ecosystem (Dominici et al., 2006). According to the Environmental Performance Index of Yale University, poor air quality is the greatest environmental threat and the most difficult challenge for public policies in middle- and low-income countries (Wendling et al., 2020). The attributable disease burden to ambient air pollution at a global, regional, and local level has been widely documented, this involves the measurement of disability-adjusted life years (DALYs), an aggregate value of years of life lost (YLLs) due to premature death and years lived with disability (YLDs) (HEI, 2019). Globally, the Institute for Health Metrics and Evaluation (IHME) has identified to air pollution as the fifth main health risk factor for the population, and it is estimated that the exposure to PM2.5 contributes to 4.9 million deaths (8.7% of all deaths worldwide), and the loss of 147 million of healthy life years (5.9% of all DALYs). The main causes of mortality worldwide due to air pollution are ischemic heart disease (35.9%), stroke (21.1%), chronic obstructive pulmonary disease (COPD; 20.4%), acute respiratory infections (15.9%), and lung and respiratory tract cancer (6.9%) (Cohen et al., 2017).\n\nThe World Health Organization (WHO) considers air pollution to be the main environmental health risk factor for the population in the Americas (Prüss-Ustün et al., 2016) due to its impact in susceptible populations, such as children younger than 5 years old, pregnant women, and elderly people (Piñeros-Jiménez et al., 2018). For Latin America and the Caribbean, it has been estimated that around 35,000 persons die annually to urban air pollution and 276,000 annual healthy life years are lost (Romieu et al., 2012).\n\nIn Colombia, few studies on ambient air pollution epidemiology have been carried out: a review of literature between 2008 and 2016 (Piñeros-Jiménez et al., 2018), 19 works were identified, which were mainly focused on the population-based analysis of the risk associated with the exposure to air pollutant on morbidity and mortality due to cardiovascular and respiratory events (Blanco-Becerra et al., 2014; Rodríguez-Villamizar et al., 2010; Salazar et al., 2011; Gaviria et al., 2011). Recently Rodríguez-Villamizar et al. (2018) conducted a multicity ecological time-series analysis with data from four major cities in the country. This analysis found for NO2, PM10, and PM2.5, statistically significant percentage increases in emergency department visits for respiratory diseases in children between 5 and 9 years old, and for circulatory diseases in persons over 60 years of age.\n\nRegarding studies of burden of disease attributable to ambient particulate matter pollution, few robust studies have been conducted (Romieu et al., 2012). In 2016, the Colombian National Health Institute estimated that 8% of 200,000 annual deaths in the country could be attributed to environmental risk factors, and calculated that 13.9% of ischemic heart disease deaths and 17.6% of chronic obstructive pulmonary disease deaths could be associated to ambient particulate matter pollution (INS, 2018). Also, the World Bank (WB) estimated 5,000 premature deaths and 69 million DALYs annually between 2002 and 2010 (Golub et al., 2014). These studies provided meaningful results of impact of air pollution in health in Colombia; however, they did not determine the magnitude of burden disease at the municipal levels where environmental phenomenon presents different magnitudes and particular local dynamics.\n\nMedellín is the second largest city in Colombia and one the most polluted in Latin America. Since 2016, Piñeros-Jiménez et al., have conducted several researches about health impacts associated with short-term exposure to PM10, PM2.5 and ozone (Piñeros-Jiménez et al., 2018; Piñeros-Jiménez et al., 2019). They developed traceability techniques based on analytical methods to identify health events from the records of different sources of health information, which allowed them to have a more precise epidemiological baseline for the measurement of health impacts. For Medellín, an ecological time series study found that a 10 μg/m3 increase in PM2.5 was associated with increase of 25.2% in the risk of respiratory diseases for children younger than 5 years old, and of 29.7% for adults of 65 years of age and over (Piñeros-Jiménez et al., 2018). Furthermore, they could establish the increases in the risk percentage of emergency room visits for asthma (2.8%), acute respiratory infection (2.0%) and pneumonia (2.2%) due to population exposure to critical air pollution episodes occurred in February and March 2015 (Nieto-López et al., 2020).\n\nDespite the advances in air pollution epidemiology research in Latin America, it has been recognized that establishing the attributable burden of disease to this environmental risk factor at the municipal level is a challenge for the academy and local management of environmental health, which requires updated information of the best quality to guide political decision-making and public planning with a territorial perspective. The aim of this study was to determine the local burden of disease to PM2.5 (LBDPM2.5) for Medellín, for which an updated epidemiological baseline focused on respiratory and circulatory events.\n\n\nMethods\n\nA descriptive study was conducted using the city as the unit of observation. The study population were all the residents in Medellín, the second major city in Colombia, between 1 January 2010 and 31 December 2016. Medellín is located in Aburra Valley in the Andes Mountains to the central-western of Colombia and an estimated population of around 2.9 million people. Additionally, it has the fastest demographic growth in the country, with a growth rate twice that of other cities.\n\nPM2.5 data were obtained from the air-quality monitoring network in Medellín. These data correspond to validated and adjusted information from eight monitoring stations distributed across the city between 1 January 2008 and 31 December 2016. Daily 24-h averages of PM2.5 were calculated. Data quality analysis identified gaps in each available pollutant dataset which were filled with the R package nnet (RRID:SCR_001905) for data imputation using an artificial neural network (Villa-Garzon, 2018). This package was also used for to obtain a unique assembled dataset for PM2.5 that represents the air pollution exposure for Medellín from information of different air monitoring stations. Daily, monthly and annually average concentrations of PM2.5 were calculated from this dataset.\n\nAll available data on morbidity and mortality population residing in Medellín during the study period were used. Data of individual deaths was obtained from death records in the deceased module of the Single Registry of Affiliates of the Health System (Registro Único de Afiliados, módulo de Defunciones (RUAF-D)). Information related to emergency department visits, medical outpatient services visits, and hospitalizations were obtained of individual records on the Provision of Health Services (Registros Individuales de Prestación de Servicios de Salud (RIPS)). All data were provided by the Social Protection System (Sistema Integrado de la Información de la Protección Social (SISPRO)). The records of people whose basic cause of death or main medical diagnosis was an event related to air pollution were included, following International Classification of Disease, ICD-10.\n\nThe acute events studied were ischemic heart disease (I20–I25), cerebrovascular diseases (I60–I69), influenza and pneumonia (J09–J18), and others acute lower respiratory tract infection (J20–J22). The chronic events studied were malignant neoplasms of respiratory and intrathoracic organs (C30–C39), in situ neoplasms (D00–D09), and chronic lower respiratory tract diseases (J40–J47).\n\nFor each health data source, a quality assessment of data was performed, considering the dimensions of completeness, consistency, accuracy, duplication and integrity for each individual record that complied with the inclusion criteria such as place of residence, year of death/medical attention, and causes of morbidity and mortality selected for this study. Underreporting of deaths was estimated with the Preston and Coale method, and the PAHO method of proportional distribution to address potential information biases (ONU, 1986). For morbidity, underreporting could not be controlled because there was no other source of information that could contrast the source used. The reference population were people living in Medellín based on time, age, and gender criteria, according to projection of the population census published by the National Department of Statistics of Colombia.\n\nTraceability strategies were defined for each event in order to identify prevalent cases in each year of analysis. These were previously designed by the research team for local studies based on secondary data (Piñeros-Jiménez, 2018), which used the descriptive model of the natural history of disease, which presents the course of all biological events, the sequential action of causes (etiology), the evolution of the disease and its outcomes (recovery, chronicity, disability, or death), as well as the pre-pathogenesis and pathogenesis phases of the disease. Annual event per patient was included and point-prevalence was estimated.\n\nWHO’s methodology for estimation of burden of disease was used (WHO 2017). DALYs calculation incorporated the number of YLLs due to premature death and the number of YLDs (Rutstein et al., 1983). YLLs estimation used the standard method, which includes all deaths at any age within the total estimated disease burden. As a standard value, the frontier national life expectancy projected for the year 2050 was considered, with a life expectancy at birth (LEAB) of 91.9 years for both men and women (Murray, 1995). The equation used for calculations was: YLL=∑x=0Ldxex∗, where L = the ultimate age of survivors; x = age of death; dx = number of deaths at x age in years; ex* = life expectancy at each age based on an ideal standard.\n\nDue to the availability of aggregated data by cause of death according to sex, age group and year, the class mark was defined as the representative value of all age intervals in the calculation of the indicator. Premature death was calculated with the difference between the class mark of the respective age group and the LEAB standard value for each one record of the database.\n\nFor calculating YLDs, the methodology of 2013 GBD guidelines by WHO was used (WHO 2017; Salomon et al., 2015), not including discounting rate of 3% and age weights. For each study event, the distribution of cases in each year were calculated according to gender and age group. Them these were divided by the number of inhabitants in Medellín in order to find the point prevalence. The disability weights per event were calculated as the following equation: YLD=Dj×pj where Dj = the disability weight for each individual j cause, and pj = the prevalence of the jth disease. Therefore, the total of annual YLDs per event in the study period corresponds to the sum of individual YLDs per age group and gender.\n\nDALYs were obtained from the sum of the total number of YLLs due to premature death and the total number of YLDs per year, gender, age group, and subgroup of diagnostic cause for each type of event (acute or chronic).\n\nTo determine the magnitude of LBDPM2.5, exposure is expressed as the fraction of disease or death to the risk factor in a population and referred to as the population-attributable fraction (PAF). Due to this requirement, in the case of Medellín, it began by defining the events to study. Air pollution-associated events were limited to those causes that have been examined in GBD studies, which already had PAF data for PM2.5 pollution, according to the IHME measurement results for Colombia (Cohen et al., 2017).\n\nAfter obtaining the frequency of YLLs, YLDs, and DALYs per event, LBDPM2.5 was calculated. This was done by considering the standardized PAF by age estimated for Colombia (Cohen et al. 2017) in relation to each one of the diagnostic groups examined in this study. LBDPM2.5 was estimated by using the following equation: LBDPM2.5 = (YLLs or YLDs or DAILYs) × PAFPM2.5 (Cohen et al., 2017; Grisales-Romero et al., 2021).\n\nResults are shown with absolute and relative frequencies along with rates/indices of each indicator considered with a constant value of 100,000 according to Medellín’s population for each year. They are complemented, where necessary, with the 95% uncertainty interval (95% UI) generated using the Bootstrap method, a resampling technique (Efron & Tibshirani, 1993). Data capture, storage, and processing was performed using the database management software pgAdmin 4 v2.1® (RRID: SCR_021066). For the generation of results and graphs, the commercial software, Microsoft Excel® (RRID:SCR_016137) was used. A free office suite alternative that could also be used for this process would be LibreOffice, which is available at https://www.libreoffice.org.\n\nThis project was approved by the Ethics Committee of the National School of Public Health of Universidad de Antioquia as declared in minutes No. 141 of April 29, 2016. All procedures performed in this project followed ethical standards contemplated in Resolution 8430 of the Ministry of Health and Social Protection of Colombia, and International Ethical Guidelines for Health-related Research Involving Humans of 2016 of the Council for International Organizations of Medical Sciences. At all times, this study used anonymized data that had the authorization of each of the sources in charge of its custody.\n\n\nResults\n\nBetween 2010 and 2016, daily concentrations of PM2.5 were 35.8 μg/m3 (min–max: 13.6–123.1 μg/m3). with important variations at each year, we could observe that, in 2016, there was an annual increase of the average PM2.5 of 21.9%, compared with the base year, 2010. Interestingly, at all years, the annually average values of PM2.5 were higher than the 25 μg/m3 value established by the Environmental National Authority (i.e., Resolution No. 610 of 2010).\n\nFebruary and April showed a higher trend towards a monthly average increase of PM2.5 pollution during the study period. In March 2016, the highest average values of the whole time series data were identified. On the other hand, October and November from 2010 to 2014 presented monthly averages with slight increases, and even for the years 2015 and 2016 the trend was downward during these months (Figure 1A–G).\n\nThere was a total 28,678 of deaths for acute and chronic diseases associated with air pollution in Medellín between 2010 and 2016, of which 3,873 deaths (13.5%) were attributed to PM2.5 pollution. The attributable deaths to PM2.5 pollution per year were similar during the seven years of studied period. 61.7% (n = 2,391) of them were for acute events, of which 75% (n = 1,793) were due to circulatory system diseases, mainly ischemic heart diseases (n = 1,550). Among diseases of the respiratory system, influenza and pneumonia showed the highest frequency in the study period (n = 598). Chronic lower respiratory tract diseases were the most frequent (n = 1081) of chronic events; 95.7% corresponded to chronic obstructive pulmonary diseases (Table 1).\n\na Mortality rate per 100,000 inhabitants.\n\nDuring the study period, 567,505 prevalent cases for events associated with air pollution were identified, 75.6% (n = 428,858) were acute events, of which 92.3% (395,761) were due to respiratory system diseases. 88,083 (15.5%) prevalent cases were attributed to PM2.5 pollution. Respiratory system diseases were the most frequent for acute attributable events, mainly for acute lower respiratory tract infections (n = 39,163). Among chronic events, the most frequent were chronic lower respiratory tract diseases (n = 21,479) (Table 2).\n\nDuring the seven-year period there was a premature YLLs of 536,772 (95% UI 524,048–549,495) due to events related to air pollution in Medellín; 13.0% (n = 71,590 (95% UI 69,843–73,339)) corresponded to LBDPM2.5 (Table 3). The attributable YLLs to PM2.5 pollution (YLLsPM2.5) showed little variation throughout the period, with an annual average of attributable mortality burden calculated in 10,227 (95% UI 9,950–10,505) of YLLs. The Figure 2A–B shows annual YLLsPM2.5 rates for males and females between 2010 and 2016. In both genders, stable losses were observed in the YLLPsPM2.5 rates with a tendency to decrease. The highest concentration of YLLsPM2.5 were presented in 2016, with annual rates for this year of 496.9 per 100,000 inhabitants for males and 378.6 cases per 100,000 inhabitants for females.\n\nYLLsPM2.5: Attributable years of life lost to ambient PM2.5 pollution.\n\nYLDsPM2.5: Attributable years lived with disability to ambient PM2.5 pollution.\n\nDALYsPM2.5: Attributable disability adjusted life years to ambient PM2.5 pollution.\n\nThe highest attributable mortality burden was found for acute events with 45,996 (95% UI 45,175-46,817) YLLsPM2.5, on the other hand, chronic events presented 25,594 (95% UI 24,454-26,734) YLLsPM2.5 for chronic events. Males had a greater contribution to the attributable mortality burden for acute events (56.1%), while females showed a slightly higher frequency of this for chronic events (50.8%). No large fluctuations were observed in the distribution of the attributable burden during period; although, in 2016 there was a slightly higher concentration of mortality due to the two types of events for both genders.\n\nWhen viewed in term of disability, a loss of 189,580 (95% UI 168,455–210,703) YLDs due to respiratory and circulatory events related to air pollution was observed. 15.1% (n = 28,618 (95% UI 25,280–31,956)) corresponded to LBDPM2.5, with an annual average of 4,086 (95% UI 3,619–4,565) YLDs. The highest proportion of attributable disability loss to PM2.5 pollution (YLDsPM2.5) occurred in 2011 and 2012, when 32,6% of YLDsPM2.5 were concentrated. Compared with 2010, in 2016 the rate of YLDsPM2.5 decreased by 36.4%, with a more marked decrease in males (Figure 2C–D). Acute events constituted 56.3% of YLDsPM2.5 (n = 16,124 (95% UI 14,902–17,346)). Females had a higher percentage contribution, both for YLDsPM2.5 due to acute events (51.4%) and YLDsPM2.5 due to chronic events (50.8%). However, throughout the study period the highest rates occurred in men.\n\nOf total LBDs associated with pollution (n = 726,353 DALYs, 95% UI 715,045-737,659), 73.9% corresponded to YLLs and the remaining to YLDs. The premature mortality due to acute events was higher than that estimated for chronic events, with 33 percentage points of difference, with a slightly greater magnitude in the male burden than the female burden (Table 1). Of total estimated DALYs, 13.8% (95% UI 13.7%–13.9%) was attributed to PM2.5 pollution (DALYsPM2.5), with an average of 14,315 DALYsPM2.5 per year (95% UI 14,005–14,626), equivalent to rate of 592.2 DALYsPM2.5 per 100,000 cases. Compared with the initial year of study in 2016, a decrease of 8.3% in total DALYsPM2.5 was observed, with decreases of 8.1%in DALYsPM2.5 due to acute events and 8.6% due to chronic events. According to the gender, distribution of DALYsPM2.5 had variations by type of event; while DALYsPM2.5 due to acute events was higher in males (54.1%), the DALYs due to chronic events were slightly concentrated in females (50.8%) (Table 3) (Figure 2E–F).\n\na LBD: Local Burden Disease.\n\nb LBDPM2.5: Attributable Local Burden Disease to ambient PM2.5 pollution.\n\nc UI 95%: Uncertainty Interval of 95% In relation to the attributable total per each event.\n\nLBDPM2.5 showed a positive gradient from 35 years of age, with significant differences among the five-year age groups. Those over 65 years of age contributed with 61.7% of the total burden, with the highest rates in the group of 80 years and older. In all the five-year age groups, LBDPM2.5 for acute events was higher than for chronic events, with considerable differences that were more marked until the age of 59 years. After 60 years of age, the differences were smaller although maintaining the trend. LBDPM2.5 for chronic events was comparable in the age groups between 15 years and 44 years; but after 45 years of age, it gradually increased until the age of 79 years, when it slowly decreases in the last age group. Only 10.3% of the total attributable burden was in the population younger than 39 years old (Table 4). Male showed the highest prevalence of LBDPM2.5, with the highest difference in the 40–44 and 55–59 age groups, and an approximate ratio of 2 to 1.\n\na % in relation to the total per age group.\n\nb % in relation to the total.\n\nFive groups provided the highest contribution to attributable premature mortality and disability according to the type of event by diagnosis group (chapter) of the seven groups analyzed (Table 5). 80.6% of premature deaths were caused by ischemic heart disease (40.1% of YLLPM2.5), chronic lower respiratory tract diseases (23.4% of YLLPM2.5) and acute infections of the lower respiratory tract (16.9% of YLLPM2.5). On the other hand, among the causes that most contributed to attributable disability were chronic lower respiratory tract diseases (43.3% of YLDPM2.5), other acute infections of the lower respiratory tract (24.3%) and influenza and pneumonia (20.1% of YLDPM2.5). In contrast, the group of neoplasms had a relatively lower contribution to LBDPM2.5, explaining 8.8% of DALYsPM2.5 (12.2% of YLLPM2.5 and 0.3% of YLDPM2.5).\n\na % in relation to the total LBDPM2.5 by group of event.\n\nb Period 2010-2016, Uncertainty ranges of 95% calculated using the bootstrap method for n = 10,000 samples.\n\nFigure 3 shows the relationship of the rates of YLLPM2.5 and YLDPM2.5 for each diagnosis group studied. The groups of causes were classified into four categories according to the relationship between the two rates: A (low mortality and low disability), B (low mortality and high disability), C (high mortality and low disability) and D (high mortality and high disability). Four of the seven groups of events studied (ischemic heart disease, cerebrovascular disease, influenza and pneumonia, and chronic lower respiratory tract diseases) were included in category D, due to their contribution to both mortality and disability. On the other hand, in situ neoplasms were included in category A, other acute lower respiratory tract infections in category B, and malignant neoplasms of respiratory and intrathoracic organs in category C.\n\nYLLsPM2.5: Attributable years of life lost to ambient PM2.5 pollution. YLDsPM2.5: Attributable years lived with disability to ambient PM2.5 pollution.\n\na Logarithmic scale.\n\nTable 6 shows the ranking of the diagnostic events according to their contribution to the LBDPM2.5. Comparing the years of beginning and end of the study period, there were no changes in the order of the groups of events. In both years, the three highest DALYPM2.5 rates were found to be due to ischemic heart disease, chronic lower respiratory tract disease, and influenza and pneumonia. Cerebrovascular diseases, chronic lower respiratory tract diseases and in situ neoplasms showed a reduction of more than 10% in the rates of DALYPM2.5 by 2016 in relation to the year of initiation of the study. The opposite occurred with malignant neoplasms of respiratory and intrathoracic organs, which showed an increase of 22.3% in DALYPM2.5 rate.\n\na per 100,000 inhabitants.\n\nb % in relation to the total attributable local burden.\n\n\nDiscussion\n\nNowadays, ambient air pollution by the criteria pollutant PM2.5 is considered one of the biggest environmental problems at the global and local level due to the impact it causes on the health of populations (Apte et al., 2018). Although cities in Latin America and the Caribbean region have shown annual average PM2.5 values that could be considered moderate if compared to cities located in Southeastern Asia and India, most of these have reported annual average higher than the levels recommended by WHO of 10 μg/m3 (Riojas, 2016). For Medellín, one of the most polluted cities of the region, the annual average PM2.5 levels during the seven years of study was 35.6 μg/m3, where more than 90% of the days had daily averages above 25 μg/m3 (Piñeros-Jiménez et al., 2018), risk factor to which approximately 3 million people are exposed. Under these conditions, in the last five years, some studies have been carried out to establish the health impacts of criteria pollutants (PM10, PM2.5, ozone and nitrogenous) with population models of a single and multiple pollutants at a local level (Piñeros-Jiménez et al. 2018, Piñeros-Jiménez et al. 2019, Rodríguez-Villamizar et al. 2018). This is the first study that seeks to establish the magnitude of such an impact by using a holistic indicator.\n\nSince the 1990s, multiple strategies have been used to gather knowledge about the burden disease caused by different risk factors. These strategies offer a holistic view of the joint effects of morbidity and mortality in the number of healthy life years lost. Environmental risk factors, mainly air pollutants, have had a growing interest among decision makers and the community at the local and global level, and have been prioritized in the political agendas promoted by research in environmental epidemiology in recent decades. Among the advances in research, the studies that analyze the magnitude of the impacts based on holistic indicators at the global and national level, supported by exposure-response functions and relative risk analysis, with the data available in the health and environmental information systems, stand out. All of which may help in transcending towards causality (Burnett et al., 2014).\n\nAir pollution epidemiological research in Latin America and Colombia has been characterized by ecological studies of time series and some panel studies, which have confirmed the short-term effects associated to criteria pollutants (Romieu et al., 2012; Piñeros-Jiménez et al., 2018). Very few studies have been carried out at the local level to document the local burden of disease attributable to air pollution (Golub et al., 2014; INS, 2018). No one has evaluated the long-term effects.\n\nIn this study, we provided a detailed view of the local burden of disease attributable to air pollution, for Medellín, one of most development cities of the country and region. Which recognizes the local character of the epidemiological phenomenon associated to air pollution, and the need for updated information to influence public environmental policy in the city. It was focused on using a synthetic indicator: DALYs, an aggregate value YLLs due to premature death and YLDs, based on up-to-date methodologies validated by experts and international organizations (Cohen et al., 2017; World Bank, 2016; WHO 2016). In the absence of local cohort studies, the PAF estimates made in the GBD study were used, which assumed a non-linear relationship between the incidence of health events and short- and long-term exposure to particulate matter and developed the integrated exposure–response curve to estimate the long-term PM2.5 exposure–response association from low exposure level to concentration as high as 1000 μg/m3 to avoid overestimating the magnitude of health effects (Burnett et al., 2014)\n\nWe found that the attributable burden disease PM2.5 pollution constituted 13.8% of the total local burden of DALYs for all the selected pollution-related events (100,208 DALYsPM2.5 out of 726,352 total DALYs,). In the study on environmental burden disease in Colombia carried out by National Health Institute of Colombia (INS), for 2016, 19% of the total national burden disease was associated to environmental risk factors (air, water, and other similar factors) (INS, 2018). Regarding air pollution, YLLsPM2.5 was calculated in 619.8 per 100,000 inhabitants. In our study, for the same year, 434.3 YLLsPM2.5 per 100,000 inhabitants was estimated. This difference can be considered reasonable, since the study cited above was carried out in a higher geographical area (national level), and it is possible that cities with a greater air pollution problem such as the capital of the country (Bogota D.C.) had a greater weight in the total estimate.\n\nAcute diseases contributed with 62.0% of DALYPM2.5, this is explained by the higher contribution of YLLsPM2.5 (74.0%) in the burden health index, mainly by ischemic heart disease, that constitute 30.5% of DALYPM2.5 for 2016 in contrast to the estimation of 15.8% from the study on the environmental burden disease in Colombia for this year (INS, 2018). Our results are consistent with the results of the study by Cohen et al. (2017) regarding the events but not the magnitudes. The number of DALYs associated to ischemic heart disease was the highest in this study, similar results was found in India State-Level Disease Burden Initiative Air Pollution Collaborators study for 2017 (2019). There is more and more evidence from prospective studies that PM2.5 exerts adverse effects particularly on the cardiovascular system, contributing substantially (mainly through mechanisms of atherosclerosis, thrombosis and inflammation) to coronary artery disease, but also to heart failure, hypertension, diabetes and cardiac arrhythmias (Hu, et al., 2018; Hajat, et al., 2019; Franklin, et al., 2015; Kauffman, et al., 2016a; Kauffman, et al., 2016b; Song, et al., 2020), which can help to explain the findings regarding this type of event in relation to the attributable burden disease.\n\nIn the case of the burden of disease attributable to acute respiratory diseases, our result differs from other studies conducted with national data. This can be observed in the estimated proportion of DALYPM2.5 for acute lower respiratory tract disease in the INS study was of 13.7% (INS, 2018), which contrasts with the 7.1% reported by us for the events of the diagnostic group of other acute lower respiratory tract infection events (J20–J22) in Medellín. Regarding the study by Golub et al. (2014), we found more approximate results, although the basis for calculating the attributable DALYs in the case of acute respiratory disease was the proxy for the reports of respiratory symptoms. These differences could be explained by the methodology used to identify the cases and calculate the indicators. In our study we used a data mining-based traceability strategy to select health events that was constructed based on the natural history of the disease. Which established that the duration of acute respiratory events was 15 days, and with this criterion grouped the records of each source of information into a data set that made up each case (Piñeros-Jiménez et al., 2018). This strategy allowed a more precise approach to the number of events and the calculation of the study indicators. This strategy allowed a more precise approach to the number of events and the calculation of the study indicators.\n\nChronic diseases of the lower respiratory tract constituted the chronic events with the greatest weight in the total of DALYsPM2.5 (38%) in our study. This result is consistent with estimations of DALYs due to chronic respiratory diseases in relation to the IHME reports. Between 2010 and 2016, the average rate of DALYs due to chronic diseases of the respiratory tract and ischemic heart diseases in Medellín, was of 172.9 and 181.7 per 100,000 inhabitants, respectively. Estimations published by the IHME show that, in 2016, around 112.2 DALYs due to chronic respiratory diseases were calculated per 100,000 inhabitants in Colombia. Also, in this period, 165.32 (106.5–217.9) DALYs due to ischemic heart disease were calculated per 100,000 inhabitants, which were associated to air pollution (Cohen et al., 2017).\n\nAmong the events included in the diagnosis group of chronic lower respiratory tract diseases were asthma (J45) and COPD (J40–J42), two of the most relevant events in relation to the attributable burden disease to exposure to air pollution, specifically for the pollutants PM2.5, NO2 and ozone (Achakulwisut et al., 2019; Anenberg et al., 2018, Cohen et al., 2017). In the case of COPD, although its impact on GBD has been established with a global point prevalence of 3.918% (95% UI (3.5111–4.3201) and a mortality rate of 41.9 deaths per 100,000 people (5.7% of all deaths from all causes) (GBD Chronic Respiratory Disease Collaborators, 2020), its risk association with some air pollutants has had a positive sign but of low magnitude and in some cases without statistical significance (Schikowski et al., 2005; Schikowski et al., 2014), including its specific association with ambient PM2.5 pollution (Atkinson RW et al., 2015; Dany Doiron et al., 2019). Globally, seven million deaths were attributed to the joint effects of environmental and domestic air pollution (Cohen et al., 2017). And it is recognized that the effects can be divided into short and long-term effects, ranging from exacerbation of existing symptoms, impaired lung function and increase in hospitalization and mortality rates. Prolonged exposure to air with a high concentration of pollutants can also increase the incidence of COPD.\n\nAir pollution can induce the development of asthma, increasing respiratory morbidity and mortality, particularly in minority groups (Nishimura et al., 2013). Annually, it is estimated that 40 million (95% UI 18–52) of new cases of pediatric asthma could be attributable to NO2 contamination, with a higher burden of new asthma cases associated with NO2 exposure per 100,000 children for the Latin American region (340 cases per year, 95% UI 150–440) (Achakulwisut et al., 2019). Likewise, it is estimated that 9–23 million and 5–10 million annual asthma emergency room visits globally could be attributable to ozone and PM2.5, respectively (Anenberg et al., 2018). Our results demonstrate an important impact of ambient PM2.5 pollution on chronic respiratory diseases that should be analyzed in more detail, with the aim of generating useful knowledge for the design of interventions and decision-making in specific groups, especially taking into account, age groups where asthma and COPD are more frequent.\n\nIn contrast with other reports, the contribution of lung and airway cancer to local DALYsPM2.5 was relatively low (8.8%), and it was explained almost exclusively by YLLsPM2.5. The Cohen study found that lung and airway cancer accounted for 16.5% of the global burden attributable to PM2.5, while recently Yin et al. reported for China that 16.6% of deaths attributed to ambient particulate matters at the national level were due to this this cause (Cohen et al., 2017; Yin et al., 2020). This difference of more than double the DALYsPM2.5 could be due to the level of analysis carried out in the different studies, but it is mainly explained by the coverage of high-cost disease care in our country, where there is a health system with great inequalities in access, which makes these types of diseases often go undiagnosed and unattended, so they are not reported to health information systems. This situation is especially worrying in the economically most vulnerable sectors of the population, there is a hidden burden of the disease that makes difficult to carry out targeted interventions according to equity criteria.\n\nThe highest proportion of DALYsPM2 was related to YLLPM2.5, at 71.4%. This apparent paradoxical effect of a significant premature mortality burden attributable to PM2.5 pollution could be explained using the protracted polarized model, which is predominant in Latin America and other regions of the world sharing the same development features. Here we find a superposition of transmissible acute diseases and non-transmissible chronic diseases, along with the reappearance of emergent diseases, which affect vulnerable human groups discriminately and disparately, as observed in the population of Medellín. Despite the improvements in the control of childhood diseases, as well as demographic changes and the increased life expectancy, conditions of inequality, poverty and extreme poverty persist, which add to the new risk factors, such as PM2.5 pollution caused by transportation and urbanization (GBD 2019 Risk Factors Collaborators, 2020). This new risk factor generates a negative impact on air quality, affecting the exposed population, accelerating disease and increasing mortality, and resulting in an unbalanced pattern of death and disability.\n\nIt is worth mentioning that the effects of air pollution on health are not directly proportional to the intensity of exposure in individuals, but it is clear that such effects exist and are dependent on other variables as well as the time and level of exposure. Air quality in high-income countries has improved in recent decades, however, adverse effects of external air pollution on health due to particulate matter continue to be a public health problem worldwide, even if levels are low (Cohen et al., 2017; Liu et al., 2021).\n\nWe can conclude that 71.4% of DALYsPM2.5 between 2010 and 2016 was due to premature death; especially YLLsPM2.5 due to acute events. A proportion of 28.6% was YLDsPM2.5. The greatest concentration of YLLsPM2.5 was associated to ischemic heart diseases and chronic lower respiratory tract diseases with a high proportion of COPD, particularly in male older than 80 years of age. Considering YLDsPM2.5, these were caused mainly by chronic lower respiratory tract diseases, influenza and pneumonia, and other acute lower respiratory tract infection which were more prevalent among the population older than 60 years of age, in both genders.\n\nOne of the greatest strengths of this study is that it was pioneers in Colombia and region in the use of the new proposed methodology to calculate the burden of disease indicators, as it uses the new GBD study (GBD 2019 Risk Factors Collaborators, 2020), which gives a higher importance to prevalence over incidence as epidemiological indicators for disability calculations, this allows establishing the basis for future studies based on our findings. The quality assessment of data from the information sources we used exhaustive and included protocols that have been previously validated (Piñeros-Jiménez et al., 2018; Piñeros-Jiménez et al., 2019), in contrast with the majority of GBD studies where it has been shown to be one of the greatest obstacles in the application of the disease burden methodology. We obtained consistency percentages of more than 90% in morbidity aspects and more than 82% in mortality aspects, which are comparable to the results of INS and Ribotta studies (INS, 2018; Ribotta et al., 2019).\n\nAmong the limitations, we can mention that the multiple sources we used respond in an unarticulated way to events follow-up, which does not allow for an optimal traceability. The effects of migration could not be considered, and it was impossible to make an adjustment of results according to the coverage of morbidity information. Also, estimations of the Population Attributable Fraction proposed by the GBD methodology, which were used for a list of specific events, could not be representative for Medellín’s population. The prevalence values that we used in this study were related only with those people who visited medical services; therefore, stating that this information can be extrapolated to obtain the actual prevalence of the diseases we examined may be risky.\n\nWe recommend developing cohort studies for the local context, which can help in the documentation of the actual attribution (attributable risk estimation) of morbidity and mortality to air pollution due to the environmental risk factors that have been explained by literature. Morbidity studies should be conducted with a focus on disability analysis at a local level, to improve the estimation of the disease burden attributable to environmental pollution, based on data that accurately show those events associated to environmental factors.",
"appendix": "Acknowledgments\n\nWe thank the Secretary of Health of Medellín for giving us access to the morbidity and mortality information databases, the local environmental authority, and the team of support professionals from the National School of Public Health of Universidad de Antioquia who supported the project.\n\n\nData availability\n\nZenodo: Underlying data for ‘Local attributable burden disease to PM2.5 ambient air pollution in Medellín, Colombia, 2010–2016’ https://doi.org/10.5281/zenodo.4646592 (Grisales-Romero et al. 2021).\n\nThis project contains the following underlying data:\n\nDataset 1_YLL_YLD_DALY_Dictionary.xlsx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\nThe environmental data needed to replicate these analyses are publicly available at https://siata.gov.co/descarga_siata/index.php/Index2/\n\nThe health data needed to replicate these analyses are publicly available at https://www.sispro.gov.co/Pages/Home.aspx\n\nThe environmental health data needed to replicate these analyses are publicly available at https://datosabiertos.metropol.gov.co/search/field_topic/medio-ambiente-3\n\n\nReferences\n\nAchakulwisut P, Brauer M, Hystad P, et al.: Global, national, and urban burdens of paediatric asthma incidence attributable to ambient NO2 pollution: estimates from global datasets. Lancet Planet Health. 2019; 3(4): e166–e178. PubMed Abstract | Publisher Full Text\n\nAnenberg SC, Henze DK, Tinney V, et al.: Estimates of the Global Burden of Ambient PM2.5, Ozone, and NO2 on Asthma Incidence and Emergency Room Visits. Environ Health Perspect. 2018; 126(10): 107004. PubMed Abstract | Publisher Full Text | Free Full Text\n\nApte JS, Brauer M, Cohen AJ, et al.: Ambient PM2.5 Reduces Global and Regional Life Expectancy. Environ Sci Technol Lett. 2018; 5(9): 546–551. Publisher Full Text\n\nAtkinson RW, Carey IM, Kent AJ, et al.: Long-term exposure to outdoor air pollution and the incidence of chronic obstructive pulmonary disease in a national English cohort. Occup Environ Med. 2015 Jan; 72(1): 42–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurnett RT, Pope CA 3rd, Ezzati M, et al.: An integrated risk function for estimating the global burden of disease attributable to ambient fine particulate matter exposure. Environ Health Perspect. 2014; 122(4): 397–403. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBlanco-Becerra LC, Miranda-Soberanis V, Hernández-Cadena L, et al.: Effect of particulate matter less than 10μm (PM10) on mortality in Bogota, Colombia: a time-series analysis, 1998-2006. Salud Publica Mex. 2014; 56(4): 363–370. PubMed Abstract | Publisher Full Text\n\nCohen AJ, Brauer M, Burnett R, et al.: Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015. Lancet. 2017; 389(10082): 1907–1918. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDominici F, Peng RD, Bell ML, et al.: Fine particulate air pollution and hospital admission for cardiovascular and respiratory diseases. JAMA. 2006; 295(10): 1127–34. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoiron D, de Hoogh K, Probst-Hensch N, et al.: Air pollution, lung function and COPD: results from the population-based UK Biobank study. Eur Respir J. 2019; 54(1): 1802140. PubMed Abstract | Publisher Full Text\n\nEfron B, Tibshirani R: An Introduction to the Bootstrapp. New York, London: Chapman and Hall: 1993; 456 p.\n\nFranklin BA, Brook R, Arden Pope C 3rd: Air pollution and cardiovascular disease. Curr Probl Cardiol. 2015; 40(5): 207–38. PubMed Abstract | Publisher Full Text\n\nGaviria C, Benavides C, Tangarife C: [Particulate air pollution (PM2.5 and PM10) and medical consultations due to respiratory disease in Medellín (2008-2009)] Rev Fac Nac Salud Pública (Medellín). 2011 [cited 2020 Dec 5]; 29(3): 241–250. Spanish. Reference Source\n\nGBD 2019 Risk Factors Collaborators: Global burden of 87 risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020; 396(10258): 1223–1249. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGBD Chronic Respiratory Disease Collaborators: Prevalence and attributable health burden of chronic respiratory diseases, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Respir Med. 2020 Jun; 8(6): 585–596. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGolub E, Klytchnikova I, Sánchez- Martínez G: Environmental Health Costs in Colombia. The Changes from 2002 to 2010.Washington: World Bank; 2014. [cited 2020 Oct 12]. 49 p. Reference Source\n\nGrisales-Romero H, Nieto-López E, Montealegre-Hernández N, et al.: Underlying data for ‘Local attributable burden disease to PM2.5 ambient air pollution in Medellín, Colombia, 2010–2016’2021. Publisher Full Text\n\nHajat A, Diez Roux AV, Castro-Diehl C, et al.: The Association between Long-Term Air Pollution and Urinary Catecholamines: Evidence from the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect. 2019; 127(5): 57007. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHealth Effects Institute: State of Global Air 2019. A special report on global exposure to air pollution and its disease burden.Boston, MA: Health Effects Institute2019. [cited 2020 Oct 06]. 22 p. Reference Source\n\nHu LW, Qian Z, Bloom MS, et al.: A panel study of airborne particulate matter concentration and impaired cardiopulmonary function in young adults by two different exposure measurement. Atmos Environ. 2018; 180: 103–109. Publisher Full Text\n\nIndia State-Level Disease Burden Initiative Air Pollution Collaborators: The impact of air pollution on deaths, disease burden, and life expectancy across the states of India: the Global Burden of Disease Study 2017. Lancet Planet Health. 2019; 3(1): e26–e39. PubMed Abstract | Publisher Full Text | Free Full Text\n\nInstituto Nacional de Salud; Observatorio Nacional de Salud: Carga de Enfermedad Ambiental en Colombia.Bogotá (Colombia): Instituto Nacional de Salud; 2018 [cited 2020 Jul 16]. 178 p. Spanish. Reference Source\n\nKauffman JD, Adar SD, Barr RG, et al.: Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study. Lancet. 2016a; 388(10045): 696–704. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKauffman JD, Spalt EW, Curl CL, et al.: Advances in Understanding Air Pollution and CVD. Glob Heart. 2016b; 11(3): 343–352. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu S, Jørgensen JT, Ljungman P, et al.: Long-term exposure to low-level air pollution and incidence of chronic obstructive pulmonary disease: The ELAPSE project. Environ Int. 2021; 146: 106267. PubMed Abstract | Publisher Full Text\n\nMurray CJ: Quantifying the burden of disease: the technical basis for disability-adjusted life years. Bull World Health Organ. 1994; 72(3): 429–45. PubMed Abstract | Free Full Text\n\nNieto-López E, Grisales-Romero H, Montealegre NA, et al.: Effects on Morbidity and Mortality of Critical Episodes of PM2.5 in the City of Medellin, 2015. Poster session presented at: 30st Conference of International Society of Environmental Epidemiology: Addressing Complex Local and Global Issues in Environmental Exposure and Health; 2018 August 26-30; Ottawa, Canada. Reference Source\n\nNishimura KK, Galanter JM, Roth LA, et al.: Early-life air pollution and asthma risk in minority children. The GALA II and SAGE II studies. Am J Respir Crit Care Med. 2013; 188(3): 309–18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrganización de Naciones Unidas: Manual X Técnicas Indirectas De Estimación Demográfica.New York: Naciones Unidas; 1986 [cited 2019 Nov 1]. 318 p. Spanish. Reference Source\n\nPiñeros-Jiménez JG, Grisales-Romero H, Nieto-López E, et al.: Contaminación atmosférica y sus efectos sobre la salud de los habitantes del Valle de Aburrá, 2008a-2017. Análisis de la exposición de corto y largo plazo. 2019. Medellín (Colombia): Área Metropolitana del Valle de Aburrá [cited 2020 Dec 1]. 100 p. Spanish. Reference Source\n\nPiñeros-Jiménez JG, Grisales-Romero H, Nieto-López E, et al.: Contaminación atmosférica y sus efectos sobre la salud de los habitantes del Valle de Aburrá, 2008b-2015. Medellín (Colombia): Área Metropolitana del Valle de Aburrá 2018 [cited 2019 Dec 1]. 114 p. Spanish. Reference Source\n\nPrüss-Ustün A, Wolf J, Corvalán C, et al.: Preventing disease through healthy environments: A global assessment of the environmental burden of disease.Geneva: World Health Organization; 2016. [cited 2020 May 10]. 146 p. Reference Source\n\nRiojas-Rodríguez H, da Silva AS, Texcalac-Sangrador JL, et al.: Air pollution management and control in Latin America and the Caribbean: implications for climate change. Rev Panam Salud Publica. 2016; 40(3): 150–159. PubMed Abstract\n\nRibotta B, Salazar L, Bertone C: [Evaluations of the Life Statistics Coverage at a Subnational Level. Recent Studies in Latin America]. Rev Gerenc y Políticas Salud (Bogotá DC). 2019 [cited 2020 Dec 5]; 18(36): 9–12. Spanish. Reference Source\n\nRomieu I, Gouveia N, Cifuentes LA, et al.: Multicity study of air pollution and mortality in Latin America (the ESCALA study). Res Rep Health Eff Inst. 2012; (171): 5–86. PubMed Abstract\n\nRodríguez-Villamizar LA, Rojas-Roa NY, Blanco-Becerra LC, et al.: Short-Term Effects of Air Pollution on Respiratory and Circulatory Morbidity in Colombia 2011-2014: A Multi-City, Time-Series Analysis. Int J Environ Res Public Health. 2018 Jul 30; 15(8): 1610. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRodríguez-Villamizar LA, Herrera-López AB, Castro- Ortiz H, et al.: [Incidence of respiratory symptoms and the association with air pollution in preschoolers: a multilevel analysis]. Cad Saude Publica (Rio de Janeiro). 2010; 26(7): 1411–8. Spanish. PubMed Abstract | Publisher Full Text\n\nRutstein DD, Mullan RJ, Frazier TM, et al.: Sentinel Health Events (occupational): a basis for physician recognition and public health surveillance. Am J Public Health. 1983 Sep; 73(9): 1054–62. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSalomon JA, Haagsma JA, Davis A, et al.: Disability weights for the Global Burden of Disease 2013 study. Lancet Glob Health. 2015; 3(11): e712–23. PubMed Abstract | Publisher Full Text\n\nSalazar-Ceballos A, Álvarez-Miño L: [The effects of particulate matter 10 (PM 10) and climatological variables in hospital admissions for respiratory diseases of children in the city of Santa Marta, Colombia, 2008-2009.]. DUAZARY (Santa Marta). 2011 [cited 2020 Sep 5]; 8(2): 127–142. Spanish.Publisher Full Text\n\nSchikowski T, Sugiri D, Ranft U, et al.: Long-term air pollution exposure and living close to busy roads are associated with COPD in women. Respir Res. 2005; 6(1): 152. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchikowski T, Adam M, Marcon A, et al.: Association of ambient air pollution with the prevalence and incidence of COPD. Eur Respir J. 2014; 44(3): 614–26. PubMed Abstract | Publisher Full Text\n\nSong L, Smith GS, Adar SD, et al.: Ambient air pollution as a mediator in the pathway linking race/ethnicity to blood pressure elevation: The multi-ethnic study of atherosclerosis (MESA). Environ Res. 2020 Jan; 180: 108776. PubMed Abstract | Publisher Full Text\n\nVilla-Garzon FA, Grisales-Vargas SC, Ospina-Galeano DI, et al.: Artificial Neural Networks to Mix Datasets from Particulate Matters and O3 in Medellin, Colombia. Paper presented at: 30st Conference of International Society of Environmental Epidemiology: Addressing Complex Local and Global Issues in Environmental Exposure and Health; 2018 August 26-30; Ottawa, Canada. Reference Source\n\nWendling ZA, Emerson JW, de Sherbinin A, et al.: Environmental Performance Index 2020.New Haven, CT: Yale Center for Environmental Law & Policy; 2020. [cited 2021 Jan 20]. 205 p. Reference Source\n\nWorld Bank: Methodology for Valuing the Health Impacts of Air Pollution: Discussion of Challenges and Proposed Solutions.Washington DC: World Bank; 2016. [cited 2020 Jan 20]. 59 p. Reference Source\n\nWorld Health Organization: Methods and data sources for global burden of disease estimates 2000-2015.Geneva: Department of Health Statistics and information Systems, WHO; 2017 [cited 2020 Jan 14]. 83 p. Reference Source\n\nWorld Health Organization: Ambient air pollution: a global assessment of exposure and burden of disease.Geneva: World Health Organization; 2016 [cited 2020 Jun 14]. 121 p. Reference Source\n\nYang Y, Tang R, Qiu H, et al.: Long term exposure to air pollution and mortality in an elderly cohort in Hong Kong. Environ Int. 2018; 117: 99–106. PubMed Abstract | Publisher Full Text\n\nYin P, Brauer M, Cohen AJ, et al.: The effect of air pollution on deaths, disease burden, and life expectancy across China and its provinces, 1990-2017: an analysis for the Global Burden of Disease Study 2017. Lancet Planet Health. 2020; 4(9): e386–e398. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "86434",
"date": "24 Jun 2021",
"name": "Pablo Enrique Chaparro Narváez",
"expertise": [
"Reviewer Expertise Public health",
"epidemiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe estimation of the burden of disease attributable to PM 2.5 in Medellín, in terms of DALYs, is novel in Colombia. It is constituted in scientific knowledge that contributes to the identification of the necessary measures to face this problem. It is a well-designed study.\nThere are a few issues that deserve attention:\nIn methods\nTo include a reference that supports the relationship between in situ neoplasms (D00-D09) and PM 2.5 (page 4)\nIn results\nIn figure 1A – G some of the data described do not match: In February and April, it is not evident a higher trend towards a monthly average increase of PM 2.5 pollution during the study period (page 5); “October and November from 2010 to 2014 presented monthly averages with slight increases”, except in 2011 (page 5); For years 2015 and 2016, the trend was not downward during these months (page 5).\n\nThe results are not presented for attributable prevalent cases to PM 2.5 pollution for in situ neoplasms (D00 – D09).\n\nPage 9: \"with a slightly greater magnitude in the male burden than the female burden (Table 1)\". This table does not discriminate by sex.\n\nPage 9: table 3, “female average LDBPM2.5 (UI 95%) YLLs 2,886 (82,820 - 2,952)”. Please, revise UI 95%\n\nPage 12: table 5, “other acute lower respiratory tract infection (J20 – J22) DALYs PM2.5 (95% UI) 1,948 (594 - 1,502)”. Please, revise UI 95%\n\nIn figure 3 identify quadrants A, B, C, D.\nI recommend to consider the following issues and address them:\nThe quality of air pollutant data.\n\nThe under-registration of RIPS. This has been presented previously in several publications (Primer Informe ONS. Aspectos relacionados con la frecuencia de uso de servicios, mortalidad y discapacidad en Colombia, 2011) (Burden of pneumococcal infection in adults in Colombia).\n\nThe influence of garbage codes to improve the comparability of data with respect to causes of death in the estimates obtained.\n\nUse of the GBD 2013 methodology of the WHO and methodology GBD Institute for Health Metrics and Evaluation IHME. The GBD IHME was mentioned in strengths (page 17).\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "6943",
"date": "06 Dec 2021",
"name": "Hugo Grisales-Romero",
"role": "Author Response",
"response": "ANSWERS TO REVIEWER COMMENT 1: To include a reference that supports the relationship between in situ neoplasms (D00-D09) and PM 2.5 (page 4). ANSWER: An exhaustive review was made of events associated with air pollution. In the review by Turner et al. (2020) on air pollution and cancer, a wide list of events is evidenced in addition to lung and respiratory cancer, which includes neoplasms in different organs and systems. In the appendices to the recent report from the 2019 Global Burden of Disease study published in The Lancet 2020, specific codes D00-D09 are included between specific events with specific Population Attributable Fractions. Reference Turner, MC, Andersen, ZJ, Baccarelli, A, Diver, WR, Gapstur, SM, Pope, CA, Prada, D, Samet, J, Thurston, G, Cohen, A. Outdoor air pollution and cancer: An overview of the current evidence and public health recommendations. In: CA Cancer J Clin. 2020: 70: 460- 479. [cited 2021 Jun 25], Available from https://doi.org/10.3322/caac.21632 COMMENT 2: In figure 1A – G some of the data described do not match: In February and April, it is not evident a higher trend towards a monthly average increase of PM 2.5 pollution during the study period (page 5); “October and November from 2010 to 2014 presented monthly averages with slight increases”, except in 2011 (page 5); For years 2015 and 2016, the trend was not downward during these months (page 5). ANSWER: We agree with the opinion of the evaluator, the corrections will be included in the second version of the manuscript, which will consist of describing the dynamics of the monthly concentrations of PM2.5, and it is observed that in the months of February and March of each year the highest averages were presented during the study years, except for 2012. Likewise, there is a greater tendency to increase the monthly average for PM2.5 for these months during the study period. In March 2016, the highest mean value of the entire time series of data were identified. On the other hand, the months of October and November from 2010 to 2016 presented monthly averages with slight increases, except for 2011 (Figure 1A-G). COMMENT 3: results are not presented for attributable prevalent cases to PM 2.5 pollution for in situ neoplasms (D00 – D09). ANSWER: Due to the few cases reported for codes D00-D09 in the Medellín information systems, we decided to exclude the information on prevalent cases attributable to PM2.5 ambient air pollution from tables 1 and 2. COMMENT 4: Page 9: \"with a slightly greater magnitude in the male burden than the female burden (Table 1)\". This table does not discriminate by sex ANSWER: The observation of evaluator is correct, the burden disease analysis by sex is presented in Table 3. The correction will be made in the second version of the manuscript. COMMENT 5: Page 9: table 3, “female average LDBPM2.5 (UI 95%) YLLs 2,886 (82,820 - 2,952)”. Please, revise UI 95% ANSWER: We reviewed the uncertainty interval of the female average LDBPM2.5 (95% UI) YLLs from table 3 and made the respective correction of upper limit of the 95% uncertainty interval. It is 2.820 COMMENT 6: Page 12: table 5, “other acute lower respiratory tract infection (J20 – J22) DALYs PM2.5 (95% UI) 1,948 (594 - 1,502)”. Please, revise UI 95% ANSWER: We reviewed the uncertainty interval of other acute lower respiratory tract infection (J20 – J22) DALYsPM2.5 (95% UI) from table 5 and made the respective correction of upper limit of the 95% uncertainty interval. It is 2.594 COMMENT 7: In figure 3 identify quadrants A, B, C, D ANSWER: Starting in the top of figure 3, from left to right, the first quadrant corresponds to C, the second quadrant to D, the third quadrant to A, and the fourth quadrant to B. COMMENT 8: The quality of air pollutant data. ANSWER: In previous studies carried out by the authors of this manuscript (Piñeros- Jiménez, 2018), the quality analysis of the daily concentrations of PM2.5 available in the Intelligent Information System and the Air Quality Surveillance Network (REDAIRE, acronym in Spanish) of the environmental authority of the metropolitan region of Aburra Valley was made. The quality of the raw data measured in each station is carried out by the Institute of Hydrology, Meteorology and Environmental Studies (REDAIRE, acronym in Spanish), who are in charge of identifying the outlier data, as well as establishing the concentration of daily averages, which are calculated with at least 75% of the hourly data valid for each day in the case of automated stations. For each dataset (n = 8), the percentage of days without available information was established and the missing daily concentrations of PM2.5 were determined using multiple imputation techniques by neural networks (Villa-Garzón, 2018). Starting from the imputed series, a representative data series of the city was assembled for each year of study, previous correlation analysis by measuring the entropy of the information based on the Bhattacharya-Hellinger-Matusita distance that allows determining the relative closeness between data sets (Li, 2015). The results presented in this manuscript show an overview of PM2.5 pollution in Medellín from assembled series, with the proper quality product of a necessary purification process that ideally shows the behavior of the pollutant in the city. Piñeros-Jiménez JG, Grisales-Romero H, Nieto-López E, Montealegre NA, Villa-Garzón FA, Agudelo R, et al. Contaminación atmosférica y sus efectos sobre la salud de los habitantes del Valle de Aburrá, 2008-2015. 2018 [Internet]. Medellín (Colombia): Área Metropolitana del Valle de Aburrá [cited 2019 Dec 1]. 114 p. Available from: https://www.metropol.gov.co/ambiental/calidad-del-aire/Biblioteca-aire/Re-analisis/ContaminacionAtmosferica_y_sus_Efectos_en_la_Salud-AMVA_2019.pdf Spanish. Villa-Garzon FA, Grisales-Vargas SC, Ospina-Galeano DI, Jiménez-Vargas DL, Pñieros-Jiménez JG. Artificial Neural Networks to Mix Datasets from Particulate Matters and O3 in Medellin, Colombia [Internet]. Paper presented at: 30st Conference of International Society of Environmental Epidemiology: Addressing Complex Local and Global Issues in Environmental Exposure and Health; 2018 August 26-30; Ottawa, Canada. Available from: https://ehp.niehs.nih.gov/doi/10.1289/isesisee.2018.O03.03.06 Li H. Nonsymmetric Dependence Measures: the Discrete Case. 2015 [cited 2021 Jun 11]; Available from: https://arxiv.org/pdf/1512.07945.pdf COMMENT 9: The under-registration of RIPS. This has been presented previously in several publications (Primer Informe ONS. Aspectos relacionados con la frecuencia de uso de servicios, mortalidad y discapacidad en Colombia, 2011) (Burden of pneumococcal infection in adults in Colombia). ANSWER: We agree with the question raised by the evaluator in relation to the underreporting of the RIPS, which corresponds to a reality inherent to the reporting dynamics of morbidity of Colombia’s information system, as this is recognized in some previous publications. However, the advances in the timeliness of information that have been achieved during the last decade due to the efforts made by the health system at the local level, particularly Medellín has achieved less underreporting than other cities in the country. It should be noted that the estimation of underreporting considers the clinical history as a source of comparison for the RIPS, which as the primary document would allow comparison with the diagnoses of interest of the RIPS (capture-recapture method). However, this procedure requires access to data that is under the habeas data considerations. We do not consider the National Demographic and Health Survey as a source of comparison with the RIPS, due to the temporal differences between the RIPS used in the present study (2010-2016) and the information from the survey, whose most current version is that of the year 2015. Added to this is the difficulty in accessing to its anonymized database. COMMENT 10: The influence of garbage codes to improve the comparability of data with respect to causes of death in the estimates obtained. ANSWER: In the mortality analysis carried out in this study, the causes that have been identified as residual or garbage codes were not considered. This was limited to the groups of causes that have been identified in the literature as related to ambient air pollution and for which the parameters for calculating burden disease indicators were available, specifically the fraction of risk attributable to the population. To define the ICD-10 codes of the events to be included in the study, a homologation and mapping was carried out with respect to the list of causes of GBD, this activity was also validated by two clinical experts. Recognizing the possible information biases derived from the erroneous assignment of codes of the basic causes of death by the health personnel, the process carried out allows the comparability of the results with other studies of the environmental burden of the disease. COMMENT 11: Use of the GBD 2013 methodology of the WHO and methodology GBD Institute for Health Metrics and Evaluation IHME. The GBD IHME was mentioned in strengths (page 17). ANSWER: Since the first study of the global burden of disease in 1993, constant updates have been made. In 2010 they introduced significant changes in the methodology for the measurement of the base metric of the Years of Life Adjusted for Disability, which were supported by the experience of around 40 working groups in the area of epidemiology, several of them providing support to the public health programs of the World Health Organization. Thus, over more than two decades this methodology has been refined and validated in national and international health analysis scenarios. In this study, the latest theoretical and methodological criteria defined by the WHO since 2013 were taken into account, omitting economic and social evaluations in the metric. In addition, to identify the disability weights associated with each of the events related to air pollution, the lists of the study of the global burden of diseases 1990-2017 updated by the IHME were used and the Attributable Fractions were considered. Population-based (FAP) associated with PM2.5 contamination standardized by age that were estimated for Colombia in a study carried out by the IHME (Cohen A., et al., 2015). COMMENT 11: Are all the source data underlying the results available to ensure full reproducibility? Partly ANSWER: We do not agree with the assessment of the reproducibility of the study made by the evaluator, The following arguments support our position: The sources of information used were official open access sources and are identified in the text and supplementary material; ii) the critical point for the reproducibility of the study is the selection of events, and this has been detailed in the manuscript and in the references that support them, mainly the previous research carried out by this team, which evaluated the impacts of short-term exposure to atmospheric pollutants in the municipalities of the Aburrá Valley (Piñeros-Jiménez et al., 2018); and iii) the manuscript describes the methodology used for the analysis of the attributable local burden disease to PM2.5 ambient air pollution, which is detailed in the study carried out by Cohen in 2015."
}
]
},
{
"id": "86980",
"date": "02 Nov 2021",
"name": "Carmen Ildes Rodrígues Fróes Asmus",
"expertise": [
"Reviewer Expertise Environmental health",
"epidemiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study aimed to determine the local burden of disease to PM2.5 for Medellín, one of Colombia's more populous and representative cities. It is a well-design study. The methodology is detailed step to step. The authors carried out a suitable description of the protocols and tools applied for the data quality assessment used in the study.\nThis article brings important information about the impact of PM2.5 exposure on disease burden in a Latin American city. Also it contributes, as a feasible model, for the fulfilment of other similar studies in other Latin American cities.\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": "7394",
"date": "05 Nov 2021",
"name": "Hugo Grisales-Romero",
"role": "Author Response",
"response": "Thank you very much for taking the time to review this manuscript. Your review was very valuable. Best regards"
}
]
}
] | 1
|
https://f1000research.com/articles/10-428
|
https://f1000research.com/articles/10-219/v1
|
17 Mar 21
|
{
"type": "Study Protocol",
"title": "Influence of surface peripheral electrical stimulation on nerve regeneration after digital nerve neurorrhaphy: study protocol for a randomized clinical trial",
"authors": [
"Enilton Mattos",
"Alex Guedes",
"Paulo Itamar Ferraz Lessa",
"Abrahão Fontes Baptista",
"Enilton Mattos",
"Alex Guedes",
"Paulo Itamar Ferraz Lessa"
],
"abstract": "We will study the influence of low intensity and frequency surface peripheral electrical stimulation (PES) on nerve regeneration of digital nerve injuries of the hand after its surgical repair in humans. Participants will be patients with acute traumatic peripheral nerve injury referred to the Hand Surgery Service of the General Hospital of the State of Bahia, a reference service in the state. These patients will undergo surgery followed by PES in the immediate postoperative period. After hospital discharge, they will be followed up on an outpatient basis by researchers, who will remotely supervise a physiotherapy program. Our hypothesis is that PES will positively influence the recovery of sensory function in patients undergoing neurorrhaphy of digital nerves of the hand. ReBEC registration: U1111-1259-1998 (12/18/2020)",
"keywords": [
"Transcutaneous Electric Nerve Stimulation",
"Peripheral Nerves",
"Nerve Regeneration",
"Electric Stimulation Therapy",
"Peripheral Nerve Injury"
],
"content": "Introduction\n\nDamage to the peripheral nervous system (axonal damage) can occur due to a variety of reasons including trauma, ischemia, or inflammation (Stoll & Müller, 1999). In response to peripheral nerve injury, morphological and functional changes can occur (Knight, 2000; Robbins, 1974), such as motor and sensory function impairment, hyperesthesia, and low-temperature intolerance (Rosén & Lundborg, 2000). The process of extensive degeneration that occurs when the axon distal to the injury degenerates is known as Wallerian degeneration, however, the proximal stump, which remains attached to the cell body, can regenerate, and grow towards the target organ (Stoll & Müller, 1999).\n\nNeural regeneration following injury is influenced by a number of factors, such as age, level and extent of the injury, time elapsed from injury to repair, and presence of associated injuries (Dunlop et al., 2019; Ruijs et al., 2005). Axonal regeneration is influenced by chemotactic and electrical tracks (Song et al., 2004; Stoll & Müller, 1999): if the tracks are not adequate (high or long), or the distance to be covered by the axonal sprouts is too large, the regenerated neurons will not be functional. This is the case of proximal injuries occurring close to the cell bodies, such as traumatic injury to the brachial plexus and injury of nerve roots in the conjugation foramen (Gordon et al., 2003). When the metabolism or nutrient supply is affected, such as in diabetes, functional regeneration is also impaired (Kennedy & Zochodne, 2005). Therefore, promoting functional regeneration is key for the peripheral nervous system to resume normal functions.\n\nStrategies to improve peripheral nerve regeneration include the use of neurotrophic factors, stem cells (Lopes et al., 2006; Tohill & Terenghi, 2004), ultrasound (Crisci & Ferreira, 2002), low-intensity LASER (Bae et al., 2004), physical exercise (Molteni et al., 2004; Seo et al., 2006), and electromagnetic fields. The latter is based on the fact that tissue injury results in an influx of calcium that causes endogenous electrical currents by increasing local electrical potentials (McCaig et al., 2002; Watson, 1998). These currents are formed through electrical gradients between the affected area and the surrounding regions and remain active throughout the regenerative process (Low & Reed, 2001). Exogenous electrical stimulation has been used to promote neural regeneration and early tissue recovery following injury.\n\nElectrical stimulation to improve the rate and speed of peripheral nerve regeneration involves the application of electrical fields of constant or varying frequency, as demonstrated in animal studies (Baptista et al., 2007; Baptista et al., 2008). Electrical currents are usually used, either flowing unidirectional (monophasic, constant or pulsed electrical currents) or bidirectional (alternate or biphasic electrical currents). The electrical currents may be administered through electrodes implanted in the nerve itself, intraoperatively, and using percutaneous or transcutaneous stimulation. Monophasic electrical currents have the advantage of unidirectionality; they can generate electrophoretic effects on membrane proteins and, thus, guide neurite growth towards the cathode (McCaig et al., 2002). However, if used at high intensity or for long periods, the monophasic electrical currents can cause harmful effects due to electrophoresis itself (Low & Reed, 2001). Although biphasic currents do not offer the risk of harmful electrophoretic effects, they are less commonly used, as they do not have the power to guide the neurites towards the target organ.\n\nThere are different types of electrodes, with some predominating over others. In general, the closer the electrode is to the nerve, the smaller the current amplitude, as there is no need to overcome the impedance exerted by the surrounding tissues.\n\nImplanted electrodes. Stimulation with implanted electrodes and different types of electrical currents have been the most used method since the 1980s in experimental models, generally for lesions in the soleus (Nix & Hopf, 1983) and sciatic (Beveridge & Politis, 1988; Kerns et al., 1991; Mendonça et al., 2003; Politis et al., 1988; Pomeranz & Campbell, 1993) nerves. All of these studies showed positive results, with improvements in functional and/or morphological parameters.\n\nOnly two studies—one on lesions of the common fibular nerve (McGinnis & Murphy, 1992) and the other on lesions of the sciatic nerve (Hanson & McGinnis, 1994)—reported negative results, with fewer regenerating fibers, formation of neuromas, and a lower rate of myelination in the stimulated groups. However, in these studies, one of the electrodes was placed inside a small silicone tube that joined the two sectioned stumps, leading to the interaction of the single-phase electric current with the material of the tube. Deleterious effects arose due to the lack of alternating current and, consequently, destruction of part of the tube, with physical impediment to the passage of neurites.\n\nTo avoid tissue destruction, although the electrical currents used in all of the above-mentioned studies were monophasic, electrical current amplitudes were extremely low (below the sensitive threshold in the µA range). Stimulation was usually performed continuously for a few weeks prior to analysis.\n\nPercutaneous electrostimulation. Percutaneous electrodes are usually acupuncture needles inserted into the skin and connected to an electric current generator. Electric currents through percutaneous electrodes have been used in experimental models and perhaps they are, of the methods studied so far, the simplest to apply in clinical practice. This type of stimulation has been used in models of sciatic nerve injury (Chen et al., 2001; Inoue et al., 2003; McDevitt et al., 1987; Pomeranz et al., 1984), with the best results achieved when the cathode was placed distal and the anode proximal to the lesion. Monophasic electrical currents were used, with amplitudes below the sensory threshold, yet reaching the intensity of 1 mA (much higher than that used in techniques with implanted electrodes).\n\nIntraoperative electrostimulation. In intraoperative electrostimulation, the nerve is stimulated shortly following injury, for varying periods of time. Studies on intraoperative electrostimulation have mostly used the sciatic (Scott, 1991) and femoral (Al-Majed et al., 2000a; Al-Majed et al., 2000b; Al-Majed et al., 2004; Brushart et al., 2002) nerves. The first studies used monophasic electrical currents; the most recent ones used alternating currents with pulse frequencies of 20 Hz (Al-Majed et al., 2000a; Al-Majed et al., 2000b; Al-Majed et al., 2004; Brushart et al., 2002). The latter allowed more precise and faster reinnervation; increased the expression of brain-derived neurotrophic factor (BDNF), tyrosine receptor kinase B (TrKB), Tα1-tubulin, and growth associated protein 43 (GAP-43), and other genes/proteins associated with regeneration; and reduced expression of neurofilaments (a phenomenon associated with regeneration). This model has been the only one to be translated to humans, so far. Gordon et al. (2010) evaluated the same electrical stimulation protocol in patients with denervation of the muscles of the thenar region due to carpal tunnel syndrome. They observed that the treatment accelerated axonal regeneration without affecting function. Intraoperative electrostimulation differs from others, in addition to the form of stimulation, for the brief time it is used (approximately 1–2 hours of stimulation following injury).\n\nThin-film wireless implantable nerve stimulators. Using widely established technology, wireless devices dedicated to peripheral nerve stimulation have been used to improve functional recovery in a rodent model, without the additional time needed to provide direct stimulation during the surgical procedure (Ray et al., 2017). This strategy has not yet had practical application in humans.\n\nSurface electrodes. The use of transcutaneous surface electrodes is a non-invasive option that can be used for a longer period, especially when associated with biphasic electrical currents. Its handling is practical and simple, avoiding the reactions provoked by implant surgery or percutaneous stimulation.\n\nPrevious studies have evaluated the influence of peripheral electrical stimulation (PES) through surface electrodes on the regeneration of tissues such as tendons (Burssens et al., 2003; Burssens et al., 2005), skin (Kaada &Emru, 1988; Kjartansson et al., 1988; Khalil & Merhi, 2000; Liebano et al., 2003), and bone (Kahn, 1982), with varying results. This modality is associated with effects such as increased blood flow (from Sandberg et al., 2007; Vries et al., 2007) and collagen synthesis (Burssens et al., 2005). However, electrical currents with amplitudes above 1 mA are needed, which may be related to decreased concentrations of adenosine triphosphate (ATP) (Cheng et al., 1982) and, consequently, inhibition of peripheral nerve regeneration.\n\nElectrical fields may influence blood circulation/perfusion, promoting an increase in axonal sprouting and nerve regeneration (McCaig et al., 2005). Low frequency electrical currents can selectively activate sensory C fibers and increase the expression of neuropeptides such as substance P, which generate vasodilation (Burssens et al., 2005; Kashiba & Ueda, 1991; Kjartansson et al., 1988). Also, low-frequency PES (2–10 Hz) is usually associated with rhythmic muscle contraction, which can have circulatory effects (Dobsák et al., 2006). However, recent evidence has suggested that high-frequency PES, which is used without producing muscle contraction, also increases circulation. de Vries et al. (2007) demonstrated an increase in coronary circulation as a result of high-frequency PES.\n\nThe most studied effects of PES are related to pain control. Analgesia caused by high-frequency PES activates δ-opioid receptors, while low-frequency PES activates µ-opioid receptors (Kalra et al., 2001; Sluka & Walsh, 2003). Sinatra & Ford (1979) demonstrated that the chronic use of morphine for 14 days leads to a delay in peripheral nerve regeneration, as reflected by a lower number of axonal profiles, decreased removal of myelin debris, and hypertrophy and proliferation of Schwann cells. Zeng et al. (2007) also demonstrated that exposure to morphine, acting via µ-opioid receptors, increases the regeneration of unmyelinated fibers, while inhibiting the regeneration of myelinated fibers after ischiatic nerve crush injury.\n\nThe fundamental difference between the studies that showed stimulating or inhibitory effects on the regeneration of the peripheral nervous system via the activation of opioid receptors was the prolonged time of use, which may have led to the development of pharmacological tolerance. Chandran & Sluka (2003) demonstrated that repeated high- and low-frequency PES for 20 minutes a day, led to opioid tolerance on day 4. Mao et al. (2002) demonstrated that this effect is mediated by the N-methyl-D-aspartate (NMDA)–caspase pathway, which leads to apoptosis of neuronal cells in the spinal cord. Therefore, the prolonged use of PES can lead to the development of opioid tolerance and neurotoxicity of the cells involved in regeneration. A brief use of PES, which does not lead to opioid tolerance, could however, be an important strategy to promote regeneration (de Assis et al., 2014), but this has not so far been investigated in humans.\n\nOur overall aim is to study the influence of PES on peripheral nerve regeneration in humans. Specifically, we will study the influence of PES on recovery of sensory function, and on the social participation of patients undergoing neurorrhaphy of digital nerves of the hand.\n\n\nProtocol\n\nThis is a randomized, double-blinded, controlled clinical trial that will be carried out in a reference tertiary general hospital in Bahia, Brazil. This protocol has been registered at ReBEC (U1111-1259-1998 on 18th December 2020) and follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist ( de Santana Riberio de Mattos et al., 2021d ). Patients undergoing neurorrhaphy for injuries caused by transection of digital nerves in the hand will be involved in the study. Half the participants will have PES (Endophasys, KLD, Brazil) performed immediately after surgery and before hospital discharge and the other half will receive a SHAM treatment. The participants and outcome assessors will be blinded to patient allocation. The electrodes will be placed in the same position and for the same amount of time for the intervention group as the sham group. The outcome measures evaluators will not know which intervention was assigned to the participants.\n\nA convenience sample of adult patients (over 18 years old of both sexes) with acute traumatic digital nerve injury referred from others health centers to the General Hospital of the State of Bahia to undergo surgical repair within a maximum of 2 weeks after the injury will be included. Patients with metal implants at the surgery site, who have a history of seizures, who have a cardiac pacemaker, or who have a local infection or skin lesion that prevents the application of surface electrodes will be excluded from the study.\n\nBasic material: Endophasys Electrostimulator – KLD, Brazil and silicone-carbon electrodes (used to perform electrostimulation in the patients).\n\nAll materials required for this study are available as extended data (de Santana Ribeiro de Mattos et al., 2021a).\n\nThe Hand Surgery Service of the General Hospital of the State of Bahia is the foremost public tertiary trauma hospital and act mainly as referral center for other institutions in Bahia, Brazil. Outpatient Federal University of Bahia Physiotherapy Department will support the patients after surgery. The available facilities at these centers are listed in the extended data (de Santana Ribeiro de Mattos et al., 2021b).\n\nFigure 1 shows a flow diagram of the participants’ journey through the study. Patients will be divided and allocated to two groups: group A (surgery + PES); or group B (surgery + sham). A simple randomization strategy will be performed to achieve balanced groups, using an online resource (randomization.com). The hidden allocation and electrical stimulation will be performed by a professional not involved in other stages of the study. Opaque and sealed envelopes will be used to address participant allocation. Participants will only be randomized if they provide informed consent to participate in the trial.\n\nFollowing surgery, both groups will additionally receive 1 hour of either electrical stimulation (group A) or sham (group B). In total, two silicone-carbon and gel electrodes (measuring 1 × 1 cm) will be used for all participants, with one placed exactly proximal and the other exactly distal to the surgical site. The two groups will receive the following therapeutic regimens:\n\n• Group A: Surgery + PES. The electrodes will produce a square-pulsed, biphasic, symmetrical current at a frequency of 20 Hz, pulse width of 0.4 ms, and amplitude at the motor threshold of the median nerve, for 1 hour directly after surgery (n = 16);\n\n• Group B: Surgery + sham PES. The electrodes will produce a square-pulsed, biphasic, symmetric electric current at a frequency of 20 Hz, pulse width of 0.4 ms, and amplitude at the motor threshold of the median nerve, for 1 hour directly after surgery (the same as Group A) but the electrostimulator will be turned on only until the patient is aware of it, after which the amplitude will be set to zero (n = 16).\n\nIn the first post-operative review, the patient will be evaluated by the doctor at the outpatient clinic. A physiotherapist specialized in the area and blinded to the intervention will guide on the rehabilitation protocol that will be monitored remotely by electronic means available to the patient (WhatsApp, Skype, etc.). Patients will undergo a hand sensory re-education protocol based on the one proposed by Dellon & Jabaley (1982) for a period of 3 months. This protocol involves exercises for discrimination of static and dynamic touch and objects of different shapes, sizes, and textures guided by the physiotherapist, and the patient is also stimulated to perform a home program exercises. This will involve a total of 20 remote monitored sessions lasting about 30 minutes each, carried out, on average, twice per week. No videos or photos of the patients will be acquired to guarantee the patient’s privacy and data confidentiality.\n\nPatients will be evaluated in person after every 10 treatment sessions by the main author of the study, who is responsible for the surgical and postoperative follow-up of the study participants but blinded to group allocation.\n\nParticipants must complete a total of 4 face-to-face assessments to document the results:\n\n- 1 pre-intervention/electrical stimulation\n\n- 1-week post-electrical stimulation\n\n- 1 after 10 rehabilitation sessions\n\n- 1 after all 20 rehabilitations sessions\n\nThe research will be completed within 1 year.\n\n- Primary Outcome: Improvement of peripheral nerve regeneration of digital nerves in the hand measured using quantitative sensory tests (Semmes-Weinstein monofilaments and two-point discrimination tests measured and compared in the four presential assessments). The difference between the two treatment arms (group A x group B) measured through the sensory tests (SWM and 2PD) will be evaluated after randomization.;\n\n- Secondary Outcome: Improvement of sensory functions and social participation of the individual submitted to neurorrhaphy of digital nerves of the hand measured through questionnaires (Cold Sensitivity Severity Scale described by McCabe et al. (1991), and the Pain Disability Index questionnaire recommended by Novak et al., 2010).\n\nSemmes–Weinstein monofilament test (SWM). The Semmes–Weinstein monofilament test is used to assess the perception of pressure thresholds, which reflect the reinnervation of peripheral targets. Using scored probes, the assessment of perception of touch/pressure is measured and recorded. This test is a prime marker of functional recovery and provides quantitative data that can be used to monitor the patient during the course of nerve regeneration (Wang et al., 2013).\n\nSubjects were asked to place their hands over a table, and keep their eyes closed during this test. Each filament, starting with the smallest caliber, was tested over the pulp side of the affected finger. The filament was applied perpendicularly for 1 to 1.5 s in three trials. A positive response in at least 2 of the 3 trials marked the sensory threshold (Gordon et al., 2010). We used the test results for data analysis.\n\nTwo-point discrimination test (2PD). The two-point discrimination test, first described by WEBER in 1835 (Dunlop et al., 2019), is an established assessment tool for tactile gnosis (Wang et al., 2013). It is defined as the distance between compass points necessary for the patient to feel two contacts (Rosén & Lundborg, 2000). Ideally, it is recorded as an absolute value compared to the corresponding portion of the contralateral, uninjured finger. Normal values in an undamaged strip of the finger vary from 2 to 6 mm (Table 1).\n\nClassification schemes for the two-point discrimination test such as the Medical Research Council (1954), modified by MACKINNON & DELLON (Modified Highet Classification), allow to divide into groups of value ranges according to the sensitive threshold of recovery (Table 2).\n\ns2PD=static two-point discrimination; m2PD=moving two-point discrimination.\n\nCold Sensitivity Severity Scale (CSS). The development of cold sensitivity is quite common after surgery and hand injury. After certain types of injuries, such as amputation and nerve damage, hypersensitivity can cause severe disability. The Cold Sensitivity Severity Scale developed by McCabe et al. (1991) provides a reliable scale to measure cold sensitivity. The CSS scale includes four questions about events in the home that cause cold-related symptoms. To respond to each item, the patient is asked to place an X on a 100 mm line reflecting the severity of the symptom. The line had indicators at 25 mm intervals and underlying descriptors. The score for each item was then measured in millimeters from the beginning of the line, with the sum of the appropriate four-item subscale giving the cold-sensitivity severity score.\n\nPain Disability Index. The Pain Disability Index is a seven-item questionnaire designed to assess the extent to which pain interferes in the domains of daily life (family and household responsibilities, recreation, social activity, occupation, sexual behavior, self-care, and life support activity). Each item is rated on a scale from 0 (no disability) to 10 (total disability). The final score (ranging from 0 to 70) is calculated by adding the scores of each item, with a higher score indicating a higher level of disability due to pain (Figure 2). The consistency, validity, and reliability of this questionnaire has been tested and proved to be useful in studies of nerve damage (Novak et al., 2010).\n\n(Reproduced from Wang et al., 2013).\n\nPatient allocation and statistical analysis will be done by a researcher (AFB) who will be blinded to the procedures and groups. A simple randomization will be performed using sealed and opaque envelopes. There will be 16 patients per group (groups A and B), totaling 32 patients. The sample size is based on the study by Gordon et al. (2010), as this is the only randomized clinical trial in the literature. We estimated the sample considering a repeated measures analysis of variance (ANOVA) test with interaction between and inter factors, with an effect size of 0.26 (according to Gordon et al., 2010), alpha-type error of 5%, power of 80%, two groups, three measures, with correction between factors of repeated measures of 0.5, and correction of non-sphericity of 1. These parameters resulted in 26 individuals in the total sample (13 per group), which were increased by 20% to compensate for possible losses, resulting in a final sample of 32 patients (16 per group). The selection of the sample to compose the two groups will be carried out by an experienced (>10 years) hand surgeon, through the clinical examination and application of evaluation tools (Semmes-Weinstein monofilaments, two-point discrimination tests, Cold Sensitivity Severity Scale and the Pain Disability Index).\n\nThe collected data will be recorded in a hand-registered logbook and typed in EXCEL, archived in Google Drive. The Cold Sensitivity Severity Scale and Pain Disability Index questionnaires are applied to each participant in the last evaluation by the hand surgeon to be answered individually and, at the end of the collection, are imported in excel format and archived in Google Drive. All data will be entered manually and electronically and stored on a password-protected laptop, computer hard drive, and external storage device in possession of the responsible for search and virtually shared with the supervisor researcher. Participant files will be stored in numerical order and stored in a secure and accessible place and manner. Participant files will be maintained in storage for a period of 5 years after completion of the study.\n\nAll statistical tests will be performed using SPSS (V25.0, IBM Corporation, New York, USA). The data will be evaluated in a paired and non-paired way. For paired evaluations (intra-group comparisons), repeated measures ANOVA or the Friedman test will be used, followed by the Student–Newman–Keuls post-test. For non-paired assessments (comparisons between groups), analysis of variance of a measure (one-way ANOVA or the Kruskal–Wallis test) will be used, followed by the Student–Newman–Keuls post-test. The choice of tests will depend on the normality or the nature of the data.\n\nFor statistical analysis, the 95% confidence interval will be considered, with an alpha of 5% (P < 0.05) and power of 80%. Descriptive analysis will be done through the averages or medians associated with the applicable dispersion measures (standard deviation or quartiles 25/75). Both the measurements of the variables in each study and the statistical analysis will be performed blindly.\n\nThe independent variable for both groups will be the use of electric currents. The dependent variables will be derived from the pre- and post-treatment assessments (Semmes-Weinstein monofilaments, two-point discrimination, Cold Sensitivity Severity Scale and Pain Disability Index).\n\nPatients will be informed orally at the time of admission to the hospital about the nature of the study (including the description of the procedures that will be used, possible discomforts and risks and expected benefits, existing alternative treatment methods, monitoring and assistance approaches, and responsible staff) using accessible language.\n\nPatients will receive clarifications before and during the study regarding the methodology, stating that we will not use a placebo group, and inclusion in a control group is possible. They will be informed about their freedom to refuse to participate or withdraw from the study, at any stage of the research, without any penalty nor prejudice to care; the confidentiality of their data; the absence of reimbursement of expenses resulting from the participation of the research; and the forms of indemnity in the event of any damages resulting from the research in accordance with the ethical standards and regulations of human studies of the Helsinki declaration (2014).\n\nThe procedures that we will use do not generate vital risks. The risks are minimal for patients, since we will use low-intensity biphasic electrical currents, which do not generate electrolytic effects on the skin, in addition to surface electrodes. The stimulation will be done only once, thus minimizing the possibility of skin irritation. None of the assessment procedures creates risks for skin injuries. If there are any complications regarding the procedures, patients will be immediately referred to the doctors who accompany them and are part of the project.\n\nThe project was submitted to the Research Ethics Committee of the Faculty of Medicine of Bahia, Federal University of Bahia. Patients who agree to participate in the study will sign an informed consent form on admission (extended data), according to Resolution No. 466 of December 12, 2012, of the National Health Council.\n\nThe information provided by the patients, as well as all data collected from the research will be kept confidential, to preserve their identity. Data will be kept in a file with a key from the Research Group on Musculoskeletal Dynamics at the Federal University of Bahia (UFBA), under the responsibility of Prof. Abrahão Fontes Baptista.\n\nThe study findings will be published in a thesis and research article. This work is linked to the master’s degree of Enilton de Santana Ribeiro de Mattos (Graduate Program of the Bahiana School of Medicine and Public Health, under the guidance of Prof. Abrahão Fontes Baptista and co-supervision of Prof. Alex Guedes).\n\nThe study will start after the project has been approved by the Research Ethics Committee (CEP) of the Faculty of Medicine of the Federal University of Bahia, Federal University of Bahia and upon receiving all the materials needed. The study is scheduled to run for 10–12 months from October 2020 to October 2021 as described in Table 3 (we are at the Treatment Stage according to the Milestone schedule as of February 2020).\n\n\nDiscussion\n\nThe main contributions of this study are discussed below.\n\nThe use of electric currents to promote peripheral nerve regeneration has been studied in experimental animal models, and, essentially, through invasive techniques. Surface electrodes are cheaper and offer minimal potential risk for the patient. Despite these advantages, in general, studies with humans address the use of electrical currents to generate contraction of the denervated muscle, but not to directly promote regeneration. This study could provide novel, useful, and practical strategies to treat patients with peripheral nerve damage.\n\nWe are involved with a project that has already been approved by the PAPPE Public Notice of the State of Bahia Foundation for Research Support, for the creation of functional electrical stimulation devices for patients with peripheral nerve damage. For this collaboration between the Polytechnic School and the Institute of Health Sciences, both from UFBA, some data would be important for the manufacture of these devices. It is necessary to know whether electrical currents, as they are being tested in this project, may or may not influence peripheral nerve regeneration, so that we can complete the planning of the functional electrical stimulation device.\n\nPeripheral nerve injuries are clinical entities that are usually underdiagnosed and undertreated. This has consequences, such as worker incapacity, with repercussions on their families and means of work. Transection injury treatments are usually exclusively surgical. However, strategies to speed recovery and return to function are extremely important both for the patients to have a greater chance of returning to work and to minimize costs related to associated complications.\n\nIn the city of Salvador, patients with peripheral nerve damage who have low purchasing power are usually operated on at the general hospital of the state and tend to have difficulties in carrying out their rehabilitation, as they do not have a service available for this situation. This research project is part of a larger perspective, with the creation of a reference service for the rehabilitation of patients with peripheral nerve damage, which should work within the Physiotherapy Service of Professor Edgard Santos University Hospital Complex, Federal University of Bahia. In addition to patients with digital nerve injuries, this service can serve all other patients who are operated on in acute situations or who have chronic neuropathies and need specialized care.\n\n\nData availability\n\nNo data are associated with this article.\n\nFigshare:\n\nList of study materials: https://doi.org/10.6084/m9.figshare.13636685 (de Santana Ribeiro de Mattos et al., 2021a)\n\nAvailable facilities: https://doi.org/10.6084/m9.figshare.13636694 (de Santana Ribeiro de Mattos et al., 2021b)\n\nParticipant information sheet and consent form: https://doi.org/10.6084/m9.figshare.13681825 (de Santana Ribeiro de Mattos et al., 2021c)\n\nFigshare: SPIRIT checklist for ‘Influence of surface peripheral electrical stimulation on nerve regeneration after digital nerve neurorrhaphy: study protocol for a randomized clinical trial.\n\nhttps://doi.org/10.6084/m9.figshare.13584764.v1 (de Santana Ribeiro de Mattos et al., 2021d)\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\nAl-Majed AA, Brushart TM, Gordon T: Electrical stimulation accelerates and increases expression of BDNF and TrKB mRNA in regenerating rat femoral motoneurons. Eur J Neurosci. 2000a; 12(12): 4381–4390. PubMed Abstract\n\nAl-Majed AA, Neumann CM, Brushart TM, et al.: Brief electrical stimulation promotes the speed and accuracy of motor axonal regeneration. J Neurosci. 2000b; 20(7): 2602–2608. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAl-Majed AA, Tam SL, Gordon T: Electrical stimulation accelerates and enhances expression of regeneration-associated genes in regenerating rat femoral motoneurons. Cell Mol Neurobiol. 2004; 24(3): 379–402. PubMed Abstract | Publisher Full Text\n\nBae CS, Lim SC, Kim KY, et al.: Effect of Ga-As laser on the regeneration of injured sciatic nerves in the rat. In Vivo. 2004; 18(4): 489–495. 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São Paulo: Manole, Chapter 21, 1998; 311–337.\n\nZeng YS, Nie JH, Zhang W, et al.: Morphine acts via mu-opioid receptors to enhance spinal regeneration and synaptic reconstruction of primary afferent fibers injured by sciatic nerve crush. Brain Res. 2007; 1130(1): 108–113. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "86882",
"date": "22 Jun 2021",
"name": "Yumin Yang",
"expertise": [
"Reviewer Expertise Influence of surface peripheral electrical stimulation on nerve regeneration"
],
"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 manuscript, and it deserves to be accepted. This article studied the influence of low intensity and frequency surface peripheral electrical stimulation (PES) on nerve regeneration of digital nerve injuries of the hand after its surgical repair in humans. This study could provide novel, useful, and practical strategies to treat patients with peripheral nerve damage. If the effects of different stimulus intensity, time and stimulus parts can be studied more systematically, it will be a more perfect study.\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": "6834",
"date": "24 Jun 2021",
"name": "ENILTON MATTOS",
"role": "Author Response",
"response": "Dear professsor Yumin Yang, Thank you very much for the considerations. Best regards, Enilton Mattos"
}
]
},
{
"id": "98628",
"date": "16 Nov 2021",
"name": "Jonas Kolbenschlag",
"expertise": [
"Reviewer Expertise Peripheral Nerve",
"Microcirculation"
],
"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 a highly interesting study protocol and the planned study has been thoughtfully conceptualized. I have no major concerns to raise, but I wonder whether the authors plan to include patients undergoing direct repair of non-segmental nerve defects only? I think this is implicated by using the term neurorrhaphy in the title of the manuscript but is not clearly stated in the protocol itself. Although I would deem an investigation of the effects of PES very interesting, I would recommend only to include patients with direct repair of non-segmental lesions. An experimental and control(SHAM) group, respectively, with segmental nerve damages could be included in further experiments however, to study the effects of PES following reconstruction of segmental nerve lesions.\nAll in all, I consider the work at hand highly interesting and a valuable addition to the field.\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": "7505",
"date": "06 Dec 2021",
"name": "ENILTON MATTOS",
"role": "Author Response",
"response": "Thank you for the good comment. We agree with your comment that the repair of non-segmental nerve defects is not clearly stated in the protocol and we have corrected it. Best regards, Enilton Mattos"
}
]
}
] | 1
|
https://f1000research.com/articles/10-219
|
https://f1000research.com/articles/10-947/v1
|
21 Sep 21
|
{
"type": "Research Article",
"title": "Flow cytometry of bone marrow aspirates from neuroblastoma patients is a highly sensitive technique for quantification of low-level neuroblastoma",
"authors": [
"Neha Jain",
"Shaista Sattar",
"Sarah Inglott",
"Susan Burchill",
"Jonathan Fisher",
"Andreea-Madalina Serban",
"Rebecca Thomas",
"Chris Connor",
"Niharendu Ghara",
"Tanzina Chowdhury",
"Catriona Duncan",
"Giuseppe Barone",
"John Anderson",
"Neha Jain",
"Shaista Sattar",
"Sarah Inglott",
"Susan Burchill",
"Jonathan Fisher",
"Andreea-Madalina Serban",
"Rebecca Thomas",
"Chris Connor",
"Niharendu Ghara",
"Tanzina Chowdhury",
"Catriona Duncan",
"Giuseppe Barone"
],
"abstract": "Background: Bone marrow involvement is an important aspect of determining staging of disease and treatment for childhood neuroblastoma. Current standard of care relies on microscopic examination of bone marrow trephine biopsies and aspirates respectively, to define involvement. Flow cytometric analysis of disaggregated tumour cells, when using a panel of neuroblastoma specific markers, allows for potentially less subjective determination of the presence of tumour cells. Methods: A retrospective review of sequential bone marrow trephine biopsies and aspirates, performed at Great Ormond Street Hospital, London, between the years 2015 and 2018, was performed to assess whether the addition of flow cytometric analysis to these standard of care methods provided concordant or additional information. Results: There was good concurrence between all three methods for negative results 216/302 (72%). Positive results had a concordance of 52/86 (61%), comparing samples positive by flow cytometry and positive by either or both cytology and histology. Of the remaining samples, 20/86 (23%) were positive by either or both cytology and histology, but negative by flow cytometry. Whereas 14/86 (16%) of samples were positive only by flow cytometry. Conclusions: Our review highlights the ongoing importance of expert cytological and histological assessment of bone marrow results. Flow cytometry is an objective, quantitative method to assess the level of bone marrow disease in aspirates. In this study, flow cytometry identified low-level residual disease that was not detected by cytology or histology. The clinical significance of this low-level disease warrants further investigation.",
"keywords": [
"neuroblastoma",
"paediatric cancer",
"bone marrow",
"flow cytometry",
"histology",
"RTqPCR",
"minimal residual disease"
],
"content": "Introduction\n\nNeuroblastoma is the most common extracranial solid tumour of childhood (Xie, Onyskio and Morrison, 2018). A combination of stage of disease, patient age, tumour histology and tumour biology are used to risk stratify patients for treatment (Monclair et al., 2008). Metastatic disease in patients more than 18 months of age places a patient in the high-risk category. Consequently, accurate staging at the time of diagnosis is critical. These patients receive multimodal treatment with chemotherapy, myeloablative chemotherapy and autologous stem cell rescue, surgery, radiation therapy and immunotherapy. Approximately 50% of those diagnosed with neuroblastoma have high-risk stage M disease, with poor overall survival of <50% (Tas et al., 2020).\n\nConsistent with recommendations from the International Neuroblastoma Risk Group (INRG), evaluation of both bone marrow cores (trephines) and aspirates is reported to most accurately detect bone marrow disease (Aronica et al., 1998); a combination of bilateral cores and aspirates is associated with 94.7% sensitivity (Parsons et al., 2017). Further, addition of immunohistochemistry to histological assessments can lead to increased inter-observer agreement (Parsons et al., 2016). The INRG Staging System (INRGSS) defines bone marrow infiltration as any involvement of bone marrow aspirate or trephines detected by the either or combination of cytology, histology, and/or immunohistochemical techniques, with >10% bone marrow involvement being one of the criteria used to distinguish between stage M and Stage MS disease (Monclair et al., 2008; Beiske et al., 2009; Burchill et al., 2017). A revision of the International Neuroblastoma Response Criteria (INRC) outlined that follow-up bone marrow samples with ≤5% involvement would represent minimal disease (Park et al., 2017).\n\nAlternative methods, including flow cytometry, immunocytology and quantitative reverse transcriptase polymerase chain reaction (RTqPCR), are currently being evaluated as more sensitive and specific methods for the detection of low-level disease than cytological or histological assessment (Tsang et al., 2003; Corrias et al., 2004; Beiske et al., 2005; Ferreira-Facio et al., 2013; Uemura et al., 2019). Flow cytometry is a well-validated method of detecting bone marrow infiltration in haematological malignancies but its role in solid paediatric cancers is not established. Studies have demonstrated that flow cytometry can detect disease at lower levels than histopathology (Komada et al., 1998; Tsang et al., 2003; Szantho et al., 2018). The first triple colour flow cytometry assay to detect neuroblastoma was developed in 1998 (Komada et al., 1998). This has subsequently been optimised and today CD45-/CD56+/CD81+/GD2+ cells by flow cytometry have been accepted to represent neuroblastoma cells (Swerts et al., 2004; Ferreira-Facio et al., 2013). Disialoganglioside (GD2) is detected in the vast majority of neuroblastoma cells, but also expressed by melanomas, gliomas and focally in rhabdomyosarcomas and osteosarcomas (Beiske et al., 2005; Ferreira-Facio et al., 2013). Importantly, GD2 is not expressed by normal bone marrow cells (Swerts et al., 2004). CD56 antibody is present on a subset of CD4+, and CD8+ T–cells and NK cells in peripheral blood, as well as neural derived cells and tumours (Beiske et al., 2005). CD45 is present on all human leukocytes but absent on neuroblastoma cells. Using flow cytometry, Komada et al. (1998) were able to detect a single neuroblastoma cell in up to 1 × 104/105 mononuclear cells. Szantho et al. (2018) analysed 36 samples from 16 patients and concluded that flow cytometry was highly specific and more sensitive than immunohistochemistry, as more cells can be evaluated. However, other studies have suggested that flow cytometry is 10-fold less sensitive than immunocytology or quantitative reverse transcriptase polymerase chain reaction (RTqPCR) (Swerts et al., 2004; Uemura et al., 2019).\n\nThe role of minimal residual disease (MRD) in neuroblastoma is increasingly under investigation, although its clinical utility is yet to be defined. In haematological malignancies PCR-based detection of MRD has become part of the routine method for risk stratification and ongoing monitoring of patients during treatment, with an escalation in treatment if there is inadequate MRD response. Corrias et al. (2004) used immunocytology to detect MRD in bone marrow of patients with localised neuroblastoma and found no significant difference in overall survival of patients with MRD compared to those without detectable MRD in bone marrow. In patients with metastatic disease there was no difference in overall survival by bone marrow disease detected by MRD using either immunocytology or PCR techniques. The Children’s Oncology Group (COG) also showed no difference in overall survival for patients with localised disease that had bone marrow involvement detected by immunocytology alone at diagnosis (Seeger et al., 2000). In the same study, COG demonstrated a clear correlation between increasing tumour burden in bone marrow and poor event free survival in those patients with stage M disease, but no difference in survival if bone marrow infiltration was only detected by immunohistochemistry and not by cytology (Seeger et al., 2000). Conversely, others have shown a poorer prognosis in those patients with neuroblastoma detected by flow cytometry but negative by immunophenotyping (Popov et al., 2019) and poor overall survival in those with neuroblastoma detectable by RTqPCR after induction therapy (Druy et al., 2018). These studies have been limited by the small number of analysed samples. Flow cytometry does have an advantage over immunocytology as it helps identify cases that have lost GD2 expression. This is increasingly important as future treatment concentrates on targeting GD2 expression either though GD2-antibodies or experimentally through GD2 targeting CART-cells (Schumacher-Kuckelkorn et al., 2016).\n\nIn this study, our aim was to compare flow cytometry with the combination of histological and immunohistological assessment of trephines and cytological review of bone marrow aspirates, to determine if there is a difference in detection of positive results between the various methods and if flow cytometry can provide any additional information.\n\n\nMethod\n\nThe study was performed as an internal evaluation of bone marrow results by flow cytometry in neuroblastoma, which had been introduced as a standard additional technique at Great Ormond Street Hospital, London in 2015. Samples from consecutive patients diagnosed with neuroblastoma at our institution between June 2015 to March 2018 were evaluated. Samples taken at any time point of treatment/surveillance were included in the review.\n\nDisease stage for each patient was based on the INRG staging system (Monclair et al., 2009) and risk stratification was as the per the Children’s Cancer Leukaemia Group (CCLG) Guidelines (Morgenstern et al., 2015). At each time point, samples for cytology of aspirate, flow cytometry of aspirate, and histology/immunocytology of trephine biopsy were taken from the left and/or right side, which were then grouped by side of collection. Bone marrow aspirates and trephines reports issued as part of routine of care were reviewed, which included morphological and flow cytometric assessment of aspirates, and morphology plus immunohistochemical staining of trephine biopsies. Flow cytometry was performed 12–60hrs post collection of bone marrow aspirates. Neuroblastoma cells were identified by using live/dead gating followed by identification of CD45−/Lin neg/CD56+/GD2+ stained populations.\n\nFor final analysis any patients with missing data for flow, aspirate or trephine analyses were excluded (Figure 1). Any difference between the results of the trephine histology/immunohistochemistry, aspirate morphology, or flow cytometry were recorded. Significance testing was performed using unpaired t-test with Welch’s correction, with a p-value ≤ 0.05 considered as significant.\n\nEight patients also had bone marrow aspirates collected for RNA testing, performed by RTqPCR, as part of the European HR-NBL1/SIOPEN trial (ClinicalTrials.gov registration number: NCT01704716) (Viprey et al., 2014). The results from RTqPCR and flow cytometry analyses were compared, in order to establish if there are any correlations between the two assays. RNA was extracted and RTqPCR for the neuroblastoma mRNAs paired like homeobox 2B (PHOX2B) and tyrosine hydroxylase (TH) performed according to standard operating procedures (Viprey et al., 2007, 2014). PHOX2B and TH are established neuroblastoma mRNAs (Stutterheim et al., 2008; Brownhill and Burchill, 2017; Uemura et al., 2019).\n\nFor statistical analysis, the Log2 delta Ct values from the RTqPCR were converted to linear values for correlation with flow values by Pearson coefficient and correlation of flow with aspirate morophogy or trephine immunohistochemistry was performed using Welch's T test. Statistical analyis we performed using Prism software version 9.\n\n\nResults\n\nA total of 392 bone marrow samples from 72 patients were analysed. Complete bone marrow, trephine and flow cytometry data was available for 302 samples (Figure 1). RTqPCR results were available for 26 samples from 15 patients. A total of 15 samples from eight patients had both flow cytometry and RTqPCR data available (see Underlying data).\n\nThere was concordance in a negative result across all three modalities for 216/302 samples and a concordance of 38/86 for positive results across all three modalities (Figure 2A), with a further 14/86 (16%) samples positive by flow cytometry and either cytology of aspirates or histology of trephine. Of the 86 samples that were positive by at least one test, 14/86 (16%) were positive by flow cytometry alone. Taken together, trephine and aspirate morphology detected 20/86 (23%) positives that were negative by flow cytometry (trephine only n = 11, cytology of aspirates only n = 3, both trephine and cytology of aspirates n = 6) (Figure 2A).\n\nA) Venn diagram of all positive cases. B) Negative trephine results in blue, positive trephine results in pink. 216 negative samples by all modalities excluded from analysis. Box and whisker plot showing the Mean and standard deviation of results *p-value 0.0056 by Welch’s t-test. C) Negative cytology results in red, positive cytology results in green. 216 negative samples by all modalities excluded from analysis. Box and whisker plot showing the Mean and standard deviation of results, **p-value 0.0027 by Welch’s t-test.\n\nFlow cytometry provides the additional benefit of allowing enumeration of the neuroblastoma cells within the bone marrow sample by calculating the positively gated events and negative gated events. We performed an absolute numerical comparison of flow cytometry results against the binary trephine and aspirate results (Figure 2B and 2C) to determine if numerical flow cytometry results correlate with the aspirate morphology or trephine categorisation. Bone marrow samples that were positive by analysis of trephines were significantly more likely to be positive than negative on flow cytometry (p = 0.0027) and the same was true for samples positive for cytology (p = 0.0056), suggesting a good concordance between these modalities. When comparing trephine and flow cytometry, 18 samples were positive by flow cytometry but not positive on trephine histology. These samples had a percentage detection range of 0.0130% to 5.3% (Figure 2B). Similarly, when comparing flow cytometry and cytology, there were 24 samples positive by flow cytometry, which were negative by cytology (Figure 2C). These samples had a percentage detection range from 0.0041% to 3.75%. Therefore, flow cytometry of bone marrow aspirates detects low-level disease not reported after analysis of trephines or cytology of bone marrow aspirates.\n\nA total of 14 samples from nine patients were positive solely on flow cytometry. These patients represent potential cases where flow cytometry may be useful for detecting bone marrow disease below the combined threshold of cytology and trephines. All nine of these patients were diagnosed as high-risk (Table 1). The level of disease detected by flow cytometry was low ranging from 0.008% to 2.37%. Only two patients (patient 5 and 7) had no radiological evidence of metastatic skeletal disease at the time of bone marrow sampling. Patient 5 had radiological localised disease and had bone marrow sample taken at diagnosis. This patient was treated as high-risk due having a MYCN amplified tumour and is now 42 months post diagnosis with no evidence of progression or relapse. Patient 7 had stage M high-risk neuroblastoma; the bone marrow sample was taken after completion of high dose chemotherapy with busulfan and melphalan. This patient is now 38 months post diagnosis with no evidence of relapse. Thus, the clinical follow up of these cases with low-level disease by flow cytometry does not provide any support for altering staging or treatment in such patients.\n\nL2 is localised unresectable disease and M denotes metastatic disease.\n\nTo further evaluate the results of flow cytometry, we compared 15 samples from eight patients who had corresponding RTqPCR performed for mRNA using PHOX2B and TH markers. We performed simple linear regression modelling on RTqPCR and flow cytometry data for matched samples (Figure 3). For PHOX2B the R2 co-efficient was 0.8090 (p-value < 0.0001) and for TH R2 co-efficient was 0.8697 (p-value < 0.0001). This excellent correlation between RTqPCR and flow cytometry further validates the flow cytometry results.\n\nSimple linear regression between RTqPCR and flow cytometry for fifteen samples A) R2 co-efficient 0.8090 (p-value < 0.0001) and B) R2 co-efficient was 0.8697 (p-value < 0.0001). Where PHOX2B is homeobox 2B, and TH is tyrosine hydroxylase.\n\n\nDiscussion and conclusion\n\nIn comparing flow cytometry, histology and cytology of aspirates results, our investigations show a good concordance across all three modalities for negative samples (72%). Taking positivity for either trephine and/or cytology of aspirates samples together, there is was also good concordance for positive results 52/86 (61%), though both flow cytometry (23%) or combination of histology/cytology (16%) did miss samples that were positive by the other modality. Furthermore, there was also good correlation between RTqPCR and flow cytometry results where both were available, providing further validation to flow cytometry results. Results positive by flow cytometry alone generally had low-level disease. There is increasing literature to suggest that clinically significant MRD in neuroblastoma can be detected using RTqPCR for neuroblastoma mRNAs (Burchill et al., 2001; Viprey et al., 2014; Druy et al., 2018; van Wezel et al., 2016). These studies commonly include the two markers we have investigated, TH and PHOX2B mRNA. The persistence of bone marrow positivity is associated with poorer prognosis (Horibe et al., 2001; Druy et al., 2018; Popov et al., 2019).\n\nFlow cytometry is a routine test in diagnostic laboratories, which does require the development of expertise for analysis of results. Our results show some discordance between cytology/histology/flow cytometry. This discordance could be related to sampling differences, as different samples may be taken for analysis by various parts of diagnostic laboratories. Further, neuroblastoma cells have a propensity to aggregate. During flow cytometry analysis, clots are removed and samples filtered, which may lead to removal of some neuroblastoma aggregates. Bone marrow aspirates and trephine samples are not disaggregated, which may account for some disparity in results. Further, an element of subjectivity is present in the histological/cytology analysis of bone marrow trephines and aspirates, whereas flow cytometry provides an unequivocal characterisation of individual neuroblastoma cells.\n\nFlow cytometry may be particularly useful for defining disease in patients who do not have adequate trephine biopsies or cells available for review on aspirates. It could serve as an additional quick and cost-effective tool for detection of low-threshold disease in patients with neuroblastoma. However, the presence of 20/86 samples with positivity by either cytology or histology analysis but no detectable neuroblastoma by flow cytometry, whilst may be accountable by sampling differences, highlights the importance of expert haematological and histopathological analysis of samples from these children. The clinical significance of low-level disease, detected using different methods, in neuroblastoma continues to be explored globally and remains to be seen.\n\n\nData availability\n\nOpen Science Framework: Flow cytometry analysis of neuroblastoma bone marrow. <registration DOI>\n\nThis project contains the following underlying data:\n\n- De-identified HRNBL PCR and flow data.xlsx\n\n<License statement>\n\nhttps://osf.io/5c7ts/\n\n\nEthic statement\n\nThe evaluation of results from bone marrow flow cytometry was a routine retrospective evaluation of standard of care procedures and not a formal research study. As such it did not require ethics committee approval. Consent for marrow aspirates and standard of care analysis was obtained from all patients using standard hospital consent procedures.\n\n\nCompeting interests\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe author(s) declared that no grants were involved in supporting this work.",
"appendix": "References\n\nAronica PA, Pirrotta V, Yunis EJ, et al.: Detection of neuroblastoma in the bone marrow: biopsy versus aspiration. J Pediatr Hematol Oncol. 1998; 20(4): 330–334. PubMed Abstract | Publisher Full Text\n\nBeiske K, Ambros PF, Burchill SA, et al.: Detecting minimal residual disease in neuroblastoma patients-the present state of the art. Cancer Lett. 2005; 228: 229–240. PubMed Abstract | Publisher Full Text\n\nBeiske K, Burchill SA, Cheung IY, et al.: Consensus criteria for sensitive detection of minimal neuroblastoma cells in bone marrow, blood and stem cell preparations by immunocytology and QRT-PCR: recommendations by the International Neuroblastoma Risk Group Task Force. Br J Cancer. 2009; 100: 1627–1637. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBrownhill SC, Burchill SA: PCR-based amplification of circulating RNAs as prognostic and predictive biomarkers – focus on neuroblastoma. Pract Lab Med. 2017; 7: 41–44. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBurchill SA, Lewis IJ, Abrams KR, et al.: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA are an independent poor prognostic indicator. J Clin Oncol. 2001; 19(6): 1795–801. PubMed Abstract | Publisher Full Text\n\nBurchill SA, Beiske K, Shimada H, et al.: Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group. Cancer. 2017; 123: 1095–1105. PubMed Abstract | Publisher Full Text\n\nCorrias MV, Faulkner LB, Pistorio A, et al.: Detection of neuroblastoma cells in bone marrow and peripheral blood by different techniques: accuracy and relationship with clinical features of patients. Clin Cancer Res. 2004; 10: 7978–7985. PubMed Abstract | Publisher Full Text\n\nDruy AE, Shorikov EV, Tsaur GA, et al.: Prospective investigation of applicability and the prognostic significance of bone marrow involvement in patients with neuroblastoma detected by quantitative reverse transcription PCR. Pediatr Blood Cancer. 2018; 65: e27354. PubMed Abstract | Publisher Full Text\n\nFerreira-Facio CS, Milito C, Botafogo V, et al.: Contribution of multiparameter flow cytometry immunophenotyping to the diagnostic screening and classification of pediatric cancer. Plos One. 2013; 8(3): e55534. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHoribe K, Fukuda M, Miyajima Y, et al.: Outcome prediction of molecular detection of minimal residual disease in bone marrow for advanced neuroblastoma. Med Pediatr Oncol. 2001; 36: 203–204. PubMed Abstract | Publisher Full Text\n\nKomada Y, Zhang XL, Zhou YW, et al.: Flow cytometric analysis of peripheral blood and bone marrow for tumour cells in patients with neuroblastoma. Cancer. 1998; 82: 591–599. PubMed Abstract\n\nMonclair T, Broduer GM, Ambros PF, et al.: The International Neuroblatoma Risk Group (INRG) Staging System: an INRG task force report. J Clin Oncol. 2008; 27(2): 298–303. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMorgenstern DA, Herd F, Tweddle D, et al.: Guidelines for treatment of patients with low/intermediate risk neuroblastoma. Children’s Cancer and Leukaemia Group (CCLG) Neurblastoma Special Interest Group (SIG). 2015.\n\nPark JR, Bagatell R, Cohn SL, et al.: Revisions to the International Neuroblastoma Response Criteria: A consensus statement from the NCI-Clinical Trials Planning Meeting. J Clin Oncol. 2017; 35(22): 2580–2587. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParsons LN, Gheorghe G, Yan K, et al.: Improving detection of metastatic neuroblastoma in bone marrow core biopsies: a proposed immunohistochemical approach. Pediatr Dev Pathol. 2016; 19: 230–236. PubMed Abstract | Publisher Full Text\n\nParsons LN, Gheorghe G, Yan K, et al.: An evidence-based recommendation for a standardized approach to detecting metastatic neuroblastoma in staging and bone marrow biopsies. Pediatr Dev Pathol. 2017; 20(1): 38–43. PubMed Abstract | Publisher Full Text\n\nPopov A, Druy A, Shorikov E, et al.: Prognostic value of initial bone marrow disease detection by multiparameter ow cytometry in children with neuroblastoma. J Cancer Res Clin Oncol. 2019; 145: 535–542. PubMed Abstract | Publisher Full Text\n\nSchumacher-Kuckelkorn R, Volland R, Grandehandt A, et al.: Lack of immunocytological GD2 expression on neuroblastoma cells in bone marrow at diagnosis, during treatment, and at recurrence. Pediatr Blood Cancer. 2016; 64: 46–56. PubMed Abstract | Publisher Full Text\n\nSeeger RC, Reynolds CP, Gallego R, et al.: Quantitative tumour cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children’s Cancer Group Study. J Clin Oncol. 2000; 18(24): 4067–4076. PubMed Abstract | Publisher Full Text\n\nStutterheim J, Gerritsen A, Zappeij-Kannergieter L, et al.: PHOX2B is a novel and specific marker for minimal residual disease testing in neuroblastoma. J Clin Oncol. 2008; 26(33): 5443–5449. PubMed Abstract | Publisher Full Text\n\nSwerts K, De Moerloose B, Dhooge C, et al.: Detection of residual neuroblastoma cells in bone marrow: comparison of flowcytometry with immunohistochemistry. Cytometry Part B (Clinical Cytometry). 2004; 61B: 9–19. PubMed Abstract | Publisher Full Text\n\nSzantho E, Karai B, Ivady G, et al.: Comparative analysis of multicolour flow cytometry and immunohistochemistry for the detection oof disseminated tumour cells. Appl Immunohistochem Mol Morphol. 2018; 26: 305–315. PubMed Abstract | Publisher Full Text\n\nTas ML, Reedijk AMJ, Karim-Kos HE, et al.: Neuroblastoma between 1990 and 2014 in the Netherlands: increased incidence and improved survival of high risk neuroblastoma. Eur J Cancer. 2020; 124: 47–55. PubMed Abstract | Publisher Full Text\n\nTsang KS, Li CK, Tsoi WC, et al.: Detection of micrometastasis of neuroblastoma to bone marrow and tumour dissemination to hematopoietic autografts using flow cytometry and reverse transcriptase-polymerase chain reaction. Cancer. 2003; 97: 2887–2897. PubMed Abstract | Publisher Full Text\n\nUemura S, Ishida T, Thwin KKM, et al.: Dynamics of minimal residual disease in neuroblastoma patients. Front Oncol. 2019; 9: 455. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVan Wezel EM, Decarolis B, Stutterheim J, et al.: Neuroblastoma messenger RNA is frequently detected in bone marrow at diagnosis of localised neuroblastoma patients. Eur J Cancer. 2016; 54: 149–158. PubMed Abstract | Publisher Full Text\n\nViprey VF, Corrias MV, Kagedal B, et al.: Standardisation of operating procedures for the detection of minimal disease by QRT-PCR in children with neuroblastoma: quality assurance on behalf of SIOPEN-R-NET. Europ J Cancer. 2007; 43(2): 341–350. Publisher Full Text\n\nViprey VF, Gregory WM, Corrias MV, et al.: Detection of mRNA in bone marrow and blood by RTqPCR predicts event-free and overall survival in children with stage 4 neuroblastoma at diagnosis; a SIOPEN Molecular Monitoring Group study. J Clin Oncol. 2014; 32: 1074–1083. PubMed Abstract | Publisher Full Text\n\nXie L, Onysko J, Morrison H: Childhood cancer incidence in Canada: demographic and geographic variation of temporal trends (1992-2010). Health Promot Chronic Dis Prev Can. 2018; 38(3): 79–115. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "94970",
"date": "22 Oct 2021",
"name": "Godelieve A. M. Tytgat",
"expertise": [
"Reviewer Expertise Pediatric oncologist",
"translational research PIs"
],
"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\nFlow cytometry of bone marrow aspirates from neuroblastoma patients is a highly sensitive technique for the quantification of low-level neuroblastoma.\nIn this study, the authors undertake a very nice study to look at the sensitivity and specificity to study NBL cells in the bone marrow by flow cytometry. As there have been studies demonstrating the use of this technique, larger studies that actually compare this technique to other techniques on the same samples are lacking.\nIn this work, the group studies the detection of NBL cells in a total of 392 samples of 72 patients. The set-up of the paper and the analyses are well done and well described. The article reads well and has a nice flow.\nThere are some small questions/comments:\nIn the methods, the authors describe that 8 patients had BM aspirates collected for RNA testing, and a few sentences later in the results they describe that PCR results were available for 26 samples from 15 patients. Please correct and align the actual numbers here.\n\nFurthermore, in the results, patient disease course of flow cytometry-only positive samples, the authors state that in their cohort the clinical follow-up of these cases with low-level disease by flow does not provide any support for altering staging or treatment in such patients. The study is not designed nor powered for such an analysis. We know that in patients with no BM metastases, detected by conventional techniques, low levels of mRNA or DNA and even NBL cells by flow can be detected, which has no impact on the outcome. So I agree with this conclusion and would like to emphasize that this can even be addressed stronger.\n\nThe time points of sampling can be added to the table.\n\nLooking at Table 1, I wonder what were the results of earlier and later BM samples for patient 7? Did they become negative at a later time point for flow? Please add this information to the text.\n\nFinally, did the authors look at the paired samples of each patient (left and right side) and investigate the con- and discordances? Also, with respect to the different techniques?\n\nWe test the BM involvement from 2 to 4 sides for each time point. How do the authors deal with the 2 sides? Did they merge the results? Please add this information to the paper.\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": "7503",
"date": "06 Dec 2021",
"name": "JOHN ANDERSON",
"role": "Author Response",
"response": "Thank you for your detailed review. PCR numbers; sorry for the error in the methods part which has been corrected to state the following: “Patients with high risk neuroblastoma treated on the European HR-NBL1/SIOPEN trial (ClinicalTrials.gov registration number: NCT01704716) (Viprey et al, 2014) also had bone marrow aspirates collected for RNA testing, performed by RTqPCR.” The results section is unchanged. Impact of low-level disease on disease outcome. We agree that this could be stated even more forcefully. The sentence has been changed to the following: “Thus, the current study adds to existing understanding that in patients with no bone marrow metastases detected by conventional techniques, low levels of disease in the form of mRNA or DNA or neuroblastoma cells can be detected. There is no evidence that this low level disease can alter outcomes, and the clinical follow up of these cases in the current study does not provide any support for altering staging or treatment in such patients.” Timing of sampling of positive flow results added to the table. This has been done. Patient 7 details: the following new test has been added: “Patient 7 had stage M high-risk neuroblastoma with positive bone marrow morphology at diagnosis which became negative following induction. Following high dose chemotherapy with busulfan and melphalan high dose chemotherapy, the left sided aspirate was positive on flow cytometry but negative on morphology. Subsequent analyses were all negative.” Concordance between left and right sites. We have added this information to the first results section with the following additional text: “All comparisons involved evaluation of separate aspirate or trephine from left and right iliac crests respectively. We found low levels of intrapatient discordance between results from the two sites for both morphology (8 discordant results from 163 sampling episodes = 5%) and trephine (10/163 = 6%). Interestingly only one sampling event showed discordance in both aspirate and trephine.”"
}
]
},
{
"id": "94971",
"date": "26 Oct 2021",
"name": "Toby Trahair",
"expertise": [
"Reviewer Expertise Neuroblastoma",
"acute lymphoblastic leukaemia",
"minimal residual disease detection"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 describes an analysis of bone marrow flow cytometry (FC) to identify bone marrow (BM) minimal residual disease (MRD) in consecutive patients diagnosed with neuroblastoma (NB) from a single centre, Great Ormond Street Hospital (GOSH). This is a laboratory-based comparative study focused on the comparison of NB BM MRD with morphology on BM aspirate, BM trephine and in a small number of cases to correlate with qRT-PCR for NB specific transcripts.\nMRD has an established role in the management of acute lymphoblastic leukaemia (ALL) and is routinely used in ALL clinical management. MRD in combination with clinical and genetic factors remains one of the most important clinical tools to guide therapy and risk stratification in both newly diagnosed and relapsed ALL1,2,3,4,5,6,7. The two major techniques used to measure MRD in ALL are flow cytometry or quantitative PCR8,9,10. The European Scientific foundation for Laboratory Hemato Oncology (ESLHO, https://eslho.org/about/) has established consortia to promote the innovation, standardisation, quality control and education of laboratory diagnostics including flow MRD (EuroFlow)10 and quantitative PCR MRD (EuroMRD)8,9. The International Neuroblastoma Risk Group (INRG) Task Force developed standard recommendations for the detection of residual neuroblastoma using immunocytology on BM cytospins or smears and/or qRT-PCR on BM11. The INRG Task Force felt that the volume of bone marrow for analysis post-chemotherapy by flow cytometry may limit the sensitivity to detect residual NB to approximately 1 NB per 104 BM cells11, however, this is a level of sensitivity similar to what can be achieved using FC MRD in ALL MRD10. However, the use of FC in the assessment of residual NB in BM remains clinically underdeveloped and it is a technology that may be easily and widely adapted to assessing treatment response in HR-NB.\nCurrently, MRD and liquid biopsy are at an earlier stage of development in paediatric solid tumours and NB compared to ALL. The role of MRD in solid tumours continues to be explored within clinical research and/or clinical trials but is not currently used to modify risk classification or treatment. There are many evolving technologies that have the capacity to detect and quantify either residual tumour cells (e.g. immunocytology, flow cytometry, qRT-PCR for genes expressed in NB cells12, DNA based assays to detect NB cells13,14,15) or products secreted by tumour cells (e.g. cell-free tumour DNA16,17, exosomal miRNA18,19) which could be used to assess NB treatment response. So a challenge in the field is to clearly identify the methods and techniques of MRD/liquid biopsy which are prognostic and/or predictive in NB and which can be implemented in the clinical setting.\nThe strengths of the current study are that it describes using FC to measure BM MRD in a consecutive cohort of 72 children with NB treated at Great Ormond Street Hospital. 392 BM samples were collected from these patients at various time points during their treatment. The study team has compared FC with immunocytology (BM aspirate) and histology (BM trephine). There were a limiting number of patients where qRT-PCR analysis was also available. In terms of the patient cohort, there is very limited detail on the clinical characteristics of the cohort, treatment or exact timing of the BM sample in relation to treatment received and clinical outcome. The only clinical information that is presented is for a subset of 9 patients with high-risk neuroblastoma (HR-NB) with FC positive marrows. In terms of FC methodology, the timing of FC varied from 12-60 hours post collection of the BM sample. The major experimental aim was a comparison of results between the different methodologies, so there is a focus on the comparative analysis of different techniques on individual samples. For negative samples (216) there was good concordance across all three techniques used (FC, trephine and aspirate morphology). The discordances arise in 86 samples which were found to be positive by at least one technique, with only 38/86 (44%) samples positive by all three assays. Each assay identified positive samples which were negative by both other techniques: FC 14/86 (16%), trephine histology 11/86 (13%), and 3/86 (3.5%) by aspirate. For the small number of patients who had both FC and qRT-PCR results, there was a good correlation between both techniques.\nOverall, the data shows that there is promise in using FC to assess NB MRD. As noted by the study team, FC is widely available and routinely used to assess haematologic malignancy. Undertaking these studies within the context of routine clinical practice is important as ultimately it can facilitate transfer into clinical practice. The EuroFlow, EuroMRD, and INRG consortia highlight the importance of the standardisation of sample collection, processing, workflow, analysis and reporting of samples8,9,10. In this study, it’s not clear whether the time between collection and running the FC to assess NB MRD, between 12-60 hours, may have had an impact on the results. Specifically, are there differences in samples run at 12 versus 60 hours?\nIn the GOSH cohort, it’s not clear how the FC assay performs with different input BM cell numbers and whether there were adequate cell numbers for each sample at each time point for the analysis. Assay performance and correlation are likely to be related to the amount of BM sample available for analysis and the levels of residual disease present within the sample. In ALL FC MRD, setting a threshold for the minimum number of BM cells to be analysed by FC is a key feature to permit sensitive detection of rare ALL cells after starting treatment10. The performance of the FC, IC and qRT-PCR assays can be directly compared using spike-in experiments with NB cells and BM MNC, which, although not without limitations, allows an estimation of assay performance under different controlled conditions (e.g. BM cell number and dilution of NB cells).\nAs discussed, it’s known that solid tumours and NB form clumps in the BM and it’s possible that a false negative FC result may occur from NB clumps being filtered out of the sample prior to the FC analysis (identified by the study team as a limitation) or as a consequence of NB being a “patchy” disease within the BM, so there may have been minimal or no NB at the site sampled by BMA, yet there may be clear evidence of BM disease at other sites on functional scanning (e.g. MIBG or FDG-PET CT scan). It would be helpful to understand how each of the marrow assessment methodologies compares with the measured INRC metastatic response20 in the cohort.\nWhether there is additional value arising from FC NB MRD can’t really be assessed in this cohort due to the limited amount of clinical and laboratory data. It’s likely that the potential impact of NB MRD measured by any technique will be strongly influenced by the underlying genetics and risk classification of the individual patient. It’s known in ALL, MRD cutoffs are strongly influenced by the underlying ALL biology and genetics21. It’s not unreasonable to hypothesise that the same holds true of NB, so the potential utility of NB FC BM MRD will be different in INRG Ms infants (low risk), in INRG M infants (intermediate risk) and in INRG M older children (high risk). An analysis of the data stratified by the patient’s risk classification may be informative, depending on the numbers. However, it’s possible to hypothesise that the role of FC to assess residual BM NB cells will be of most value in patients with high-risk disease.\nAlthough GOSH had introduced BM FC as a routine standardised assessment from 2015 onwards, the underlying objective(s) of assessing NB MRD by BM FC isn’t clearly stated in the submission. In managing ALL, assessing treatment response by MRD forms an integral component of the final ALL risk classification which occurs at the end of induction chemotherapy (i.e. after treatment has commenced). In ALL, rapid clearance of ALL and MRD negativity at the end of induction chemotherapy identifies patients with improved survival, and conversely slow ALL response with persisting high MRD levels at end induction identifies patients with decreased survival. In NB, risk classification is completed at diagnosis, prior to treatment initiation and is not modified by treatment response22. Therefore, a potential role for NB MRD (measured by any methodology) to modify INRG risk stratification may not be likely. However, the clinical assessment of NB treatment response is critical and determines post-induction treatment allocation. So analogous to treatment response measurement in ALL, the tempo and completeness of treatment response in HR-NB is important and prognostic. HR-NB patients with inadequately responding disease have a poor chance of survival. One of the major clinical issues facing clinicians managing HR-NB is the early identification of patients with (i) inadequately responding disease or (ii) those who ultimately have a high risk of disease recurrence and poor survival. So standardised response assessment and MRD assessment at earlier time points in HR-NB induction chemotherapy might provide an opportunity to stratify patients to different treatments before the end of induction chemotherapy. Conversely, the role of MRD at later time points in treatment will be different, e.g. the early detection of relapsing disease in patients with a prior good response to treatment. So, in this context, whilst it’s important to assess the concordance of different laboratory assays which measure the same variable, it remains difficult to define the clinical significance of NB BM FC in this heterogenous cohort with samples taken at multiple time points and where the linked clinical data isn’t available. The value of this dataset will come into its own when it is more comprehensively linked and analysed with matching clinical and response information, specifically with clinically used and/or validated endpoints, such as INRC disease response, progression-free survival and overall survival.\nThe data presented here represent an incremental step in using NB FC for MRD assessment. However, to take the field of liquid biopsy/MRD assessment forward in neuroblastoma, the ideal will be to prospectively define clear objectives for MRD assessment at different treatment time points (e.g. early or mid-induction versus later in therapy), collect appropriate samples at standardised time points, and directly compare multiple liquid biopsy/MRD methodologies against each other and also with the use of clinically validated endpoints.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7504",
"date": "06 Dec 2021",
"name": "JOHN ANDERSON",
"role": "Author Response",
"response": "Thank you for an extremely comprehensive review of the article which constitutes by itself an important contribution to the discussion. No specific requests for clarification or further detail have been made apart from the request that the dataset (positivity in terms of flow, morphology, and trephines) be individually linked to clinical response to investigate the relative value of each technique as a response criterion. It is not clear if the reviewer is asking for such an analysis to be performed in the current dataset or suggesting a future prospective study. However, in our view it is not feasible to evaluate relative prognostic values of our markers in the current dataset for a number of reasons: This was a retrospective not prospective study and there is marked heterogeneity of disease type and treatment. A very limited number of discordant cases as now described in the revised manuscript (see the response to Reviewer 1). It was never the intention of this study to explore flow cytometry as a biomarker. Our ambition was relatively limited; to determine whether the technique is feasible and has broad concordance with established techniques. In this, I think the study has been successful and it raises the possibility of flow cytometry being now evaluated prospectively."
}
]
}
] | 1
|
https://f1000research.com/articles/10-947
|
https://f1000research.com/articles/10-1237/v1
|
03 Dec 21
|
{
"type": "Opinion Article",
"title": "The jury is out: a new approach to awarding science prizes",
"authors": [
"Michael Hill"
],
"abstract": "Research evaluation is often understood as something similar to a competition, where an evaluation panel’s task is to award the most excellent researchers. This interpretation is challenging, in as far as excellence it is at best a multi-dimensional concept and at worst an ill-defined term because it assumes that there exists some ground truth as to who the very best researchers are and all that an evaluation panel needs to do is uncover this ground truth. Therefore, instead of focusing on competition, the Swiss National Science Foundation focused on active decision-making and sought inspiration in the deliberation proceedings of a jury trial for the design of a new evaluation procedure of an academic award. The new evaluation procedure is based upon fully anonymised documents consisting of three independent parts (achievements, impact and prominence). Before the actual evaluation meeting, the panel, which includes non-academic experts, pre-evaluates all nominations through a pseudo-randomly structured network, such that every nomination is reviewed by six members of the panel only. Evaluation decisions are based upon anonymous votes, structured discussions in the panel, ranking as opposed to rating of nominees and data-rich figures providing an overview of the positioning of the nominee along various dimensions and the ranking provided by the individual panel members. The proceedings are overseen by an academic chair, focusing on content, and a procedural chair, focusing on the process and compliance. Combined, these elements form a highly-structure deliberation procedure, consisting of individual steps, through which nominations proceed and which each either feed into the next step or into the final verdict. The proposed evaluation process has been successfully applied in the real world in the evaluation of the Swiss Science Prize Marcel Benoist, Switzerland’s most prestigious academic award.",
"keywords": [
"Research Evaluation",
"Prize",
"Award",
"Review",
"Impact",
"Metrics"
],
"content": "Introduction\n\nPrestigious academic prizes are usually awarded based on evaluation procedures where a group of experts ultimately decides who to award. However, during evaluation, experts may rely on inappropriate metrics,1,2 and discussion dynamics in the group may stray,3,4 which in turn can result in unfair processes5,6 and unsatisfactory outcomes.7–10 These circumstances are well known, and various initiatives, such as the San Francisco Declaration on Research Assessment (DORA),11 the Leiden Manifesto,12 the Metric Tide,13 the Hong Kong Principles14 and the h-group15 have highlighted them and provided guidelines on how to improve upon them. Inspired by these initiatives, the Swiss National Science Foundation (SNSF) has devised a novel evaluation procedure for the evaluation of academic awards. Essential to its innovative features is our interpretation of research evaluation less as a competition and more as an active decision-making process.\n\nThe task of an evaluation panel is often understood as that of finding the strongest applicant. However, while evaluation panels can usually discern the weakest and strongest contestants easily, they frequently struggle to delineate unequivocally, who from the midfield they might also want to champion or discuss and which one to ultimately single out as the winner.16 Comparison of scientific track records is multi-dimensional and the method of scoring individual dimensions as well as their respective weighting is controversial and often biased. Whereas in other competitions one can call upon millimetres and milliseconds as measures of merit, in research evaluation it is the formulation of a convincing argument within the evaluation panel, which ultimately calls the winner. Therefore, rather than thinking of research evaluation as something akin to a sports competition, it may be more useful to look to a different analogy, that of a jury trial.17\n\nA jury does not have privileged access to an objective ground truth as a referee standing at the finish line might. Instead, the justification of a jury as a legal decision-making body is that it is comprised of peers and that, based on the trial proceedings, at this moment no other group of individuals are more informed and/or better qualified to make a decision upon the matter laid before them — even if a differently comprised jury might arrive at a different conclusion. The same is true for a panel of experts deciding which researcher to award. They cannot objectively establish who is the best scientist.18 Still, they can deliberate fairly and systematically upon why they might support one over another and can provide rational argumentation for this decision. It is important to note that a jury trial does not deny the presence of bias and predilection. Instead, it aims at controlling these forces by regulating deliberation and proceedings and making the final verdict democratic.19 Jury trials have their own set of challenges.20 However, in the presence of biases and other human limitations they intentionally work toward a fair and rational outcome by systematically structuring, segmenting and transparently formalising their proceedings.17,19,20 This approach is not yet widespread among academic award committees, as a brief inquiry among the world’s most established and prestigious academic prize institutions revealed (Box 1).\n\nUpon inquiry, we found that for many prestigious academic awards there are either no detailed evaluation guidelines available or they are not publicly accessible. The following anonymised quotes are drawn from responses we received from some of the world’s most prestigious academic award committees in response to the question: “[…] May I ask you to possibly send me (a link to) a description of the proceedings, which take place during the actual jury meeting (i.e. is there first a pre-selection or consultation? How are all the nominations reduced down to the final winners? Are there rules or customs for this process?). […]”:\n\n“The reason you do not find detailed information regarding the exact proceedings of the […] Committee’s work is that there are none.”\n\n“The committee is entirely free to structure their work the way they find appropriate”\n\n“The Foundation keeps matters related to your query confidential”\n\n“[…] according to the statutes of the […] Foundation, the selection is treated confidentially”\n\n“While the members of our prize Selection Committees are public, the proceedings are not”\n\n“There are no written guidelines for how the committee decides upon a winner”\n\n\nA proposal\n\nInspired by the analogy of a jury trial and the lack of such clear and transparent processes among academic prize committees, we propose a new award evaluation procedure. The procedure was also implemented in a first instance during the evaluation of the Swiss Science Prize Marcel Benoist (MBP), Switzerland’s most prestigious academic award (see Application to the Swiss Science Prize Marcel Benoist,21). The new evaluation procedure is based upon the following three core principles:\n\n• Research evaluation is an active decision-making process by the evaluation panel. It is not the description of some objective ground truth by onlookers. The evaluation proceedings need to be structured to handle the complexity of the evaluation task appropriately.\n\n• Evaluation and the documents under scrutiny should comprise of clearly delineated individual parts such that the verdict can be synthesised from the sum of many individual smaller steps. Assessment should not consist of unstructured, open-ended discussions that try to simultaneously consider all aspects of monolithic evaluation documents.\n\n• Each step of the evaluation procedure must be transparent and well-defined, easy to understand with a clearly formulated aim and comprehensible outcome, which in turn should form the basis of the next step of the evaluation and/or feed directly into the final verdict.\n\nIn addition to these three principles, we also designed the process to rely on preparatory work such that the actual evaluation meeting itself can be streamlined and managed online. Flying in international experts for evaluation meetings is arguable neither necessary nor sustainable. The evaluation process is divided into three parts: nomination, pre-evaluation and finally the evaluation panel meeting itself. Each part is subdivided into individual steps.\n\nTo nominate a potential awardee, nominators fill in clearly structured nomination documents with the help of an interactive online platform. The interface provides all necessary definitions and information and helps the nominator organise the nomination correctly into three individual sections: “achievements by the nominee”; “prominence endowed upon the nominee”; and “impact originating from the nominee’s work”. Achievements are defined in line with DORA as the\n\n“[…] actual work and output of the nominee. These may include important scientific publications, inventions, efforts, documented breakthroughs etc. Not regarded as achievements in this sense are prizes, awards and prestigious associations endowed upon the nominee (e.g. employment in famous universities, collaborations with famous people or publications in famous journals etc. […]). Here, strictly only describe what the nominee themselves have actually done or produced.”\n\nProminence, in contrast, is defined as\n\n“[…] prestigious distinctions and recognitions endowed upon the nominee by others as opposed to accomplishments attained by the nominee themselves [they] may include awards, titles, distinctions, nominations, and prestigious association such as employment in famous universities, collaborations with famous people or publications in famous journals etc (e.g., while the content of a seminal publication should be described in Achievements, the fact that it was published in a prestigious journal can be mentioned here, if you wish to do so).”\n\nThe prominence section is included because many nominators and panel members still today explicitly or implicitly rely on, independently google or outright demand such measures, especially when evaluating highly prestigious prizes. Rather than deceiving ourselves about these circumstances, we instead try to impose honesty and transparency in their use by strictly containing prominence information to one dedicated section. The definition of impact is the same as outlined in the assessment framework and guidance on submissions of the Research Excellence Framework 2014 (www.ref.ac.uk/2014), which defines impact as\n\n“[…] an effect on, change or benefit to the economy, society, culture, public policy or services, health, the environment or quality of life, beyond academia.”\n\nNominators are asked to keep their statements in the three sections concise and comprehensible to both an educated audience and non-expert members of the public, avoiding jargon. They are informed transparently about how the evaluation panel will use their statements. All information is provided directly within the online nomination mask such that no additional submission guidelines or further documentation are necessary. The same information texts are provided to the members of the evaluation panel. Separating the nomination text into three sections this way allowing the members of the evaluation panel to easily assess the actual achievements of the individual researcher independently of their prestigious associations, and the impact of their work without it being conflated with the work’s quality. Furthermore, it allows evaluators to easily refer to, evaluate and comment on these different aspects of a nomination independently and to compare them individually across nominations.\n\nAny claims made by nominators within the achievements and impact sections have to be supported by references. No more than ten references, distributed freely across these two sections, can be used. Citations are entered into the text as bracketed numbers (e.g. [3]). The actual reference itself, however, only consists of information about the reference type (e.g. “journal article”, “book”, “radio interview”, “code” etc) and the respective abstract, synopsis or description, deliberately omitting any information about author, title, journal, publisher or publication date etc. Furthermore, upon submission of a nomination, the achievements and impact sections are anonymised such that they contain no names, gender or other identifying information but referred only to “the nominee” or the gender-neutral pronoun “they”. Any mention of, for example, institutions, collaborators or associations are also replaced with neutral references such as “at a Swiss university”, “with an established collaborator” or “as editor of an established journal” etc. Fully anonymised nominations can then be generated by separating the prominence section from the now anonymised achievements and impact sections. These fully anonymised nominations, consisting only of the achievements and impact sections with anonymised citations and without any mention of institutions or journal names etc, are then sent to evaluation panel members for pre-evaluation (Figure 1A).\n\n(A) During pre-evaluation, each nomination (in this case, for example, “Nomination C”) consists of the fully anonymised achievement (Ach) and impact (Imp) sections only (without the prominence sections). References contain only a description of the reference type (e.g. “Journal Article”) and the respective abstract or synopsis. (B) “Nomination C” is then reviewed by a subset of evaluation panel members (here panellist 3 through 7), who each compare the nomination to a different set of other nominations respectively (in this case with some overlap). Each panellist ranks their set according to their personal overall preference (i.e. “who should win the prize?”, overall ranking (OR)) and additionally distribute gold (G), silver (S) and bronze (B) medals for the achievements and impact section respectively.\n\nNominations are sent out to the individual panel members to review ahead of the panel meeting. The panel is comprised of at least seven and up to 11 members. In addition to international academic experts, it also includes two non-academic representatives of society and is age- and gender-balanced.\n\nThe nominations are distributed in a systematic, pseudo-random manner. They are assigned to panellists randomly albeit within the confines that every nomination is reviewed by six members of the panel only and that those six reviewers always include one of the two non-academic panel members and the panel’s topic-expert (e.g. all psychology nominations are read by the psychologist in the panel etc, Figure 1B). Furthermore, we ensure that each panel member’s individual collection of nominations to review is different to all others panel members’ sub-sets such that each nomination is compared to different nominations in every case and every nomination is compared to every other nomination at least once (Figure 1B). Importantly, this network distribution of nominations means that each panel member has to only pre-evaluate a sub-set of nominations (the number of which will depend on the total number of submitted nominations) instead of all of them, thus reducing the burden on the evaluators. In turn, the evaluation panel members have to commit to reading through their respective sub-set of nominations in full, including all the abstracts provided in the reference list, while also formally and explicitly committing to not seeking out additional information beyond what was provided (i.e. no googling of nominees etc).\n\nThe panel members are asked to pre-evaluate their respective sub-set of nominations in two steps. In the first step, they only receive the fully anonymised achievements and impact sections of the nominations in their respective sub-set (i.e. without the prominence section, Figure 1A). These anonymised nominations have to be monotonically ranked according to the evaluation criteria and the individual panel member’s personal assessment. Additionally, panel members are asked to assign an equal number of gold, silver and bronze medals across the individual achievements and impact sections respectively. If, for example, a panel member has to pre-evaluate 15 nominations in their sub-set, they would have to separately assign five bronze, five silver and five gold medals for achievements and for impact, respectively. The medals provide an intuitive way of generating tercile rankings of achievements and impact, in line with the overall ranking (i.e. first is better than second etc., Figure 1B). Finally, we ask panel members to guess who the nominated person is, if they believed they have an idea, to keep tabs on the extent to which anonymisation was successful.\n\nAll assessments throughout the whole evaluation procedure are always based on rankings instead of ratings. The advantage of using rankings (specifically weaker than/ stronger than) instead of ratings (generally weak/strong) is that they are internally normalised, thus mitigating the risk that a very generous or overly strict panel member might skew the evaluation. For example, by strictly specifying the number of gold, silver and bronze medals that can be allocated by a panel member, the chance of receiving more or fewer medals of a particular kind is independent of the individual panel members to whom the nomination is allocated. Instead, it is only a function of those individual panel members’ evaluation of the respective nomination compared to the other nominations within their sub-set.\n\nTo further facilitate comparison across nominations, average and median values are calculated after pre-evaluation for each nomination based on the overall ranking and the medals it receives from the panel members who pre-evaluated it. The average overall ranking of a nomination is calculated as the mean value across its individual sub-set rankings. The average achievement and impact medals are calculated as the mean values across its individually assigned medals [defined as Gold = 1, Silver = 2, Bronze = 3 (Figure 2A), calculations of the median scores are done analogously]. These statistics are simple though calculating the mean across ranking data is, to some extent imperfect. However, presenting data in this very straight forward form allows all panel members to always easily and intuitively understand the statistics and their underlying data, which is crucial if they are to accountably argue based upon them (Figure 2).\n\n(A) To provide an overview, the pre-evaluation data for the example of “Nomination C” from Figure 1 is listed in the table. Replacing the medals with numbers (gold = 1, sliver = 2, bronze = 3), allows for the calculation of ranks (here only the average ranks are shown), which in turn allows for a positioning of each nomination relative to the others for the overall ranking (OR), the achievement ranking (ACH) and the impact ranking (IMP) respectively (plots). (B) In actual fact, the information provided in these rank plots needs to be substantially richer to be genuinely informative. It consists of the number of panellists who evaluated a nomination (n), the mean and median ranking value (red and blue dots respectively), the raw individual rankings from the panellists (gray dots) as well as the mean and median ranking (right y-axis) for each nomination (shown is the normalised overall ranking across 24 nominations based upon real-world evaluation plots but populated with random data for data-protection reasons, similar plots are also generated for the achievement and impact rankings respectively).\n\nIn the second step of pre-evaluation, after returning their rankings, the panel members are provided with a detailed report and the full set of non-anonymised nominations. The analysis report provides three important results: (1) a detailed overview of all individual rankings and their mean and median positions across all nominations (see above); (2) a threshold calculated based upon these results, where only the nominations above this threshold are going to be considered further in the evaluation panel meeting; and (3) additional analyses of potential biases in the data.\n\nThe threshold is drawn based upon the following rule:\n\n“Include only nominees with a mean AND median rank of seven or better in the overall ranking, OR a mean AND median rank of three or better in the achievement OR impact ranking.”\n\nThe panel members are then asked to indicate in writing whether they agree with the analysis and thresholding of nominees as described in the analysis report; or feel that one of the excluded nominees should still be included in the further evaluation. In the latter case, the panel member has to then also state in writing why the respective nominee should be singled out despite being below the analysis report’s threshold. Any such argument has to also be presented personally at the beginning of the panel meeting so that the panel can vote to support or reject the proposition.\n\nThe additional analysis in the report consists of correlation tests between the panel members’ rankings and additional parameters to illuminate any potential relationship between them, which might indicate a certain degree of bias. We compare the rankings of panel members from the same or similar research areas to those of panel members from other research areas than the respective nomination and we also correlate the panel member’s rankings against the gender and age of the nominee. A correlation between rank and age would not necessarily be unexpected as more senior researchers have had more opportunity to excel. Nonetheless, these additional analyses can provide some insight into any potential systematic trends in the data, which might have to be addressed during the panel meeting, if they are of potential concern.\n\nAlong with the analysis report, the panel members are also provided with the full set of all original, non-anonymised nominations, now also including the prominence sections. The complete set of original nominations is offered to the panel members for their information only and they are not required to do any more work in preparation for the evaluation meeting at this point, except read the small set of nominations remaining above the threshold, in case they have not done so already as part of their own pre-evaluation sub-set. The panel members are, however, encouraged to read through all nominations and to revisit their own original sub-set, this time with added information such as name, gender, institution, and all the prestigious distinctions and recognitions outlined in the prominence section to the extent they feel necessary such that they can agree with the proposed thresholding and the resulting inclusion and exclusion of nominees. They can also use this information to argue against the thresholding if need be (see above).\n\nThe evaluation panel meeting is held online and led by two chairs. The academic chair is responsible for the content of the evaluation, and a separate, independent procedural chair is responsible for the evaluation process and compliance. The procedural chair guides the panel through the different steps of the evaluation. Whenever an individual nominee is discussed, all data on the respective nomination is displayed on screen: the panel members who pre-evaluated the nomination and the ranks and medals they assigned, the resulting position across all overall rankings and all achievement and impact medal rankings (Figure 2), the nomination synopsis, recusals, etc. The data allows for informed discussions (e.g. “nomination A ranked higher in achievements than nomination B”) and targeted questions (e.g. “why did panellist 7 give nomination C only a bronze medal for impact?”). Voting is conducted digitally and anonymously. All results are displayed as soon as the last vote is cast.\n\nIf a panel member at this stage strongly supports a nomination that they had originally ranked low, this becomes apparent quickly as all ranking information is displayed. Thus, if panellists change their mind because they now know who they are talking about, this can and should be discussed and challenged by the panel. The procedural chair is also tasked to look out for such discrepancies and highlight them, thus increasing transparency in the argumentation for or against a nomination.\n\nAll nominations, which are evaluated in the panel meeting (i.e. those that remained after thresholding), are discussed individually in detail to decide if they should be removed from the competition or forwarded to the final evaluation round. Each discussion starts off with a short plea against the respective nomination by the panel member who had pre-evaluated it and ranked it lowest compared to the other five pre-evaluators. Their statement is then followed by an argument for the nomination by the panel member who had ranked it highest during pre-evaluation. The two opening statements can then be commented upon by the remaining four pre-evaluators and then discussed further in the full panel. Finally, an anonymous vote is taken, whether the nomination should be put forward or whether it should be eliminated, before moving on the next nomination. To keep the process efficient, only a limited number of nominations can be brought forward to the final discussion (e.g. three to five nominations).\n\nWhile the initial discussions strictly focus on individual nominations only (i.e. should this nomination be put forward for this prize), the final session opens the floor to comparative discussions across all nominations (i.e. should this nomination be awarded over that nomination). It nonetheless is equally carefully structured to ensure fairness. All nominations and panel members are given equal air-time and the procedural chair intervenes when secondary or anecdotal information about a nominee is introduced. Such information is neither transparent nor fair and can work only for or against nominees familiar to members of the panel. The two non-academic panel members have the same rights and responsibilities as all the other panel members throughout the evaluation, in this step they do have one additional task, however, which is to confirm officially to the panel that in their view the remaining nominations are indeed impactful beyond academia, giving them a certain veto right in that regard. Once the comparative discussion converges on a few finalists, votes are cast to decide on the top two candidates and ultimately the winner. The first vote askes the panel members to individually rank all remaining nominations. The rankings reveal the final top two candidates from which a second vote between the two finalists declares the winner. The second vote is necessary to ensure that the majority of the panel ultimately cast their vote for the final winner.\n\n\nApplication to the Swiss Science Prize Marcel Benoist\n\nThe MBP is the most prestigious academic prize in Switzerland. Founded in 1920 it awards scholars who “[…] made the most useful discovery […] that is of particular relevance to human life” and is therefore in its essence an impact prize. The award is rotated tri-annually through natural, biological and medical sciences, and the humanities and social sciences. Since 2018 the Swiss National Science Foundation is responsible for the evaluation of the MBP, in partnership with the Marcel Benoist Foundation.\n\nThe process presented here has been successfully applied to the evaluation of the MBP four times so far.21 The individual nomination sections consisted of: achievement, 800 words; impact, 800 words; and prominence, 500 words. Anonymisation took roughly four hours per nomination. However, not sending nominations out for external peer review also saved time, making the overall preparation efforts relatively efficient. Pre-evaluation and thresholding worked well and in one instance predicted the winner. Discussions during the evaluation meeting relied significantly on the information provided in the on-screen pre-evaluation data resulting in good discussion dynamics and transparent decision-making processes.\n\nCompliance of individual panel members (e.g. no googling of nominations) and overall adherence to DORA guidelines (e.g. weighting the actual achievements of a nomination higher than the journal in which it was published) were some of the main challenges, which we encountered during the implementation of this process; they are, however, not unique or particular to this evaluation procedure. The process presented here heavily relies on preparation ahead of the actual evaluation meeting; due diligence in vetting nominations and good preparation especially by the procedural chair are crucial to ensure smooth and efficient evaluation. Overall, the experience with this evaluation procedure has been very positive and the SNSF will continue using it for the evaluation of the MBP and possibly other prizes in the future and some of its aspects are now also being adapted to other funding procedures.\n\n\nDiscussion\n\nMany ideas, both tried and new, were combined in the design of this evaluation procedure22,23: interpreting evaluation as more similar to a jury trial than a competition, segmenting and anonymising nominations, pre-evaluation, selectively assigning nominations to a network of panellists, using rankings instead of ratings, including non-academic experts in the evaluation panel, conducting voting anonymously and through dedicated infrastructure, displaying all nominee-specific and comparative evaluation data to the panel during discussions, dividing up the chairing duties between an academic and a procedural chair. Together, these innovations form a coherent, transparent and well-defined structure of individual steps, through which nominations proceed and within which panel members are supported in their deliberations.\n\nDespite best efforts, for prestigious awards some nominees will almost always be familiar to at least some panellists while others may remain unrecognised. At the same time, maintaining the anonymity of nominations during panel discussions is difficult and often not feasible. Acknowledging these challenges, we propose a pragmatic middle ground where nominations are kept anonymous during pre-evaluation but anonymity is then lifted in a controlled manner ahead of the meeting allowing for non-anonymous discussions.23,24 This approach provides the added benefit that it can also highlight biases originating solely from personal or prominence-based information as they stand in visible contrast to the pre-evaluation ranking based on the anonymised texts. Fully automated anonymisation for academic texts is, to our knowledge, not available or not reliable enough. However, a surge in privacy requirements, not least due to the General Data Protection Regulation (EU) 2016/679 have led to a proliferation of anonymisation tools,25 which, for example in combination with Research Organization Registry data, could, in future, be adapted for such purposes.\n\nThe evaluation process described here relies on nomination texts, which is unfortunate in those cases where a superficial nomination may disadvantage an otherwise very strong nominee. It is important to make nominators aware of this potential confound and the importance of a high-quality nomination on their part. Tampering with the process by, for example, adding additional information where needed, is not appropriate as it undermines the very essence of a nomination award. Such intervention leads down a slippery slope where one might as well just ask for the name of the person to be nominated and then leave the collection and selection of arguments to dedicated experts.\n\nNomination awards can also result in multiple nominations being submitted for some nominees but not for others. This can create an unfair advantage as multiple nomination texts provide opportunity to describe different accomplishments and to cite more works than just one text (although there will of course be some overlap between nominations). At the same time, multiple nominations may generate an implicit bias simply by suggesting that “more people think this person should win than that person”. Both situations need to be avoided, as the winner should be determined by the evaluation panel and not a majority vote from nominators.\n\nTo control for such circumstances, one can divide up multiple nominations for the same nominee among the pre-evaluators such that, for example, three panel members pre-evaluate only one and the other three the other nomination. During the second step of pre-evaluation, both nominations can then be provided along with all other non-anonymised information. As with the prominence section, panel members can now still change their mind based upon the additional information but any such changes are again highlighted due to their contrast to the original ranking data, allowing for the panel to call them out and discuss them transparently.\n\nDORA encourages that evaluators read the work they are asked to assess as opposed to relying on short-cuts such as journal-derived metrics.11 However, if evaluation organisers expect their evaluators to adhere to these guidelines, then they must also ensure that evaluators will actually be able to fulfil this mandate. You cannot commit to DORA and at the same time send out publication lists that are too long for evaluators to realistically read with due diligence. To address this problem, we only allowed for ten references to be cited across all three text sections (achievements, impact, prominence). However, for every ten nominations this would nevertheless add up to 100 papers to read, which is still a lot. Reducing the number of references even further may be difficult as academic awards, such as the MBP, are often given for a large body of work as opposed to a single project. Instead, we provided an abstract for each of the ten references and in turn asked the panel members to commit to reading all abstracts for every nomination in their sub-set. Providing abstracts instead of citations or full text publications also allowed us to maintain anonymity during pre-evaluation.\n\nResearchers have a right to fair evaluation as they can make or break their careers.26 Furthermore, small systematic biases can sum up to damage progress.27 Despite best efforts, evaluators and evaluation processes are frequently — and to some extent inevitably — implicitly biased, and nominees may therefore not always be given their fair chance. The under-representation of women in academia generally and amongst academic awardees specifically is one example of the cumulative impact that biases at every stage of a scientific career can have.28–30 We believe many of the techniques discussed here could be transferred to other prize evaluations and assessments at other career stages, such as the hiring of faculty and the awarding of fellowships or grants. We hope that they may inspire change. High-quality and fair research evaluation requires not only a change in culture and a commitment to do better but most importantly also the actual implementation of fair and transparent processes.\n\nResearch evaluation functions as a gatekeeper of science. By assessing grant proposals in funding organisations, we determine who will be a scientist and what research will be conducted. By evaluating submissions to academic journals, we determine which research will be communicated to which audience. By evaluating nominees for academic prizes, we decide what research we want to celebrate and what academic role models we create for future generations. It is paramount to ensure that we can argue coherently and transparently how these important verdicts are reached in each of these situations.\n\n\nData availability\n\nNo data are associated with this article",
"appendix": "Acknowledgements\n\nThe author wants to thank Michaela Strinzel for discussions, input on the manuscript and help with implementing these ideas in the evaluation of the MBP; Prof Matthias Egger for the opportunity, support, discussions, and input on the manuscript; Dr Katrin Milzow for support, discussions and feedback; Julius Mattern for help with Figure 2.\n\n\nReferences\n\nMüller R, de Rijcke S : Thinking with indicators. Exploring the epistemic impacts of academic performance indicators in the life sciences. Res. Eval. 2017; 26: 157–168. Publisher Full Text\n\nSmaldino PE, McElreath R: The natural selection of bad science. R. Soc. Open Sci. 3: 160384. PubMed Abstract | Publisher Full Text\n\nLamont M: How Professor Think: Inside the Curious World of Academic Judgment. Cambridge, MA: Harvard University Press; 2009. 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}
|
[
{
"id": "101950",
"date": "11 Mar 2022",
"name": "David Moher",
"expertise": [
"Reviewer Expertise Knowledge Synthesis",
"Open Science",
"Researcher 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\nPrecis of paper\nHill describes a novel ‘case’ study for awarding Switzerland’s most prestigious academic prize, namely, the Swiss Science Prize Marcel Benoist. The prize is rotated tri-annually through natural, biological and medical sciences, and the humanities and social sciences. The conceptual approach Hill describes is analogous to a jury trial in the legal system. The assessment for the prize has three core principles (and subdivisions): nomination; pre-evaluation; and an evaluation meeting (held online). The author indicates that this new process has been used four times for the prize.\nMy assessment\nThe topic is very important with insufficient investigation and thought, particularly on the part of funders. Too few funders are actively engaging in alternatives to the current unfortunate models. It is not a myth that after a grant application submission, colleagues email wishing me “the best of luck” or “fingers crossed”. There is a recognition in the researcher community that how grants and/or prizes are awarded is a box of unclear processes; perhaps not reproducible.\n\nThis article very clearly describes the entire process of the prize evaluation. This is important and well done. The is a strong reliance on the work of DORA, advocating movement away from useless and non-evidence-based metrics and processes towards one that get to the heart of research evaluations. Importantly the author discusses getting at the ‘ground’ truth. I wasn’t sure what this term meant. Is it analogous to the ‘gold standard’? I fear many readers won’t understand the ground truth.\n\nIn part 2 - pre-evaluation, please provide some clarify about the time the nominations were sent to panel members in advance of the evaluation meeting. Similarly, please indicate whether other EDIA (equity, diversity, inclusiveness, and accessibility) beyond age and gender were considered.\n\nA limitation of the paper for me is the lack of a discussion around the potential generalizability of using this approach for grant applications beyond prizes. Can this approach be considered for grant applications more generally? Did the author have an opportunity to survey the ‘jury’ as to their ease/difficulty using the approach, level of satisfaction with the process?\n\nThe pandemic has forced most of us to exist online. This has sometimes resulted in a variety of connectively problems, postponement of meetings, etc. Can the author comment on connectivity problems and how different time zones posed any problems? I’ve often been asked to join meetings at 04:00. Not likely!\n\nAnother limitation of the paper was a lack of discussion around additional experimentation. For example, anonymizing certain parts of the process. In the 1980s, some medical journals were interested in whether double blinding manuscripts versus open was worth the effort in terms of quality of peer review – no was the general answer (e.g., Justice AC, Cho MK, Winker MA, Berlin JA, Rennie D. Does masking author identity improve peer review quality? A randomized controlled trial. PEER Investigators. JAMA. 1998 Jul 15;280(3):240-2. doi: 10.1001/jama.280.3.240. Erratum in: JAMA 1998 Sep 16;280(11):968. PMID: 9676668; van Rooyen S, Godlee F, Evans S, Smith R, Black N. Effect of blinding and unmasking on the quality of peer review: a randomized trial. JAMA. 1998 Jul 15;280(3):234-7. doi: 10.1001/jama.280.3.234. PMID: 9676666). Does the author think there is merit in thinking about experimenting with blinding versus open aspects of the described process for the prize evaluation?\n\nThe author points out various advantages of having the evaluation meeting online. Another one (not mentioned) is the reduction of a carbon footprint which perhaps meets an environmental/climate policy of a funder.\n\nThere is growing evidence of gender bias in the assessment of grant applications (e.g., Franco MC, Helal L, Cenci MS, Moher D. The impact of gender on researchers' assessment: A randomized controlled trial. J Clin Epidemiol. 2021 Oct;138:95-101. doi: 10.1016/j.jclinepi.2021.05.026. Epub 2021 Jun 9. PMID: 34118367; Witteman HO, Hendricks M, Straus S, Tannenbaum C. Are gender gaps due to evaluations of the applicant or the science? A natural experiment at a national funding agency. Lancet 2019;393:531–40. doi: 10.1016/S0140-6736(18)32611-4). I did not see a discussion as to whether the proposed approach might mitigate such bias(es).\n\nShould the paper (end) with a clarion call for other funding organizations to initiate a discussion/pilot and evaluation of alternative ways to assess prizes and grant funding more generally? As indicated in the opening paragraph of the paper, several initiatives have called/alluded to this. Researchers deserve better than “best of luck”.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "126982",
"date": "05 Apr 2022",
"name": "Virginia Barbour",
"expertise": [
"Reviewer Expertise Publication ethics",
"journal peer review"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 paper that describes the approach for the awarding of the Swiss Science Prize over the last four cycles of the Prize. The paper outlines the rationale for the approach, especially as it relates to more usual practices, and the challenges associated with the adoption and the ways that they have mitigated the challenges.\nComments:\nThe paper is valuable in itself as a description of an approach but in my view would benefit, if available, from an analysis of changes in nominations, and awardees of the prize in order to support the adoption of the new process.\n\nThe title gives a wrong impression of the paper. “The Jury is out” implies that something has not yet been decided. I appreciate there is a wish to have a catchy title, but it seems that a decision has been made to change this award process.\n\nThe paper does a good job of explaining the process that was adopted, and which is now in use, for the awarding of the Swiss Science Prize. The process of awarding science (and other academic) prizes is similar in many ways to the process of awarding research grants, though one notable extra step is the nomination process for prizes. The insights presented here may therefore be of interest to others involved in awarding prizes, as well as those involved in grants.\n\nAlthough the introduction provides some background to the transition to the new process and the problems with current systems it would have been valuable to know whether any other model was considered.\n\nIn the discussion, the author touches on the importance of the nomination texts in determining who proceeds through for further evaluation. This seem such an important step in the process that it would seem to be worth discussing further. It would be useful to know how many nominations are received and if that number has changed with the adoption of the new process.\n\nWas there a specific rationale for change? For example, was there under-representation of women or other groups in the those who were nominated and also in who made it through to the final stages or the awardees? Related to this point, are there any data on whether there was any change in who was nominated, who was awarded a prize, or who ended up in the final deliberations? The paper would benefit from a presentation of this analysis. Is there any plan for future evaluation?\n\nThere is good recognition of how hard it is to fully anonymise applications and there is a good description of the steps that were taken. The author mentions that panel members are asked about whether they could guess who the nominees were. Are there any data on how successful anonymisation actually was?\n\nIt would be interesting to know more about the composition of the judging panel. Were there any changes to that composition between the previous and new models of judging?\n\nIs there any plan to survey the panel members on their views on the new process?\n\nThe author mentions that there are plans to expand the process to other prizes. It would be useful to know if any changes in the process will be required for such an expansion.\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? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1237
|
https://f1000research.com/articles/10-1235/v1
|
03 Dec 21
|
{
"type": "Opinion Article",
"title": "COVID-19, pseudo-declining skin cancer rates and the rise of teledermatology",
"authors": [
"Joanna Ludzik",
"Claudia Lee",
"Alexander Witkowski",
"Joanna Ludzik",
"Alexander Witkowski"
],
"abstract": "In late 2019, the world was introduced to the novel SARS-CoV-2 virus that shook the global medical community. By early 2020, the new coronavirus strain led to the rapid spread of a disease that earned its classification as a pandemic, prompting authorities to enforce new health regulations that significantly limited access to in-person medical evaluations, and resulted in a significant reduction in skin cancer diagnosis volume over the course of the pandemic. Skin cancer is amongst the most common and frequently diagnosed cancers, with incidence rates steadily increasing for the past few decades, until recently when world-wide changes to the health system drastically reduced opportunities for screening, diagnosis and management. In order to optimize patient treatment in the midst of the pandemic, practicing providers relied heavily on remote alternatives, sparking a huge spike in teledermatology practices globally. The successful adoption of widescale teledermatology allowed improved triage of concerning skin lesions requiring urgent face-to-face assessment, which helped mitigate the repercussions of delayed diagnosis and management. The detrimental consequences of the COVID-19 pandemic have permanently changed the way we view and practice medicine, and it is imperative that the medical community continues to improve modern healthcare, through continued technological innovations that will advance this new technologically-reliant age of medicine.",
"keywords": [
"Skin cancer screening",
"teledermoscopy",
"covid-19",
"coronavirus",
"teledermatology",
"melanoma",
"mobile dermoscopy"
],
"content": "Introduction\n\nFor the last few decades, the incidence rate of skin cancer, both melanocytic and non-melanocytic, has been consistently rising, likely due to the increase in sun exposure and increased skin cancer screening practices by clinical providers. Despite the rising incidence rates worldwide, improvement in early detection and thus early treatment of skin cancer, specifically melanoma, has led to an overall reduction in mortality from this disease for the past several years.1 However, the unprecedented onset of the COVID-19 crisis suspended many scheduled medical and surgical activities, which introduced new barriers to prompt cancer screening and early detection of disease. This is a reasonable explanation for the significant reduction in skin cancer diagnosis reported by many countries during this period. Neglecting skin cancer throughout the outbreak may be associated with increased rates of mortality, morbidity and health care expenses. Therefore, in order to minimize these negative consequences while simultaneously abiding to strict health regulations, many international institutions favored the increased practice of teledermatology, to meet the continued need for treatment of acute and chronic skin diseases.2 It remains unknown exactly how long the consequences of the COVID-19 crisis will continue to negatively impact health systems, but the increased utility of telemedicine services will likely be around for the foreseeable future.3 The dermatology community should prioritize improving the efficacy, accuracy and availability of these virtual services in order to preserve the quality of patient care in our ever-evolving society.\n\n\nSkin cancer screening and management during the COVID-19 pandemic\n\nIt is well established that the most important prognostic factor that influences the survival of skin cancer patients is the time of correct diagnosis and start of treatment, especially for melanoma, which is highly fatal.4 This understanding is what prompted most practicing dermatologists to be proactive in detecting concerning skin lesions early and treating them as soon as possible, which has improved the overall outcomes of skin cancer patients in recent years. Traditionally, the standard of care for diagnosing skin cancer involves face-to-face evaluation, usually utilizing advanced imaging modalities such as a dermatoscope, with a skin specialist deciding the optimal course of treatment. However, due to limited access to in-person care imparted by the COVID-19 pandemic, many countries have reported a drastic decline in skin cancer diagnosis during this period, suggesting that many skin cancer patients are going undiagnosed and untreated.4–8 In a 2020 study conducted in the United Kingdom (UK), Andrew et al. reported a shocking 68.61% decrease in skin cancer diagnosis made during the pandemic.5 Similar findings were described in a retrospective study done in Italy that reported a striking 60% decline in new melanoma diagnosis, as well as a 30% reduction in relative surgical activity during the lockdown.6 Although skin cancer may be identified clinically via dermatoscopic evaluation by a trained expert, clinically equivocal lesions are often biopsied and diagnosis is confirmed after histopathological analysis. The unexpected COVID-19 crisis posed new challenges to pathology services, that expectedly reduced histopathological diagnosis of skin cancer, as highlighted in a study done in Romania, contributing to the overall global decline in skin cancer rates during the outbreak.7 All these studies compared these new findings to trends in skin cancer diagnosis seen pre-COVID, suggesting that skin cancer is being underdiagnosed rather than truly declining in prevalence. This is further supported in another article that reports an increased mean Breslow thickness amongst primary melanoma patients diagnosed after COVID-19-related lockdown restrictions were lifted.8 The delay in early detection and management will likely result in poorer prognosis and health outcomes for these patients.\n\n\nTeledermatology during the COVID-19 pandemic\n\nDue to the sudden appearance of this epidemiological emergency, the strict health restrictions enforced to minimize viral transmission, and the necessity to move almost the entirety of the healthcare force toward providing COVID-19-related services, many previously scheduled clinical and surgical procedures were postponed.9 This has been limiting access to high-quality, timely interventions, which is pivotal in determining a favorable outcome, thus decreasing patients’ satisfaction and negatively influencing the quality of life for skin cancer patients. One way in which health systems evolved to maintain these essential health services in the field of dermatology during this time, was by offering remote healthcare alternatives. Teledermatology, a subdivision of telemedicine, makes it feasible to connect virtually with quality health care providers, and receive care for nonessential ailments and issues, without exposing either the health care provider or the receiver to the undue risk of infection. This is facilitated by data collection, exchange and analysis over a long distance by various methods of communication, including the audio, video and digital imaging storage that constitute a virtual consultation.10 Over the course of the pandemic, countries have reported a 10- to 15-fold increase in teleconsultations, and studies reporting experiences with teledermatological services during this time, showed that a continuation of the care for chronic dermatological patients is to a large extent possible only by means of teledermatology.11 Moreover, since the availability of surgical procedures during this time is limited only to patients requiring urgent time-sensitive intervention, teledermatology has also proven to be an excellent tool in triaging high-risk cases that need prioritized face-to-face evaluations. As the demand rises and we become more reliant on these virtual health services, it becomes increasingly important to advance telehealth practices in order to optimize patient care. The incorporation of teledermoscopy and teledermatopathology has been shown to significantly improve the diagnostic accuracy and reliability of teledermatology services by approximately 15%, while only adding an average of one to two additional minutes to the consultation.12 In addition, newer applications to teledermoscopy such as mobile dermoscopy, in which mobile devices (smartphones) with dermatoscopic attachments are used to capture and store dermoscopic images, can be taken directly by the patient and provide a convenient in-office-like visit from the comfort of one’s home. Previous studies have reported adequate patient satisfaction with teledermatology services; however, a recent survey evaluating patients’ satisfaction specifically during the pandemic reported increased satisfaction.10 Dermatologists in hospitals and practices were able to compensate at least partially for the restricted personal dermatological care of skin cancer patients under the COVID-19 pandemic circumstances, through an extension of teledermatological services. The increased practice and clinical utility of teledermatology enabled continuous care for skin cancer patients during this challenging time, that helped mitigate the consequences of delayed management. While not a replacement for traditional practice, teledermatology has proven to be a safe and efficient adjuvant service, that might shape dermatological patient care well beyond the pandemic. Further evaluation of the accuracy of clinical and dermatoscopic imaging submitted by patients during the COVID-19 pandemic should be carried out, to determine the potential limitations or improvement of care depending on the modality chosen.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nLeiter U, Keim U, Garbe C: Epidemiology of Skin Cancer: Update 2019. Adv. Exp. Med. Biol. 2020; 1268: 123–139. PubMed Abstract | Publisher Full Text\n\nStadler PC, Senner S, Frey S, et al.: Teledermatology in times of COVID-19. J. Dermatol. 2021 May; 48(5): 620–624. Epub 2021 Mar 14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaddukuri S, Patel J, Lipoff JB: Teledermatology Addressing Disparities in Health Care Access: a Review [published online ahead of print, 2021 Mar 12]. Curr Dermatol Rep. 2021; 10: 40–47. Publisher Full Text\n\nBaumann BC, MacArthur KM, Brewer JD, et al.: Management of primary skin cancer during a pandemic: multidisciplinary recommendations. Cancer. 2020; 126: 3900–3906. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAndrew TW, Alrawi M, Lovat P: Reduction in skin cancer diagnoses in the UK during the COVID-19 pandemic. Clin. Exp. Dermatol. 2021 Jan; 46(1): 145–146.PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarruscotti S, Giorgini C, Brazzelli V, et al.: A significant reduction in the diagnosis of melanoma during the COVID-19 lockdown in a third-level center in the Northern Italy. Dermatol. Ther. 2020 Nov; 33(6): e14074. Epub 2020 Aug 13. PubMed Abstract | Publisher Full Text\n\nCocuz IG, Cocuz ME, Niculescu R, et al.: The Impact of and Adaptations Due to the COVID-19 Pandemic on the Histopathological Diagnosis of Skin Pathologies, Including Non-Melanocyte and Melanoma Skin Cancers-A Single-Center Study in Romania. Medicina (Kaunas). 2021; 57(6): 533. Published 2021 May 27. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRicci F, Fania L, Paradisi A, et al.: Delayed melanoma diagnosis in the COVID-19 era: increased breslow thickness in primary melanomas seen after the COVID-19 lockdown. J. Eur. Acad. Dermatol. Venereol. 2020 Dec; 34(12): e778–e779. Epub 2020 Sep 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElmas ÖF, Demirbaş A, Düzayak S, et al.: Melanoma and COVID-19: A narrative review focused on treatment. Dermatol. Ther. 2020 Nov; 33(6): e14101. Epub 2020 Aug 25. PubMed Abstract | Publisher Full Text\n\nSharma A, Jindal V, Singla P, et al.: Will teledermatology be the silver lining during and after COVID-19?. Dermatol. Ther. 2020 Jul; 33(4): e13643. Epub 2020 Jun 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nElsner P: Teledermatology in the times of COVID-19 - a systematic review. J. Dtsch. Dermatol. Ges. 2020 Aug; 18(8): 841–845. Epub 2020 Jul 27. PubMed Abstract | Publisher Full Text\n\nUppal SK, Beer J, Hadeler E, et al.: The clinical utility of teledermoscopy in the era of telemedicine. Dermatol. Ther. 2021 Mar; 34(2): e14766. Epub 2021 Jan 21. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "126786",
"date": "12 Apr 2022",
"name": "Alessandro Laghi",
"expertise": [
"Reviewer Expertise Teledermatology",
"dermoscopy",
"and rare genetic dermatology diseases"
],
"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 the authors did a good job summarizing how the pandemic has affected dermatology, specifically with skin cancer screening. Although the article does not deliver any groundbreaking information and similar articles detailing this phenomenon of decreased skin cancer incidences seen during Covid-19, it does a good job of summarizing what is being seen across many countries and highlights how rather than a true decline in skin cancer rates, we are likely seeing a large sum of people being underdiagnosed. It also did a decent job highlighting the potential of teledermatology to fix this issue and they could even have expanded this topic more. For example, they could have focused on the controversial role played by artificial intelligence in teledermatology since it may be extremely useful, but the majority of patients who have skin cancer are elderly patients and often are inexperienced with new technology and may struggle in navigating various teledermatology systems without assistance. In closing, although teledermatology has its place during the pandemic and its use will be implemented in the future for sure, in-person evaluations will still hold their place post-pandemic.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1235
|
https://f1000research.com/articles/10-1228/v1
|
02 Dec 21
|
{
"type": "Study Protocol",
"title": "Risk factors for premature coronary artery disease (PCAD) in adults: a systematic review protocol",
"authors": [
"Adeel Khoja",
"Prabha H. Andraweera",
"Zohra S. Lassi",
"Mingyue Zheng",
"Maleesa M. Pathirana",
"Anna Ali",
"Emily Aldridge",
"Melanie R. Wittwer",
"Debajyoti D. Chaudhuri",
"Rosanna Tavella",
"Margaret A. Arstall",
"Prabha H. Andraweera",
"Zohra S. Lassi",
"Mingyue Zheng",
"Maleesa M. Pathirana",
"Anna Ali",
"Emily Aldridge",
"Melanie R. Wittwer",
"Debajyoti D. Chaudhuri",
"Rosanna Tavella"
],
"abstract": "PCAD possesses a public health challenge resulting in years of productive life lost and an escalating burden on health systems. Objective of this review is to compare modifiable and non-modifiable risk factors for PCAD compared to those without PCAD. This review will include all comparative observational studies conducted in adults aged >18 years with confirmed diagnosis of PCAD (on angiography) compared to those without PCAD. Databases to be searched include; PubMed, CINAHL, Embase, Web of Science, and grey literature (Google Scholar). All identified studies will be screened for title and abstract and full-text against the inclusion criteria on Covidence software. Data relevant to exposures and outcomes will be extracted from all included studies. All studies selected for data extraction will be critically appraised for methodological quality. Meta-analysis using random-effects model will be performed using Review Manager 5.3. Effect sizes for categorical risk factors will be expressed as odds ratios with 95% confidence intervals. For risk factors measured in continuous form, mean difference (if units are consistent) otherwise standardized mean difference (if units are different across studies) will be reported. Heterogeneity between studies will be assessed using I2 test statistics. GRADE will be used to assess the certainty of the findings.\nSystematic review registration number: PROSPERO Registration # CRD42020173216",
"keywords": [
"Coronary artery disease",
"premature coronary artery disease",
"risk factors",
"age",
"gender"
],
"content": "Introduction\n\nCoronary artery disease (CAD) is the most common type of heart disease and remains the leading cause of death worldwide, accounting for over 350,000 deaths each year.1 The prevalence of CAD based on the global burden of disease (GBD) data is 154 million which translates into approximately one-third of the global burden of cardiovascular disease and 2% of the overall GBD.2 Furthermore, in 2019, every fifth adult aged <65 years died from CAD.1 The mortality of CAD over the last three decades in adults ≥65 years has declined to 5% among women and 4% among men. In contrast, over the last two decades, there has been a minor improvement of only 0.1% in terms of CAD mortality among adults <55 years of age.3\n\nCAD is defined as the reduction of blood flow to the heart muscle due to the build-up of plaque (atherosclerosis) in the arteries of the heart.4 Premature coronary artery disease (PCAD) is defined as CAD occurring in men and women younger than 45 and 55 years respectively, but these cut-offs tend to vary from 45 to 65 years of age, as evident in different studies.5–8 Early-onset CAD is used interchangeably with PCAD or often termed as CAD in young adults.9 Late-onset CAD is defined as CAD experienced in men aged >55 years and in women aged >65 years.10 Late-onset CAD is also used interchangeably with the normal occurrence of CAD. The prevalence of PCAD in a large survey done in German cardiac rehabilitation centres revealed 37% for men aged <55 years and women aged <65 years, while the prevalence for CAD was 67% for men aged >55 years and women aged >65 years.10\n\nGlobally, PCAD represents a significant burden and an important public health challenge resulting in years of productive lives lost and an increased burden on health systems. More than four-fifths of those who present with PCAD have at least one modifiable risk factor.10,11 Overall, the incidence of PCAD has minimally declined and of even more concern is that the prevalence in individuals <65 years with three major known risk factors (i.e. diabetes, hypertension, and obesity) has increased between 2000 to 2016. This translates into more risk burden and mortality rates in young adults experiencing PCAD.12 The known modifiable risk factors for PCAD include, but are not limited to, smoking, high blood pressure, diabetes mellitus, physical inactivity, obesity, dyslipidaemia, and psychosocial stress.13,14 Non-modifiable risk factors include, but are not limited to, age, gender, ethnicity, family history of heart disease, and homocystinuria.15,16 The following three paragraphs will be talking about gender differences on the incidence of PCAD and comparing risk factors for PCAD compared to those without PCAD.\n\nGender differences in risk profiles have a substantial impact on the incidence of premature coronary artery disease based on earlier systematic reviews.17,18 In general, women tend to be 10 years older than men at the time of the first episode of CAD.17 Women also experience atypical symptoms of CAD such as fatigue, cramps in the abdomen, anxiety, nausea, and vomiting, and indigestion at the time of initial presentation.17,19 Studies have reported a longer time duration from symptom onset to diagnosis among women with CAD.20,21 In addition, the population attributable risk (PAR) of conventional risk factors for PCAD among men (aged ≤55 years) and women (aged ≤65 years) accounted for 93% and 97%, respectively.22 Therefore, it is critical to identify differences in risk factors between men and women having PCAD.\n\nDifferent patterns of risk factors for premature compared to late-onset CAD have been highlighted by an earlier systematic review and data from a population-based registry.10,23 Conventional risk factors such as; smoking, family history of CAD, opium use, and dyslipidaemia are considered to be dominant in PCAD as compared to risk factors such as; hypertension, obesity, sedentary lifestyle and diabetes mellitus which are more prevalent among those who experience late-onset disease.6,10,23,24\n\nDifferent patterns of risk factors for patients with PCAD compared to healthy individuals having normal coronary arteries have been identified by a systematic review and a large-scaled survey done in Iran, which revealed that risk factors such as; dyslipidaemia (52%), cigarette smoking (66%), and strong family history of CAD (90%) individually accounted for increased risk of PCAD as compared to controls.15,25,26 Since PCAD is a multifactorial disease and genetic predisposition plays an important role in younger adults diagnosed with this disease, it is imperative to further investigate risk factors between patients with PCAD compared to those without PCAD.27\n\nAll major risk factors i.e. modifiable and non-modifiable have not been explored comprehensively in earlier systematic reviews targeting patients with PCAD.10,23,28 They either included selected risk factors for PCAD, targeted certain sub-groups, or were restricted to a specific country. To date, no comprehensive appraisal of the evidence has been conducted; and a preliminary search of PROSPERO, PubMed, Google Scholar, and the Joanna Briggs Institute (JBI) Evidence Synthesis did not identify any ongoing systematic review on the current topic. The understanding of modifiable and non-modifiable risk factors is critical for the prevention of morbidity and mortality associated with PCAD. Although, there are a number of published observational studies on PCAD risk factors, yet a thorough systematic review of the evidence is lacking. The results of this systematic review will add to the existing scientific knowledge and will inform current clinical practice guidelines. The objective of this review is to compare the prevalence of modifiable and non-modifiable risk factors in patients with PCAD compared to those without PCAD.\n\nThe objective of this review is to compare the prevalence of modifiable and non-modifiable risk factors for PCAD compared to those without PCAD among the following groups:\n\n1. Patients experiencing PCAD as compared to those experiencing late-onset CAD\n\n2. Patients experiencing PCAD as compared to healthy controls\n\nPopulation\n\nThis systematic review will consider studies that target participants of both sexes, aged ≥ 18 years with a confirmed diagnosis of PCAD on angiography. We will include studies that compare risk factors among patients with PCAD compared to those without a diagnosis of PCAD according to the two groups mentioned above.\n\nExposure of interest\n\nExposure would be risk factors (modifiable and non-modifiable). Modifiable risk factors will include (but not limited to); smoking, hypertension, diabetes mellitus, physical inactivity, obesity, high body mass index (BMI), high cholesterol, substance abuse; and the non-modifiable factors will include (but not limited to); gender, race/ethnicity, family history of heart disease, homocystinuria, polymorphism of MTHFR gene, lipoprotein a. For a detailed list of exposures (Supplementary file 1), which has been selected based on extensive literature search and clinical relevance. However, outside the usual factors reported above and in supplementary file 1, risk factors such as pollution and dust particles, dental hygiene and various infections associated with atherosclerotic plaque rupture, rheumatoid arthritis, and associated medications including non-steroidal anti-inflammatory drugs (NSAIDs), obstructive sleep apnoea, sleep hygiene, job strain and low social support will not be part of this review, since literature suggesting a stronger mechanistic association between unusual risk factors mentioned above and PCAD is lacking; and as a result, it will be difficult to perform the meta-analysis.\n\nOutcomes\n\nThe outcome of interest are patients with a confirmed diagnosis of PCAD based on angiography findings, as compared to patients with no PCAD across two study comparison groups. For this review, an age cut-off of ≤65 years (upper-limit) for both men and women will be used to differentiate PCAD from late-onset CAD. For this systematic review, controls will be defined either as healthy individuals having no disease or having any other disease not related to PCAD or CAD.\n\nTypes of studies\n\nAll comparative observational studies including prospective and retrospective cohort studies, case-control studies, and analytical cross-sectional studies will be eligible. Randomized controlled trials (RCTs), reviews including narrative and systematic reviews, conference abstracts, case series, and case reports, editorials and commentaries will be excluded.\n\n\nMethods\n\nThis systematic review protocol will follow the checklist of Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) (Supplementary file 2).29 This protocol will facilitate in conducting a systematic review and meta-analysis on modifiable and non-modifiable risk factors related to PCAD for the two review questions. Any deviations to the protocol while conducting this review will be reported in the method section of the final manuscript. The review protocol is registered in the International Prospective Register of Systematic Reviews (PROSPERO) CRD42020173216.\n\nThe search strategy aims to identify both published and non-published articles. An initial comprehensive search strategy which has been designed for PubMed in consultation with the librarian specialized in scientific medical literature at the University of Adelaide, Australia including the MeSH (medical subject headings), will be later translated across different databases for the title and abstract search (Appendix I). In addition, the reference list of all the included studies and systematic reviews that have been excluded will be cross-checked to identify any relevant studies that might be included for the review. Since this review is a non-funded PhD thesis project we lack resources for translation services, hence studies that are published in English language only and available as full-text will be considered for inclusion in this review. A search range based on publication year will not be set to allow more studies to be part of this review.\n\nThe following databases will be searched from inception: PubMed (MEDLINE), CINAHL (EBSCOhost), Embase (Elsevier), and Web of Science (Clarivate). The search for non-published (grey literature) and ongoing studies will include Google Scholar (https://scholar.google.com/), ClinicalTrials.gov (https://clinicaltrials.gov/), American Heart Association (https://www.heart.org/), American College of Cardiology (https://www.acc.org/), the World Health Organisation (https://www.who.int/), and the Centres for Disease Control and Prevention (https://www.cdc.gov/).\n\nAll identified citations will be collated and exported to a reference management software EndNote X9 (Clarivate Analytics, PA, USA) and initial duplicates will be removed at this stage. The studies will then be imported to online systematic review software, Covidence (https://www.covidence.org/). The second stage of duplicate removal will be performed on Covidence. Title and abstract screening will be undertaken independently by two reviewers (AK, MP) for assessment against the inclusion criteria of the review. The second stage will consider studies that meet the inclusion criteria and will be retrieved in full and articles will be uploaded on Covidence. The full-text of the selected studies will be assessed independently by two reviewers (EA, MW). Full-text articles that do not meet the eligibility criteria will be excluded and reasons for exclusion will be presented in the appendix section of the main systematic review. The results of the overall search and the studies included for meta-analysis will be presented as a PRISMA flow diagram (please refer to Figure 1).29 Disagreement at any stage that arises between reviewers will be resolved through discussion or in consensus with a third reviewer (RT or MA).\n\nAll studies selected for data extraction will be critically appraised for methodological quality independently by two reviewers (ZSL, PA) using a standardized critical appraisal tool for comparative observational studies designed by National Heart, Lung, and Blood Institute (NHLBI) (Appendix II).30 This quality assessment tool is designed to assist reviewers in focusing on concepts that are key for critical appraisal of the internal validity of a study and it is not designed to provide a list of factors comprising a numeric score. This tool is specific to individual types of included study designs. It includes items for evaluating potential flaws in study methods, including sources of bias (e.g., patient selection, performance, attrition, and detection), confounding, study power, the strength of causality in the association between exposures and outcomes, and other factors. When assessing quality, reviewers can select “yes,” “no,” or “cannot determine/not reported/not applicable” in response to each item on the tool. For each item where “no” is selected, reviewers are instructed to consider the potential risk of bias that can be introduced by that flaw in the study design. Cannot determine and not reported are also noted as representing potential flaws. Reviewers are instructed to rate this tool on the range of items included in each tool as mentioned above, to judge each study to be of “good”, “fair”, or “poor” quality. A “good” study has the least risk of bias, and results are considered to be valid. A “fair” study is susceptible to some bias deemed not sufficient to invalidate its results while a “poor” rating indicates a significant risk of bias.\n\nAuthors of the included studies will be contacted to obtain any missing information if needed. Disagreements that arise as a result of this appraisal will be resolved through discussion or in consensus with a third reviewer (RT or MA). The findings of this appraisal will be tabulated in a quantitative form and the studies will not be excluded based on the methodological quality. This assessment will in turn provide a thorough evaluation of the quality of evidence and the role of bias on the findings. For studies that are included more than once due to reporting of the data for at least one of the two review questions, the assessment of the methodological quality for each review question will be performed separately.\n\nData will be extracted from the included studies using a structured data extraction form designed by the authors. Data extraction will be performed independently by two reviewers (MZ, AA).\n\nThe data extracted will include authors, publication year, study design, country of publication, time of assessment for PCAD, inclusion criteria for determination of cases, which will be defined as patients having PCAD, while controls will be defined as patients experiencing late-onset CAD or healthy controls (having no disease or without the disease of interest) (Appendix III, IV). To account for confounding, data on age, gender, and geographical settings will be extracted. All data will be extracted in alignment with the review questions. If a given study, fulfils the criteria of being included in more than one comparison group, the data extracted from that study will be analysed for each relevant comparison group. In addition, evaluation of duplicate published studies will be undertaken, the reviewers will identify the primary publication from the given set of studies from the same project. The primary study will be the one that has; the maximum sample size, maximum centres/countries involved, and maximum relevant outcomes reported.\n\nAny disagreements that arise as a result of this appraisal will be resolved through discussion or in consensus with a third reviewer (RT, MA). Authors of the included studies will be contacted for any missing data if and when required.\n\nThe meta-analysis will be performed using RevMan software (Review Manager version 5.3) for each modifiable and non-modifiable risk factor. A random-effects model will be selected to account for heterogeneity in population across studies due to variation in genetic makeup including ethnic and racial differences. An overall pooled analysis of patients with PCAD compared to those without PCAD will be performed on crude estimates i.e. events, totals, mean and standard deviation from the included papers, stratified by age, gender, and geographical settings. For continuous variables, if the quantitative units vary across studies, Standard Mean Difference (SMD) and if the units are consistent then Mean Difference (MD) with respective 95% confidence intervals (Cls) will be reported. For dichotomous variables, odds ratio (OR) and 95% Cls will be reported.\n\nSubstantial heterogeneity between studies will be considered if the I2 statistic exceed 30-50% and by visually inspecting the forest plots. If high levels of heterogeneity between studies are identified, further exploration of the data will be conducted by sub-group analysis. Sub-group analysis will be performed on age, gender, and geographical settings (high compared to low-income countries) for patients with PCAD compared to those without PCAD. In addition, sensitivity analysis will also be performed on studies that score “good” or “fair” after excluding studies that score “poor” on the NHLBI quality assessment tool to evaluate the effect on outcomes. To assess publication bias, funnel plots with 10 or more studies will be plotted to visualise all the included studies for meta-analysis. At instances, where statistical pooling is not possible, the findings will be represented in a narrative form in the tables and figures as deemed appropriate to aid in data presentation.\n\nTo grade the certainty of evidence generated, this review will utilise the Grading of Recommendations Assessment, Development and Evaluation (GRADE)31 approach and a Summary of Findings (SoF) table will be created using GRADEpro GDT (McMaster University, ON, Canada). The SoF table will include the following information where appropriate: absolute effects for all exposures (modifiable and non-modifiable risk factors), an estimate of relative effect, number of participants with associated studies and a ranking of the quality of evidence-based on the risk of bias, directness, heterogeneity, precision, and risk of publication bias of the review results. The outcomes to be reported in the SoF table will include PCAD, late-onset CAD and healthy controls (Appendix V).\n\n\nDiscussion\n\nTo the best of our knowledge, this review will be the first to observe a comprehensive list of risk factors including modifiable and non-modifiable for PCAD across subpopulations. This review is anticipated to classify research gaps in the existing literature and provide evidence for further studies on risk factors for PCAD. Moreover, this review will also conduct sub-group analyses by comparing risk factors for PCAD between LMICs versus HICs (geographical settings).\n\nWe acknowledge the potential limitations as part of this systematic review. We will limit our search to articles published in English only, so might miss studies published in other languages. The other limitation is, that non-conventional risk factors such as; pollution and dust particles, dental hygiene and various infections associated with atherosclerotic plaque rupture, rheumatoid arthritis, and associated medications including non-steroidal anti-inflammatory drugs (NSAIDs), obstructive sleep apnoea, sleep hygiene, job strain and low social support will not be part of this review, since literature suggesting a stronger mechanistic association between the risk factors mentioned above and PCAD is lacking, as a result, it will be difficult to perform meta-analysis.\n\nThe findings of this review will support academics, researchers, healthcare professionals, relevant stakeholders and policy makers to focus on modifiable and non-modifiable risk factors for PCAD specific to age and gender and design appropriate preventive strategies as early as practical in order to significantly reduce the risk of PCAD and associated cardiovascular diseases later in life. The results of this systematic review will be publicly available and will be disseminated via academic presentations (both locally and internationally) and through peer-reviewed publications.\n\n\nData availability\n\nFigshare: Risk factors for premature coronary artery disease (PCAD) in adults: a systematic review protocol, https://doi.org/10.6084/m9.figshare.17078507.v2.32\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: Risk factors for premature coronary artery disease (PCAD) in adults: a systematic review protocol, https://doi.org/10.6084/m9.figshare.17078486.v2.33\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAuthors contribution\n\nAK, PHA, MAA, ZSL conceived and designed the study. AK drafted the manuscript, secured funding for this systematic review, and is the guarantor of the systematic review. AK, PHA, and ZSL developed the search strategy, research questions and study design. MZ, EA, MRW, MMP, AA, DDC, AK, PHA, ZSL designed the tables for data extraction, will perform data extraction, and also evaluate the quality of all included studies in the systematic review. PHA, ZSL, MZ contributed to the introduction section and supplementary files 1 and 2. AK, PHA, ZSL will contribute to data synthesis and meta-analysis. RT and MAA provided direction, mentorship and extensively revised the manuscript. All the authors reviewed and approved the final manuscript as submitted and agreed to be responsible for all aspects of the work.\n\n\nFunding\n\nThis systematic review protocol is part of a student based doctoral thesis project. Adeel Khoja is in his second year of doctorate, affiliated with Adelaide Medical School, The University of Adelaide and is currently on a fully-funded scholarship, “Adelaide Scholarship International” which covers all the cost associated with his thesis project and has no role in developing the review protocol.\n\n\nStudy status\n\nCurrently, we have completed the screening of title and abstract for this comprehensive systematic review and have retrieved papers for full-text screening. After that, we will start data extraction of all those included full-text studies.\n\n\nConflicts of interest\n\nThe authors declare no conflict of interest.",
"appendix": "Acknowledgments\n\nWe would like to express our sincere gratitude to Vikki Langton, the University Liaison Librarian at the University of Adelaide for her assistance and guidance on developing the search strategies.\n\n\nReferences\n\nBenjamin EJ, Muntner P, Alonso A, et al.: Heart disease and stroke Statistics-2019 update a report from the American Heart Association. Circulation. 2019; 139: e56–e528. Publisher Full Text\n\nCollaborators G: Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.2018.\n\nWilmot KA, O’Flaherty M, Capewell S, et al.: Coronary heart disease mortality declines in the United States from 1979 through 2011: evidence for stagnation in young adults, especially women. Circulation. 2015; 132(11): 997–1002. PubMed Abstract | Publisher Full Text\n\nMendis S, Puska P, Norrving B, et al.: Global atlas on cardiovascular disease prevention and control: World Health. Organization. 2011.\n\nMohammad AM, Jehangeer HI, Shaikhow SK: Prevalence and risk factors of premature coronary artery disease in patients undergoing coronary angiography in Kurdistan, Iraq. BMC Cardiovasc. Disord. 2015; 15(1): 155. PubMed Abstract | Publisher Full Text\n\nKhot UN, Khot MB, Bajzer CT, et al.: Prevalence of conventional risk factors in patients with coronary heart disease. JAMA. 2003; 290(7): 898–904. Publisher Full Text\n\nAchari V, Thakur A: Association of major modifiable risk factors among patients with coronary artery disease–a retrospective analysis. JAPI. 2004; 52: 103–108. PubMed Abstract\n\nPanwar RB, Gupta R, Gupta BK, et al.: Atherothrombotic risk factors & premature coronary heart disease in India: a case-control study. Indian J. Med. Res. 2011; 134(1): 26.\n\nChristiansen MK: Early-onset Coronary Artery Disease Clinical and Hereditary Aspects. Dan. Med. J. 2017; 64(9).\n\nReibis R, Treszl A, Wegscheider K, et al.: Disparity in risk factor pattern in premature versus late-onset coronary artery disease: a survey of 15,381 patients. Vasc. Health Risk Manag. 2012; 8: 473. Publisher Full Text\n\nPillay A, Naidoo D: Atherosclerotic disease is the predominant aetiology of acute coronary syndrome in young adults. Cardiovasc. J. Afr. 2018; 29(1): 36–42. PubMed Abstract | Publisher Full Text\n\nVikulova DN, Grubisic M, Zhao Y, et al.: Premature atherosclerotic cardiovascular disease: trends in incidence, risk factors, and sex-related differences, 2000 to 2016. J. Am. Heart Assoc. 2019; 8(14): e012178. PubMed Abstract | Publisher Full Text\n\nMalakar AK, Choudhury D, Halder B, et al.: A review on coronary artery disease, its risk factors, and therapeutics. J. Cell. Physiol. 2019; 234(10): 16812–16823. Publisher Full Text\n\nMannsverk J, Wilsgaard T, Mathiesen EB, et al.: Trends in modifiable risk factors are associated with declining incidence of hospitalized and nonhospitalized acute coronary heart disease in a population. Circulation. 2016; 133(1): 74–81. PubMed Abstract | Publisher Full Text\n\nPoorzand H, Tsarouhas K, Hozhabrossadati SA, et al.: Risk factors of premature coronary artery disease in Iran: A systematic review and meta-analysis. Eur. J. Clin. Investig. 2019; 49(7): e13124. PubMed Abstract | Publisher Full Text\n\nTabei SMB, Senemar S, Saffari B, et al.: Non-modifiable factors of coronary artery stenosis in late onset patients with coronary artery disease in Southern Iranian population. Journal of Cardiovascular and Thoracic Research. 2014; 6(1): 51–55. PubMed Abstract | Publisher Full Text\n\nLawton JS, editor. Sex and gender differences in coronary artery disease. Seminars in thoracic and cardiovascular surgery. Elsevier; 2011.\n\nKnopp RH: Risk factors for coronary artery disease in women. Am. J. Cardiol. 2002; 89(12): 28–34. Publisher Full Text\n\nChandra NC, Ziegelstein RC, Rogers WJ, et al.: Observations of the treatment of women in the United States with myocardial infarction: a report from the National Registry of Myocardial Infarction-I. Arch. Intern. Med. 1998; 158(9): 981–988. PubMed Abstract | Publisher Full Text\n\nWenger NK: You’ve come a long way, baby: cardiovascular health and disease in women: problems and prospects. Circulation. 2004; 109(5): 558–560. PubMed Abstract | Publisher Full Text\n\nDaly C: 13 Gender differences in the management and clinical outcome of stable angina. Circulation. 2006; 113: 490–498. Publisher Full Text\n\nYusuf S, Hawken S, Ôunpuu S, et al.: Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364(9438): 937–952. PubMed Abstract | Publisher Full Text\n\nMorovatdar N, Bondarsahebi Y, Khorrampazhouh N, et al.: Risk Factor Patterns for Premature Versus Late-Onset Coronary Artery Disease in Iran. A Systematic Review and Meta-Analysis. Open Cardiovasc. Med. J. 2019; 13(1): 5–12. Publisher Full Text\n\nDiniz MA, Tavares DS: Risk factors for cardiovascular diseases in aged individuals in a city in the state of Minas Gerais. Texto Contexto–Enferm. 2013; 22(4): 885–892. Publisher Full Text\n\nChesebro J, Fuster V, Elveback L, et al.: Strong family history and cigarette smoking as risk factors of coronary artery disease in young adults. Heart. 1982; 47(1): 78–83. Publisher Full Text | Free Full Text\n\nHatmi Z, Tahvildari S, Motlag AG, et al.: Prevalence of coronary artery disease risk factors in Iran: a population based survey. BMC Cardiovasc. Disord. 2007; 7(1): 32. PubMed Abstract | Publisher Full Text\n\nFreitas AI, Mendonça I, Brión M, et al.: RAS gene polymorphisms, classical risk factors and the advent of coronary artery disease in the Portuguese population. BMC Cardiovasc. Disord. 2008; 8(1): 15. PubMed Abstract | Publisher Full Text\n\nRao M, Xavier D, Devi P, et al.: Prevalence, treatments and outcomes of coronary artery disease in Indians: a systematic review. Indian Heart J. 2015; 67(4): 302–310. PubMed Abstract | Publisher Full Text\n\nMoher D, Shamseer L, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst. Rev. 2015; 4(1): 1. PubMed Abstract | Publisher Full Text\n\nStudy Quality Assessment Tools. National Heart, Lung, and Blood Institute; November 10 2020. Reference Source\n\nGuyatt GH, Oxman AD, Vist GE, et al.: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336(7650): 924–926. PubMed Abstract | Publisher Full Text\n\nKhoja A, Andraweera P, Lassi Z, et al.: Risk factors for premature coronary artery disease (PCAD) in adults: a systematic review protocol. figshare. Journal Contribution. 2021. Publisher Full Text\n\nKhoja A, Andraweera P, Lassi Z, et al.: Risk factors for premature coronary artery disease (PCAD) in adults: a systematic review protocol. figshare. Journal Contribution. 2021. Publisher Full Text"
}
|
[
{
"id": "101953",
"date": "13 Dec 2021",
"name": "Nida Zahid",
"expertise": [
"Reviewer Expertise NCDS",
"Mental health",
"Cancer",
"Male infertility"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: It is a study protocol of a systematic review to assess the risk factors for premature coronary artery disease (PCAD) in adults. Understanding modifiable and non-modifiable risk factors is critical for preventing morbidity and mortality from PCAD. All major risk factors, both modifiable and non-modifiable, have not been thoroughly investigated in previous systematic reviews among patients with PCAD. They either included specific risk factors for PCAD, targeted specific subgroups, or were limited to a single country. There has been no comprehensive appraisal of the evidence to date, despite the fact that there have been a number of published observational studies on PCAD risk factors, a comprehensive systematic review of the evidence is lacking. The findings of this systematic review will contribute to existing scientific knowledge and inform current clinical practice guidelines.\nComments: Data Synthesis: 1. The authors have mentioned that for dichotomous variables odds ratio will be reported, however odds ratio may not be applicable for cohort studies and cross sectional studies for which the appropriate measures of association are relative risk and prevalence ratio respectively. 2. The authors have mentioned in the title that it will be a systematic review, however in the methodology they have mentioned they will perform meta-analysis. Please make it consistent with the title.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "7574",
"date": "15 Dec 2021",
"name": "Adeel Khoja",
"role": "Author Response",
"response": "Thanks so much for reviewing our systematic review protocol and providing us with feedback/comments. As per the first comment by the reviewer: 1. The authors have mentioned that for dichotomous variables odds ratio will be reported, however odds ratio may not be applicable for cohort studies and cross sectional studies for which the appropriate measures of association are relative risk and prevalence ratio respectively. Response: Thanks for this comment. We totally agree with the reviewer's comment. We will go as per the manner in which the studies have reported raw (crude) data and based on the two objectives of this systematic review, we assume the majority of the studies to be case-control in nature and hence we will report odds ratio. However, if we have cohort and cross-sectional studies as part of our systematic review, we will report relative risk and prevalence ratio accordingly. 2. The authors have mentioned in the title that it will be a systematic review, however in the methodology they have mentioned they will perform meta-analysis. Please make it consistent with the title. Response: Thanks for this comment. Since this is a protocol and we have planned for meta-analysis but this is not definitive at this stage. We will perform meta-analysis after looking at the number of studies for the two objectives outlined in the protocol."
}
]
},
{
"id": "101954",
"date": "19 Jan 2022",
"name": "Sobiya Sawani",
"expertise": [
"Reviewer Expertise Communicable and non communicable diseases"
],
"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 seems a very interesting and comprehensive systematic review protocol targeting modifiable and non-modifiable risk factors for patients with premature coronary artery disease and comparing it to those without premature coronary artery disease. I strongly believe this is one of the rarest systematic review stratifying on age, gender and geographical settings (comparing high-income countries versus low-income countries). I would suggest the authors to make age categories as per the articles that form part of the meta-analysis (after data extraction), in order to explore risk factor profile in lieu to the defined age categories for premature coronary artery disease and this can be part of the sub-group analysis as you may not see more burden in the age bracket of 18-25 years; also the risk factors (modifiable and non-modifiable) may vary. In addition, this systematic review will be further strengthened by quality assessment and sensitivity analysis of studies that score good or fair on the quality assessment too, NHLBI after excluding studies that score poor. I also like the thought that four different databases will be included as part of this systematic review.\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": "7731",
"date": "21 Jan 2022",
"name": "Adeel Khoja",
"role": "Author Response",
"response": "Thanks for the comments in regard to our systematic review protocol. As suggested, we will stratify on age in order to explore risk factors (modifiable and non-modifiable) specific to age brackets for patients with premature coronary artery disease as part of our meta-analysis and sub-group analyses."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1228
|
https://f1000research.com/articles/10-1227/v1
|
02 Dec 21
|
{
"type": "Software Tool Article",
"title": "NaijaCovidAPI: an application programming interface for retrieval of COVID19 data from the Nigerian Center for Disease Control web platform",
"authors": [
"Emmanuel Baldwin Mbaya",
"Babatunde Alao",
"Philip Ewejobi",
"Innocent Nwokolo",
"Victoria Oguntosin",
"Emmanuel Adetiba",
"Emmanuel Baldwin Mbaya",
"Babatunde Alao",
"Philip Ewejobi",
"Innocent Nwokolo",
"Emmanuel Adetiba"
],
"abstract": "Background: In this work, a COVID19 Application Programming Interface (API) was built using the Representational State Transfer (REST) API architecture and it is designed to fetch data daily from the Nigerian Center for Disease Control (NCDC) website. Methods: The API is developed using ASP.NET Core Web API framework using C# programming language and Visual Studio 2019 as the Integrated Development Environment (IDE). The application has been deployed to Microsoft Azure as the cloud hosting platform and to successfully get new data from the NCDC website using Hangfire where a job has been scheduled to run every 12:30 pm (GMT + 1) and load the fetched data into our database. Various API Endpoints are defined to interact with the system and get data as needed, data can be fetched from a single state by name, all states on a particular day or over a range of days, etc. Results: The results from the data showed that Lagos and Abuja FCT in Nigeria were the hardest-hit states in terms of Total Confirmed cases while Lagos and Edo states had the highest death causalities with 465 and 186 as of August 2020. This analysis and many more can be easily made as a result of this API we have created that warehouses all COVID19 Data as presented by the NCDC since the first contracted case on February 29, 2020. This system was tested on the BlazeMeter platform, and it had an average of 11Hits/s with a response time of 2905milliseconds. Conclusions: The extension of NaijaCovidAPI over existing COVID19 APIs for Nigeria is the access and retrieval of previous data. Our contribution to the body of knowledge is the creation of a data hub for Nigeria's COVID-19 incidence from February 29, 2020, to date",
"keywords": [
"COVID19 API",
"NCDC",
"REST architecture",
"ASPNET Core Web"
],
"content": "Introduction\n\nThe Coronavirus disease 2019, known as COVID-19, was termed by the team of Taxonomy of Viruses as SARS-COV-2.1 The first case occurred in December 2019 in a place known as WUHAN at the Hubei province in China.2,3 Like a wildfire, it grew and reached 233 countries with millions of confirmed cases and deaths.4\n\nNigeria recorded its first case on February 28, 2020, when an Italian man working in Nigeria returned from Italy to Lagos. This was confirmed by the Lagos University Teaching Hospital.5 Since the incidence of the index case, the number of deaths, confirmed, active and discharged cases, has been on the increase in Nigeria and the rest of the world.6\n\nData has become increasingly important in research to produce discoveries with the introduction of computers, which brought with them computing, simulation, and modelling. Furthermore, because most of the research on COVID-19 are funded by national governments, the data and outcomes are publicly available.7–9\n\nThe World Health Organization (WHO) has designed a dashboard that gives real-time data about the global statistics of the COVID-19 outbreak. In addition, Coronatracker was developed to provide real-time news, statistics and to curb the spread of fake information about the disease.4,10 For instance, in Nigeria, the Presidential Task Force (PTF) on COVID-19 gave daily updates from the case's onset for about 8 months. The NCDC has developed a platform to provide information in respect of the daily incidences on its website and other social media platforms.6 These platforms were developed to provide real-time data for public health and research purposes. To analyze research datasets, Python has continued to increase its popularity amongst researchers in scientific domains where MATLAB and SPSS previously dominated. Most often, Python’s Panda’s library uses Comma Separated Values (CSV) file format to provide data for downloads from online platforms.11 Another alternative is to provide an Application Programming Interface (API) for users to have access to data from web portals.\n\nAPI has existed since the advent of the Internet for the exchange of data between two or more programs. It has gotten a high level of acceptance recently that “pundits” are saying we are in the API economy. This position might likely be because people are now more interconnected through different types of applications like never, and individuals are now demanding online services at a higher rate than ever. Notably, API has now made it possible for businesses to connect for enhanced capacity and profitability far beyond what has been known historically.12\n\nBig corporations such as Uber, Airbnb, PayPal, and a host of others depend on several APIs and developer services, with Uber paying Google the sum of $58 million for its map services. Nigeria is not left behind in this race as several start-ups have jumped into the API economy with companies such as Paystack, who developed APIs to fast-track payments using Cards (credit and debit) and direct bank transfers.13,14\n\nIn this paper, we report the development and deployment of a RESTful API to scrape COVID-19 data from the NCDC website and expose its response in JavaScript Object Notation (JSON) format. We built a web scraper that scrapes the daily updates from the NCDC website and archives them on a cloud database. Furthermore, we developed a Web API that allows users/developers to consume the data in JSON format.\n\nThe rest of this paper contains a literature review, the methods, the results, and the conclusions.\n\n\nLiterature review\n\nApplication Programming Interface (API) is the intermediary between software; it states how the interaction will be as well as the data formats.14 This section focuses on the previous works done by scholars concerning different application domains.\n\nA RESTful API developed using JavaScript; scrapes data from the NCDC website and exposes its response in JSON. The application gives real-time data as it appears on the NCDC website with details across each state; details such as deaths, confirmed cases, cases on admission, discharged and the total number for each segregated data at the national level.6,15\n\nBreast cancer is the second leading cause of mortality among women worldwide; nevertheless, a tiny proportion of men are also at risk. Early detection of this condition is critical since therapy can then be started, enhancing the chance of survival. The authors created an application that can assist health professionals in the prediction and complement the detection of breast cancer. This prediction will be accomplished by training a model using Google Prediction API. The API has integration with various programming languages such as Java, GO, JavaScript, Python, PHP and Ruby.16\n\nResearchers, physicians, and the general public, more than ever, face a massive challenge in keeping up with the rapid pace of findings and advancements of the influx of clinical trials. To address this issue, researchers combed the ClinicalTrials.gov database for COVID-19-related clinical trials, created unique reports to summarize results, and made meta-data accessible through APIs.17\n\nThe research was carried out on characterizing illicit COVID-19 product sales. This involved collecting COVID-19-related data from Twitter and Instagram posts using a combination of site scraping on Instagram and filtering the public streaming Twitter API for keywords correlated with suspect COVID-19 marketing and sales. Data were analyzed using Natural Language Processing (NLP) and deep learning to classify possible buyers, who were then manually annotated for desired characteristics. They had used a personalized data dashboard to visualize illegal trading posts to provide public health information.18 Also, a reusable dataset using publicly accessible and crowd-verified data on the COVID-19 outbreak in Kerala from government bulletins and media outlets as part of a citizen science initiative via a front-end Web application and a JSON repository, which acts as an API for the front end, this was visualized and produced as a dashboard.19\n\nThe traditional APIs were previously built using Simple Object Access Protocol (SOAP) web service, an XML (Extensible Markup Language) based protocol for accessing web service over HTTP. This comes with some disadvantages that have been addressed in a new trend of APIs. API is now being migrated towards REST interface because of its simplicity, ability to support more straightforward programmatic access by returning either XML or JSON.20 However, REST API is now becoming a new norm across various web services because of its improvement over performance, scalability and flexibility compared to SOAP services. Another advantage of REST that cannot be ignored over SOAP is that it consumes fewer resources, as well as its operation, do not include different standard and heterogeneous procedures that make it easier to tear domain and compose it when compared to SOAP.\n\nIt is understood that there is a significant difference in using SOAP web service and REST web devices. A web service was developed by TogoWS that explained these differences, an integrated web service that gives uniform access to database resources, parsers for database entries and converters for major data formats’.21 Web services can be categorized into data-retrieval services and analysis services. Both types of services can be exposed using either the REST or the SOAP architecture. In some cases, REST is better suited for data-retrieval services, and SOAP is more suitable for analysis services because REST is easily mapped to resource URIs. In contrast, SOAP usually requires a long execution time or complex parameters.22 Furthermore, SOAP architecture brings output in XML, while REST gives output in JSON in most cases.\n\nFrom our extensive review, REST architecture is mostly utilized in the literature and is was adopted for this study. In the existing COVID API, gaps identified include the previous day's data are unavailable and so one cannot go back in time to assess the curve of the virus, data is retrieved in bulk, and one cannot select a particular state to inspect data for that state only. The work at hand overcomes these gaps by adding features that will make available useful data to researchers.\n\n\nMethods\n\nTo realize the objective of this work, the following tools and frameworks were engaged to develop the web scraper, which fetches data from the NCDC website then the data is warehoused on MS SQL Server. Furthermore, a Web API that has endpoints for data to be consumed in JSON is developed.\n\n1. ASP.NET Core Web API framework: This is a framework used for building HyperText Transfer Protocol (HTTP) services that are accessible from various platforms/clients including but not limited to web browsers, mobile devices, desktop applications etc.\n\n2. Entity Framework (EF) Core: It is an Object and Relational Mapping (ORM) framework that supports code first and database first approach. It is an open-source, lightweight, extensible and cross-platform with support for several database engines. It is used to communicate with the database and EF Core makes it possible to carry out Create, Read, Update and Delete (CRUD) operations and much more without explicitly writing Structured Query Language (SQL) scripts.\n\n3. HTML Agility Pack: It is an agile HTML parser that we used for the web scrapping component of the system. It supports XPath (XML Path Language) and uses it to build a read/write Document Object Model (DOM).\n\n4. SQL Server Management Studio: This is an IDE for writing SQL queries and scripts; design, deploy and manage databases from MS SQL Server to Azure SQL Database.\n\n5. Postman: It is an open-source tool for API testing, monitoring and publishing.\n\n6. Swagger: this is an Interface Description Language (IDL) used for describing RESTful API. It helps to give a visual look at the various API endpoints and to execute the commands.\n\n7. Hangfire: An easy way to perform background processing in.NET and.NET Core applications without the need of Windows Service or a separate process required.\n\n8. Blazemeter: BlazeMeter is an online open source-based, enterprise-ready platform that unifies all the functionality needed in carrying out various tests such as functional testing, performance testing, API testing and much more.\n\nThe application block diagram is shown in Figure 1. The different procedures that were carried out to develop the application are hereafter described.\n\nTo web scrape a web page, one has to understand the Hypertext Mark-up Language (HTML) structure and then use the XPath of the element(s). The NCDC daily update has details for every state concerning their COVID cumulative data and the national summary of cases. Figure 2 is a screenshot of the NCDC website showing the data that can be gotten from the webpage.\n\nUpon study of the source code of the NCDC website, the HTML elements containing the confirmed cases, active cases, deaths, and discharges have an XPath of “//h2[@class = 'text-right text-white']” and that can be used to fetch all nodes that have such structure. First, the package was downloaded using NuGet Packages, then added to the project automatically by Visual Studio, and then imported into the class that will handle the scraping of data.\n\nAfter data was scrapped, a validation was done to ensure that the date of the data was yesterday's date (this is because the real-time data on the NCDC website is the previous day's data). If the data validation failed, the scraping was rescheduled for another two hours, but if the validation passed, the data was stored in the database.\n\nFigure 3 shows the Unified Modelling Language (UML) Class Diagram for this system. The HomeController is the class that handles all HTTP requests, and the various endpoints are represented in the form of methods. Annotation was used to state the HTTP method to respond and the GET method for all the endpoints.\n\nThe DatabaseContext class is the intermediary between the database and the system. The created tables are defined as properties with a returned type of DbSet. The DatabaseContext class inherits from the DbContext superclass and the superclass as a method of OnModelCreating, which is used to state the properties (such as Primary Key, Foreign Key, etc.) as defined in the tables.\n\nDataService class implements the IDataService interface. It is good programming practice to use interfaces to model multiple inheritances, a feature that some object-oriented languages support that allows a class to have more than one superclass. The DataService type makes use of Language Integrated Query (LINQ) statements to execute queries on the database.\n\nThe DataModel is the model of data fetched from the NCDC website and the data model to be saved in the database. The DataModel class has the properties that capture the data needed from the NCDC website. Other details such as Sampled Cases, Confirmed Cases, Active Cases, Discharged, and Deaths at a national level are captured by the ScrapeData() method.\n\nAfter data has been scrapped, a test was performed to ensure that the data fetched is the latest from the website. To achieve that, the date of the scraped data is compared with the previous day's data (since that data in the NCDC website is a reflection of data in the last day) to ensure that it is not already captured. If the information does not pass this test, it will not be processed further, and then the routine is scheduled after two hours because it means the website has not been updated.\n\nIf the data passes the test, the SaveData() method will be called to store the data in the database. Entity Framework was adopted to handle database transactions rather than writing Structured Query Language (SQL) scripts directly into the code.\n\nSince data will need to be fetched from the NCDC website daily, the scrapping process was automated. Hangfire was adopted to achieve this automation as it is an open-source library that supports background jobs, which perform fire-and-forget, delayed and recurring, long-running, short-running, CPU or I/O intensive tasks inside ASP.NET applications and No Windows Service or Task Scheduler is required.\n\nWe utilized the delayed and recurring jobs option. Under the recurring option, the job was scheduled to run by 12:30 pm (GMT +1). This decision was made because the NCDC website is not normally updated in the early hours of the day. The delayed jobs option happen in instances where after data has been fetched but failed the date test (i.e., the data fetched has not been updated), it will be rescheduled to run after two hours.\n\nThe Hangfire package (Hangfire.AspNetCore and Hangfire.SqlServer) has to be installed from the NuGet Packages before it can be used in a project. After installation, it was registered with the Startup class in the ConfigureServices to use SQL Database using the already created connection while in the Configure method. Afterwards, it registered the Hangfire Dashboard and Server, which are additional services to monitor the background service and status.\n\nThe scraper is scheduled to run at 12:30 pm (GMT + 1), it uses what is known as cron expression. Cron expression uses five (5) asterisks (*) and asterisk mean every minute of every hour of every day of every month and every day of the week as shown in Table 1. If for any reason it fails the date test, it is rescheduled to run in the next two (2) hours.\n\nAfter successfully scheduling a job(s), the Hangfire Dashboard gives a graphical overview and status of each job on whether it was successfully executed or not, the scheduled jobs, the recurring jobs and much more. Figure 4 shows the Hangfire Dashboard showing the recurring job.\n\nAPI endpoints are the channels through which other applications can communicate or consume an API. Table 2 lists the various endpoints that this API will provide. Endpoints are the point of entry, i.e., the Universal Resource Locator (URL). The state parameter is expecting a valid name of a state in Nigeria even states with more than one word such as Akwa Ibom are also acceptable. The date parameters take a date in the following format only DD-MM-YYYY.\n\n\nImplementation\n\nThe API can be access using any Web Browser or Software for consuming APIs such as Katalon Studio, Parasoft SOAtest, Eggplant, Postman etc. Figure 7 shows a Graphical User Interface powered by Swagger that makes the API usuable even by non – technical person while software such as Postman, Eggplant etc. need a level a technical understanding to know how to consume the API.\n\n\nOperation\n\nThe API was designed with on a system with the following properties\n\n• Processor: Intel(R) Core (TM) i5-4300U CPU @ 1.90 GHz 2.50 GHz\n\n• RAM: 12GB\n\n• OS: Windows 10 Pro x64\n\n• IDE: Visual Studio 2019\n\n• DBMS: Microsoft SQL Server Management Studio 18.9.2\n\nA minimum software requirement needed to run this should be able to run Visual Studio 2019.23\n\n\nResults & discussion\n\nThis section briefly presents the results of the various tests conducted on the NigeriaCovid19API. Since this system is designed to fetch COVID19 data as showcased on the NCDC website and give a JSON response to API calls, data here is only warehoused and no manipulations were done on it. The tests were carried out to ascertain the functionality of the various API endpoints and ensure that data has been fetched successfully. This section presents the test we carried out with Postman, Swagger and MS SQL Server on a localhost computer.\n\nAfter data has been fetched, it was warehoused on an MS SQL Server and to confirm that the data has been stored successfully, we ran a READ operation (i.e., a SELECT instruction to fetch data from the database) to ascertain that data was successfully fetched and stored as shown in Figure 5.\n\nPostman was developed to help with monitoring and testing APIs. We engaged it to inspect the API endpoints and their responses. Figure 6 shows the JSON response for the/api/data endpoint which gives the latest data in the database.\n\nSwagger is a User Interface (UI) that gives a graphical interface for interacting with a REST API. It allows a user to visually interact and test an API. It uses the XML tags and annotations to get the output alongside the additional features for testing the API. Figure 7 shows the general UI for Swagger and Figure 8 shows the JSON response for/api/data endpoint which gives the latest data in the database. Figure 9 shows the JSON response for api/data/s/lagos, which gives all the data for the Lagos state.\n\nBlazeMeter is an online open source-based, enterprise-ready platform that unifies all the functionality needed in carrying out various tests such as functional testing, performance testing, API testing and much more. API monitoring enables you to assess the impact of application performance enhancements. We may compare performance before and after the adjustments using historical response timing data.\n\nTo create a Test, logon to the BlazeMeter Website, Select Create Test, Select the Performance Test, Select the Enter URL and type in the URL request for the API, select the number of users to be used for testing, the duration (for the free package, you have to use the default location if you want to use a different location, you have to upgrade your account) and attach the necessary header variables were needed.\n\nThe API was tested on this platform and Figure 10 shows the summary, Figure 11 shows the response time and Figure 12 shows the hits. Throughput is the number of requests completed in a time interval and the system had an average of 11Hits/s with a response time of 2905 ms.\n\nThe volume of transactions created overtime during a test is referred to as throughput. It can also be described as the maximum capacity of a website or application. The number of concurrent users is the number of users who are actively using the app or website at any given moment, where we had 20 for the test. The number of hits per second generated by those concurrent users will be determined solely by their interactions with the app.\n\nIn Figure 11, Response Time is the time that passed to perform the request and receive a full response while the Latency is the time from sending the request, processing it on the server-side, to the time the client received the first byte. The time it takes for data or a request to travel from the source to the destination is known as network latency. Network latency is measured in milliseconds.\n\nIn Figure 12, the number of HTTP requests sent by the user(s) to the Web server in a second is referred to as hits per second. The overall load put by concurrent virtual users on the server, regardless of whether they are executed successfully or not on the server-side, is measured in hits per second.\n\nUpon successful deployment24 and testing of the API, data were extracted, and charts plotted to show the rate of infection, death and recovery rate and state with highest numbers as shown in Figures 13, 14 and 15 respectively. Figures 13 and 14 have two vertical lines, red and blue. The red line indicates the end of the first wave and commencement of the second wave while the blue signifies the end of the second wave and the start of the third wave.\n\nInitially as seen in Figure 13, the spread in Nigeria was slow with single digits after the first case was recorded, mainly at Lagos and Abuja but as the days goes by the number of active cases grew to reach a maximum of 12, 915 (as at August 2020) cases in Lagos state and the nationwide total confirmed cases kept raising to around 182,000 as at August 2021.\n\nThe first death in Nigeria as a result of COVID-19 was recorded on the 23rd of March 2020, the person had returned from medical treatment from the United Kingdom and with the rising number of cases, the Federal Government of Nigeria under the advice of the Presidential Task Force on the Control of COVID-19 placed a ban on all international flights in and out of the country except for emergency and essential flights. The death has continued to increase from Ogun state to other experiencing deaths of patients and hitting a peak of 465 deaths in Lagos state, however, many patients were able to recover and were discharged from the centres with a total of 166,826 persons across the nation as seen in Figure 14. The Line graph in the Figure looks like a straight line and that is because, in comparison with the Total Rate of Discharge, the total deaths seems small with a peak value of 2219 as of August 2021.\n\nLagos state is the hardest hit in terms of the number of confirmed cases with a total of 68220 cases, FCT Abuja reached 20158 cases, Kaduna 9195 cases, Plateau having 9205, Rivers having 8486 cases, Oyo with 7571 and Ogun having 5035 cases. Figure 15 shows the most affected states with a total confirmed case above 5,000 as of August 2021. The high level of cases in Abuja and Lagos can be attributed to the active community case search and testing. This public health response has led to the detection of more asymptomatic cases at the community level as stated by Ref. 2.\n\nNigeria shares land borders with the Republic of Benin in the west, Chad and Cameroon in the east, and Niger in the north. Figure 16 shows the confirmed cases in comparison with border countries and Nigeria having the highest number of confirmed cases and followed by Cameroun with cases above 75,000 cases as of August 2021 while Benin, Nigeria and Chad having cases below 25,000 cases.\n\nAs shown in Figure 17, in comparison with the top (5) hit countries on the continent of Africa, Nigeria is the tenth on the continent as of August 2021 in terms of the number of confirmed cases with 180,000 cases while South Africa was the most affected on the continent with over 2.5 million cases, followed by Morocco over 750,000 cases, then Tunisia coming forth with about 600,000 cases and Ethiopia coming fifth on the continent with around 300,000 cases.\n\n\nConclusion\n\nKnowing the importance of data to research, we have designed and developed an API that gives a JSON response to HTTP requests. It was built using the REST architecture and it is designed to fetch data from the NCDC website daily with the data being warehoused on MS SQL Server. Postman and Swagger were used to testing that Data endpoints to ensure the appropriate data is fetched as defined by the API endpoint, SQL Queries to select data were used to ensure that the database is properly populated with the right data and BlazeMeter was used to test the performance of the whole system and it achieved an 11Hits/s with a response time of 2905 ms. Its advantage over existing COVID19 APIs for Nigeria is the access to previous data which means that researchers and data enthusiasts can use the API to data as required by their various research needs with a simple URL rather than having to comb through the archives of the NCDC website to get the data they need. Simply put, this system makes Nigeria’s COVID19 data access to be easily accessible even by non -technical individuals with our user interface powered by swagger. The source codes and the dataset used in this paper are available as open-source on GitHub.25,26\n\n\nData availability\n\nSoftware available from: https://zenodo.org/record/572685126\n\nSource code available from: https://github.com/emmaraj/CovidApiNigeria25\n\nArchived source code as at time of publication: https://doi.org/10.5281/zenodo.572685126\n\nLicense: MIT License",
"appendix": "Acknowledgements\n\nThe authors acknowledge the financial support offered by Covenant University in the actualization of this research work for publication.\n\n\nReferences\n\nJohnpaul M, Madububa BI: The Trend of COVID-19 in Nigeria The Trend of COVID-19 in Nigeria.2020; vol. 16(4): pp. 43–51. Publisher Full Text\n\nAbdullahi IN, Emeribe AU, Ghamba PE, et al.: Public health, socioeconomic responses, and associated challenges against coronavirus disease 2019 pandemic in nigeria. Open Access Maced. J. Med. Sci. 2020; 8(T1): 122–125. Publisher Full Text\n\nDg M, Yt G: COVID-19 In Nigeria: Where are We?. Yenagoa Med. J. January, 2021; 3(1).\n\nWHO Coronavirus (COVID-19) Dashboard|WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. (accessed Apr. 24, 2021). Reference Source\n\nDr Osagie Ehanire: Nigeria Centre for Disease Control.2020. (accessed Apr. 13, 2021). Reference Source\n\nNCDC Coronavirus COVID-19 Microsite. (accessed Apr. 24, 2021). Reference Source\n\nData|Definition of Data by Merriam-Webster. (accessed Apr. 24, 2021). Reference Source\n\nResearch|Definition of Research by Merriam-Webster. (accessed Apr. 24, 2021). Reference Source\n\nTripathi M, Chand M, Sonkar SK, et al.: A brief assessment of researchers’ perceptions towards research data in India. IFLA J. 2017; 43(1): 22–39. Publisher Full Text\n\nAmira F, et al.: CoronaTracker: World-wide COVID-19 Outbreak Data Analysis and Prediction.March, 2020.\n\nMcKinney W, et al.: Pandas: A Foundational Python Library for Data Analysis and Statistics. Python High Perform. Sci. Comput. 2011; vol. 14(no. 9): pp. 1–9.\n\nOfoeda J, Boateng R, Effah J: Application programming interface (API) research: A review of the past to inform the future. Int. J. Enterp. Inf. Syst. 2019; 15(3): 76–95. Publisher Full Text\n\nLevine D: APIs are the next big SaaS wave|TechCrunch.Sep. 06, 2019. (accessed Apr. 26, 2021). Reference Source\n\nKene-Okafor T: Why API fintech startups are becoming a big deal in Nigeria – Techpoint Africa.Nov. 04, 2020. (accessed Apr. 26, 2021). Reference Source\n\ncovid-19-nigeria-api. (accessed Apr. 26, 2021). Reference Source\n\nCorr AR, Federal U, Sobral C: Application for predicting breast cancer through Google Prediction API. vol. 458(no. July): pp. 50–53. 2018.\n\nAlag S: Analysis of COVID-19 clinical trials: A data-driven, ontology-based, and natural language processing approach. PLoS One. 2020; 15(9): e0239694–e0239613. PubMed Abstract | Publisher Full Text\n\nMackey TK, et al.: Big data, natural language processing, and deep learning to detect and characterize illicit COVID-19 product sales: Infoveillance study on Twitter and Instagram. JMIR Public Heal. Surveill. Jul. 2020; 6(3). PubMed Abstract | Publisher Full Text\n\nUlahannan JP, et al.: A citizen science initiative for open data and visualization of COVID-19 outbreak in Kerala, India. J. Am. Med. Inform. Assoc. Dec. 2020; 27(12): 1913–1920. PubMed Abstract | Publisher Full Text\n\nPadmanaban R, Thirumaran M, Anitha P, et al.: Computability evaluation of RESTful API using Primitive Recursive Function. J. King Saud Univ. - Comput. Inf. Sci. 2018. Publisher Full Text\n\nKatayama T, Nakao M, Takagi T: TogoWS: integrated SOAP and REST APIs for interoperable bioinformatics web services. Nucleic Acids Res. Jul. 2010; 38: W706–W711. PubMed Abstract | Publisher Full Text\n\nFielding R: Architectural Styles and the Design of Network-based Software Architectures.2000.\n\nMicrosoft: Visual Studio 2019 System Requirements|Microsoft Docs. (accessed Nov. 26, 2021). Reference Source\n\nNaijaCovidAPI.Aug. 30, 2021. (accessed Aug. 30, 2021). Reference Source\n\nMbaya E: CovidApiNigeria. Github. Sep. 06, 2021. (accessed Sep. 06, 2021). Reference Source\n\nBaldwin ME: emmaraj/CovidApiNigeria: NaijaCovidAPI (v1.0.0). Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "209133",
"date": "13 Oct 2023",
"name": "Xiaojin Li",
"expertise": [
"Reviewer Expertise Ontology-driven Clinical Data Management including data capture",
"integration",
"cross-cohort faceted query",
"data visualization",
"and temporal query."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study presents the development of a COVID-19 API in Nigeria, built with REST architecture, ASP.NET Core Web API, and deployed on Microsoft Azure, enabling data retrieval from the NCDC website, with key findings highlighting the impact of COVID-19 in Lagos and Abuja, and its contribution as a comprehensive data hub for COVID-19 incidence in Nigeria from February 29, 2020, to the present. The following comments are intended to improve the quality of the paper.\nThis study lacks substantial innovation, as the author primarily demonstrates the creation of the COVID-19 dataset API using existing tools and tests it with commonly utilized API testing tools.\n\nThe API's functionality is somewhat limited, focusing primarily on supporting date and regional queries. The potential for more complex queries, though challenging, could significantly enhance its utility and contribution.\n\nThere is an absence of discussion regarding the scalability of the application. While the dataset of 200,000 people is relatively small in the context of COVID-19 studies, it would be interesting to explore the performance of the application with a dataset of several million people and its adaptability for use with other epidemiological electronic health record (EHR) data.\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? No\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "226449",
"date": "25 May 2024",
"name": "Micheal Olaolu Arowolo",
"expertise": [
"Reviewer Expertise Bioinformatics",
"Machine learning",
"Data science",
"Computer science"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReview of literature should discuss limitations of existing studies more review of literatures should be studied \"Reference 1 \" Discuss figures, tables, algorithms used extensively Discus dataset extensively In results and discussion, discuss work done, results obtained and compare with existing works in literature Conclusion should discuss work done, results obtained, significance, limitations, and future plans\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": "280858",
"date": "20 Jun 2024",
"name": "Alejandro Zunino",
"expertise": [
"Reviewer Expertise software engineering"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe paper describes the design, implementation and empirical evaluation of a REST API for accessing Nigeria’s COVID19 data. The idea is valuable, since it enables researchers to consume data through the API for any purpose. The paper has two issues that needs to be addressed. First, its focus it not clear. It first describes the importance of APIs, REST and related technologies. This is aligned with the paper goals. However, the paper then focuses on discussing COVID data (Figures 12-17), which is out of the scope of an API and the paper. Second, assuming the core of the paper is the API and its design, from the description shown in Figure 3, it is clear that its design does not follow good practices such as hexagonal or clean architecture. Note that the data model is tied to the persistence and the API in HomeController. As a consequence, a minor change such as exposing the API using a different technology would require heavy refactoring of the code. The paper should be improved by focusing on the API and improving its design/implementation following good practices.\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? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1227
|
https://f1000research.com/articles/10-1040/v1
|
12 Oct 21
|
{
"type": "Systematic Review",
"title": "Knowledge creation in IT projects to accelerate digital innovation: two decade systematic literature review",
"authors": [
"Tung Soon Seng",
"Magiswary Dorasamy",
"Ruzanna Razak",
"Maniam Kaliannan",
"Murali Sambasivan",
"Ruzanna Razak",
"Maniam Kaliannan",
"Murali Sambasivan"
],
"abstract": "The interactivity and ubiquity of digital technologies are exerting a significant impact on the knowledge creation in information technology (KC-IT) projects. According to the literature, the critical relevance of KC-IT is highly associated with digital innovation (DI) for organisational success. However, DI is not yet a fully-fledged research subject but is an evolving corpus of theory and practise that draws from a variety of social science fields. Given the preceding setting, this study explores the interaction of KC-IT with DI. This work provides a systemic literature review (SLR) to examine the literature in KC-IT and its connection to DI. A SLR of 527 papers from 2001 to 2021 was performed across six online databases. The review encompasses quantitative and qualitative studies on KC-IT factors, processes and methods. Three major gaps were found in the SLR. Firstly, only 57 (0.23%) papers were found to examine the association between KC and IT projects. These works were analysed for theories, type of papers, KC-IT factors, processes and methods. Secondly, the convergence reviews indicate that scarce research has examined TMS and trust in KC-IT as factors. Thirdly, only 0.02% (5) core papers appeared in the search relevant to KC in IT projects to accelerate DI. The majority of the papers examined were not linked to DI. A significant gap also exists in these areas. These findings warrant the attention of the research community.",
"keywords": [
"Knowledge Creation",
"Digital Innovation",
"Digital Economy",
"Systematic Literature Review",
"IT Projects",
"Information Technology",
"Transactive Memory System",
"Trust"
],
"content": "Introduction\n\nKnowledge is an important asset for promoting organisational change in the 21st century.1 Knowledge comprises a complicated blend of individual experiences, beliefs, relevant information and personal perspective.2 Moreover, knowledge is a driver of worldwide competitiveness in Industry 4.0 (I4.0). Knowledge helps businesses integrate machinery and processes, as complemented by cutting-edge technology.3\n\nKnowledge creation (KC) is an on-going process to acquire new context, views and knowledge and thus transcends the limits of the old to a new self.4 In this study, the theory of organisational knowledge creation (TOKC) from Nonaka and Takeuchi was adopted as the primary theoretical base given its prevalence as the most significant theoretical model in KC studies.5,6 TOKC explained the organisational KC process through the four modes of conversion including Socialisation, Externalisation, Combination and Internalisation (SECI) of the concepts and embodying knowledge to create product value.4 The Current KC paradigm has shifted to encompass wider areas such as energy, education and high technology.7 A New KC model integrates the SECI process with grey knowledge (half tacit and half explicit knowledge) in high technology projects. The model promotes time as a new dimension in cross-cultural IT industries.8\n\nIT interactivity and pervasiveness are shifting the conversation around the value of KC and digital innovation (DI) for organisational performance.9 DI refers to the application of emerging technologies in a broad variety of innovation.10 Organisations in the digital economy require digital technology to support business innovation. IT workers today need new skills because they perform in dynamic environments that frequently require new abilities. In this context, DI is essential as technology evolves.\n\nFrom the individual perspective, people may benefit from a transactive memory system (TMS) as it enables KC to generate expert knowledge within a community or organisation.11 Past KC literature stressed trust as an important feature for the externalisation of tacit knowledge.4 However, hardly any empirical evidence on TMS and trust on KC was provided. Given the above context, this work seeks to answer the call from Pagona et al.12 and Holmström13 to dive further into the intricacies of DI. We aim to highlight the research gaps in KC in IT project research and it is an important component for DI. A total of 57 papers were found relevant to this study.\n\nThis study’s research questions are as follows:\n\n1. Is there a research gap in KC-IT in connection to DI?\n\n2. Is there a research gap in TMS and trust affecting KC-IT?\n\n3. What is the current view of KC-IT literature in terms of the KC process, method and factor?\n\n4. What are the underlying theories used by the literature?\n\nThe research objectives of this work are as follows:\n\n1. To identify research gaps in KC-IT linking to DI.\n\n2. To evaluate TMS and trust as a possible element for KC-IT\n\n3. To understand the current view of the KC-IT literature in terms of the KC process, method and factor.\n\n4. To identify the underlying theories used by the literature.\n\n\nReview method\n\nThis work offers a systematic literature overview to identify research gaps and limitations in KC-IT on DI. Key aspects in the KC-IT toward attaining DI were investigated using TOKC as a theoretical basis. The systematic literature review was conducted according to the five stages proposed by Tranfield et al.14:\n\na. Planning the review;\n\nb. Identifying and evaluating studies;\n\nc. Extracting and synthesising data;\n\nd. Reporting descriptive findings; and\n\ne. Utilising the findings to inform research and practice.\n\nInstitutional Review Board Statement: Research Ethical Committee (REC) of Multimedia University (EA1382021). The study was conducted according to the guidelines and approved by the Research Ethical Committee (REC) of MULTIMEDIA UNIVERSITY.\n\nThis paper provides a comprehensive overview of existing work with emphasis on established and emerging critical factors. TMS and trust as KC factors in IT were investigated. Figure 1 shows this study’s scope.\n\nThe strategy for the selection of databases and methods are based on Moher et al.15 Methods include searching keywords around terms for KC (the concept) and IT projects (the context) in online databases, including AISeL, IEEE, Emerald, SSCI, Scopus and ProQuest.\n\nThe study’s keywords cover context and content. The search found 24,293 KC papers, but only 527 had keywords for IT projects (Table 1). Per the criteria, only 57 papers actually addressed KC in IT projects. These papers were classified using Mitchell and Boyle’s16 three major KC dimensions. The KC process refers to the investigations of the measurements or practices performed within KC. The KC factors refers to variables that contribute causally to KC, and the KC method focuses on employing tools or solutions to improve KC.\n\nInclusion and exclusion criteria\n\nThe inclusion and exclusion criteria for the paper search are presented in Figure 2.\n\nKeywords\n\nWe focused on two main research areas: (1) KC, (2) IT projects, and (3) DI. For the first area, we included terms such as ‘knowledge creation’ and ‘KC’ (abbreviations). The next key terms used were ‘project’, ‘IT project’, ‘IT projects’ and ‘digital innovation’. Each of these keywords was searched with the keyword ‘Knowledge creation’ individually. The search was subsequently extended by adding more keywords. Table 2 presents the keyword sets used for this research.\n\nSearch strategy\n\nWe sifted through papers that discussed KC in IT projects for DI. Our strategy was to identify papers through major online databases. We searched six online databases that encompass a vast range of KC as well as IT project-related research and are popular databases for social science study.\n\n1. Association of Information Systems Electronic Library (AISeL)\n\n2. Emerald\n\n3. ProQuest\n\n4. Scopus\n\n5. IEEE\n\n6. Science Direct\n\nA detailed of search strategy is presented in Figure 3.\n\nWe extracted papers from the aforementioned sources on the basis of the following extraction process (Figure 4).\n\nFigure 4 recaps our basis for selecting papers to review. The extraction process was adopted from Moher et al.15 As indicated regarding the main databases and other options that were utilised, only KC papers linked to IT projects and/or DI were selected for further review. The following subsection presents a report of the papers that were relevant according to our selection criteria.\n\nStages 3, 4 and 5 of Tranfield et al.14 will be presented in the form of findings and the discussion.\n\n\nResult\n\nTable 3 presents the outcomes from the inclusion conditions and the extraction process mentioned above. A total of 527 papers were identified, 8 papers were removed due to duplicate records and 519 papers were screened. Out of 519 papers, 462 were excluded as irrelevant to the study context. Finally, 57 papers were chosen for analysis. In this part, we further categorised the papers to indicate their respective types.\n\nFigure 5 provides a bar chart to highlight the research gap according to the keyword search of KC, KC + Project, KC + IT Project and DI. The KC papers amounted to 24,293. The fractions of the total KC papers can be seen as 55.9% (13,573) on KC in projects, 2.15% (57) on KC in IT projects and 0.02% (5) papers were related to KC in IT project for DI.\n\nThe KC + IT Project papers are divided into three sub categories: KC Process, KC Method and KC Factor. The number of units is indicated in the parentheses, and a pie chart is presented in Figure 6 to reflect the percentages. Figure 4 reveals that 41.8% of the research papers are sub categorised under the KC Factor and 36.4% under the KC Method. Meanwhile, 21.8% papers were related to the KC Process.\n\nThe papers are divided into two main categories of conceptual and empirical papers. A total of 23 conceptual papers (40.4%) and 34 empirical papers (59.6%) were identified. Conceptual papers lack actual test findings. On the contrary, empirical papers consist of evidence-based research and inputs for testing and findings. Figure 7 presents the percentages of papers by categories.\n\nA total of 50 countries were involved in empirical research (Table 3). Iran has the highest count of empirical research (4 papers), followed by Australia, Brazil, China, South Africa and United States with 3 papers each.\n\nThe complete summary of all the 57 papers is shown in Tables 5, 6 and 8 and according to 3 categories: the KC Method (20 papers), KC Factor (23 papers) and KC Process (12 papers).\n\n\nDiscussion\n\nOnly two papers, those by Ordieres-Meré et al.17 and Van den Berg,18 were pertinent to KC in IT projects for DI. The findings reveal that 0.9% papers are related to KC in IT projects for DI (Table 5), but no empirical evidence is presented. The first paper was written by Ordieres-Meré et al. and stated that Industry 4.0 is considered to have a strong association with economic, environmental and social.17 The second paper was written by Van den Berg who developed a paradigm for DI skills encompassing ‘meta-knowledge’ which is the information necessary to drive soft skills.18 The rest of the papers include the work of Park et al. who presented novel concepts for organising work.19 Kyakulumbye et al. found that relevance and usability are crucial for evaluating systems.20 Shimamoto analysed the strategy for Japanese chemical industry R&D from 1980 to 2010.21 These three papers are not related to KC in IT project for DI. Furthermore, research on KC in IT project for DI is lacking.\n\nTMS and trust were found to be important factors to KC-IT. However, our literature review only shows two journals that identify TMS as positively related to KC22,23 (refer to the plotting in Table 4). Four journals examine the trust relationship with KC but did not associate their frameworks with DI. This situation is a new research gap for us.24,25,26,27 We proposed that this research gap should be filled according to the theoretical framework (Figure 7).\n\nTable 4 shows the details of the search results by keywords and units of analysis.\n\nTable 5 shows the details of 20 KC method papers by the theory used, respondent group and key findings.\n\nTable 6 shows the details of 23 KC factor papers by the theory used, respondent group and key findings.\n\nTable 7 shows the details of KC Factors by independent variables, dependent variables and whether the papers mentioned TMS and Trust.\n\nTable 8 shows the details of 12 KC process papers by the theory used, respondent group and key findings.\n\nThe proposed theoretical framework suggests that TMS and trust are important factors for influencing the KC. The KC will enable DI to create new products and services.\n\nKC-IT literature can be classified into three categories (see Tables 9 and 10) of the KC process, method and factor. The papers are presented in the following table by three categories as suggested by Mitchell and Boyle.16 The benefit of viewing KC-IT literature in three categories include a better understanding of the current landscape of KC-IT.\n\nKC Factor: This dimension included 23 papers. We further classified the papers into three sub-dimensions of KC factors as suggested by Thani and Mirkamali28 (Table 11). Table 12 presents the summary of the 5 papers obtained when we have searched for the keyword combination of KC IT Project for DI. However, only 2 papers were found to have some relation to KC-TI-DI\n\n• Goodwill, commitment, ethic of contribution, high care, atmosphere, wise leadership, love and friendship.24\n\n• Intention, autonomy, redundancy, variety.52\n\n• Basic skills of knowledge creation, motivation, time management, professional ethic, learning, teaching responsibility.28\n\n• Shared goal and hope.60\n\n• Creativity.62\n\n• TMS22,23 and Trust.24-27\n\n• Knowledge network, graduate education, organization effectiveness.47\n\n• Organizational culture and social capital.49\n\n• Leadership, teamwork, corporate culture, and human resource management.50\n\n• Organizational communication, feedback promotion, policy formulation, information sharing.53\n\n• Organizational identity, mobility direction, human capital.51\n\n• Enabling structure, knowledge-creating culture, collaborative management, sabbatical, workforce development, interdisciplinary studies.28\n\n• Team safety and team learning.57\n\n• Talent management processes.58\n\n• Organic structure and organizational culture59 and Information culture.61\n\n• Library, laboratory, infrastructure28 and Social media.56\n\nA total of 25 different theories were employed in the 57 papers analysed. 34 papers have used the TOKC by Nonaka and Takeuchi as the kernel theory.4 The theories are listed in Table 13.\n\nHowever, hardly any research mentioned TOKC in KC-IT-DI papers. Therefore, this scarcity is a research gap.\n\nLimited research is available in KC in IT projects for DI. Therefore, the KC-IT-DI literature is in its infancy and may warrant additional research. DI is important to the nation.29 KC-IT offers additional benefits, including improving existing processes, introducing new business models and setting up new service channels.8 To modernise products and services, KC-IT should be closely associated with DI.30\n\nAnother limitation is the choice of keywords, which is determined by the study's emphasis. As a result, it is possible publishing bias. If the keywords are widened to cover non-specific fields of study, more articles may be acquired.\n\nFuture research should be carried out in the following areas:\n\n1. More research focusing on KC-IT-DI will help researchers understand the significance of KC-IT in DI. Researchers may gain a better grasp of the issues afflicting the KC community.\n\n2. TMS foster individuals to distribute and exchange tacit knowledge for their own advantage, as indicated by Dunaway and Sabherwal22 and Çetin.23 Therefore, exploring how TOKC plays its roles in TMS is recommended.\n\n3. Examining new variables or dimensions in the KC-IT-DI relationship is a means of extrapolating novel aspects to boost KC and innovation in the IT industry in the context of volatility, uncertainty, complexity, and ambiguity.\n\n\nConclusion\n\nThree main points are addressed in this study. Firstly, the SLR found gaps in KC-IT linkage to DI. Secondly, TMS and trust are essential to KC. Finally, KC-IT-DI research limitations were addressed. This work advances the understanding of IT project management by studying the underlying factors to comprehend KC’s role in IT projects. This article mentions previous contributions other than the current concerns. This research focused on KC for interdisciplinary study. The implications herein provide relevant research and education references for researchers and the public. This work will also help scholars by offering directions. The shortcoming of the current study highlights the challenges in KC-IT-DI research. Furthermore, this article revealed a gap in KC in relation to IT projects, and the community is asked to research further to fill this gap.\n\n\nData availability\n\nDOI: https://doi.org/10.6084/m9.figshare.14870655.v1\n\nThis project contains the following data:\n\nThis dataset is analysed for theories, type of papers, Knowledge Creation and Information Technology (KC-IT) factors, process, and method.75\n\nFigshare. PRISMA checklist 2020\n\nDOI: https://doi.org/10.6084/m9.figshare.16692208.v1.76\n\nFigshare. PRISMA checklist\n\nDOI: https://doi.org/10.6084/m9.figshare.16657309.v1.77\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
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}
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[
{
"id": "97965",
"date": "01 Nov 2021",
"name": "Ab Razak Che Hussin",
"expertise": [
"Reviewer Expertise IT adoption and digital business improvement."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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:\nIt may be necessary to explain a little more why KC is important in IT projects. After that, the relationship between IT and DI projects also needs to be properly explained for better understanding.\n\nThere are differences between IT and IT projects and therefore please be sure to use them consistently in questions, objectives, and throughout the paper.\nReview Method:\nThe 6 databases covered in the SLR are good.\n\nKeywords, steps and extraction process are well executed.\nResult:\nFurther explanation is needed for each of Figures 5, 6, and 7 in terms of how they can be interpreted to the objectives of this study.\n\nFigure 8 may not be relevant here because it suddenly appears and there is no explanation about it. It may be moved at the end of the paper, or it may not be relevant in the SLR paper.\nDiscussion:\nThe descriptions in the discussion should follow the sequence of SLR questions so that they are easy to understand.\n\nThe key findings in each table can be taken from the table and explained in the paragraph after each table. This will improve the readability of the paper.\nTheory for KC-IT-DI:\nIt may be necessary to clarify KC-IT-DI requirements that do not exist in current SLRs.\n\nFigure 8 seems relevant to be placed here with further explanation of it.\nLimitations in current research and recommendations for future investigation:\nThe section title is not about limitations in current research. It should be a limitation of the previous study because the current study refers to the research conducted by the authors of this paper.\nConclusion:\nGood.\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": "7436",
"date": "19 Nov 2021",
"name": "Soon Seng Tung",
"role": "Author Response",
"response": "Dear Dr Razak We thank you for all the valuable comments. We trust that the revised paper has addressed all the concerns. Thank you. Below are the author response to comments: Introduction It may be necessary to explain a little more why KC is important in IT projects. After that, the relationship between IT and DI projects also needs to be properly explained for better understanding. There are differences between IT and IT projects and therefore please be sure to use them consistently in questions, objectives, and throughout the paper. Author Response to Comments - Paragraphs in introduction is now improved. - Relationship between IT and DI projects has been explained. - Word ‘IT’ has been updated to ‘IT project’ accordingly. Review Method The 6 databases covered in the SLR are good. Keywords, steps and extraction process are well executed. Author Response to Comments - Thank you for these comments. Result Further explanation is needed for each of Figures 5, 6, and 7 in terms of how they can be interpreted to the objectives of this study. Figure 8 may not be relevant here because it suddenly appears and there is no explanation about it. It may be moved at the end of the paper, or it may not be relevant in the SLR paper. Author Response to Comments -Further explanation for Figures 5 and 7 is now added to indicate KC-IT research gaps. - Further explanation for Figure 6 depicted the objective of the study to understand the current view of the KC-IT literature in terms of sub categories. - Figure 8 placement was recommended by the editorial board hence no relocation was made. Discussion The descriptions in the discussion should follow the sequence of SLR questions so that they are easy to understand. The key findings in each table can be taken from the table and explained in the paragraph after each table. This will improve the readability of the paper. Author Response to Comments - Thank you for this comments. The descriptions in the discussion follows the sequence of SLR questions. - For example, it begins with answering the research gap in KC-IT in connection to DI. Next, the description highlighted TMS and trust affecting KC-IT. Third, it explains current view of KC-IT literature in terms of the KC process, method and factor. Lastly, discusses the underlying theories used by the literature. - Key findings in Table 4 and 5 are now improved. Theory of KC-IT DI It may be necessary to clarify KC-IT-DI requirements that do not exist in current SLRs. Figure 8 seems relevant to be placed here with further explanation of it. Author Response to Comments - The requirement for KC-IT-DI is the linkages between them. We have highlighted this in findings. - Explanation on Figure 8 is now provided. Limitations The section title is not about limitations in current research. It should be a limitation of the previous study because the current study refers to the research conducted by the authors of this paper. Author Response to Comments - Limitation of past studies are added. Conclusion Good. Author Response to Comments - Thank you for this comment."
}
]
},
{
"id": "96845",
"date": "02 Nov 2021",
"name": "Mohammad Jabbari",
"expertise": [
"Reviewer Expertise Information Systems",
"Systems Analysis and Design",
"Conceptual Modeling",
"Digital Innovation"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 aims to investigate knowledge creation in information technology projects for digital innovation through a systematic literature review. The study identified three main research gaps and proposed a framework to fill the gap. While I think the study is a relevant study and can provide potential contributions, I see major issues in the study that needs to be addressed.\nFirst: a good SLR \"should strive to identify thematic gaps and theoretical biases, propose some future research directions, including alternative theoretical underpinnings, and not just stop at the summarizing/synthesizing stage.\" (Rowe, 2014, pg. 2501). This study claims that they have proposed a theoretical framework (Figure 7) that could potentially suggest future research directions. However, it is not clear how the framework was developed based on the findings of the SLR. I suggest that the authors include a section and discuss their framework development based on the results.\n\nSecond: The studly lacks a strong background. For example, the background should clearly specify what the authors mean by KC-IT:\nDo they mean KC during the IT development lifecycle? How does it differ from documentation, such as technical or user documentation? How can KC happen in IT projects? Do the authors mean DI for future IT projects, or do they mean DI in general which may include DI for business innovation, DI for product innovation, etc?\nIn summary, the scope of the work should be clearly explained and justified.\n\nThird: the results in Table 4 clearly show that the search results for KC, IT and DI is 5 papers. Then the authors conclude that only 5 papers \"are relevant to KC in IT projects to accelerate DI\". Are these the same 5 papers identified through the search process or did you do some other analysis? A brief descriptive summary of search results may not provide enough contribution. You may need to explain your tables and figures in a more theoretical way.\n\nFourth: this study only analyzed 57 papers. The way results are reported is confusing. The results should explain how the results are derived from 57 papers, not the 527 papers! The percentage reported in the abstract and in the text should be out of 57 studies.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Partly\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Partly\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? No",
"responses": [
{
"c_id": "7513",
"date": "02 Dec 2021",
"name": "Soon Seng Tung",
"role": "Author Response",
"response": "We thank you for all the valuable comments. We have addressed the comments as below: Introduction The study lacks a strong background. For example, the background should clearly specify what the authors mean by KC-IT: Do they mean KC during the IT development lifecycle? How does it differ from documentation, such as technical or user documentation? How can KC happen in IT projects? Do the authors mean DI for future IT projects, or do they mean DI in general which may include DI for business innovation, DI for product innovation, etc? Response to Comments: Thank you for these comments. We have included the following sentences in the text now. KC-IT is referring to transfer of expertise and knowledge generated at different time in IT project. It is beyond the IT development lifecycle (Xiang et al., 2021). KC-IT does not limited to create documentations but it involves social media that overcomes the limitations in the traditional KC activities (Wagner et al., 2014, Panahi et al., 2016). For example, project team members create their project knowledge and expertise via social media platform. DI is essential for general business process and market offerings as technology evolves (Nasiri et al., 2020) Result In summary, the scope of the work should be clearly explained and justified. Fourth: this study only analyzed 57 papers. The way results are reported is confusing. The results should explain how the results are derived from 57 papers, not the 527 papers! The percentage reported in the abstract and in the text should be out of 57 studies. Response to Comments: Thank you for the comments. We have now rephrased it as follows: A total of 527 papers were identified by referring to the keyword search for KC-IT. 57 papers were found for the keyword search KC-IT-DI which belongs to subset of KC-IT. Discussion Third: the results in Table 4 clearly show that the search results for KC, IT and DI is 5 papers. Then the authors conclude that only 5 papers \"are relevant to KC in IT projects to accelerate DI\". Are these the same 5 papers identified through the search process or did you do some other analysis? A brief descriptive summary of search results may not provide enough contribution. You may need to explain your tables and figures in a more theoretical way. This study claims that they have proposed a theoretical framework (Figure 7) that could potentially suggest future research directions. However, it is not clear how the framework was developed based on the findings of the SLR. I suggest that the authors include a section and discuss their framework development based on the results. Response to Comments: Thank you for the valuable comment. We have explained the result under the discussion section to relate to the theory. We have now inserted new headings and described the proposed framework which was developed based on the findings in Table 7. Past literature showed that transactive memory system (TMS) (Çetin, 2019) and Trust (Sankowska, 2013, Tootell, 2020, Wang et al., 2020) are positively related to KC. Hence, we include TMS into the framework. Recommendation for future investigations A good SLR \"should strive to identify thematic gaps and theoretical biases, propose some future research directions, including alternative theoretical underpinnings, and not just stop at the summarizing/ synthesizing stage.\" (Rowe, 2014, pg. 2501). Response to Comments: Thank you for these comments. We have added this line in the future investigation: ‘Present review suggested alternative theoretical underpinning such as investigate moderating effects relates to KC-IT-DI and factors that have underpinned existing research. (Paul et al., 2021)’ References: Xiang, Z., Fesenmaier, D. R., & Werthner, H. (2021). Knowledge creation in information technology and tourism: A critical reflection and an outlook for the future. Journal of Travel Research, 60(6), 1371-1376. Wagner, H., Finkenzeller, T., Würth, S., & Von Duvillard, S. P. (2014). Individual and team performance in team-handball: A review. Journal of sports science & medicine, 13(4), 808. Panahi, S., Watson, J., & Partridge, H. (2016). Conceptualising social media support for tacit knowledge sharing: physicians’ perspectives and experiences. Journal of Knowledge Management. Nasiri, M., Ukko, J., Saunila, M., & Rantala, T. (2020). Managing the digital supply chain: The role of smart technologies. Technovation, 96, 102121. Çetin S: The Effects of Transactive Memory Systems, Collective Mind and Innovative Culture on Knowledge Creation Capability. Business & Management Studies: An International Journal. 2019;7(1):563–578. 10.15295/bmij.v7i1.1092 Sankowska A: Relationships between organizational trust, knowledge transfer, knowledge creation, and firm’s innovativeness. Learn. Organ. 2013;20(1):85–100. 10.1108/09696471311288546 Tootell A, Kyriazis E, Billsberry J, et al.: Knowledge creation in complex inter-organizational arrangements: Understanding the barriers and enablers of university-industry knowledge creation in science-based cooperation. J. Knowl. Manag. 2020;25(4):743–769. 10.1108/JKM-06-2020-0461 Wang D, Li B: Behavioral Selection Strategies of Members of Enterprise Community of Practice—An Evolutionary Game Theory Approach to the Knowledge Creation Process. IEEE Access. 2020;8:153322–153333. 10.1109/ACCESS.2020.3018188 Paul, J., Lim, W. M., O’Cass, A., Hao, A. W., & Bresciani, S. (2021). Scientific procedures and rationales for systematic literature reviews (SPAR‐4‐SLR). International Journal of Consumer Studies."
}
]
}
] | 1
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https://f1000research.com/articles/10-1040
|
https://f1000research.com/articles/9-969/v1
|
11 Aug 20
|
{
"type": "Case Report",
"title": "Case Report: A case of encephalopathy presenting the lentiform fork sign on MRI in a diabetic dialysis patient - diabetic uremic syndrome or metformin-related encephalopathy?",
"authors": [
"Yuri Ishizaki",
"Ryuzoh Nishizono",
"Masao Kikuchi",
"Hiroko Inagaki",
"Yuji Sato",
"Shouichi Fujimoto",
"Ryuzoh Nishizono",
"Masao Kikuchi",
"Hiroko Inagaki",
"Yuji Sato",
"Shouichi Fujimoto"
],
"abstract": "Basal ganglia lesions showing an expansile high signal intensity on T2-weighted MRI are termed the lentiform fork sign. This specific finding is mainly observed in diabetic patients with uremic encephalopathy with metabolic acidosis, although there are also reports in patients with ketoacidosis, dialysis disequilibrium syndrome, intoxication, and following drug treatment (e.g., metformin). A 57-year-old Japanese man on chronic hemodialysis for four years because of diabetic nephropathy was admitted to our hospital for relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance. Brain T2-weighted MRI showed the lentiform fork sign. Hemodialysis was performed the day before admission, and laboratory tests showed mild metabolic (lactic) acidosis, but no uremia. Surprisingly, metformin, which is contraindicated for patients with end-stage kidney disease, had been prescribed for six months in his medication record, and his sluggish speaking and dysarthria appeared gradually after metformin treatment was started. Thus, the encephalopathy was considered to be related to metformin treatment. He received hemodialysis treatment for six consecutive days, and his consciousness disturbance and dysarthria improved in one week. At the eight-month follow-up, the size of the hyperintensity area on MRI had decreased, while the mild gait disturbance remained. Considering the rapid onset of gait and consciousness disturbance immediately before admission, diabetic uremic syndrome may also have occurred with metformin-related encephalopathy, and resulted in the lentiform fork sign, despite the patient showing no evidence of severe uremia on laboratory data.",
"keywords": [
"lentiform fork sign",
"basal ganglia lesion",
"diabetic uremic syndrome",
"metformin",
"consciousness disturbance"
],
"content": "Introduction\n\nMetabolic encephalopathy with abnormal basal ganglia lesions has been reported in hemodialysis patients. Ingestion of some types of mushroom, star fruit, and drugs (e.g., anti-herpes virus drugs) can cause encephalopathy in these patients1–3. In particular, diabetic dialyzed patients can present with bilateral symmetrical low densities in the basal ganglia on brain computed tomography (CT), with a bilateral symmetrical hyperintensity in the same area and a lentiform fork sign on T2-weighted MRI4–10. In addition to diabetic uremic syndrome (DUS)4,5, the lentiform fork sign can be observed in severe metabolic acidosis11–13, dialysis disequilibrium syndrome14, and metformin-associated encephalopathy (ME)6,7. The pathogenic basis of this sign is considered to relate to cytotoxic edema based on the severity of metabolic acidosis8,11. Intensive dialysis is a therapeutic option for removing the uremic toxins, to correct metabolic acidosis and remove medications. Herein, we present a case of a 57-year-old Japanese man in whom the lentiform fork sign was a clue for the differential diagnosis of ME or DUS. Metformin tends to increase lactate production and result in metabolic acidosis in ME6,7,9,10, while chronic hyperglycemia with coexistence of uremic toxins and metabolic acidosis is the main mechanism in DUS4,5. Which of these is the main cause in our case presenting with the lentiform fork sign is discussed below.\n\n\nCase report\n\nA 57-year-old Japanese man who had been on maintenance hemodialysis three-times weekly for four years because of diabetic nephropathy developed gait and consciousness disturbance, fatigue, numbness in his left upper limb, and a slow response during conversation approximately 10 days before admission. His wife denied him taking mushrooms or star fruit, which can cause consciousness disturbance in hemodialysis patients. There were no abnormal neurologic findings on physical examination. However, bilateral symmetrical basal ganglia lesions were noted on brain CT (Figure 1a).\n\nOn admission to our hospital, his consciousness was disturbed, such as he only could open his eyes following calling, and he had difficulty sitting alone. He showed a tonic planter reflex on physical examination. His blood pressure was 190/91 mmHg, and his heart rate was 104 beats per min. Atrial blood gas showed a pH of 7.37, bicarbonate ion of 18.1 mEq/L, and lactic acid of 6.2 mmol/L. Serum calcium, vitamin B1, and blood aluminum levels were all within the acceptable range. Kidney function data sampled the day after dialysis, blood urea nitrogen, and serum creatinine were consistent with dialysis. His HbA1c was 5.8% on admission.\n\nBrain MRI showed bilateral symmetrical basal ganglia lesions with an expansile high signal intensity (lentiform fork sign) on T2-weighted sequences (Figure 1b), which was not seen on MRI taken one-year prior when he developed a right thalamic lacunar infarction.\n\na, e Head computed tomography (CT) and b–d head MRI (T2-weighted image). a, b High-resolution lesions in the bilateral symmetrical basal ganglia were evident at admission. c, d The bilateral symmetrical basal ganglia lesions gradually improved on the 18th hospital day and at three-month follow-up. e However, the basal ganglia lesions remained at eight-month follow-up.\n\nIn his medication history, he had taken metformin for six months. His wife said that his sluggish speaking and dysarthria appeared gradually after starting metformin treatment (Figure 2). His plasma metformin concentration was extremely high (25,700 ng/mL). Thus, we considered that metformin may have initially caused the encephalopathy. However, we also considered the possibility of DUS, because his gait and consciousness disturbance appeared relatively rapidly approximately 10 days before hospitalization. DUS typically occurs in uncontrolled uremic patients with diabetic mellitus.\n\nSince that time, he developed gradual symptoms of sluggish speaking and dysarthria, while numbness of his left upper limb, gait disturbance, and consciousness disturbance appeared 10 days before admission. He received emergency consecutive hemodialysis for six days, after which he awoke, and was gradually able to walk and talk. *Walking was possible, but wobbling during walking remained at eight-month follow-up.\n\nIn either case, we stopped metformin treatment, and immediately performed intensive hemodialysis (four hours per day) for six days after hospitalization to remove metformin and uremic toxin, and to correct metabolic acidosis. The first dialysis session reduced his lactic acid levels from 6.0 to 1.3 mmol/L. After six consecutive sessions of hemodialysis, his consciousness was restored, and his tonic planter reflex disappeared. After starting meals, linagliptin was chosen as an anti-diabetic drug to replace metformin.\n\nOn the 18th hospital day, T2-weighted brain MRI revealed a modest improvement in the lentiform fork sign (Figure 1c). The patient was gradually able to sitting alone, walk, and talk with staff and his wife. He was discharged from our hospital within one month.\n\nAt three-month follow-up, the lentiform fork sign was further improved on brain MRI (Figure 1d). However, at eight months after the onset, he still complained movement disorders, such as a wobble when walking and body tilting when resting. Brain lesions were still evident on CT scan (Figure 1e).\n\n\nDiscussion\n\nHerein, we report a diabetic hemodialysis patient with consciousness disturbance who presented with the lentiform fork sign on T2-weighted brain MRI. This finding appears in the basal ganglia, which is vulnerable to addictive toxins and metabolic products8,12. The lentiform fork sign is comprised of the following elements: 1) the lateral arm, formed by the edematous external capsule and extending from the anterior end of the putamen to the stem; 2) the stem, created by merging of the edematous external and internal capsules at the inferoposterior end of the putamen; and 3) the medial arm, which extends from the stem anteriorly up to one third of the medial edge, where it splits into two slightly less T2/FLAIR-hyperintense branches engulfing the globus pallidus11,12,15. In the present case, brain MRI showed the same expansile high signal intensity (Figure 1b). The lentiform fork sign is rare but non-specific. Thus, a differential diagnosis should be considered (Table 1)8,11–15, of which ME or DUS may be the cause in the present case.\n\n*The lentiform fork sign mainly occurs in patients with diabetic kidney disease.\n\nThe use of metformin in dialyzed patients can cause drug accumulation in the brain, leading to neurological abnormalities, difficulties of speech and walking, with worsening of sensory disturbance, tiredness, drowsiness, and weakness (i.e., ME)6,7,9,10. Metformin is first-line drug used in type 2 diabetes mellitus. However, it is contraindicated in patients with an estimated glomerular filtration rate <30 mL/min/1.73 m2, because of an increased risk of lactic acidosis. Acidosis can damage the basal ganglia, resulting in cytotoxic edema7, which is sometimes irreversible despite intensive hemodialysis to remove metformin and lactic acid, and to correct acidosis.\n\nAlternatively, DUS is characterized by acute or subacute progression with a variety of movement disorders such as gait disorders, dysarthria, parkinsonism, and consciousness disturbance. DUS can cause bilateral symmetrical basal ganglia lesions on brain CT and T2-weighted MRI4,5 in patients with diabetic nephropathy, even if they are not on hemodialysis. To date, approximately 30 cases of DUS have been reported, many of which are Asian. The reported risk factors of DUS include a high level of HbA1c before and at hemodialysis, and increasing metabolic acidosis. Hyperglycemia damages the microvasculature, resulting in a fragile vascular smooth muscle, and the accumulation of uremic toxins and/or metabolic acidosis can damage the blood-brain-barrier, leading to altered metabolism and homeostasis in the brain. This can result in basal ganglia injury, including angiogenic edema, which is reversible and shows favorable prognosis.\n\nThe clinical presentation in our case was not helpful for differentiating ME and DUS, because these symptoms were indistinguishable (Table 2). Initial hemodialysis improved lactic acidosis, although intensive hemodialysis for six consecutive days was required to improve his consciousness. The lentiform fork sign on MRI improved at first, although brain CT findings at eight-month follow-up showed low density signals in those regions, and his neurological sequelae remained, suggestive of continued cytotoxic edema. ME was likely the main cause of injury in our case. Nevertheless, the patient’s condition worsened relatively rapidly before admission, similar to that seen in DUS. DUS can also contribute to cytotoxic edema in the basal ganglia, and has a variable progression. Thus, DUS may have also contributed to the encephalopathy in our case.\n\nME, metformin-associated encephalopathy; DUS, diabetic uremic syndrome.\n\nIn summary, we report a diabetic hemodialysis patient with encephalopathy presenting as the lentiform fork sign derived from ME and/or DUS. In dialysis patients showing gait and consciousness disturbance, the lentiform fork sign on brain CT and T2-weighted MRI may be useful for differential diagnosis.\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": "Acknowledgements\n\nWe thank Edanz Group (https://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.\n\n\nReferences\n\nAkiyama H, Matsuoka H, Okuyama T, et al.: The acute encephalopathy induced by intake of sugihiratake mushroom in the patients with renal damage might be associated with the intoxication of cyanide and thiocyanate. Food Safety. 2015; 3(1): 16–29. Publisher Full Text\n\nAuxiliadora-Martins M, Alkmin Teixeira GC, da Silva GS, et al.: Severe encephalopathy after ingestion of star fruit juice in a patient with chronic renal failure admitted to the intensive care unit. Heart Lung. 2010; 39(5): 448–452. PubMed Abstract | Publisher Full Text\n\nDelluc A, Mocquard Y, Latour P, et al.: Encephalopathy and acute renal failure during acyclovir treatment. Rev Neurol (Paris). 2004; 160(6–7): 704–706. PubMed Abstract | Publisher Full Text\n\nWang HC, Cheng SJ: The syndrome of acute bilateral basal ganglia lesions in diabetic uremic patients. J Neurol. 2003; 250(8): 948‒955. PubMed Abstract | Publisher Full Text\n\nFinelli PF, Singh JU: A syndrome of bilateral symmetrical basal ganglia lesions in diabetic dialysis patients. Am J Kidney Dis. 2014; 63(2): 286–288. PubMed Abstract | Publisher Full Text\n\nKang YJ, Bae EJ, Seo JW, et al.: Two additional cases of metformin-associated encephalopathy in patients with end-stage renal disease undergoing hemodialysis. Hemodial Int. 2013; 17(1): 111–115. PubMed Abstract | Publisher Full Text\n\nSimon SP, Thomas J: Metformin-associated encephalopathy in hemodialysis. Indian J Nephrol. 2019; 29(3): 194–196. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKim DM, Lee IH, Song CJ: Uremic encephalopathy: MR imaging findings and clinical correlation. ANJR Am J Neuroradiol. 2016; 37(9): 1604–1609. PubMed Abstract | Publisher Full Text\n\nAbdel SC, Carland JE, Graham GG, et al.: Is the use of metformin in patients undergoing dialysis hazardous for life? A systematic review of the safety of metformin in patients undergoing dialysis. Br J Clin Pharmacol. 2019; 85(12): 2772–2783. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVecchio S, Giampreti A, Petrolini VM, et al.: Metformin accumulation: lactic acidosis and high plasmatic metformin levels in a retrospective case series of 66 patients on chronic therapy. Clin Toxicol (Phila). 2014; 52(2): 129–35. PubMed Abstract | Publisher Full Text\n\nKumar G, Goyal MK: Lentiform Fork sign: a unique MRI picture. Is metabolic acidosis responsible? Clin Neurol Neurosurg. 2010; 112(9): 805–812. PubMed Abstract | Publisher Full Text\n\nGrasso D, Borreggine C, Perfetto F, et al.: Lentiform fork sign: a magnetic resonance finding in a case of acute metabolic acidosis. Neuroradiol J. 2014; 27(3): 288–292. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSaini AG, Sreevilasan SK, Singh P, et al.: Lentiform fork sign due to severe metabolic acidosis. BMJ Case Rep. 2017; 2017: bcr2017222871. PubMed Abstract | Publisher Full Text | Free Full Text\n\nda Rocha AJ, Maia AC Jr, da Silva CJ, et al.: Lentiform fork sign in a child with dialysis disequilibrium syndrome: a transient MRI pattern which emphasizes neurologic consequence of metabolic acidosis. Clin Neurol Neurosurg. 2013; 115(6): 790–792. PubMed Abstract | Publisher Full Text\n\nBeltz EE, Mullins ME: Radiological reasoning: hyperintensity of the basal ganglia and cortex on FLAIR and diffusion-weighted imaging. AJR Am J Roentgenol. 2010; 195(3 Suppl): S1–8. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "95340",
"date": "27 Sep 2021",
"name": "Shashwati Sarkar",
"expertise": [
"Reviewer Expertise Endocrine disorders",
"Assisted reproductive technology",
"Infertility",
"Gynaecology",
"Obstetrics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary: It is prudent to avoid Metformin in Diabetic patients with chronic renal insufficiency. Metformin toxicity can cause lactic acidosis induced encephalopathy eventually leading to multi-organ failure and death. Lentiform fork sign is a specific MRI finding in basal ganglia of these patients probably due to vasogenic edema induced by metabolic acidosis. Suspicion about Metformin intake will help in an early diagnosis and treatment.\nA few suggestions to the authors:\n\nRestrict the number of words in the title. Too many medical terms are used.\n\nCase Report: Correction - Arterial Blood Gas analysis.\n\nMention the Glasgow Coma Score.\n\nDUS may have a subacute presentation. Yoshiko Nishimura et al.2 have reported a case of Diabetic Uremic Syndrome where the clinical features developed over 3 months. In your case, ME seems to be the primary diagnosis and DUS may be considered as a differential diagnosis rather than a contributory factor.\n\nAdd these References:\n\nMetformin-induced encephalopathy: the role of thiamine1.McGarvey et al. (2018) suggested that Metformin may cause thiamine deficiency in patients with end-stage diabetic renal failure, resulting in a specific type of encephalopathy. A quick resolution of the signs and symptoms was observed on stopping the drug in these patients.\n\nA case of subacute Parkinsonism presenting as bilateral basal ganglia lesions by MRI in Diabetic uremic Syndrome.2\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": "7311",
"date": "20 Oct 2021",
"name": "Yuri Ishizaki",
"role": "Author Response",
"response": "Dear Dr. Shashwati Sarkar Sen, Thank you for your valuable comments about my case report. We respond to each suggestion as follows. 1) Restrict the number of words in the title. Too many medical terms are used. As suggested by the reviewer, we shorten the title to “A Case of Encephalopathy Presenting the Lentiform Fork Sign on MRI in a Diabetic Dialysis Patient”. 2) Case Report: Correction - Arterial Blood Gas Analysis. Thank you for pointing it out. We corrected “Atrial blood gas” to “Arterial blood gas analysis”. 3) Mention the Glasgow Coma Score. We mentioned the Glasgow Coma Scale Score of E3V4M6 in the first line of the case report section. 4) DUS may have a subacute presentation. Yoshiko Nishimura et al. have reported a case of Diabetic Uremic Syndrome where the clinical features developed over 3 months. In your case, ME seems to be the primary diagnosis and DUS may be considered as a differential diagnosis rather than a contributory factor. Thank you for your comment. In our case, there was not enough evidence to diagnose ME. The first reason was the thiamin level was not decreased, even though metformin may induce thiamin deficiency. (We added serum thiamin value in the part of the case presentation.) Furthermore, thiamin deficiency can be caused by malnutrition and loss of water-soluble vitamins in the hemodialysis progression, but the patient did not have the symptoms of weight loss and seemed not to be undernourished. Secondly, the level of metabolic (lactic) acidosis on admission was also much mild not so high. Thirdly, as shown in Fig. 2, although the patient had had sluggish speaking and dysarthria and these findings had been gradually worsening six months before starting taking metformin, the relatively rapid-onset gait disturbance, severe dysarthria, and consciousness disturbance had appeared ten days before admission, which was a subacute progression. We could say that it was difficult to distinguish between ME and DUS, just considering the appearance of the findings. That is why we cannot necessarily diagnose ME, and we listed the two differential diagnoses, ME and/or DUS. We added the following sentences in the Discussion section: According to the previous reports, hemodialysis patients are at risk for thiamin deficiency which is induced to encephalopathy, because they are in the condition of malnutrition and tend to lose water-soluble vitamins in the hemodialysis procedure [16, 17]. Furthermore, thiamin deficiency may be a possible mechanism in metformin-induced encephalopathy [18]. In our case, the thiamin level was not decreased and severe lactic acidosis was not observed. In addition to these, the occurrence of gait disturbance, severe dysarthria, and consciousness disturbance was subacute even though sluggish speaking and dysarthria had been gradually worsening six months before starting taking metformin as shown in Fig.2, and the patient was neither malnutrition nor weight loss. That is why it was not necessarily ME. References We also read the two references which you indicated. According to Reference #1, thiamine must be a key to diagnose Metformin-induced encephalopathy. In the part of that we showed the thiamin level of our case, we quoted reference #1. On the other hand, we did not add reference #2 because it is written in Japanese and we thought that reader cannot understand it well. Furthermore, we quoted two more references to mention that our case is not necessarily ME in the perspective of thiamin level in hemodialysis patients (Szu-Chun H et al, AJKD, 2001). Sincerely yours, Yuri Ishizaki"
}
]
}
] | 1
|
https://f1000research.com/articles/9-969
|
https://f1000research.com/articles/10-1222/v1
|
01 Dec 21
|
{
"type": "Method Article",
"title": "Improved retinal vessel segmentation using the enhanced pre-processing method for high resolution fundus images",
"authors": [
"Aziah Ali",
"Aini Hussain",
"Wan Mimi Diyana Wan Zaki",
"Wan Haslina Wan Abdul Halim",
"Wan Noorshahida Mohd Isa",
"Noramiza Hashim",
"Aini Hussain",
"Wan Mimi Diyana Wan Zaki",
"Wan Haslina Wan Abdul Halim",
"Wan Noorshahida Mohd Isa",
"Noramiza Hashim"
],
"abstract": "Background: By diagnosing using fundus images, ophthalmologists can possibly detect symptoms of retinal diseases such as diabetic retinopathy, age-related macular degeneration, and retinal detachment. A number of studies have also found some links between fundus image analysis data and other underlying systemic diseases such as cardiovascular diseases, including hypertension and kidney dysfunction. Now that imaging technology is advancing further, more fundus cameras are currently equipped with the capability to produce high resolution fundus images. One of the public databases for high-resolution fundus images called High-Resolution Fundus (HRF) is consistently used for validating vessel segmentation algorithms. However, it is noticed that the segmentation outputs from the HRF database normally include noisy pixels near the upper and lower edges of the image. In this study, we propose an enhanced method of pre-processing the images so that these noisy pixels can be eliminated, and thus the overall segmentation performance can be increased. Without eliminating the noisy pixels, the visual segmentation output shows a large number of false positive pixels near the top and bottom edges. Methods: The proposed method involves adding additional padding to the image before the segmentation procedure is applied. In this study, the Bar-Combination Of Shifted FIlter REsponses (B-COSFIRE) filter is used for retinal vessel segmentation. Results: Qualitative assessment of the segmentation results when using the proposed method showed improvement in terms of noisy pixel removal from near the edges. Quantitatively, the additional padding step improves all considered metrics for vessel segmentation, namely Sensitivity (73.76%), Specificity (97.53%), and Matthew’s Correlation Coefficient (MCC) value (71.57%) for the HRF database. Conclusions: Findings from this study indicate improvement in the overall segmentation performance when using the proposed double-padding method of pre-processing the fundus image prior to segmentation. In the future, more databases with various resolutions and modalities can be included for further validation.",
"keywords": [
"Pre-processing",
"retinal vessel segmentation",
"fundus image"
],
"content": "Introduction\n\nRetinal images play a very important role in ensuring the early detection of symptoms relating to ocular diseases. Early detection will in turn enable timely treatment of eye diseases, which in most cases may significantly decrease the patients’ risk of total vision loss.1 With the global prevalence of eye diseases being gradually on the rise annually, the World Health Organization has encouraged nations to have routine retinal screening in place.2 This is intended to diagnose diseases such as diabetic retinopathy (DR), glaucoma and age-related macular degeneration (AMD) early enough so treatment can be administered before worse disease progression.3 Most hospitals are equipped with fundus cameras that can be used to generate fundus images by imaging a patient’s retina, samples of which are shown in Figure 1.\n\nTo assist ophthalmologists in performing efficient and accurate fundus image diagnosis, many studies have been conducted to automatically extract important parameters from a fundus image,4–9 mainly focusing on automatic retinal blood vessel segmentation and then estimating vessel parameters from the segmentation output.10–12 Figure 2 shows a typical flow of blood vessel segmentation procedure.\n\nThe blue-shaded box indicates the pre-processing steps focused in this study.\n\nFor validation of the blood vessel segmentation methods, most researches apply their methods to data from two popular benchmark databases, namely Digital Retinal Images for Vessel Extraction (DRIVE)13 and Structured Analysis of the Retina (STARE).14 However, it should be noted that these databases consist of images which are at a much lower resolution when compared to the fundus images produced by current modern fundus cameras. The images in the DRIVE database have resolution of 565 by 584 pixels while images in STARE have resolution of 700 by 605 pixels. This is because the databases date back to the early 2000s, and the fundus cameras of the time did not have the capability to produce high resolution images.\n\nMore recent studies have started to include databases with higher resolution fundus images, such as the High-Resolution Fundus (HRF) database.15 The images in the HRF database have resolution of 3504 by 2336 pixels, markedly higher than images in the DRIVE and STARE databases. Figure 1b shows a sample image from the HRF database.\n\nFrom Figure 1, it can be seen that the region of interest (ROI) in the DRIVE image is surrounded by dark pixels. However, this is not the case with the image from the HRF database, Figure 1b. The top and bottom edges of the image are not surrounded by the dark area as in Figure 1a. This may result in noisy vessel segmentation output with false positive vessel pixels near the top and bottom images. To the best of our knowledge, this specific problem has not been addressed in the literature.\n\nIn this study, we investigated a simple and efficient way to eliminate the noisy pixels in segmentation output for fundus images whose ROIs are not fully surrounded by dark pixels, such as the case with images in HRF database. The proposed method is to be applied in the pre-processing step of retinal blood vessel segmentation workflow, illustrated as the shaded blue box in Figure 2. In order to validate the effectiveness of the proposed pre-processing step, vessel segmentation procedure based on an adapted Bar-Combination Of Shifted FIlter REsponses (B-COSFIRE) filter that we previously published16 is performed on the pre-processed output.\n\n\nMethods\n\nPre-processing is one of the key steps in retinal blood vessel segmentation techniques, which helps to ensure that the initial fundus image is optimised for the subsequent vessel detection phase. The original red green blue (RGB) format of digital fundus images is not the optimal form for the accurate detection of retinal blood vessels from an image processing point of view due to the natural colours in fundus images that poorly contrast with the retinal background vessels. Issues such as inconsistent illumination across the image, lesser contrast between retinal blood vessels and the retinal background as well as noisy images are other concerns that need to be addressed during the pre-processing step, so that the input image for the vessel segmentation step will be of better clarity in terms of retinal blood vessel structures.\n\nIn this study, the pre-processing method employed by Soares17 is used as the basis since it is considered the established method for this purpose.18 Figure 3 illustrates the overview of the pre-processing steps where the first step is to extract the green channel image (GCI) from the color fundus image. The GCI displays a noticeably better vessel appearance, while the red channel image shows low vessel-to-background contrast and the blue channel image displays low dynamic range making the vessels appear almost invisible. This decision to use only GCI is supported by most previously established methods used for segmenting retinal blood vessels from fundus images.18–21 The original code for pre-processing and vessel segmentation using B-COSFIRE can be obtained here.\n\nAs discussed earlier, the ROI for a fundus image is the colored region inside the circular region on the image. The ROI refers to the non-dark area in the middle of the fundus image, which shows the retina. There is a strong contrast between the ROI and the dark area surrounding the ROI from the extracted GCI. Thus, there is a high probability of detecting false vessel pixels for areas just outside the ROI. To minimise this effect on the segmentation output, Soares suggested that the ROI needs to be identified and expanded by padding it with additional interpolated pixels.17\n\nThe procedure starts with converting the fundus image from RGB to the CIELab color scheme. CIELab is a way to represent colours using three numerical values, namely L*, a*, and b*.22 For this ROI identification step, only the L* component or the luminosity component is used as it shows good contrast between the ROI and the black background. An optimum value for a threshold is then estimated using Otsu’s method to transform the L* image into a mask image, as illustrated in Figure 3. The white pixels (pixel value 1) are all the pixels in the ROI, while the black pixels are all the pixels outside the ROI (pixel value 0).\n\nThe mask image is then used to locate the pixels that are located at one pixel distance from the outer border of the ROI in GCI using four-neighbourhood connectivity to define the neighbour pixels. After the set of neighbouring pixels is identified, the ROI is eroded by several pixels to minimise the contrast between the ROI and the artificial ROI region (padding) that is added in the next step. Then, the mean value for each of the pixels in the padding obtained earlier is calculated by considering eight-neighbourhood connectivity. Next, each original neighbouring pixel value is then replaced with the mean pixel value calculated in the previous step. This set of altered pixels is then included as part of the ROI, thus effectively enlarging the ROI by one pixel over the original border. These steps are repeated for a few iterations, where each iteration adds a one-pixel border to the ROI. In this study, the erosion size used is 5 pixels while the number of iteration used is 20 iterations, as applied by Azzopardi et al.23 in their B-COSFIRE implementation.\n\nUsing this method as proposed by Soares does not add any new pixels to the image, which means the original size is maintained and the top and bottom edges are still not surrounded by the dark pixels. It only converts the grayscale values of pixels surrounding the ROIs with values interpolated from the pixels just inside the ROI border. What we are proposing in this study is the addition of new pixel areas surrounding the original image, thus effectively adding to the resolution of the original image.\n\nIn our proposed method, prior to changing the values of the pixels just outside the ROI as in Soares’s method, both the GCI and the mask image are padded with an additional 50 layers of zero-valued (black) pixels on all four borders, referred to as double padding. Using the information from these padded images as the input to the Soares’s padding method, a double-padded image is then produced with the resolution increased by 100 pixels in both height and width. This image is then used to produce a contrast-adjusted image in the next step to highlight the vessel structures. This is the only difference from the original Soares method, which we will refer to as single padding.\n\nAfter the border of the ROI is padded on the fundus image, the next step is to perform image enhancement on the padded fundus image, so that the vessel structures are enhanced in their appearance. A commonly used pre-processing method for fundus image analysis called contrast limited adaptive histogram equalisation or CLAHE24 is employed in this study. CLAHE is a variation of the histogram equalisation (HE) method, which is a technique used to transform pixels on an image based on its histogram.\n\nThis enhanced pre-processing step is performed on all 45 images in the HRF database before they are processed for segmenting the retinal blood vessels. To ensure validity and reliability, the standard performance metrics for vessel segmentation assessment are adopted to quantify the difference in segmentation performance with and without the proposed enhancement method.\n\n\nResults & discussion\n\nAs described in the introduction section, the modified B-COSFIRE16 filter is used to extract the vessel features from the pre-processed output images. Sample outputs of the pre-processed images with their corresponding vessel feature images using the single padding and double padding pre-processing methods are displayed in Table 1. By observing the HRF feature image produced using single padding in Table 1, dark lines can be seen on both the top and bottom borders of the vessel feature image. These dark lines will be highly likely to be segmented as false vessel pixels when processed for segmentation. However, the vessel feature image produced using the double padding method does not have these dark lines, thus decreasing the possibility of having a large number of false positive vessel pixels.\n\nAnother visible improvement is in terms of the brightness level of vessel pixels in the double-padded vessel feature image as opposed to single-padded. To confirm that double padding is better than single padding for the purpose of vessel segmentation, another comparison is performed on segmentation results using the different padding methods.\n\nTable 2 shows segmentation outputs using the different padding methods, together with their zoomed-in versions. Apart from the apparent improvement in much reduced noisy pixels on top and lower border of the ROI, subtle improvements in vessel appearance are also observed. In general, double padding helps in further enhancing the vessel features, with most vessels appearing brighter compared to single padding outputs, including the smaller vessels. It is found that using double padding in pro-processing results in the successful removal of false positive pixels near the top and bottom image borders of all 45 segmentation output images in the HRF database. In order to quantify the improvement of the segmentation performance when using the proposed method, Table 3 summarises the performance metrics for segmentation using the different padding methods. Following the metric selection in our previous study, four metrics are included, namely Sensitivity (Sn), Specificity (Sp), Balanced Accuracy (B-Acc) and Matthew’s Correlation Coefficient (MCC).\n\nAs expected, the application of double padding results in improved segmentation performance where performance values are increased across all the four considered metrics. This is attributed to the successful removal of the noisy pixels near the top and bottom borders of all images in HRF database, thus decreasing the number of false positive pixels and improving the overall segmentation performance.\n\n\nConclusion\n\nIn this study, we proposed a simple but effective method to improve blood vessel segmentation performance for images with the ROI reaching the image borders. The simple method of adding additional layer of dark pixels around the image proves to be effective in removing the noisy pixels at the image borders. Quantitatively, the additional padding step also managed to improve all the four considered metrics for vessel segmentation, namely Sensitivity (73.76%), Specificity (97.53%), Balanced-Accuracy (85.64%) and MCC value (71.57%) for the HRF database. This method has only been validated on a single high-resolution fundus image database for now, so in the future more databases should be included for validation to attest the robustness of the proposed methods on multiple databases. The proposed improvement method, while simplistic in nature, could prove to be very effective in increasing overall vessel segmentation performance, particularly for images that are not fully surrounded by dark pixels such as HRF database images.\n\n\nData availability\n\nThe HRF database can be accessed at https://www5.cs.fau.de/research/data/fundus-images/.",
"appendix": "Acknowledgments\n\nWe would like to thank our collaborator from Department of Ophthalmology, Universiti Kebangsaan Malaysia Medical Center, especially Dr Wan Haslina and her team for their valuable inputs for this study.\n\n\nReferences\n\nFlaxman SR, et al.: Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis. Lancet Glob. Health. Dec. 2017; 5(12): e1221–e1234. PubMed Abstract | Publisher Full Text\n\nYau JWY, et al.: Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012; 35: 556–564. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBernardes R, Serranho P, Lobo C: Digital Ocular Fundus Imaging: A Review. Ophthalmologica. Oct. 2011; 226(4): 161–181. PubMed Abstract | Publisher Full Text\n\nSubramanya Jois SP, Harsha S, Harish Kumar JR: Automatic Optic Disc Localization Using Particle Swarm Optimization Technique. IEEE Region 10 Annual International Conference, Proceedings/TENCON. 2019; vol. 2018-Octob: pp. 1718–1722.\n\nFu D, Liu Y, Huang Z: A review of retinal vessel segmentation and artery/vein classification. Lecture Notes in Electrical Engineering. 2018; 459: 727–737. Publisher Full Text\n\nNoor NM, Khalid NEA, Ariff NM: Optic cup and disc color channel multi-thresholding segmentation. Proceedings - 2013 IEEE International Conference on Control System, Computing and Engineering, ICCSCE 2013. 2013; pp. 530–534.\n\nKhan MAU, Carmichael JN, Sarirete A, et al.: Thin Vessel Detection and Thick Vessel Edge Enhancement to Boost Performance of Retinal Vessel Extraction Methods. Procedia Computer Science. 2019; 163: 618–638. Publisher Full Text\n\nAbramoff MD, Garvin MK, Sonka M: Retinal imaging and image analysis. IEEE Rev. Biomed. Eng. 2010; 3: 169–208. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNunley KA, et al.: Long-term changes in retinal vascular diameter and cognitive impairment in type 1 diabetes. Diab. Vasc. Dis. Res. May 2018; 15(3): 223–232. PubMed Abstract | Publisher Full Text\n\nChalakkal RJ, Abdulla WH, Hong SC: Fundus retinal image analyses for screening and diagnosing diabetic retinopathy, macular edema, and glaucoma disorders. Diabetes and Fundus OCT. Elsevier; 2020; pp. 59–111.\n\nMittal K, Rajam VMA: Computerized retinal image analysis - a survey. Multimed. Tools Appl. Aug. 2020; 79(31–32): 22389–22421. Publisher Full Text\n\nGarg M, Gupta S: Retinal blood vessel segmentation algorithms: A comparative survey. Int. J. Bio-Science Bio-Technology. 2016; 8: 63–76. Publisher Full Text\n\nStaal J, Abràmoff MD, Niemeijer M, et al.: Ridge-based vessel segmentation in color images of the retina. IEEE Trans. Med. Imaging. 2004; 23(4): 501–509. PubMed Abstract | Publisher Full Text\n\nHoover A: Locating blood vessels in retinal images by piecewise threshold probing of a matched filter response. IEEE Trans. Med. Imaging. 2000; 19(3): 203–210. PubMed Abstract | Publisher Full Text\n\nBudai A, Bock R, Maier A, et al.: Robust Vessel Segmentation in Fundus Images. Int. J. Biomed. Imaging. Dec. 2013; 2013: 1–11. Publisher Full Text\n\nAli A, Zaki WMDW, Hussain A: Retinal blood vessel segmentation from retinal image using B-COSFIRE and adaptive thresholding. Indones. J. Electr. Eng. Comput. Sci. Mar. 2019; 13(3): 1199–1207. Publisher Full Text\n\nSoares JVB, Leandro JJG, Cesar RM Jr, et al.: Retinal vessel segmentation using the 2-D Gabor wavelet and supervised classification. Medical Imaging. 2006; 25(9): 1214–1222. PubMed Abstract | Publisher Full Text\n\nMoccia S, De Momi E, El Hadji S, et al.: Blood vessel segmentation algorithms — Review of methods, datasets and evaluation metrics. Comput. Methods Prog. Biomed. May 2018; 158: 71–91. PubMed Abstract | Publisher Full Text\n\nFraz MM, et al.: Blood vessel segmentation methodologies in retinal images – A survey. Comput. Methods Prog. Biomed. 2012; 108(1): 407–433. PubMed Abstract | Publisher Full Text\n\nRoseline RH, Priyadarsini RJ: Survey on Ocular Blood Vessel Segmentation. Int. J. Adv. Res. Comput. Sci. Softw. Eng. 2017; 7: 318. Publisher Full Text\n\nBadar M, Haris M, Fatima A: Application of deep learning for retinal image analysis: A review. Computer Science Review. 01-Feb-2020; vol. 35: p. 100203. Elsevier Ireland Ltd. Publisher Full Text\n\nZhang X, Wandell BA: A spatial extension of CIELAB for digital color-image reproduction. J. Soc. Inf. Disp. 1997; 5: 61. Publisher Full Text\n\nAzzopardi G, Strisciuglio N, Vento M, et al.: Trainable COSFIRE filters for vessel delineation with application to retinal images. Med. Image Anal. 2015; 19(1): 46–57. PubMed Abstract | Publisher Full Text\n\nPizer SM, et al.: Adaptive Histogram Equalization and its Variations. Comput. Vision, Graph. Image Process. Sep. 1987; 39(3): 355–368. Publisher Full Text"
}
|
[
{
"id": "155703",
"date": "01 Dec 2022",
"name": "Gilbert Yong San Lim",
"expertise": [
"Reviewer Expertise Computer vision",
"machine 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\nThis paper introduces a double-padding enhancement to the commonly-known Soares pre-processing pipeline (referred to as single-padding), which is applied to retinal images before vessel segmentation. Experiments with the B-COSFIRE filter before and after these two padding methods are claimed to produce a significant improvement in vessel segmentation performance (Table 3). However, there are a number of concerns:\nIn the Introduction section, both DRIVE and HRF images are shown, and STARE is also discussed. However, the actual experiments appear to only take place for HRF images. As such, it might be considered to use actual HRD data in the figures (e.g. Figure 2), and to describe the actual number of images and training/validation/test splits used for the HRF data in producing the results (Table 3).\n\nIn the ROI border padding section, it is stated that the proposal in the study is the addition of new pixel areas surrounding the original image, thus effectively adding to the resolution of the original image. This might be explained in greater detail, perhaps using a figure.\n\nOn Table 2, other than the difference at the top edge, double padding appears to predict an additional blob, just slightly below the centre of the zoomed-in image. It might be explained as to how this happened, since double-padding would appear to differ at the edges only.\n\nTable 3 claims a large improvement in sensitivity for double vs. single padding (0.7376 vs. 0.6461), with next to no change in specificity. However, as understood, double-padding should reduce the number of pixels predicted as part of the vessels, due to reducing noise, which is also observed in Table 2 where the double padded image has much less noise at the top edge. This would seem to improve specificity instead of sensitivity.\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? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Partly",
"responses": []
},
{
"id": "148528",
"date": "01 Dec 2022",
"name": "Haidi Ibrahim",
"expertise": [
"Reviewer Expertise Digital image processing"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper describes a simple modification towards a pre-processing method, originally proposed by Soares et al.,ref 17, to improve the edge detection outputs for retinal fundus images. The improvement is by adding zero-padding of size 50 pixels at each border of the image (thus, the image's height and width are increased by 100 pixels). However, there are some comments about this paper:\nIs this method only applicable for high resolution fundus images (as stated in the title)? Or it can also be used for DRIVE and STARE datasets?\n\nA brief description on the edge detection method used, B-COSFIRE, should be given.\n\nLast sentence, before Section \"Methods\". \"In order to validate the effectiveness of the proposed pre-processing step, vessel segmentation procedur ebased on an adapted Bar-Combination Of Shifted FIlter REsponses (B-COSFIRE) filter that we previously published [16] is performed on the pre-processed output.\" This sentence indicates that B-COSFIRE was proposed by the authors. Yet, the source code's link provided in the line before \"ROI border padding\", shows that the filter was proposed by other researchers, i.e., Azzopardi et al. [23]. (As in the source code page, the paper should also cite one more paper: [2] \"N. Strisciuglio, G. Azzopardi, M. Vento, and N. Petkov\" - Supervised vessel delineation in retinal fundus images with the automatic selection of B-cosfire filters. Machine Vision and Applications. doi:10.1007/s00138-016-0781-71). Thus, the sentence should be rephrased.\n\nDouble padding is the main contribution of the paper. Thus, Section \"Double Padding\" should be elaborated more. For example, why the authors chose 50 layers, and not other number? Besides, better to explain why double padding can change the segmentation outcome, theoretically. Is the padding size related to the image size?\n\nIn Table 1, the main differences are the edges on the top and bottom part of the image. How crucial the blood vessels at the borders for the diagnosis? If they are not crucial, can we just remove the edges, by masking?\n\nIn Table 2, the Zoomed-in versions are actually not from the same region. They are slightly different. Please check carefully.\n\nIn Table 2, why the edges are different? Would be nice if the authors could explain on how the double padding can modify the segmentation outcome.\n\nBetter to provide equations for Sn, Sp, B-Acc, and MCC.\n\nIn the Acknowledgement, the authors (which also include Dr Wan Haslina), acknowledge Dr Wan Haslina. Seems like an author to thank herself. If the contributions by Dr Wan Haslina is not adequate as a co-author, please remove from the list of authors. On the other hand, if Dr Wan Haslina contributes to the writing of this paper, please remove the acknowledgement.\n\nFrom 24 references, only 6 (i.e., 25%) are from year 2019 and above. There are no papers from year 2021 and 2022. Please add more recent journal publications.\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? Partly\n\nIf any results are presented, are all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions about the method and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1222
|
https://f1000research.com/articles/10-1219/v1
|
01 Dec 21
|
{
"type": "Case Report",
"title": "Case Report: Poor oral hygiene leading to an emergency condition: A case report of Ludwig’s angina",
"authors": [
"Prashant Pant",
"Oshan Shrestha",
"Pawan Budhathoki",
"Nebula Devkota",
"Prabin Kumar Giri",
"Dhan Bahadur Shrestha",
"Prashant Pant",
"Pawan Budhathoki",
"Nebula Devkota",
"Prabin Kumar Giri",
"Dhan Bahadur Shrestha"
],
"abstract": "Ludwig’s angina (LA) is a rapidly spreading and potentially life-threatening infection having an odontogenic infection as the most common source. It involves the floor of the mouth and neck. Modernization in medical care has made this entity rare and of low mortality at the present but it is still feared as a lethal entity due to rapidly progressive airway obstruction that follows. Here we report a case of a 15-year-old male who suffered from LA. Presenting symptoms and findings of the examination helped in the clinical diagnosis. Immediate intubation, use of broad-spectrum antibiotics, and treatment of complications aided the patient’s recovery. LA should be considered for differential diagnosis in the case of neck swelling especially in those having a history of poor oral hygiene and recent dental procedures. Management of LA and its complications should always involve doctors from multiple disciplines.",
"keywords": [
"airway obstruction",
"ENT emergency",
"Ludwig’s angina",
"oral hygiene"
],
"content": "Introduction\n\nLudwig’s angina (LA) was first reported and published by a German physician Wilhelm Frederick von Ludwig in 1836. He described it as a throat infection that was different from other typical throat infections with specific characteristics; peculiar hardness of the involved tissue, swelling beneath the tongue, edema of the neck, and sparing of the glands.1 Modernization in medical care has made this entity rare and of low mortality at the present. But it is still seen in emergency settings and is still feared as a lethal entity due to the rapidly progressive airway obstruction that follows.2,3 To highlight this most feared complication of LA, the word ‘angina’ is added as its origin is a Latin word ‘angere’, which means ‘to strangle’.4\n\nOdontogenic infection, especially pre-apical infection of mandibular molars, is the most common origin of Ludwig’s angina and this predominance of dental etiology has been well backed up by evidence.2,3 Other less common etiologies include peritonsillar abscess, mandibular fracture, or other facial trauma. Although males and age groups from 20 to 40 years are commonly affected by LA,4 it has also been reported in neonates, children, and the elderly.3 Causative agents are usually a mix of both aerobic and anaerobic bacteria, including mouth organisms like streptococci or staphylococci.5\n\nHere, we report a case of a 15-year-old male who developed LA, was overwhelmed by its complications and later recovered from it. Also, there was an incidental finding of a roundworm in his respiratory tract. This case report is presented in line with the CARE guidelines.6\n\n\nCase presentation\n\nA 15-year-old male presented to the emergency department with concerns of swelling over his submandibular region (for nine days), fever (for four days), dysphagia, dysphonia, and drooling (for two days). Meticulous history taking revealed that the patient had experienced pain in his mandibular teeth recently, but he did not seek any medical attention for it. He had no known history of allergy, no history of trauma nor surgical or dental procedures. When asked about his personal history, he stated that he inconsistently brushed his teeth, and he had a habit of eating sugary items and drinking carbonated drinks. There was also no practice of visiting a dentist regularly in the patient’s family. On the day of the presentation, physical examination showed a fever of 102 degrees Fahrenheit, pulse rate of 143 beats per minute, respiratory rate of 37 breaths per minute, and blood pressure of 133/90 mmHg. Remarkable findings on examination were halitosis, firm and tender swelling which extended from one angle of the mandible to the other with bilateral involvement of submandibular space and sublingual space, restriction of mouth opening with an inter-incisor gap of 2 cm, swollen tongue, which was lifted up, and dental carries over both his mandibular first molars. However, examination for stridor, headache, cyanosis and regional lymph node involvement were negative (Figure 1).\n\nThe diagnosis of LA was made by judging the clinical picture: firm, tender, bilaterally symmetric swelling of sublingual space and submandibular space, presence of carious teeth, and history of poor oral hygiene. The patient was immediately admitted to the intensive care unit (ICU) and management was started promptly due to the possible impending airway obstruction. A vertical midline incision just above the sternal notch was given to perform an emergency tracheostomy, but couldn’t be performed successfully due to the purulent discharge coming out of the incision site. Then emergency endotracheal (ET) intubation was performed with the help of direct rigid laryngoscopy under general anesthesia. Multiple incisions along the angle of the mandibles were performed for drainage of the neck swelling. The patient was put on clindamycin (300 mg) and meropenem (1 gm) intravenously for 12 days and carious teeth (both mandibular first molars) were extracted. Elective tracheostomy was performed eight days later (Figure 2).\n\nDischarge can be seen coming from the vertical incision that was carried out to perform emergency tracheostomy.\n\nOn the third day of admission, while suctioning and caring for secretion from the ET tube, a roundworm came out of the ET tube. Adult worm identification examination confirmed that it was Ascaris lumbricoides. However, eosinophils were not raised and there was no trace of other worms and their eggs on the X-ray. For deworming, oral albendazole 400 mg was administered for three days. As the patient was being monitored regularly for possible complications of LA, empyema thoracic and loculated effusions were noticed on the fourth day of admission. Chest-tube insertion was carried out for its management. Our patient was also prescribed vancomycin (40 mg/kg) for 14 days as urine culture tested positive for Enterococcus species on the twelfth day of ICU admission (Figures 3 and 4).\n\nAfter successfully managing a series of complications and close monitoring for up to 26 days, the patient was transferred to the pediatric ward from the ICU. The patient recovered very well and faced no new issues. The tracheostomy was closed, and discharge was planned for the patient. Our patient and his parents were counseled about his clinical condition and the interventions carried out. Our patient was prescribed mupirocin (2%) ointment for application over the closed incision sites and prednisone tablets (5 mg, once a day, for five days) along with pantoprazole tablets (40 mg, once a day, for one month). He was called for a follow-up two weeks after discharge (Figures 5 and 6).\n\n\nDiscussion\n\nWe report a case of LA that originated from an odontogenic infection. Prabhu et al.7 concluded that odontogenic infections with poor oral hygiene are consistent in the majority of cases. Firstly, infection originates in the subgingival pocket then spreads to the musculature of the floor of the mouth. This infection now progresses below the mylohyoid line gaining access to sublingual space. Since the roots of the second and third mandibular molars lie below the mylohyoid line, infection of these teeth are most frequently involved in the development of LA. The infection then spreads to the submandibular space from the sublingual space. Okoje et al.8 pointed out in their study that the first mandibular molar can be involved in the development of LA but at low frequency. In our patient, there was the presence of unattended carious mandibular molars which acted as the source of infection.\n\nDiagnosis of LA is made based upon the clinical picture, and laboratory tests are of little immediate value.9 Grodinaky’s criteria for diagnosis of LA includes the involvement of more than one space usually bilaterally, the presence of gangrene with serosanguineous, putrid infiltration with very little or no frank pus, sparing of glandular structures and spread is through continuity not by lymphatics.3 As soon as we diagnosed the patient, he was intubated and admitted to the ICU due to the possible impending airway obstruction. This is the most feared complication of LA and this was to be considered with the utmost emergency. After securing the airway, early treatment of the underlying cause was important to avoid a lethal outcome. We removed the patient’s carious teeth, and he was put under broad-spectrum antibiotics. Since causative agents are usually a mix of both aerobic and anaerobic bacteria, the aim while using antimicrobials should be to cover all possibilities.4,5 Besides airway complications, our patient also showed empyema and pleural effusion on radiological examination. Empyema and pleural effusion are some of the noted complications of LA.2 This was only noticed later when radiological examinations were carried out as the priority was to intubate the patient and secure the airway first. Enterococcus species were isolated from the urine of the patient and this is thought to be hospital-acquired as Enterococcus species are a common cause of nosocomial urinary tract infection.10\n\nLA is not only a subject of concern of dental, otorhinolaryngology, and respiratory disciplines but a matter that raises multidisciplinary concern due to its other complications: mediastinitis, aspiration pneumonia, rupture of the carotid artery, thrombophlebitis of the internal jugular vein, necrotizing fasciitis, and osteomyelitis.2\n\n\nConclusion\n\nAlthough LA is a rare entity, it should be considered for differential diagnosis in cases of neck swelling especially in those having a history of poor oral hygiene and recent dental procedures. This condition spreads aggressively and demands aggressive management with the priority of securing the airways first and the use of broad-spectrum antimicrobials. Complications of LA require special attention from multiple disciplines. The practice of good oral hygiene is not just about the oral cavity but is also about life-threatening conditions like LA.\n\nOur 15-year-old patient has developed a positive outlook towards the condition he went through. He understands the clinical state he was in and is thankful to the entire hospital, especially the nurses who took care of him during his hospital stay. The patient understands the importance of maintaining good oral hygiene.\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": "Acknowledgements\n\nWe would like to acknowledge the role played by Dr Ramesh Bhattarai and Mr. Manoj Pradhan during the study.\n\n\nReferences\n\nMurphy SC: The person behind the eponym: Wilhelm Frederick von Ludwig (1790–1865). J. Oral Pathol. Med. 1996; 25: 513–515. PubMed Abstract | Publisher Full Text\n\nSpitalnic SJ, Sucov A: Ludwig’s angina: Case report and review. J. Emerg. Med. 1995; 13: 499–503. Publisher Full Text\n\nPatterson HC, Strome M, Kelly JH: Ludwig’s angina: An update. Laryngoscope. 1982; 92: 370–378. PubMed Abstract | Publisher Full Text\n\nMarcus BJ, Kaplan J, Collins KA: A case of Ludwig angina: A case report and review of the literature. Am. J. Forensic Med. Pathol. 2008; 29: 255–259. Publisher Full Text\n\nSaifeldeen K, Evans R: Ludwig’s angina. Emerg. Med. J. 2004; 21: 242–243. Publisher Full Text\n\nRiley DS, Barber MS, Kienle GS, et al.: CARE guidelines for case reports: explanation and elaboration document. J. Clin. Epidemiol. 2017; 89: 218–235. PubMed Abstract | Publisher Full Text\n\nPrabhu ES: Nirmalkumar, Acute fascial space infections of the neck: 1034 cases in 17 years follow up. Ann. Maxillofac. Surg. 2019; 9: 118–123. PubMed Abstract | Publisher Full Text\n\nOkoje VN, Ambeke OO, Gbolahan OO: Ludwig's angina: An analysis of cases seen at the University College Hospital, Ibadan. Ann. Ibadan Postgrad. Med. 2018; 16: 61. (accessed July 28, 2021). Free Full Text\n\nAn J, Madeo J, Singhal M: Ludwig Angina. StatPearls; 2021. (accessed July 7, 2021). Reference Source\n\nFelmingham D, Wilson APR, Quintana AI, et al.: Enterococcus Species in Urinary Tract Infection. Clin. Infect. Dis. 1992; 15: 295–301. Publisher Full Text"
}
|
[
{
"id": "146406",
"date": "19 Aug 2022",
"name": "Widiana Ferriastuti",
"expertise": [
"Reviewer Expertise Head and neck radiologist"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 Figure 6., \"Timeline showing major events\", the timeline of the patient's examination to diagnosis and treatment can be improved by being made in narrative form, so that the storyline is more understandable from each event.\n\nIn the second paragraph of the \"Discussion\" section, \"Diagnosis of LA is made based upon the clinical picture, and laboratory tests are of little immediate value\". Here the authors can add the \"before and after treatment\" supporting laboratory data, so that the causing factors of the ascaris lumbricoides presence can be made more clinically understandable.\n\nFor example, in the article referenced here, page 3104 conveys the results of the lab exam before and after the patient's examination, so that it can be used as supporting data to determine medical conditions and ensure patient safety.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? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Yes\n\nIs the case presented with sufficient detail to be useful for other practitioners? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1219
|
https://f1000research.com/articles/10-1217/v1
|
30 Nov 21
|
{
"type": "Research Article",
"title": "Augmented reality emotion recognition for autism spectrum disorder children",
"authors": [
"Han Foon Neo",
"Chuan Chin Teo",
"Quan Fong Yeo",
"Chuan Chin Teo",
"Quan Fong Yeo"
],
"abstract": "Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder that affects brain development. The prevalence of ASD is one in 68 children. Low social motivation is the main cause in developing social communication skills deficiency. As a result, it is becoming difficult for them to express themselves, to be able to manage social interactions, and they lack the ability to comfort others and even share their own feelings. This study aimed to design a mobile application based on augmented reality (AR) focusing on social interactions and communication aspect for children with ASD. The scope is in emotion recognition, which makes use of emotional icons to help them improve their social skills, more specifically on helping them to recognize various emotions. The emotions are represented by emojis inspired by Dr. Paul Ekman who has created the basic six emotions, namely happiness, sadness, disgust, fear, surprise, and angry. Additional emotions such as confound face, winking with tongue, cold sweat, blowing kiss, flushed, sleepy, disappointed, and winking are included. AR is able to gage the children’s attention when they view the animated emojis. The application enables the children with ASD to be more willing in recognizing different emotional expressions and improve their social skills by expressing their own feelings. The scope of the study is limited to emotion recognition. It is developed based on literature reviews without guidance of any certified ASD specialist. AR is an interactive technology that places digital information in our physical world in real time, providing precise registration in all three dimensions. Existing literature proved that the traditional face-to-face teaching methods have failed to increase the interest and ability of ASD children because the teacher has full control in the classroom. This study adds value to the existing works to incorporate AR as additional intervention in treating ASD children.",
"keywords": [
"augmented reality",
"autism spectrum disorder",
"emotion recognition",
"emoji",
"emotion expression",
"interactive technology"
],
"content": "Introduction\n\nChildren with autism spectrum disorder (ASD) have difficulty learning to understand, recognize, and manage emotions. This challenge has to be embraced as learning to understand emotions can help ASD children to respond to other people. Traditional teaching methods such as using everyday interactions and tools like emotion cards and social stories lack interactive elements to provide immersing experience and interest for children with ASD. This has caused them having difficulty to stay motivated and focused during learning, thus making them lose their interests quickly and stop learning. Hence, their potential development in proper study and communicating with others will be reduced or delayed due to the non-effective way of teaching.\n\nCurrent intervention methods for children with ASD are limited. These intervention methods are mostly based on in-person or social skill-group behavioral therapies done by professional therapists. The therapy is normally once every week over a time frame of at least 12 weeks. During the session, the therapist teaches special social skill and conducts activities such as role playing and discussion. The practice presents an opportunity for the ASD children to rehearse the social skills repeatedly. However, it is usually difficult to be accessed by parents or caregivers due to lack of talents in this field. Moreover, these intervention methods are usually costly, which most families cannot afford.\n\nTechnology has played a pivotal role in facilitating learning for the ASD children. It is well received and easily adapted since most of the applications are in the form of tablets. The emerging augmented reality technology has garnered attention especially children due to its immersive and engaging experience. Although augmented reality (AR) applications are widely used in multiple fields such as medical training, tourism industry, and military, there are fewer AR applications that are targeted or developed for children with ASD. Often, these AR applications lack therapeutic effects that help them to familiarize themselves in various social situations.\n\nAR is a technology that still on its early development; therefore, it is hard to find practical AR applications that focus on helping children with ASD in recognizing emotions. These applications are mostly on its preliminary period or only for research purposes. Hence, the purpose of this research is to create a mobile-based application making use of AR to enable children with ASD to learn emotions in a more intuitive way.\n\nThe contribution of this research is the proposed of a friendly user interface design integrate with AR functionality as an excited motivation to retain the ASD children’s learning time span. This paper is divided into several sections. Section 2 introduces the key concepts related to ASD and we have provided a review of a couple of existing applications. Section 3 presents the methodology and the proposed application screen designs are shown in Section 4. Finally, Section 5 presents the conclusion and its limitations.\n\n\nLiterature review\n\nASD is a complex brain development disorders that cause difficulties in serious developmental aspects such as social skills and behavioral challenges. The prevalence of ASD is one in 68 children. It affects people to behave differently from average people from communicating and interacting to learning.\n\nIt was suggested that low social motivation is the cause for children with ASD having an issue in developing social communication skills as they hardly focus on social information such as other people’s emotional behavior and faces.1 Moreover, they are also less likely to express their feelings such as pleasure and happiness when interacting with others. Children with ASD often struggle in understanding and responding to emotion in other people’s facial expressions.2 As a result, it is becoming difficult for these children to manage their social interactions even though they genuinely wanted to develop relationships.3 Children with ASD may also lack the ability to comfort others or share their own emotions. Sometimes, they may interpret a situation incorrectly and respond with unintended behavior or emotions.4\n\nCommunication has been the biggest challenge for parents with children with ASD as they lack the ability to respond and communicate appropriately with their parents.5 The growing number of children with ASD has definitely effected a modern educational systems trend.6 Face-to-face teaching method has failed to increase the interest and ability of children with ASD because a teacher is having full control in the delivery.7 Eventually, AR has been introduced to provide an alternative intervention for children with ASD.8\n\nAR has been around for decades and by fundamental terms, it is the concept of blending the real and virtual world. It is an interactive technology that places digital information in our physical world in real time, providing precise registration in all three dimensions.9 It is also worth mentioning that AR is considered a revolution and originated from virtual reality (VR). The basic difference is that AR is based on the camera field, while VR is not. Through AR, new possibilities for educational learning have emerged as the capability to combine the real and virtual world may further improve the quality of provided education.10 In this way, the engagement for children with ASD can be further enhanced and their motivation and learning interest can also be increased.11\n\nThere are quite a number of prototypes and applications proposed by researchers to improve emotion recognition targeted at ASD children. An intuitive augmented and alternative communication application was created to assist children with ASD in expressing their own emotions to their parents.12 Users can choose an emoji that represent their current emotion or needs. Text and audio that represent the emoji will be shown and played when user taps on the emoji. Users can send their message to the selected contacts. The sent contacts will receive a speech output message that represents the user’s current emotion or needs. It uses emoji in a user-friendly way to enable children with ASD to express themselves easily through the application. Also, parents can understand the emotions and needs of their children more easily and act accordingly in an efficient way through recorded feedbacks and actions in the application.\n\nChildren with ASD struggle to understand other people’s emotions and express their own emotion in the same way including recognizing facial expression. AR-based self-facial modeling (ARSFM) is a system, which users can see their own virtual three-dimensional (3D) facial expressions through an augmented mirror.13 3D head models are first created using users’ frontal and side face photo in 3D Facial Studio 3.0. Next, head models are animated in 3Ds Max 2012 to create six facial expression models that correspond to our basic emotions according to the Facial Action Coding System, namely, happiness, sadness, fear, disgust, surprise, and anger. These models are then finished with Unity game engine and Vuforia. To use the ARSFM system, a therapist will guide the users. Users are required to read through a scenario scripts and choose to wear one of the six facial expressions’ masks that is matched to the scenario. In the augmented mirror, users will see the pre-animated facial expression overlay on their own face to indicate the correct facial expression matching to the scenario.\n\nAn AR-based video modeling storybook was created to teach users to recognize emotions’ pattern in the storybook and then watching the story’s video clips with a tablet.14 Users are required to concentrate on the corresponding social stimulus and mimic facial expressions and emotions. They are also encouraged to pretend to feel those emotions. By observing facial expressions, it is useful in teaching children with ASD to practice recognizing, understanding, and responding to facial emotions more appropriately in daily social scenarios.\n\nFacial Emotion Expression Training (FEET) was developed to provide feedback to users in real time by detecting facial expressions and emotion problems.15 With FEET, users have to proceed through four levels: level one displays a simple cartoon face with basic emotions, level two displays a short recording of child actor showing emotions, level three displays only facial expression corresponding to a narration of short story mixing with background music, and level four displays an avatar showing an emotion. Every level, users are required to mimic the facial expression of the displayed contents using their own perception of the feeling, and feedback will be given by FEET throughout the session. The proposed system is able to accurately detect and categorize emotion in facial expression in real time and also improve facial expressions’ recognition of children with ASD.\n\nAn AR puzzle-style application was created, which required users to interact with a tablet device with a frontal camera.16 There are two stages: a customization stage and an emotion guessing stage. In the customization stage, users create a emoji based on their own preferences with the help of various AR markers representing different emotions, colors, and shapes. After users are satisfied with their emoji, they will proceed to the second stage that requires them to guess the facial expression of a different emoji using the markers. Constructive feedback will be given when users accomplish the guessing, or users will be redirected to the right answer. With a design of clear visual clues, the AR puzzle-style application aimed to improve emotion recognition skills of children with ASD and keep their attention without any confusion.\n\n\nMethodology\n\nHumans experience the six basic emotions and these feelings are represented by emojis inspired by Dr. Paul Ekman, the psychologist who has created the basic six emotions in the Emoji Recognition Chart in the 1970s, namely, happiness, sadness, disgust, fear, surprise, and angry. Humans also experience more complex feelings such as embarrassment, guilt, shame, trust, and anticipation. Hence, we have also included additional complex emojis such as confound face, winking with tongue, cold sweat, blowing kiss, flushed, sleepy, disappointed, and winking.\n\nThe AR feature is embedded to motivate the children with ASD to experiment with an array of emotions. The user needs to set a predefined area to trigger the AR feature. Indirectly, this enables the user to practice and reinforce the motor skills in setting the boundaries of the plane. The scripting in this research is based on C# programming and Unity software. Hence, the technical requirement to run the application is to use a touch-based device with an Android version 5 and a camera with minimum of 3 megapixels.\n\nFor the system evaluation, a preliminary assessment was carried out on ten subjects. The objective was to assess the usability of the application in terms of their perception using a survey. There are three steps involved during data collection. Firstly, we showed the respondent the mobile application and spent approximately 10–15 min instructing them. The respondent then spent another 15 min exploring the application. Finally, we conducted a survey by providing an online questionnaire. The whole process took 30–40 min to complete. In the questionnaire, there are altogether nine questions rated according to a 5-point Likert scale. Due to inaccessibility to children with ASD during the COVID–19 nation lockdown, the ten subjects were neurotypical children who were randomly chosen aged between 6 and 12 years. The respondents were fluent in using smartphone technology, and this reduces unnecessary risk in accessing the application.\n\n\nResults\n\nBased on the research gaps found through literature review, a solution of AR emotion recognition for ASD children was proposed. The prototype is shown in Figures 1 to 5. In the Main Menu page, users could choose to learn, trigger the AR feature, or play the quiz.\n\nAs shown in Figure 1, users can learn the basic emojis and emotions through 2D emoticons. The purpose was to ensure that user understands and recognizes the emoji facial features, such as smiling happily. The emoticons available are based on emoji recognition, namely, happiness, sadness, disgust, fear, surprise, and angry. More emoticons are included, which have slightly complicated emotions such as confound face, winking with tongue, cold sweat, blowing kiss, flushed, sleepy, disappointed, and winking.\n\nIn Figure 2, AR is the main element of the proposed prototype. It uses AR functions to enable users to learn emotions and interact with emojis. It has two modes: single mode and multiple mode, one with single types of emoji and the other are combined with multiple different emojis. In the single mode, the user will first be shown a panel (pop-up message), which instructs them how to use the AR functions. After the panel is dismissed, the PLANE TOGGLE button and DETAILS button are shown. Users can instantiate the emoji by touching the screen. Also, they can interact with it by selecting it, which a transparent bounding box will be shown, and then users can scale, move, and rotate the emoji.\n\nUsers first click on the Dismiss button and move the smartphone device around the floor/table/carpet to draw up a boundary for the plane. Once the plane area is set, users just need to instantiate the emoji that you would like to see. In this case, the happiness emoji is chosen. You can keep on instantiate Happiness emoji and it will keep on appearing. When the user taps on the Happiness emoji, a message would appear telling the user the attributes of Happiness emoji, such as it is a smiling facial expression, it means a relaxed mood, and it shows a pleasant way of speaking.\n\nIn the multiple mode, users will also be shown a panel (pop-up message), which instructs them how to use the AR functions. After the panel is dismissed, the PLANE TOGGLE button and EMOJI OPTION buttons are shown. Users can instantiate different types of emoji by touching the screen. Also, they can interact with it by selecting it, which a transparent bounding box will be shown, and then users can scale, move, and rotate the emoji. Users can also take photo of their favorite emoji or emoji that represents their emotions to be saved in an album.\n\nThe album stores all the photos that users have taken in AR mode. Users can view their collections here and can also delete photos, which they do not want to keep. Parents also can view these photos to perhaps know their children’s emotional state. These photos are kept in the internal storage of the phone. Users can do the quiz once they feel ready to challenge themselves. Users can challenge the quiz and collect an emoji trophy. Trophies awarded are stored in the Trophy room as shown in Figure 5. The Quiz menu has the main elements such as the PLAY icon, TROPHY ROOM icon, INFO icon, and RESET icon. Users need to finish the quiz in one shot to collect all trophies. Once wrong, users will be prompted a wrong window and auto quit to Quiz menu. If correct, users will be prompted to a page, which showcases a rotating 3D emoji trophy that they have collected. The collected emojis are automatically stored in the Trophy room.\n\nThe initial Trophy room is empty and emoji trophies will be added once users have completed each question. The emoji in the Trophy room is animated in different ways to reflect the real-world actions based on that emotions. Various emotions will be displayed in the Trophy room after completing all quiz questions.\n\nThe preliminary evaluation examined the children’s perception of the application. In terms of whether the application is fun, six of them agreed, while one disagreed, and three felt neutral. In assessing whether the respondents feel that the applications help them to understand emotions better, six agreed, two disagreed, and the other two were neutral. In terms of learning contents, 30% of respondents think that it is useful. 90% of the respondents agreed that the application interface was very easy to use and user friendly, while 80% of them were excited by the AR feature. Regarding the photo feature, 60% of the respondents enjoyed using it, while eight of them thought that the quiz was fun. Six respondents agree that they like the Trophy room feature, and 80% of respondents will recommend this application to others. The summary of the results is shown in Figure 6.\n\nAs a summary of the preliminary evaluation, we obtained a mean value of 3.98 and standard deviation of 0.9757. We can conclude that overall, the respondents are positive about the application’s usefulness.\n\n\nDiscussion and conclusion\n\nThe respondents have shown a positive perception toward the application. This is due to the reason that they felt that the application is helpful in facilitating ASD children to recognize emotions easily. In terms of fun, since the respondents are neurotypical children, they might be more adept in using the emojis in their life when sending messages through WhatsApp or Telegram as compared to the ASD children. Hence, the emojis do not appear as new or enticing to them. However, the respondents feel that the application is user friendly. This aspect is important as a user-friendly tool will not burden the ASD children. One of the characteristics of ASD children is their inability to express their emotion or they do not feel for an emotion; hence, a novel approach created in the application enables the ASD children to share their emotion with their parents or peers through sharing of pictures. In addition, we believe that the AR feature is interesting and engages the children’s motor skills at the same time as relaying the emojis over the fixed physical space.\n\nAR is able to engage the children’s attention when they view the animated emojis in the self-defined plane area. The scene can be snapshot to be saved in the photo album. The application enables the ASD children to be more willing in recognizing different emotional expressions and improve their social skills by expressing their own feelings. The scope of the study is limited to emotion recognition. It is developed based on literature reviews without guidance of any certified ASD specialist. AR is an interactive technology that places digital information in our physical world in real time, providing precise registration in all three dimensions. Existing literature proved that the traditional face-to-face teaching methods have failed to increase the interest and ability of ASD children because the teacher is having full control in the classroom. This study adds value to the existing works to incorporate AR as additional intervention in treating ASD children.\n\n\nAuthor contributions\n\nH.F.-N. is the corresponding author and is the supervisor for this project. She has contributed to writing and editing the research paper. C.C.-Teo is responsible for proofreading the research paper, while Y.Q.F. has contributed in application development and original draft preparation.\n\n\nData availability\n\nFigshare: Underlying data for ‘Augmented reality emotion recognition for autism spectrum disorder children’. https://doi.org/10.6084/m9.figshare.1694372817\n\n\nEthics approval and consent to participate\n\nThe conduct of this research has obtained the ethical approval number EA0872021 issued by the Research Ethics Committee, Multimedia University. Written informed consent from the respondents’ guardians was obtained prior to the data collection process.",
"appendix": "Acknowledgements\n\nWe would like to thank the respondents for willing to participate in the survey amid COVID-19 lockdown.\n\n\nReferences\n\nBai Z: Augmenting imagination for children with autism. ACM International Conference Proceeding Series. 2012; 327–330. Publisher Full Text\n\nBai Z, Blackwell AF, Coulouris G: Exploring expressive augmented reality: The fing AR puppet system for social pretend play. Conference on Human Factors in Computing Systems - Proceedings, 2015-April. 2015; 1035–1044. Publisher Full Text\n\nBanire B, Al Thani D, Makki M, et al.: Attention Assessment: Evaluation of Facial Expressions of Children with Autism Spectrum Disorder. Lecture Notes in Computer Science (Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 11573 LNCS. 2019; 32–48. Publisher Full Text\n\nChung S, Oh U: Exploring the design space of an augmented display for conveying facial expressions for people with autism. Adjunct Proceedings of the 2019 IEEE International Symposium on Mixed and Augmented Reality, ISMAR-Adjunct 2019. 2019; 435–437. Publisher Full Text\n\nLakshmiprabha NS, Santos A, Mladenov D, et al.: [Poster] An Augmented and Virtual Reality System for Training Autistic.2014; 277–278.\n\nEscobedo L, Nguyen DH, Boyd L, et al.: Mosoco.2012; 2589. Publisher Full Text\n\nNincarean D, Alia MB, Halim NDA, et al.: Mobile Augmented Reality: The Potential for Education. Procedia - Soc. Behav. Sci. 2013; 103(May): 657–664. Publisher Full Text\n\nTomi AB, Rambli DRA: An interactive mobile augmented reality magical playbook: Learning number with the thirsty crow. Procedia Com. Sci. 2013; 25: 123–130. Publisher Full Text\n\nAzuma RT: A survey of augmented reality. Presence: Teleoperators and Virtual Environ. 1997; 6(4): 355–385. Publisher Full Text\n\nKaramanoli P, Tsinakos A: Use of augmented reality in terms of creativity in school learning. CEUR; 2015.\n\nSyahputra MF, Arisandi D, Lumbanbatu AF, et al.: Augmented reality social story for autism spectrum disorder. J. Phys. Conference Series. 2018; 978(1): 012040. Publisher Full Text\n\nSharma P, Upadhaya MD, Twanabasu A, et al.: “Express Your Feelings”: An Interactive Application for Autistic Patients. Lecture Notes in Computer Science (Including Subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics), 11573 LNCS. 2019; 160–171. Publisher Full Text\n\nChen CH, Lee IJ, Lin LY: Augmented reality-based self-facial modeling to promote the emotional expression and social skills of adolescents with autism spectrum disorders. Res. Dev. Disabil. 2015; 36: 396–403. Publisher Full Text\n\nChen CH, Lee IJ, Lin LY: Augmented reality-based video-modeling storybook of nonverbal facial cues for children with autism spectrum disorder to improve their perceptions and judgments of facial expressions and emotions. Comput. Hum. Behav. 2016; 55: 477–485. Publisher Full Text\n\nWhite SW, Abbott L, Wieckowski AT, et al.: Feasibility of Automated Training for Facial Emotion Expression and Recognition in Autism. Behavior Therapy. 2018; 49(6): 881–888. PubMed Abstract | Publisher Full Text\n\nDaniel VLT, Ting H, Photchara R, et al.: An AR puzzle application for improving emotion recognition for as children. ACM International Conference Proceeding Series. 2019; 52–56. Publisher Full Text\n\nNeo H-F, Teo C-C, Fong YQ: Underlying data for ‘Augmented reality emotion recognition for autism spectrum disorder children’.2021. Publisher Full Text"
}
|
[
{
"id": "119493",
"date": "14 Feb 2022",
"name": "Gonzalo Lorenzo Lledó",
"expertise": [
"Reviewer Expertise Augmented reality",
"virtual reality",
"robotics and autism"
],
"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 my opinion the article is not of a high enough standard to be published in a scientific journal. I have some questions:\nWhat is the aim of the research? It does not appear in the abstract, for example, and neither does it appear in the article.\n\nI understand that a series of questionnaires are used and answered by the parents, what do the parents have to do in the whole design process? Why are these data not shown in the results?\n\nWhat are the specific research questions/objectives of the study?\n\nIt would be necessary to separate discussions and conclusions. Moreover, the discussions are more an extension of the introduction than a critique of the results obtained. The same mistake occurs with the conclusions.\n\nThe article lacks scientific rigour. I advise the authors:\n\nIntroduction. Method 2.1.- Characteristics of the participants. 2.2.- Instrument 2.3.- Design 2.4.- Procedure Results Discussions Conclusions.\n\nThe references used are old, AR is a field in continuous progress and there are a large number of works in the period 2020-2022.\n\nA pre-test and post-test could have been carried out to check the effectiveness of the application in a pilot test. The descriptive study carried out is poor.\n\nWhat contribution do the authors make to the field of work? What is the reason for carrying out this study and what improvements does it present with respect to the previous ones? All this is not clear either.\nAll these reasons are enough to reject the article.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": []
}
] | 1
|
https://f1000research.com/articles/10-1217
|
https://f1000research.com/articles/10-791/v1
|
11 Aug 21
|
{
"type": "Research Article",
"title": "Hematologic and coagulopathy parameter as a survival predictor among moderate to severe COVID-19 patients in non- ICU ward: a single-center study at the main referral hospital in Surabaya, East Java, Indonesia",
"authors": [
"Siprianus Ugroseno Yudho Bintoro",
"Ni Made Intan Dwijayanti",
"Dana Pramudya",
"Putu Niken Amrita",
"Pradana Zaky Romadhon",
"Tri Pudy Asmarawati",
"Arief Bachtiar",
"Usman Hadi",
"Ni Made Intan Dwijayanti",
"Dana Pramudya",
"Putu Niken Amrita",
"Pradana Zaky Romadhon",
"Tri Pudy Asmarawati",
"Arief Bachtiar"
],
"abstract": "Background : This research aimed to examine and analyze risk factors for death, hematologic parameters and coagulation in COVID-19 patients at RSUD Dr. Soetomo Surabaya, one of the referral centers for probable COVID-19 patient cases in East Java. Method : This was a retrospective analytical study by taking secondary data on patients with probable COVID-19 cases who were treated in hospital isolation rooms from May to September, 2020. Result : Of 538 probable COVID-19 patients, 217 tested positive, with an average age of 52.11±13.12 years, and there were 38 death cases. Hematologic parameters, such as white blood cell, neutrophil and lymphocyte counts, were significantly different in the deceased group. On the other hand, coagulation parameters, consisting of D-dimer, CRP, PT, and aPTT showed significantly similar value in the deceased group. Univatiate analysis concluded that chronic kidney disease, diabetes mellitus, coronary heart disease, WBC, NLR, and PPT counts could predict the mortality, while multivariate analysis revealed that coronary heart disease was the only significant independent predictor of mortality. Conclusion : This research shows that hematologic and coagulation parameters were increased in the majority of COVID-19 patients and the deceased group. While the number of neutrophils and WBC increases, the number of lymphocytes decreases significantly with increasing disease severity. Coronary heart disease is an independent predictor of mortality.",
"keywords": [
"COVID-19",
"comorbid",
"hematology",
"coagulopathy",
"good health",
"and well-being"
],
"content": "Introduction\n\nIn December 2019, China reported a mysterious pneumonia case of unknown cause which had spread rapidly in Wuhan city. The World Health Organization (WHO) named this virus as the 2019 novel coronavirus (2019-nCoV),1,2 and the name was changed to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) by the Coronaviridae Study Group (CSG) of the International Committee on Taxonomy of Viruses; the official name of the disease caused by the virus is COVID-19.2,3 COVID-19 is a major health concern at this time, especially for the elderly, due to the SARS-CoV-2 virus.4,5 This coronavirus has become the main pathogen, causing an outbreak of respiratory disease until it has been declared a pandemic, and spreading rapidly throughout the world, including Indonesia.6 COVID-19 has become a global problem today due to the high transmission and mortality rates.7\n\nAs reported by Huang et al., patients with COVID-19 present primarily with fever, myalgia or fatigue, and dry cough.7 Although most patients are considered to have good prognoses, elderly patients, as well as those with underlying chronic conditions, may have worse outcomes. Severe patients may experience shortness of breath and hypoxemia within one week of disease onset, which can rapidly progress to acute respiratory distress syndrome (ARDS) or end-organ damage. Chronic cardiac and metabolic disease, the presence of acute inflammation as well as decreased organ (heart, kidney, liver, and hematology) function experienced by patients at the beginning of treatment, can increase the risk of death due to COVID-19 infection.8,9\n\nThe need for COVID 19 patients to be hospitalized varies widely from country to country as it depends on the prevalence of community testing and admission criteria.2,10 However, it is estimated that one in 5–10 adult patients with disease severity and sufficient criteria to be hospitalized. Most of the patients with severe acute respiratory infections or severe acute respiratory syndrome were managed according to the case definition of WHO. The criteria for intensive care also vary from country to country. Old age, chronic disease, and male gender are consistently associated with increased mortality.10\n\nHematologic and coagulation parameters were important for predicting the severity of COVID-19. The occurrence of disseminated intravascular coagulation (DIC) is a common finding in deceased COVID-19 patients.11 In addition, administering anticoagulant therapy to high-risk patients is effective in reducing mortality.12,13\n\nThe first COVID-19 case in Indonesia was announced on March 2, 2020, about four months after the first case in China.14 The first cases in Indonesia in March 2020 were two cases; and after that on March 6, two cases were found again. COVID-19 cases continue to grow. In the beginning, there were hundreds of cases added; and until now, the number of cases has increased to thousands. On March 17, 2020, the government of East Java reported the first case of COVID-19, and as of July 31, 2020, there were 22,098 confirmed cases with a fairly high mortality rate of 7.6%.16 Meanwhile, in Surabaya City in July 2020, there were 8,691 confirmed COVID-19 patients. The RSUD Dr. Soetomo (RSDS) Surabaya is one of the referral centers for probable COVID-19 patient cases in East Java. Based on the total cases, it is necessary to collect data, including clinical manifestations, risk factors, hematologic parameters, and coagulation which aggravate the condition of COVID-19 patients.17\n\nSeveral studies related to clinical manifestations and risk factors for COVID-19 patients have been reported previously; however, this research is based on relatively small sample size, and the risk factors that lead to poor clinical outcomes have not yet been well explained. In addition, deceased patients in probable and confirmed cases of COVID-19 at RSDS Surabaya had often presented with comorbidities, such as diabetes mellitus, high blood pressure, heart disease, hematological disorders, old age, chronic lung disease, stroke, and kidney disorders. This leads to discussion around which comorbid, hematologic parameters and coagulation factors may become predictive of COVID-19 mortality.\n\n\nMethods\n\nThis was a retrospective analytical study, performed by taking secondary data on patients with probable COVID-19 cases who were treated at the special isolation room (non-intensive care) of the Department of Internal Medicine of the teaching hospital of RSUD Dr. Soetomo between May and September, 2020. The sample consisted of deceased and survived patients at the special isolation room (non-intensive care) of Internal Medicine of RSUD Dr. Soetomo, who had been hospitalized with probable COVID-19. The inclusion criterion was hospitalization with probable COVID-19 in patients who were more than 18 years old. The exclusion criterion was incomplete care clinical data. This research began with sample selection including all COVID-19-probable hospitalized patients (a total of 538 probable cases); then a diagnosis of COVID-19 was examined using reverse-transcription polymerase chain reaction (RT-PCR), carried out through nasal swab. RT-PCR results showed 297 patients were positive (55.2%) and 241 patients were negative (44.8%). Of the 297 positive patients with COVID-19, 80 patients had incomplete medical record data, therefore, 217 patients met the inclusion criterion and were included in the study (see Figure 1).\n\nApproval from the local ethics committee was obtained for this research; written informed consent was obtained from patients during hospitalization. Then from the hospital infromation database system, we retrieved patient characteristics such as age, gender, comorbidities, signs and symptoms, and laboratory results, including hemoglobin, white blood cell (WBC), neutrophil, lymphocyte, and platelet counts, D-dimer level, C-reactive protein (CRP), prothrombin time (PT), and activated partial thromboplastin time (aPTT).\n\nData analysis was performed using SPSS version 25 (Chicago, IL, USA; RRID:SCR_002865); JASP (RRID:SCR_015823) is an open access alternative. Patient characteristics (see Table 1) are presented as mean ± standard deviation or median, and interquartile ranges of 25th and 75th percentiles (IQR 1–3) or minimum and maximum, depending on the continuous distribution variable. Normality tests were performed and a comparison test for normal distribution data by an independent sample t-test and a Mann–Whitney test, otherwise. Comparison for the caterogical variables were performed using Pearson's and Fisher's Exact Chi-squared tests. Survival analyses and Kaplan–Meier survival curves were performed for hemoglobin, white blood cell, neutrophil, lymphocyte, neutrophil–lymphocyte ratio, D-dimer, PT, aPTT, and CRP.\n\n* Fischer Exact test.\n\n** Mann-Whitney test.\n\nEvaluation the independent predictors of mortality was perfomed by univariate and multivariate Cox regression analysis. Threshold mortality predictor from the laboratory parameter was performed;the receiver–operating curve (ROC) analysis associated with the area under the curve (AUC) was used to find the optimal threshold value of the laboratory rate parameter to predict the progression of mortality in the study group. The AUC was interpreted as excellent if 0.9 < AUC < 1; good if 0.8 < AUC < 0.9; moderate if 0.7 < AUC < 0.8; poor if 0.6 < AUC < 0.7; and fail if 0.5 < AUC < 0.6.\n\n\nResults\n\nAs many as 538 patients with probable COVID-19 were included during the study period. Based on the total, 288 (53.5%) were males, with the mean ± SD age of 51.69 ± 13.67 years. More than half of the patients (63.7%) had elemental diseases, including diabetes mellitus (34%), hypertension (32.5%), and CKD (22.7%). All the patients with probable COVID-19 experienced symptoms on arrival, including complaints of shortness of breath (48.7%), cough (40%), fever (32%), and limp (24%). Some patients also complained of diarrhea and headache but the percentage was low at 10.2% and 3.2%, respectively.\n\nIn total, we included 217 hospitalized patients with a diagnosis of COVID-19; their were 116 male patients and the male-to-female ratio was 1.14. The average age of this retrospective research was 52.11 ± 13.12 years. The most common chronic disease (comorbid) among patients was diabetes (33.2%). The clinical and demographic characteristics and laboratory results are shown in Table 1.\n\nFrom 217 patients, 38 patients (17.5%) died. They were significantly older than those who survived (mean 58.42 ± 12.78 versus 50.77 ± 12.83 years, respectively; p < 0.001). The majority of the deceased patients had at least one comorbidity (73%), while 56.4% of the patients who survived had comorbid factors (p = 0.049). The common comorbidities that were significantly different were diabetes mellitus, hypertension, and coronary heart disease in the group of deceased patients than in those who survived. In deceased patients, the white blood cell, neutrophil, and lymphocyte counts were significantly different to the survived patients. The same was true for D-dimer, CRP, PPT and aPTT (see Table 2).\n\n* Kruskal-Wallis test.\n\nInflammatory markers (leukocyte, C-reactive protein, neutrophill count and NLR) were significantly higher in the deceased group than in the group who survived. While the normal leukocyte and neutrophil counts were significantly more common in the patients who survived, and lymphopenia was significantly more common in deceased patients (p = 0.048). Meanwhile, the frequency of thrombocytopenia and the increase in D-dimer were comparable between the two groups.\n\nThe ROC analysis using sensitivity and specificity based on mortality predictor revealed that there was an optimal cut-off value for several laboratory parameters including WBC count, neutrophil count, CRP level, D-dimer, and NLR count. The largest AUC value was CRP with a cut-off value of ≥1.85 (sensitivity = 94.7% and specificity = 72.1%). NLR, WBC count, neutrophil count, D-dimer, and CRP as mortality predictors showed good results (see Table 3).\n\nThe Kaplan–Meier graph showed that there was a significant association between mortality and leukocyte count, neutrophil count, NLR, PT, and CRP (p < 0.05, respectively) (see Figure 2). Lower survival rate was shown from leukopenia, leukocytosis, neutrophillia, high NLR, high CRP, and prolonged PT (p = 0.015; p = 0.018, p = 0.003, p = 0.035, and p = 0.03, respectively).\n\nWe included age (as a categorical variable of under and over 65 years old), presence of chronic kidney disease, diabetes mellitus, coronary heart disease, and indicators, such as WBC count, NLR, CRP, PT, aPTT, and D-dimer for determining the predictors of mortality. In the univariate analysis, the independent predictors of mortality were shown from presence of chronic kidney disease, diabetes mellitus, coronary heart disease, WBC count, NLR, and PPT. However, based on the Cox multivariate regression analysis, only coronary heart disease significantly became the independent predictor of mortality (see Table 4).\n\n\nDiscussion\n\nSignificant differences were found in the demographic and clinical variables, and hematologic and coagulation parameters between the deceased and surviving COVID-19 patients. We included age in the risk factor for COVID-19 mortality, whereas the age had a p-value <0.05. The age factor appeared to be crucial for the outcome of COVID-19. The average age of the deceased patients was 58 years old and was significantly older than the surviving patients. This was in accordance with previous studies which stated that 80% of deaths in COVID-19 were of adulthood, therefore, old age can be said to be a risk factor for COVID-19 mortality.15,16 Increasing age also increased the percentage of COVID-19 mortality from 5% in the youngest age patients, to 55% at the oldest age.17\n\nGender was proven to be a risk factor for mortality in COVID-19 patients, which was higher for men than for women. This was due to the fundamental differences in the immunological systems of men and women, differences in lifestyle, and the prevalence of smoking.18 In this research, although statistically insignificant, the percentage of the number of male COVID-19 patients was higher, both overall and in the group of deceased patients. The higher mortality rates were associated with the higher chronic comorbidities in men, e.g., diabetes mellitus, kidney disease, hypertension, heart disease, lung disease, and smoking.19\n\nThe comorbid factors of diabetes mellitus, heart disease, and chronic kidney disease in COVID-19 patients could be the risk factors of death in this research, with a p-value of <0.05. This result was similar to the meta-analysis study conducted by Mantovani et al., who stated that the prevalence of diabetic patients hospitalized due to COVID-19 was 14.34%, and 11.06% in patients in Asian countries. Meanwhile, the prevalence in non-Asian countries was higher, which was 23.34%. The risk of worsening the condition to require treatment in intensive care was two times greater in diabetes patients.20 Likewise, elderly patients with diabetes belonged to the group at risk of death.21\n\nFor the hematologic parameters in this research, the leukocyte, neutrophil counts, lymphocyte count, and NLR were significantly different in the deceased patients than in the surviving patients. This research results were consistent with several previously published studies.22,23 On the other hand, the platelet count in this research was comparable between the groups of deceased and surviving patients. This was in contrast with the results of a meta-analysis that concluded by Lippi et al., who showed that thrombocytopenia was associated with increasing severity risk and mortality of COVID-19.24 Differences in pathophysiological mechanisms in each patient may lead to insignificant findings in this research. Many researchers have studied the changes in peripheral blood cell counts in COVID-19, and the results were that in infected patients, the white blood cell and neutrophil count increased, while the lymphocyte and platelet counts decreased.25 In the other cases, coagulation abnormalities (prolonged PT and aPTT) and intravascular coagulopathy (DIC) were so correlated with low platelet count.26\n\nThe extreme inflammation is usually evidenced by elevated serum of CRP, IL-6, and PCT which indicate the increasing of COVID-19 severity.27 High levels of CRP and procalcitonin in COVID-19 patients are also associated with the progression of ARDS, myocardial injury, and death.27,28 The presence of secondary bacterial infection would be an additional explanation of this increase in inflammatory biomarkers. This is consistent with this research which showed that serum CRP levels were significantly higher in the cohort of deceased COVID-19 patients. Therefore, we believe that the use of CRP as a biomarker in monitoring the progress and severity of COVID-19 patients will be beneficial.\n\nIn a systematic review, Vidali et al. concluded a correlation between increasing D-Dimer levels and the incidence of complications and death from COVID-19. Significantly higher serum D-dimer levels were showed in COVID-19 patients with acute respiratory distress syndrome (ARDS) and the group of deceased patients.29 However, our results showed that D-dimer levels were comparable between both groups of deceased and survived patients, this result could be due to differences in measurement methods as disclosed by Favaloro et al. who stated several things regarding the measurement and reporting quality of D-dimers such as the measurement method, cut-off value, or D-dimer unit [D-dimer unit (DDU)] can lead to different research results.30\n\nPT and aPTT prolongation may occur during severe COVID-19, yet the increase is less severe than that observed in bacterial sepsis and DIC.34 A meta-analysis conducted by Henry et al.28 found that patients with severe and fatal COVID-19 had significantly higher coagulation parameters (especially PT) than patients with the non-severe disease. This is consistent with this research where there was an increase in aPTT (but not statistically significant) and a significant increase in PT with p < 0.05 in the group of deceased patients. Although it is not completely clear how SARS-CoV-2 activates the coagulation cascade, it may be associated as a byproduct of cytokine storms.31 Researchers detected a significant extension in coagulation tests in this research, consistent with previously published studies.25,32 The mechanism of these changes is still not fully explained, however, the extension of the coagulation test, i.e., increased PT and aPTT, can be considered as a marker of disease severity and activation of the coagulation cascade and virus-induced cytokine storm.31,33\n\nFor as much as this research was a retrospective study, several parametes were not completely listed such as level of ferritin, fibrinogen, procalcitonin, and IL-6, hence we considered this as one of our research limitation. Since the development of complications that have occured in patients are not thoroughly documented, we can not confidently say that inflammatory and coagulation factor disorders are more common in severe COVID-19. The only outcome measure of this research was patient mortality in hospital. Although researchers evaluated platelet count and D-dimers, the International Society on Thrombosis and Hemostasis (ISTH) scores of the research’s patients were not calculated, and therefore, patients who had mild-to-moderate coagulation disorders and those who had a DIC could not be distinguished.\n\n\nConclusion\n\nThis research indicates that hematologic and coagulation parameters are increased in the majority of COVID-19 patients and the group of deceased patients. While the neutrophil count and WBC increase, the lymphocyte count decreases significantly along with the increase in disease severity. Coronary heart disease is an independent predictor of mortality.\n\n\nData availability\n\nFigshare: Underlying data for ‘Hematologic and coagulopathy parameter as a survival predictor among moderate to severe COVID-19 patients in non- ICU ward: a single-center study at the main referral hospital in Surabaya, East Java, Indonesia’. https://doi.org/10.6084/m9.figshare.14673060.\n\nThe project contains the following underlying data:\n\n• Hema_Coagul_parameter_COVID.xlsx (main data).\n\n• readme.docx (index).\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 was received from the patients during hospitalization.",
"appendix": "Acknowledgments\n\nResearchers greatly appreciate to Dr. Joni Wahyuhadi., dr., Sp.BS(K) as the director in Dr. Soetomo General Teaching Hospital who has facilitated us in conducting research and Dr. Soebagjio Adi Soelistijo, dr.,Sp.PD.,KEMD.,FINASIM for giving us the opportunity to get research grant and facilitating us to collect data in internal medicine wards and intellectual discussion leading to research idea.\n\n\nEthical statement\n\nThe research ethics committee Dr. Soetomo General Academic Hospital (No: 0039/KEPK/VIII/2020).\n\n\nReferences\n\nZhou P, Lou YX, Wang XG, et al.: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature. 2020; 579(7798): 270–3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWHO: Clinical management of COVID-19, interim guidance 27 May 2020.2020. 55 p. Reference Source\n\n(WHO) WHO: Coronavirus disease COVID-2019 - Situation Report – 142 Data. Saf Risk Pharmacother . 2020, 1; 8: 3–8. 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. Publisher Full Text\n\nJi W, Wang W, Zhao X, et al.: Cross-species transmission of the newly identified coronavirus 2019-nCoV. J Med Virol. 2020 Apr 19; 92(4): 433–40. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhifzhon Azwar M, Setiati S: COVID-19 and Indonesia. Acta Med Indones. 2020; 52(1): 84–9. Reference Source\n\nHuang C, Wang Y, Li X, et al.: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb; 395(10223): 497–506. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYang W, Cao Q, Qin L, et al.: Clinical Characteristics and Imaging Manifestations of the 2019 novel coronavirus disease (COVID-19): A Multi-center study in Wenzhou City, Zhejiang, China. J Infect . 2020; 80(February): 388–93. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nWenham C, Smith J, Morgan R: COVID-19: the gendered impacts of the outbreak. Lancet. 2020; 395(10227): 846–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLancet T: The gendered dimensions of COVID-19. Lancet. 2020; 395(10231): 1168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMantovani A, Byrne CD, Zheng M: Diabetes as a Risk Factor for Greater COVID-19 Severity and in-Hospital Death: A Meta-Analysis of Observational Studies. Nutr Metab Cardiovasc Dis. 2020; 30(January): 1236–48. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang B, Li R, Lu Z, et al.: Does comorbidity increase the risk of patients with COVID-19. Aging (Albany NY) . 2020; 12(7): 6049–57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu Y, Du X, Chen J, et al.: Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19. J Infect . 2020; 81(January): e6–12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTatum D, Taghavi S, Houghton A, et al.: Neutrophil-to-Lymphocyte Ratio and Outcomes in Louisiana COVID-19 Patients. Shock. 2020; 54(5): 652–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLippi G, Plebani M, Michael B: Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis. Clin Chim Acta . 2020; 506(January): 145–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHenry BM, de Oliveira MHS, Benoit S, et al.: Hematologic, biochemical and immune biomarker abnormalities associated with severe illness and mortality in coronavirus disease 2019 (COVID-19): a meta-analysis. Clin Chem Lab Med. 2020; 58(7): 1021–8. PubMed Abstract | Publisher Full Text\n\nBao C, Tao X, Cui W, et al.: SARS-CoV-2 induced thrombocytopenia as an important biomarker significantly correlated with abnormal coagulation function, increased intravascular blood clot risk and mortality in COVID-19 patients. Exp Hematol Oncol . 2020; 9(16): 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChen G, Wu D, Guo W, et al.: Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 2020; 130(5): 2620–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang I, Pranata R, Lim MA, et al.: C-reactive protein, procalcitonin, D-dimer, and ferritin in severe coronavirus disease-2019: a meta-analysis. Ther Adv Respir Dis. 2020 Jan 2; 14(6): 175346662093717. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVidali S, Morosetti D, Cossu E, et al.: D-dimer as an indicator of prognosis in SARS-CoV-2 infection: a systematic review. ERJ Open Res . 2020; 6(2): 260–2020. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFavaloro EJ, Thachil J: Reporting of D-dimer data in COVID-19: Some confusion and potential for misinformation. Clin Chem Lab Med. 2020; 58(8): 1191–9. PubMed Abstract | Publisher Full Text\n\nMarietta M, Coluccio V, Luppi M: COVID-19, coagulopathy and venous thromboembolism: more questions than answers. Intern Emerg Med. 2020; 15(8): 1375–87. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIba T, Levy JH, Levi M, et al.: Coagulopathy in COVID-19. J Thromb Haemost . 2020; 18(9): 2103–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJose RJ, Manuel A: COVID-19 cytokine storm: the interplay between inflammation and coagulation. Lancet Respir Med. 2020 Jun; 8(6): e46–7. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "91679",
"date": "27 Aug 2021",
"name": "Andhika Rachman",
"expertise": [
"Reviewer Expertise immunology",
"cancer thrombosis and platelet"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of this study is to evaluate and analyze risk factors of death, hematological and coagulation factors for COVID patients at RSUD Dr. Soetomo Surabaya. The parameters used in this manuscript were Hb, WBC, Neu#, lim#, NLR, platelet count, aPTT, PT, D-dimer, and CRP.\n\nThe statement \"significantly different in the deceased group\" might need to be rephrased to make it more clear.\n\nIn the discussions section under \"survival analysis\" it is stated that \"leukopenia, leukocytosis, neutrophilia, high NLR, CRP and PT correlates with survival\". This might confuse the readers. The writers might need to rephrase the statements to make it more in line with the abstract and with following statements.\n\nThe writers might need to detail the inclusion criteria used in the study. The writers stated that probable patients are included in the study, but the analysis is aimed more towards confirmed cases (the 217 subjects). In figure 1, it is indicated that 217 confirmed patients with complete data proceeded to statistical analysis.\n\nThe covid-19 degree of severity of the patients should be explained in more detail. This might help the reader to contextualize the term \"non-ICU\".\n\nKruskal Wallis method of analysis was not explained in the methods section.\n\nThe table 2 \"comparison of the laboratory results in deceased and survived patients\" may need some explanations. One example is that the writer used \"above-normal result percentages\".\n\nSome grammatical errors might need to be addressed in the article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": "7093",
"date": "07 Sep 2021",
"name": "Siprianus Ugroseno Yudho Bintoro",
"role": "Author Response",
"response": "Dear Reviewer, Thank you for reviewing and sending the feedback. We are going to revise it real soon. Warm regards, Research Team"
}
]
},
{
"id": "91683",
"date": "31 Aug 2021",
"name": "Azlan Bin Husin",
"expertise": [
"Reviewer Expertise clinical hematology",
"benign hematology",
"malignant hematology",
"autologous hematopoietic stem cell transplant"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPolicy or criteria for hospital admission is important information to be included or at least discussed\n\nInclusion of patients who were not having COVID19 is not relevant in this research, unless author want to compare between positive vs negative group\n\nThis study used secondary data retrieved in respective manner; hence the documentation for informed consent from each patients is irrelevant\n\nOperational definition for relevant co-morbidities were not available eg: thyroid disease (hypothyroid or hyperthyroid) or coronary artery disease (was it based on coronary angiogram or ECG or echocardiogram only or self declaration), etc.\n\nMortality should be defined - whether it is overall or specific of any term\n\nShould look into more meaningful key points to compare between this study results with other published reports.\n\nEg: a) Regarding age: comparing mean age is better. While discussing on this point it is important to consider relevant differences in study population (eg: hospital admission criteria that may include age, presence of co-morbidity etc)\n\nSome statements were too strong and not supported by cited reference e.g. paragraph 2 (regarding gender issues), paragraph 3 (on elderly and diabetes), and paragraph 4 (about pathophysiologic mechanism) of the discussion.\n\nDiscussion on D-dimer should be supported by comparing the method and cut off point used in this study versus with other published data. Should also look into possible confounding factors like superimposed infection or may be smaller number of patients\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? No",
"responses": [
{
"c_id": "7105",
"date": "21 Sep 2021",
"name": "Siprianus Ugroseno Yudho Bintoro",
"role": "Author Response",
"response": "Dear reviewer, Thank you for reviewing and sending the feedback. We are going to revise it real soon. warm regards, Research Team"
},
{
"c_id": "7468",
"date": "19 Nov 2021",
"name": "Siprianus Ugroseno Yudho Bintoro",
"role": "Author Response",
"response": "Comment 1: Policy or criteria for hospital admission were compliant with hospital policy which are: confirmed or suspected Covid-19, who are symptomatic plus any of following criteria. Age > 65 years. Clinical or radiologic evidence of pneumonia. O2 saturation Spo2 < 99 %. Acute respiratory distress syndrome. COPD CKD Acute compilation of diabetes mellitus. Obesity (BMI ≥ 40). Acute malignancy. Other to illness by physician description. We included inclusion and exclusion criteria in Methods paragraph 2 in the revised version. Comment 2: We appreciate your very helpful comments. We included the probable patients to show the magnitude of Covid-19 probable cases in our referral hospital. Comment 3: We appreciate your very helpful comment. However we already have the informed consent to use patient’s secondary administrative during their time of admission. Comment 4: Thank you for your very helpful comment. Comorbidities were recorded at admission by attending clinical staff (board certified interns), either by history taking, records from previous visits in our hospital, or previous laboratory result assessment, or patient reporting. We added it in the manuscript: Methods paragraph 2 Comment 5: Thank you for your suggestion. In patients with confirmed Covid-19 we use the definition of mortality based on the WHO definition: death resulting from a clinically compatible illness in a probable or confirmed Covid-19 case, unless there is a clear alternative cause of death that cannot be related to Covid-19 (e.g trauma). There should be no periode of complete recovery between the illness and death. Comment 6: We appreciate your comment, we revised our manuscript in Discussion, paragraphs 1 to 4. Significant differences were found in the demographic and clinical variables, and hematologic and coagulation parameters between the deceased and surviving COVID-19 patients. We included age in the risk factor for COVID- 19 mortality, whereas the age had a p-value <0.05. The age factor appeared to be crucial for the outcome of COVID-19. The average age of the deceased patients was 58 years old and was significantly older than the surviving patients. This was in accordance with previous studies that older age has been reported as an important independent predictor of mortality in SARS-Cov2.15,16 Increasing age also increased the percentage of COVID-19 mortality, the age-dependent defects in T-cell and B-cell function could lead to a deficiency in control of viral replication and more prolonged proinflammatory responses, potentially leading to poor outcome. 17 Comment 7: Gender was suspected to be a risk factor for mortality in COVID-19 patients, which was higher for men than for women. This is thought to be due to differences in the immunological systems of men and women, differences in lifestyle, and the prevalence of smoking.18 In this research, although statistically insignificant, the percentage of the number of male COVID-19 patients was higher, both overall and in the group of deceased patients. The higher mortality rates were associated with the higher chronic comorbidities in men, e.g., diabetes mellitus, kidney disease, hypertension, heart disease, lung disease, and smoking.19 The comorbidity factors of diabetes mellitus, heart disease, and chronic kidney disease in COVID-19 patients could be the risk factors of death in this research, with a p-value of <0.05. Previous studies have described that the presence of common comorbidities increase COVID-19 patients risk. This result was similar to the meta-analysis study conducted by Mantovani et al., who stated that the prevalence of diabetic patients hospitalized due to COVID-19 was 14.34%, and 11.06% in patients in Asian countries. Meanwhile, the prevalence in non-Asian countries was higher, which was 23.34%. The risk of worsening the condition to require treatment in hospital was greater in COVID-19 patients with pre-existing diabetes.20 However, the specific comorbidity by which can lead to disease progression remains unknown in COVID-19 patients.21 For the hematologic parameters in this research, the leukocyte, neutrophil counts, lymphocyte count, and NLR demonstrated significantly different result between two groups. These research results were consistent with several previously published studies.22,23 On the other hand, the platelet count in this research was comparable between the groups of deceased and surviving patients. This was in contrast with the results of a meta-analysis that concluded by Lippi et al., who showed that thrombocytopenia was associated with increasing severity risk and mortality of COVID-19.24 Differences in pathophysiological mechanisms in each patient may lead to insignificant findings in this research. Many researchers have studied the changes in peripheral blood cell counts in COVID-19, and the results were that in infected patients, the white blood cell and neutrophil count increased, while the lymphocyte and platelet counts decreased.25 In the other cases, coagulation abnormalities (prolonged PT and aPTT) and intravascular coagulopathy (DIC) were so correlated with low platelet count.26 Comment 8: Thank you for your very helpful comment. We revised the manuscript in Discussion paragraph 6. D-Dimer in our study were measured using ELFA (enzyme linked fluorescent assay) method and cut off point 0.410 µg/ml. Several literatures showed different cut off point for D-Dimer. Poudel et al., with 182 subjects, showed D-Dimer levels of 1.5 µg/ml were an optimal cut off point to predict mortality. While Zhang, 2020, with 343 subjects, shows D-Dimer level 2 µg/ml were an optimal cut off point. Guan, 2020 in China, with 1099 subjects, showed that non-survivors had a significantly higher D-dimer (median: 2.12 μg/ml) than that of survivors (median: 0.61 μg/ml). This result could be due to differences in measurement methods as disclosed by Favaloro et al. who stated several things regarding the measurement and reporting quality of D-dimers, such as the measurement method, cut-off value, or D-dimer unit [D-dimer unit (DDU)] can lead to different research results.30 Other factors in our study that can affect D-dimer level were our patients were older with median age 52, comorbidities such as cardiovascular disease and liver disease. Liver disease can affect D-Dimer elimination from blood. In this study D-dimer level was also measured on admission, very early in disease course. The half-life of D-dimer was approximately 8 hours therefore, serial measurement of D-dimer will shows more information"
}
]
}
] | 1
|
https://f1000research.com/articles/10-791
|
https://f1000research.com/articles/9-120/v1
|
18 Feb 20
|
{
"type": "Study Protocol",
"title": "The perspectives of patients and their caregivers on self-management interventions for chronic conditions: a protocol for a mixed-methods overview",
"authors": [
"Ena Niño de Guzmán",
"Laura Martínez García",
"Ana I. González",
"Monique Heijmans",
"Jorge Huaringa",
"Kaisa Immonen",
"Lyudmil Ninov",
"Carola Orrego-Villagrán",
"Javier Pérez-Bracchiglione",
"Karla Salas-Gama",
"Andrés Viteri-García",
"Pablo Alonso-Coello",
"Laura Martínez García",
"Ana I. González",
"Monique Heijmans",
"Jorge Huaringa",
"Kaisa Immonen",
"Lyudmil Ninov",
"Carola Orrego-Villagrán",
"Javier Pérez-Bracchiglione",
"Karla Salas-Gama",
"Andrés Viteri-García",
"Pablo Alonso-Coello"
],
"abstract": "Introduction: Self-management (SM) interventions are complex interventions and one of the main components of high-quality chronic disease care for which the incorporation of the perspectives of patients and their informal caregivers is crucial. We aim to identify, appraise and synthesise the evidence exploring patients’ and caregivers’ perspectives on SM interventions. More precisely, we aim to 1) describe how they value the importance of outcomes of SM interventions, and 2) identify the factors that might impact on acceptability and feasibility of SM interventions based on their preferences and experiences. Methods and analysis: We will conduct four mixed-methods overviews as part of COMPAR-EU, a European Union (EU) funded project aimed to identify the most effective and cost-effective SM interventions for chronic obstructive pulmonary disease (COPD), heart failure (HF), obesity, and type 2 diabetes mellitus (T2DM). We will search in MEDLINE, CINAHL, and PsycINFO for systematic reviews of studies addressing patients’ preferences on outcomes, or their experiences with SM alongside their disease trajectory or with SM interventions, published in English. Selection of studies and data extraction will be conducted in pairs. We will assess the overlap of studies and methodological quality. We will follow a three-step synthesis process: 1) narrative synthesis for quantitative evidence, 2) thematic synthesis for qualitative evidence, and 3) integration of findings in the interpretation phase. Additionally, we will consult on the relevance of findings with patients and their caregivers. Systematic review registration: PROSPERO CRD42019117867",
"keywords": [
"Systematic Review",
"Self-Management",
"Chronic Diseases",
"Mixed-Methods Research",
"Patient Preferences",
"Outcomes"
],
"content": "Introduction\n\nThe global burden of chronic conditions constitutes a significant public health challenge that undermines social and economic development, accounting for almost 86% of deaths and 77% of the disease burden in the WHO European Region. The increasing healthcare demands of chronic conditions lead to the development of integrated healthcare models based on patient-centred care1.\n\nSelf-management (SM) interventions are critical components of high-quality patient-centred care in chronic conditions1–3. SM can be defined as what individuals, families, and communities do to promote, maintain, or restore health and to cope with the disease or disability with or without the support of health professionals. It includes, but is not limited to, self-prevention, self-diagnosis, self-medication, and daily management of the disease and its disabilities4. Ideally, SM interventions support patients taking their individual needs and their specific context into account5. SM interventions are complex and multifaceted and may contain multiple topics, formats, and components (e.g. participants, family, facilitators, or technology) that interact with each other. Different outcomes can be defined to measure their impact based on the specific scope (e.g. behavioural, psychosocial, physiological, or utilisation outcomes) of the intervention5,6.\n\nAn increasing body of evidence suggests that SM interventions have beneficial effects for patients with chronic conditions in terms of knowledge, the performance of SM behaviours, self-efficacy, health status7 and quality of life8. However, what might be beneficial for some patients might be less beneficial for others; for that reason, it is necessary to identify which elements of SM interventions are effective and under what circumstances. Especially, it is important to consider the perspectives of patients and their caregivers to get insight into their values and preferences on specific healthcare alternatives9–11.\n\nPreference is conceived as the result of cognition, experience and reflection. Moreover, a specific preference is the consequence of what a person values12. In healthcare, patients’ preferences can be defined as the qualitative or quantitative assessments of the relative desirability or acceptability to patients of specified alternatives or choices among outcomes or other attributes that differ among alternative health interventions13.\n\nThe GRADE Evidence to Decision (EtD) framework is a decision-making tool that integrates the perspective of patients under the term values, defined as the relative importance of outcomes or health states of interest14. The patient’s preference for or against intervention is an implicit result of the relative importance of the health outcomes an individual connects to the intervention14. The patient’s preference is also implicitly related to other aspects such as attitudes, expectations and beliefs. These aspects often fall within two other EtD criteria: acceptability, whether interventions are acceptable for patients; and feasibility, whether interventions are feasible to implement from the patient’s point of view13–15. However, the methods to identify, collect and integrate this body of evidence in healthcare decision-making is still an evolving research area10 which requires more practical guidance16,17.\n\nOne method to find out the perspectives of patients and their caregivers is the development of a systematic review (SR) of studies exploring how they value the importance of outcomes or the features of the interventions that might affect their benefit-risk perceptions. This information can be obtained from quantitative and qualitative evidence reported as utility or non-utility measures (Table 1)9,14,18. Utility measures reflect how a respondent values or feels about a state of health19. Non-utility measures inform about patients’ (or their informal caregivers’) preferences and experiences with the intervention of interest derived from quantitative, qualitative or mixed methods studies14.\n\nAdapted from Zhang et al.14\n\nSince 2010, there has been an increasing number of qualitative evidence synthesis (QES) published exploring patients’ and their caregivers' experiences and perceptions regarding living with a chronic condition, some of these explicitly addressing the process of self-care20. There are also some SRs of studies exploring patients’ preferences quantitatively for different health states20.\n\nHowever, summarising this body of evidence in a complete and comprehensible way for stakeholders might be challenging. In this context, the development of overviews might represent the most suitable option to summarise this broad and complex phenomenon. Previously published overviews addressing this research area were very diverse in the length and depth of scope21–25. However, some focused more on SM interventions and included only qualitative evidence for some specific conditions, such as stroke24, rheumatic diseases, cancer and fibromyalgia21. Others explored the experience of living with a chronic condition using a quantitative22 or qualitative approaches23. Moreover, some were focused on some specific symptoms (e.g. chronic non-malignant pain25). Even though previous research had enhanced knowledge on the perspectives of patients and their caregivers on chronic conditions and SM, we consider it is required to move towards a more comprehensive approach, applying a mixed-methods approach26 including quantitative and qualitative sources of evidence, through developing overviews of systematic reviews.\n\nThis study protocol is part of a large multi-method and multi-step project: “Comparing the cost-effectiveness of self-management interventions in four high priority chronic diseases in Europe: COMPAR-EU”. This is a European Union-funded project aiming to identify the most effective and cost-effective SM interventions for patients living with chronic obstructive pulmonary disease (COPD), heart failure (HF), obesity or type 2 diabetes mellitus (T2DM).\n\nOur main objective is to identify, appraise, and analyse the perspectives of patients and their caregivers on outcomes of SM interventions for the selected chronic conditions. To provide a more detailed assessment, we will conduct four overviews (one per chronic condition). Our specific objectives are 1) to explore how patients with one of the four chronic conditions, and their caregivers, value the importance of different outcomes of SM interventions, and 2) to identify the factors that might impact the acceptability and feasibility of SM interventions based on their preferences and experiences with SM through the disease trajectory and when taking part in SM interventions.\n\n\nMethods and analysis\n\nWe will conduct four mixed-methods overviews of SRs according to the most updated methodological guidance from the Cochrane Collaboration27–29, the Joanna Briggs Institute (JBI)30 and key methodological references31–34. We adhere to the applicable items of the Preferred Reporting Items for Systematic reviews and Meta-Analyses Protocols (PRISMA-P) statement35. We registered this protocol in the PROSPERO registry: CRD42019117867. Any amendment to the protocol and the supporting rationale will be reported.\n\nType of reviews. We will consider for inclusion: 1) quantitative SRs 2) qualitative evidence syntheses QES; and 3) mixed methods research synthesis (MMRS). To be eligible for inclusion, the SRs should report as a minimum: 1) the search strategy for at least one database; 2) the list of included studies; and 3) the methods applied for synthesis36.\n\nContext/setting. We will include SRs of studies without geographical restriction and will include all settings, except those confined to inpatient care.\n\nPopulation/perspectives. We will limit inclusion to SRs of studies conducted in adult patients (18 or older) with one or more of the chronic conditions of interest (COPD, HF, obesity and T2DM), without restricting by disease severity. We will consider SRs assessing multiple chronic conditions if data for one or more of the chronic conditions we are interested in are reported separately.\n\nWe will include SRs exploring the perspectives of patients or their informal caregivers. We will include SRs assessing both perspectives if these are reported separately. We will exclude SRs addressing only healthcare providers’ or healthy population perspectives.\n\nThe phenomenon of interest/intervention. We will include SRs aimed at exploring the perspectives of patients and their caregivers on the importance of outcomes of SM interventions. Their perspectives are based on their values, preferences and experiences. As described by Zhang et al.14, preferences for or against intervention are implicitly related to the relative importance people place (or value) on the expected or definite health outcomes connected to a specific intervention. We define SM intervention as supportive interventions systematically provided by healthcare staff, peers or laypersons to increase patients’ skills and confidence in their ability to manage a chronic condition. SM interventions aim to prepare patients (and, where appropriate, informal caregivers37) to actively participate in the management of their disease37,38.\n\nWe will apply the COMPAR-EU taxonomy for the domain of outcomes of SM interventions, with 35 elements categorised in seven subdomains39: 1) empowerment, 2) level of fulfilment of the expected SM behaviours, 3) clinical outcomes (progression of disease, complications, adverse events, and mortality), 4) quality of life of patients and caregivers, 5) perceptions and satisfaction with care, 6) health care use, and 7) cost. We will not exclude SRs addressing other outcomes not listed in the COMPAR-EU taxonomy. Instead, these will be incorporated as a new category if applicable.\n\nComparison. While not addressed as an objective in these overviews, if reported, we will consider usual care as the comparison.\n\nOutcomes. We will include SRs evaluating studies reporting any of the following outcomes:\n\nUtility measures for outcomes of SM interventions; defined as how patients or their caregivers value the importance of different outcomes. Utilities are measures of the value ascribed to states of health, most often scaled from “0”, representing death, to “1”, representing perfect health; they reflect the health-related quality of life of the individual at a particular point in time40. Methods to obtain utilities can be: a) direct methods such as matching methods (i.e. standard gamble, time trade-off, or rating scales), or conjoint analysis (i.e. discrete choice experiments, contingent valuation and willingness to pay, probability trade-off, paired comparison); or b) indirect methods with multi-attribute instruments like the EuroQual-5-dimension (EQ-5D), the Short Form-6-Dimension (SF-6D), Health Utilities Index (HUI-3)14, the Patient-Reported Outcomes Measurement Information System (PROMIS-29)41, among other quality of life tools which transform results across several domains into utilities (Table 1).\n\nNon-utility measures for outcomes of SM interventions, which are the result of the assessment of preferences and experiences of patients and their caregivers with SM in the disease trajectory or with SM interventions through quantitative (e.g. surveys), qualitative (e.g. interviews, focus groups), or mixed methods studies14 (Table 1).\n\nWe will design and execute a literature search strategy in MEDLINE (accessed through PubMed), the Cumulative Index of Nursing and Allied Health Literature (CINAHL), and PsycINFO. The leading search concepts will be: 1) the perspective of patients, for which we will include a sensitive content search strategy previously published42; and 2) specific terms for each chronic condition. We will apply methodological filters limiting, to SRs, the retrieval of references using the filters available in each database, and to qualitative research, synthesis using non-controlled terms. We will consider English-language studies for inclusion without restriction on publication date. We will hand-search the reference list of overviews identified through our search strategy and will conduct a forward citation search of the included studies in Scopus43. We will establish regular search update alerts. Studies identified through these alerts and meeting the eligibility criteria will be incorporated until starting the stakeholders’ consultation.\n\nWe will manage references with Endnote X9. Pairs of authors will conduct the screening of references and selection of studies. After initial calibration with 10% of retrieved references, one author will independently select references to be included, and a second author will check the final list of included and excluded studies with reasons. Disagreements will be solved by discussion or with the help of a third author.\n\nWe will extract data using Nvivo 12 Pro44. We will design and pilot-test one form for each type of SR (quantitative, qualitative or mixed methods). After initial calibration between pairs of authors, one author will extract data from the included reviews, and a second author will check the data against the full text for accuracy. We will solve disagreements by consensus or with the help of a third author. We will collect the following information from each type of SR:\n\nGeneral characteristics: country of contacting author, year of publication, aim or phenomenon of interest, search databases, search timeframe, the number of included studies, and the number of participants.\n\nMethodological characteristics: the type of SR, the method of synthesis, methods of primary studies, the quality assessment tool, the certainty of the evidence assessment tool, and their findings.\n\nSettings: location/s (countries) of primary studies, and the context of included studies.\n\nParticipants’ main characteristics: type of respondent, the severity of the disease, demographic characteristics, and comorbidities.\n\nIntervention characteristics: target population/s, support technique/s, support delivery method/s, and expected patient (or caregiver) self-management behaviours.\n\nThemes or findings related to outcomes of SM interventions: 1) quantitative data, including health utility measures (mean, standard deviation, confidence interval) and the methods applied to obtain them; and 2) qualitative data extraction, this process overlaps with the first stage of thematic synthesis (Figure 1).\n\nLevels of interpretation: adapted from Pierce et al.24, thematic synthesis stages based on Thomas and Newman53.\n\nIn the extraction process, we will record the extent of relevant information not reported (e.g. information about age), but we will not take additional steps to get further information from primary studies29,45. For discrepant data (two or more SRs reporting different data for the same primary study), we will extract data from the SR with the highest methodological quality, and if similar methodological quality, from the review with the most updated search45. For discrepant methodological quality assessment (two or more SRs using different tools or reporting different results for the same primary study), we will report both results.\n\nWe will assess the overlapping primary studies (studies appearing in more than one review) using a citation matrix46. We will extract the references of the primary studies answering our research question within all selected reviews, calculate the “corrected covered area” (CCA), and describe the extent of overlap (slight [0 to 5], moderate [6 to 10], high [11 to 15], or very high [over 15])47. We will include all SRs that meet the eligibility criteria regardless of overlap48. We will conduct this assessment using Excel files.\n\nFor duplicated data (two or more SRs reporting the same data from the same primary study or with over 25% of overlap within primary studies), we will include data only once, selecting the one with the most complete and detailed data48.\n\nWe will use the JBI Critical Appraisal Checklist for Systematic Reviews and Research Syntheses to test the quality of the included reviews30. The JBI Checklist, which comprises 11 items, is a tool to assess the methodological quality of both quantitative SRs and QES30. After initial calibration, one author will independently apply this checklist, and a second author will check results to validate scores. We will solve disagreements through consensus or with the help of a third author. We will adopt a previously published scoring method50 that allocates “one point” to positive responses and “zero points” to negative or unclear responses, and we will calculate the percentage of positive responses for each review (sum of positive responses divided by total items tested). The quality of each SR will be ranked based on the following criteria: 0–33% of criteria met (low quality), 34–66% of criteria met (medium quality), and 67% or more of criteria met (high quality)50. We will not exclude SRs based on their quality scores.\n\nTo synthesise findings from selected SRs, we will use a mixed-methods three-step approach, with a convergent parallel analysis of quantitative and qualitative evidence51.\n\nStep 1: Quantitative evidence. To analyse and synthesise quantitative findings (utility and non-utility data), we will use narrative synthesis52. We will calculate descriptive statistics (mean, SD for variables with a normal distribution and the median, interquartile range, for other distributions).\n\nFor reporting, we will present results in summarised tables (grouping by relevant categories of outcomes). We will plot reported results, e.g. mean values, 95% confidence intervals and I2 statistic for heterogeneity (if pooled), or the range of mean values or other measures (if not pooled) across SRs, the number of studies and the number of respondents for each outcome. Where possible we will present results by country of study, location, type of respondent (patient or caregiver), respondents’ characteristics (sample size, the severity of disease), and methods used. We will perform statistical analyses using STATA software V.1453.\n\nStep 2: Qualitative evidence. We will analyse and synthesise qualitative data using a thematic synthesis49 approach using NVivo 12 Pro44. The levels of analysis will comprise second-order (primary studies) and third-order SRs constructs24,54 (Figure 1). We will not specify any a priori theme.\n\nThe synthesis process will follow the three stages of thematic synthesis49, the first two taking place concurrently: 1) text coding - line-by-line coding of the text of each SR; 2) developing descriptive themes; 3) re-interpretation and synthesis of this newly organised information, to produce analytical themes that go beyond the findings of the SRs authors (overview of SRs) (Figure 1). For this step, we will conduct a collaborative analysis with at least three review authors to consider alternative interpretations and ensure that fourth-order constructs remain grounded in the primary studies.\n\nStep 3: Integration of qualitative and quantitative evidence. We will integrate the results of these two sources of evidence in the interpretation phase of results55. For findings informing outcomes, we will organise them according to the COMPAR-EU taxonomy (or to additional outcomes, if applicable)39. For emerging themes informing about feasibility and acceptability of SM interventions, we will develop a framework, according to the classification of analytical themes. The goal of the integration phase is to categorise the importance of outcomes and provide a framework to identify the factors that influence acceptability and feasibility of SM interventions, always from the perspectives of patients and their caregivers. We will present findings using tabular formats, which will inform the development of decision-making tools for the interactive platform of the COMPAR-EU project.\n\nSub-group analysis. For quantitative evidence and depending on the sufficiency of SRs, we plan to analyse the primary outcomes according to the patient population (e.g. age, the severity of the disease, type of respondent), intervention (i.e. type of SM intervention) and setting (i.e. country). For qualitative evidence, it is not possible to specify the groups in advance, due to the nature of this synthesis.\n\nSensitivity analysis. If applicable, we will conduct a sensitivity analysis exploring the impact of the quality of the included SRs (low, medium and high) in the final synthesis of findings.\n\nAfter the integration of quantitative and qualitative findings, we will conduct an online survey with patients’ and caregivers’ representatives from each chronic condition. We will ask their feedback on the draft of summaries of perspectives of patients and their caregivers derived from the SRs. We will design a tabular format for the seven subdomains of outcomes with close and open-ended questions assessing: 1) to what extent the overview findings resound with their preferences and experiences; and 2) the relevance of findings for healthcare decision-making on SM interventions from their point of view.\n\nFor the recruitment of participants, we will invite patients’ and caregivers’ representatives through the patient’s networks collaborating in the COMPAR-EU project. We aim to include at least five patients with different profiles of gender, age group, and severity of disease and one informal caregiver for each condition. After giving their informed consent, patients will receive the link to complete the survey. Their responses will be analysed based on frequencies, and thematic analysis for the open-ended questions. After discussion within the review working group, we will include their perspectives in the discussion section of each chronic condition manuscript.\n\nEthical approval was obtained by the Clinical Research Ethics Committee of the Avedis Donabedian Research Institute, the coordinator partner of the COMPAR-EU Project (EU 754936), the University Institute for Primary Care Research (IDIAP Jordi Gol) and was signed on March 2018. We will disseminate our findings as conference abstracts, peer-review manuscripts, and in social community media. Patients’ and caregivers’ representatives participating in the draft summaries assessment will receive feedback based on their responses. Our results will inform the development of decision-making tools for the COMPAR-EU Project.\n\nSince we planned to conduct the overviews of reviews for the four conditions consecutively, we are in different points on each one: 1) we conducted the searches in the selected databases and selected the initial list of included reviews for the four conditions on March 2019; 2) we finalised the extraction of the quantitative data of SRs reporting health utilities for the four conditions on September 2019; 3) we started the extraction of qualitative data, and thematic synthesis for reviews of T2DM on November 2019 and this process is still in progress; 4) in the upcoming months we will follow with obesity, HF and COPD. Finally, we plan to publish results also in a consecutive manner during the second semester of 2020 and the first of 2021.\n\n\nDiscussion\n\nOur study will collect the perspectives of patients and their caregivers on SM interventions for four high priority chronic conditions. We will synthesise and integrate quantitative and qualitative findings describing how patients and their caregivers value the importance of outcomes of SM interventions, and the factors that might affect acceptability and feasibility of conducting these SM interventions, based on their preferences and experiences about SM, through the disease trajectory and with SM interventions.\n\nTo our knowledge, these will be the first overview of the perspectives of patients and their caregivers on SM interventions for any of these four chronic conditions using a mixed-methods approach26. We will follow the most updated methodological guidance for overviews27–34.\n\nEach overview will provide new knowledge in a summarised format about the perspectives of patients living with the four selected chronic conditions and their caregivers on SM interventions. This evidence will be readily available to inform decision-making tools (i.e. EtD frameworks and decisions aids) where, in addition to effectiveness and cost-effectiveness findings, the COMPAR-EU project will develop recommendations for SM interventions. More precisely, we will inform about the importance of outcomes of SM interventions, acceptability and feasibility considerations, through quantitative and qualitative data.\n\nAlthough patients vary greatly in their preferences10, this approach will help to identify subgroups of patients (and caregivers) that might find an acceptable risk-benefit balance for SM interventions. We will also inform about acceptability and feasibility considerations for implementation concerns of these interventions. Our findings will be incorporated into the COMPAR-EU Project final product: an interactive platform that will be designed and adapted to different profiles of end-users, including patients, caregivers, healthcare providers, policymakers, researchers and industry representatives.\n\nSome limitations include that our findings will represent a sample of primary studies published in English already included in SRs. Because of time constraints, we do not plan to update them32, so we may miss the most recent studies. Furthermore, we are not using a specific tool to assess the quality of reporting. Instead, we will describe this aspect as an overall assessment32. Finally, the overall assessment of the certainty of the evidence is out of our scope, since there is still scarce guidance on how to assess this aspect within an overview32.\n\nOur findings will help to characterise better the perspective of patients with chronic conditions and their caregivers on SM interventions, identifying challenges patients face in their daily life, which may inform and help healthcare providers to get a deeper understanding the patients’ experiences and what is important for them. In this way, they will be able to provide support to patients that better fits their needs. For policy and decision-makers, being aware of the perspective of patients will help to design patient-centred strategies to implement SM interventions.\n\nWe expect our findings will provide valuable insights to be considered in the design and conduct of future studies of SM interventions for patients living with any of these or similar chronic conditions. These overviews will help to identify gaps in research in this field and areas of potentially redundant research, reducing waste and streamlining the use of limited resources.\n\n\nData availability\n\nNo underlying data are associated with this article.\n\nOSF: The perspectives of patients and their caregivers on self-management interventions for chronic conditions. https://doi.org/10.17605/OSF.IO/GFSA556\n\nOSF: The perspectives of patients and their caregivers on self-management interventions for chronic conditions. https://doi.org/10.17605/OSF.IO/GFSA556.\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 thank Ivan Solà (Iberoamerican Cochrane Centre) for his invaluable help in the design of the search strategy. We would also like to thank Dr Rosa Suñol (Avedis Donabedian Research Institute) for her advice and feedback for the earlier version of this protocol.\n\n\nReferences\n\nEpping-Jordan JE, Pruitt SD, Bengoa R, et al.: Improving the quality of health care for chronic conditions. Qual Saf Health Care. 2004; 13(4): 299–305. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBodenheimer T, Lorig K, Holman H, et al.: Patient self-management of chronic disease in primary care. JAMA. 2002; 288(19): 2469–75. PubMed Abstract | Publisher Full Text\n\nGrady PA, Gough LL: Self-management: a comprehensive approach to management of chronic conditions. Am J Public Health. 2014; 104(8): e25–31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPilot project on the promotion of self-care systems in the European Union. European Union; 2018. Reference Source\n\nCraig P, Dieppe P, Macintyre S, et al.: Developing and evaluating complex interventions: the new Medical Research Council guidance. BMJ. 2008; 337: a1655. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTaylor SJC, Pinnock H, Epiphaniou E, et al.: A rapid synthesis of the evidence on interventions supporting self-management for people with long-term conditions: PRISMS - Practical systematic Review of Self-Management Support for long-term conditions. Health Services and Delivery Research. Southampton (UK), 2014; 2(53). PubMed Abstract | Publisher Full Text\n\nBarlow J, Wright C, Sheasby J, et al.: Self-management approaches for people with chronic conditions: a review. Patient Educ Couns. 2002; 48(2): 177–87. PubMed Abstract | Publisher Full Text\n\nMurphy LA, Harrington P, Taylor SJ, et al.: Clinical-effectiveness of self-management interventions in chronic obstructive pulmonary disease: An overview of reviews. 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J Clin Epidemiol. 2019; 116: 84–97. PubMed Abstract | Publisher Full Text\n\nSelva A, Sanabria AJ, Pequeno S, et al.: Incorporating patients' views in guideline development: a systematic review of guidance documents. J Clin Epidemiol. 2017; 88: 102–12. PubMed Abstract | Publisher Full Text\n\nZhang Y, Coello PA, Brozek J, et al.: Using patient values and preferences to inform the importance of health outcomes in practice guideline development following the GRADE approach. Health Qual Life Outcomes. 2017; 15(1): 52. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHunink MGM, Weinstein MC, Wittenberg E, et al.: Decision Making in Health and Medicine: Integrating Evidence and Values. 2nd ed. Cambridge: Cambridge University Press; 2014. Reference Source\n\nNiño de Guzmán EP, Martínez-García L, Pérez-Bracchiglione J, et al.: What do patients and their caregivers value on self-management interventions for chronic conditions? A scoping review of systematic reviews for the COMPAR-EU project. Cochrane Colloquium. 2019. Reference Source\n\nDwarswaard J, Bakker EJ, van Staa A, et al.: Self-management support from the perspective of patients with a chronic condition: a thematic synthesis of qualitative studies. Health Expect. 2016; 19(2): 194–208. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEarle CC, Chapman RH, Baker CS, et al.: Systematic overview of cost-utility assessments in oncology. J Clin Oncol. 2000; 18(18): 3302–17. PubMed Abstract | Publisher Full Text\n\nMay CR, Cummings A, Myall M, et al.: Experiences of long-term life-limiting conditions among patients and carers: what can we learn from a meta-review of systematic reviews of qualitative studies of chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease? BMJ Open. 2016; 6(10): e011694. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPearce G, Pinnock H, Epiphaniou E, et al.: Experiences of Self-Management Support Following a Stroke: A Meta-Review of Qualitative Systematic Reviews. PLoS One. 2015; 10(12): e0141803. PubMed Abstract | Publisher Full Text | Free Full Text\n\nToye F, Seers K, Hannink E, et al.: A mega-ethnography of eleven qualitative evidence syntheses exploring the experience of living with chronic non-malignant pain. BMC Med Res Methodol. 2017; 17(1): 116. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPluye P, Hong QN: Combining the power of stories and the power of numbers: mixed methods research and mixed studies reviews. Annu Rev Public Health. 2014; 35: 29–45. PubMed Abstract | Publisher Full Text\n\nHarris JL, Booth A, Cargo M, et al.: Cochrane Qualitative and Implementation Methods Group guidance series-paper 2: methods for question formulation, searching, and protocol development for qualitative evidence synthesis. J Clin Epidemiol. 2018; 97: 39–48. PubMed Abstract | Publisher Full Text\n\nNoyes J, Booth A, Cargo M, et al.: Cochrane Qualitative and Implementation Methods Group guidance series-paper 1: introduction. J Clin Epidemiol. 2018; 97: 35–8. PubMed Abstract | Publisher Full Text\n\nPollock MFR, Becker LA, Pieper D, et al.: Overviews of Reviews. In: Cochrane Handbook for Systematic reviews of Interventions. 2019. Reference Source\n\nAromataris E, Fernandez R, Godfrey CM, et al.: Summarizing systematic reviews: methodological development, conduct and reporting of an umbrella review approach. Int J Evid Based Healthc. 2015; 13(3): 132–40. PubMed Abstract | Publisher Full Text\n\nHunt H, Pollock A, Campbell P, et al.: An introduction to overviews of reviews: planning a relevant research question and objective for an overview. Syst Rev. 2018; 7(1): 39. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLunny C, Brennan SE, McDonald S, et al.: Toward a comprehensive evidence map of overview of systematic review methods: paper 2-risk of bias assessment; synthesis, presentation and summary of the findings; and assessment of the certainty of the evidence. Syst Rev. 2018; 7(1): 159. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLunny C, Brennan SE, McDonald S, et al.: Toward a comprehensive evidence map of overview of systematic review methods: paper 1-purpose, eligibility, search and data extraction. Syst Rev. 2017; 6(1): 231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLunny C, Brennan SE, McDonald S, et al.: Evidence map of studies evaluating methods for conducting, interpreting and reporting overviews of systematic reviews of interventions: rationale and design. Syst Rev. 2016; 5: 4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoher D, Shamseer L, Clarke M, et al.: Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015; 4: 1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarnett-Page E, Thomas J: Methods for the synthesis of qualitative research: a critical review. BMC Med Res Methodol. 2009; 9: 59. PubMed Abstract | Publisher Full Text | Free Full Text\n\nReinhard SC, Given B, Petlick NH, et al.: Supporting Family Caregivers in Providing Care. In: Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Rockville Agency for Healthcare Research and Quality (US). 2008. Reference Source\n\nTattersall RL: The expert patient: a new approach to chronic disease management for the twenty-first century. Clin Med (Lond). 2002; 2(3): 227–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrrego C, Ballester M, Pacheco-Barrios K, et al.: Development and external validation of a comprehensive Taxonomy of Self-Management Interventions in chronic conditions: the COMPAR-EU taxonomy. G-I-N & JBI Conference; October/November 2019; Adelaide, Australia. 2019. Reference Source\n\nTorrance GW: Utility approach to measuring health-related quality of life. J Chronic Dis. 1987; 40(6): 593–603. PubMed Abstract | Publisher Full Text\n\nHartman JD, Craig BM: Comparing and transforming PROMIS utility values to the EQ-5D. Qual Life Res. 2018; 27(3): 725–33. PubMed Abstract | Publisher Full Text\n\nSelva A, Solà I, Zhang Y, et al.: Development and use of a content search strategy for retrieving studies on patients' views and preferences. Health Qual Life Outcomes. 2017; 15(1): 126. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGreenhalgh T, Peacock R: Effectiveness and efficiency of search methods in systematic reviews of complex evidence: audit of primary sources. BMJ. 2005; 331(7524): 1064–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNVivo qualitative data analysis software. Version 12 ed: QSR International Pty Ltd. 2018.\n\nBecker L, Oxman A: Overviews of reviews. In: Handbook for Systematic Reviews of Interventions. London: The Cochrane Collaboration. Version 5.1.0. 2008. Publisher Full Text\n\nPieper D, Antoine SL, Neugebauer EA, et al.: Up-to-dateness of reviews is often neglected in overviews: a systematic review. J Clin Epidemiol. 2014; 67(12): 1302–8. PubMed Abstract | Publisher Full Text\n\nPieper D, Antoine SL, Mathes T, et al.: Systematic review finds overlapping reviews were not mentioned in every other overview. J Clin Epidemiol. 2014; 67(4): 368–75. PubMed Abstract | Publisher Full Text\n\nCooper H, Koenka AC: The overview of reviews: unique challenges and opportunities when research syntheses are the principal elements of new integrative scholarship. Am Psychol. 2012; 67(6): 446–62. PubMed Abstract | Publisher Full Text\n\nThomas JH, Newman M: Synthesis: Combining results systematically and appropriately. In: Gough D, Oliver S, Thomas J, editor. An Introduction to Systematic Reviews. London: Sage Publications Ltd. 2012.179–227. Reference Source\n\nJadczak AD, Makwana N, Luscombe-Marsh N, et al.: Effectiveness of exercise interventions on physical function in community-dwelling frail older people: an umbrella review of systematic reviews. JBI Database System Rev Implement Rep. 2018; 16(3): 752–75. PubMed Abstract | Publisher Full Text\n\nHong QN, Pluye P, Bujold M, et al.: Convergent and sequential synthesis designs: implications for conducting and reporting systematic reviews of qualitative and quantitative evidence. Syst Rev. 2017; 6(1): 61. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRodgers M, Sowden A, Petticrew M, et al.: Testing Methodological Guidance on the Conduct of Narrative Synthesis in Systematic Reviews: Effectiveness of Interventions to Promote Smoke Alarm Ownership and Function. Evaluation. 2009; 15(1): 49–73. Publisher Full Text\n\nStataCorp: Stata Statistical Software. Release 14 ed. College Station, TX: StataCorp LP. 2015.\n\nCampbell R, Pound P, Morgan M, et al.: Evaluating meta-ethnography: systematic analysis and synthesis of qualitative research. Health Technol Assess. 2011; 15(43): 1–164. PubMed Abstract | Publisher Full Text\n\nCaffery LJ, Martin-Khan M, Wade V: Mixed methods for telehealth research. J Telemed Telecare. 2017; 23(9): 764–9. PubMed Abstract | Publisher Full Text\n\nNiño de Guzmán E: The Perspectives of Patients and Their Caregivers on Self-Management Interventions for Chronic Conditions. 21st November ed. OSF. 2019. https://doi.org/10.17605/OSF.IO/GFSA5"
}
|
[
{
"id": "66199",
"date": "24 Aug 2020",
"name": "Milena Vainieri",
"expertise": [
"Reviewer Expertise Health service research",
"healthcare management"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article presents the study protocol for a systematic review of the reviews dealing with 4 main chronic diseases.\nThe methods that this group of authors intend to apply are innovative and comprehensive.\nThe only minor suggestions regard the language proofreading (for instance see the use of connects as a noun) and if the authors expect to publish a review per disease or a unique comprehensive review also comparing the 4 (potentially overlapping) diseases.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "7385",
"date": "29 Nov 2021",
"name": "Ena Niño de Guzman",
"role": "Author Response",
"response": "Comment 1: Language proofreading and publication plan Response 1 We have reviewed English grammar correctness and made some minor edits. We plan to publish one overview per disease. We have modified the text in the \" Study status\" section to clarify the reviewer's concern. The text reads: “... Finally, we plan to publish results also in a consecutive manner, one manuscript per condition, during the second semester of 2021 and the first of 2022.”"
}
]
},
{
"id": "84691",
"date": "02 Jun 2021",
"name": "Edward Zimbudzi",
"expertise": [
"Reviewer Expertise Chronic kidney disease",
"self-management",
"patient activation",
"health related quality of life",
"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\nIn this protocol, the authors seek to identify, appraise and synthesise evidence regarding patients' and caregivers' perspectives on self-management interventions. To do this, the authors will conduct four mixed-methods overviews specific to patients with chronic obstructive pulmonary disease (COPD), heart failure (HF), obesity and type 2 diabetes mellitus. Appropriate databases will be searched for systematic reviews that meet preidentified criteria followed by well described data extraction and analysis process.\n\nHere are my comments/remarks that require clarification;\nThe authors may need to make it clear from the onset that they will include patients with only one of the four conditions (if that is the case). It is important to clarify this because a number of patients have more than one condition.\n\nIn line with the point above, patients may also have a chronic condition of interest plus other chronic diseases which are not part of this study. Are they going to be excluded?\n\nThe stage of the disease does affect how patients self-manage as well as outcomes. Authors may need to provide a rationale regarding why they are not considering the stage of the disease as a variable.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Yes\n\nAre sufficient details of the methods provided to allow replication by others? Yes\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "7386",
"date": "29 Nov 2021",
"name": "Ena Niño de Guzman",
"role": "Author Response",
"response": "Eligibility criteria We will include SRs that included studies in patients with chronic conditions of interest (COPD, HF, obesity and T2DM) and without restricting by 1) disease severity, 2) the number of conditions of interest (e.g., > 1 of the chronic conditions of interest), or 3) the number of chronic conditions (e.g., ≥1 of the chronic conditions of interest plus ≥1 of other chronic conditions, except cancer or severe mental disorders). We will collect and analyse data considering these criteria if data is available. We will collect and analyse data considering disease severity and the number and types of chronic conditions if data is available. If SRs included more than one of the chronic conditions of interest, we will collect and analyse data of each condition in the corresponding overview. We have modified the text in the \"Methods and analysis - Eligibility criteria - Population/perspectives\" section to clarify the reviewer's concern. The text reads: \"We will limit inclusion to SRs of studies conducted in adult patients (18 or older) with one or more of the chronic conditions of interest (COPD, HF, obesity and T2DM), without restricting by the severity of the disease. We will consider SRs assessing multiple chronic conditions (e.g., patients with more than one of the chronic conditions of interest or patients with chronic conditions of interest plus other chronic conditions). We will exclude SRs focused on patients with the chronic conditions of interest and cancer comorbidity or severe mental disorders.\" We have modified the text in the \"Methods and analysis - Data synthesis and reporting - Sub-group analysis\" section to clarify the reviewer's concern. The text reads: \"For quantitative evidence and depending on the sufficiency of SRs, we plan to analyse the primary outcomes according to the patient population (e.g., age, the severity of the disease, number and types of chronic conditions, and type of respondent), intervention (e.g., type of SM intervention) and setting (e.g., country)\"."
}
]
}
] | 1
|
https://f1000research.com/articles/9-120
|
https://f1000research.com/articles/10-567/v1
|
14 Jul 21
|
{
"type": "Software Tool Article",
"title": "snpQT: flexible, reproducible, and comprehensive quality control and imputation of genomic data",
"authors": [
"Christina Vasilopoulou",
"Benjamin Wingfield",
"Andrew P. Morris",
"William Duddy",
"Benjamin Wingfield",
"Andrew P. Morris"
],
"abstract": "Quality control of genomic data is an essential but complicated multi-step procedure, often requiring separate installation and expert familiarity with a combination of different bioinformatics tools. Dependency hell and reproducibility are recurrent challenges. Existing semi-automated or automated solutions lack comprehensive quality checks, flexible workflow architecture, and user control. To address these challenges, we have developed snpQT: a scalable, stand-alone software pipeline using nextflow and BioContainers, for comprehensive, reproducible and interactive quality control of human genomic data. snpQT offers some 36 discrete quality filters or correction steps in a complete standardised pipeline, producing graphical reports to demonstrate the state of data before and after each quality control procedure. This includes human genome build conversion, population stratification against data from the 1,000 Genomes Project, automated population outlier removal, and built-in imputation with its own pre- and post- quality controls. Common input formats are used, and a synthetic dataset and comprehensive online tutorial are provided for testing, educational purposes, and demonstration. The snpQT pipeline is designed to run with minimal user input and coding experience; quality control steps are implemented with default thresholds which can be modified by the user, and workflows can be flexibly combined in custom combinations. snpQT is open source and freely available at https://github.com/nebfield/snpQT. A comprehensive online tutorial and installation guide is provided through to GWAS (https://snpqt.readthedocs.io/en/latest/), introducing snpQT using a synthetic demonstration dataset and a real-world Amyotrophic Lateral Sclerosis SNP-array dataset.",
"keywords": [
"GWAS",
"Quality Control",
"GWAS pipeline",
"Nextflow",
"Imputation",
"SNPs",
"Genomic Variants",
"BioContainers",
"QC",
"Population Stratification",
"GWAS",
"Anaconda"
],
"content": "Introduction\n\nGenome-Wide Association Studies (GWAS) seek to identify genetic variants that have a statistically significant association to a trait, such as a disease or other phenotype of interest. GWAS has been widely employed in a large variety of applications, including network-based and machine learning approaches1. A rapid explosion in the quantity of genomic data has created the need for systematic and standardised quality control (QC). Assuring high quality of genomic data is necessarily a complex multi-step procedure with multiple challenges, but it is essential in order to ensure reproducible and reliable results1–4. Although there are well-established steps and good practices5,6, there is no standardised and universally followed workflow, which impacts on the reproducibility and comparability of results2,4.\n\nExisting approaches, including semi-automated tools7, can involve a time-consuming \"trial and error\" approach, requiring the analyst to check the distributions of parameters in plots produced over many rounds of adjustments, and to manually enter commands in a long list of QC steps one-by-one, or in a series of shell scripts. The analyst may encounter incompatibility problems and installation difficulties as well as spending valuable time familiarizing themselves with a number of different tools that sometimes lack detailed documentation. Software architecture tools such as nextflow and BioContainers can address these issues and have been proposed as automated solutions8; however restrictions exist in terms of limited and relatively rigid QC analysis, lacking such steps as imputation, limited variety of threshold choice and plot outputs, and the requirement for users to have extensive knowledge of the software in order to tailor their analysis. Here we present snpQT (shown in Figure 1): a standardised, flexible, automatic pipeline tool that provides comprehensive quality control, with imputation and association analysis, including ready-to-publish graphs and plots for data interpretation and validation for every QC step.\n\nTo provide a reproducible and scalable pipeline, snpQT automatically loads software dependencies using Anaconda, docker, or environment modules. Each workflow expects specific inputs either from the user or from the outputs generated by other workflows. Main tools and key processes (modules) are highlighted in green. Examples of different task combinations are represented in the upper-right corner, showing the flexibility and interactivity among the implemented workflows. VCF: Variant Call File; QC: Quality Control; PCA: Principal Component Analysis; GWAS: Genome-Wide Association Studies.\n\n\nMethods\n\nsnpQT was developed as a set of nine core workflow components implemented with the nextflow workflow management system9. Each workflow component consists of independent containerised modules, using BioContainers curated by the bioinformatics community wherever possible10. Combining independent containerised modules into workflows, and enabling multiple workflow combinations, using the nextflow architecture, enables snpQT to be a reproducible and uniquely versatile tool for the analysis of human variant genomic data. Containers improve end-user experience and enable reproducible research by automatically provisioning bioinformatics software as required and improving numerical stability11. Running individual modules in independent containers also solves a common problem when installing potentially incompatible software packages, known as \"dependency hell\"12. In addition, nextflow enables caching at continuous checkpoints, so users can alter thresholds without needing to rerun earlier parts of the analysis. Briefly, if a module has the same input and parameters that a previous pipeline run has already processed, then the cached work is passed to the next module in the workflow instead of recomputing new work. This means that if a user runs multiple jobs and changes parameters at a later stage in the overall pipeline, then earlier unchanged stages are skipped, saving time.\n\nAs each genomic study is unique, this requires a tailored and flexible pipeline with informative representations of intermediate quality control data. snpQT is designed to offer multiple combinations of workflows as well as modifiable threshold parameters for multiple steps (as shown in Figure 1). Workflow A runs only once, performing a local database set up, downloading and preparing reference files13,14 and setting up specific versions of tools using Anaconda, docker or environmental modules. Workflow B has been created for the user to remap their genomic dataset from build 38 to 37 and vice versa. Workflow C performs Sample QC, including checks for missing call rate, sex discrepancies, heterozygosity, cryptic relatedness, and missing phenotypes. Workflow D performs Population Stratification: after an internal QC of the reference genome and user’s dataset, the two datasets are merged and prepared for the automatic removal of ethnic outliers using EIGENSOFT15. Principal Component Analyses are carried out before and after the outlier removal. Workflow E performs the main Variant QC, checking missing call rate, Hardy-Weinberg equilibrium deviation, minor allele frequency, missingness in case/control status, and generates covariates for GWAS, based on a user-modifiable number of Principal Components (or users may provide a covariates file). Workflow F is for pre-imputation quality control, preparing the dataset for imputation, while Workflow G performs local phasing and imputation using shapeit416 and impute517. Workflow H performs post-imputation QC where poorly imputed variants are removed, different categories of duplicated variant IDs are handled and the phenotypes of the dataset are updated. The workflows’ structure also allows for users to upload their data to an external imputation server, or use a different reference panel. Workflow I performs GWAS with and without adjustment of covariates (if the covariates are not provided by the user, snpQT uses the first five Principal Components generated from population stratification in Workflow D), outputting summary statistics, along with a Manhattan plot and a Q-Q plot.\n\nAs it can be challenging to choose the correct threshold for a metric, snpQT provides a \"Make report\" module in each of the main Workflows C, D, E, and I, that provides interactive HTML reports summarising all the plots for both before and after the chosen thresholds have been applied, enabling the user to easily inspect and check if the chosen thresholds are appropriate. Detailed summary logs and graphs are also provided throughout, depicting the total number of samples and variants in each step, for users who need easy and fast inspection of the processes, as well as for users who want a more-in-depth report prompting users towards the locations of intermediate files and logs.\n\nsnpQT is implemented in nextflow, R and Unix command line utilities. The minimum software requirements to run snpQT are Java 8, nextflow v20.10.0, and a POSIX-compatible operating system (tested on CentOS 8). The hardware requirements scale with input data and workflows: typically quality control checks require less than 16GB of RAM and 4 cores on large datasets of 40,000 individuals. However, imputation requires significant computing power - up to 50GB of RAM per chromosome per core. As well as those already listed, the following tools are used: picard (https://broadinstitute.github.io/picard/), PLINK18, PLINK2.019, samtools20, and snpflip (https://github.com/biocore-ntnu/snpflip).\n\nThe latest release of the 1,000 Genomes Project data13 is used as a reference panel in both VCF and processed PLINK2 formats14. A part of the population stratification and variant QC implementation was inspired by the work of 6. Optional software requirements include Docker, Anaconda, and Environment Modules which provide a simple method to install and run the underlying collection of bioinformatics software described above.\n\nAnaconda is suitable for users who are not interested in performing local imputation and who do not have root access in their machines. Users can still run pre-imputation and post-imputation QC, as well as all the remaining QC-related workflows of snpQT.\n\nDocker requires root access, which enables the installation of impute5, which is used for imputation\n\nEnvironment modules are useful to run all stages of the pipeline in HPC environments, where root access is not available, but require some user configuration because installed packages and package names are custom to each HPC environment\n\nFull documentation of snpQT, including an installation guide, a Quickstart explanation of workflow combinations and commands, a complete description of workflows, and an in-depth tutorial are provided at https://snpqt.readthedocs.io/en/latest/. The following Use Case section gives examples of input and output with explanatory context, and explains all of the key parameters needed to make use of snpQT.\n\n\nUse case\n\nThis section provides a guide through the snpQT Quality Control pipeline, explaining the steps and demonstrating the application of the tool, using a synthetic dataset which is free and available with the tool. Plots shown are based on this synthetic dataset, which has some artificial structure but is adequate for demonstration purposes. The online tutorial includes plots with natural distributions, derived from a real-world Amyotrophic Lateral Sclerosis dataset of 2,000 samples (1,000 cases and 1,000 controls) taken from a restricted-access dbGaP project21.\n\nBefore downloading and running snpQT, depending on their needs, the user should have downloaded nextflow (v20.10.0) and Docker or Anaconda. To begin installation, the repository can be cloned and set up can be initiated by running the following commands:\n\n\n\nBefore starting to use any of the implemented workflows, it is necessary to set up a local database of reference and auxiliary files that snpQT requires to run. Because of the large volume of reference data in imputation workflow, we have designed two types of database. The first is the core reference database, which is sufficient for build conversion, sample and variant quality control, population stratification, pre-imputation and post-imputation. The second database is required only for local imputation, and downloading the latest release of the 1,000 Genomes Project data. In either case, it is necessary to first set up the core database:\n\n\n\nThe above command will download the core reference files, prepare them and store them in a db/ folder in the snpQT directory. On the test system this took around 1 hour to complete, but this will vary depending on the system and network. The core dataset requires ~43GB of initial storage of intermediate files, which are stored in the work/ directory. These can be removed after set up using nextflow run main.nf –download_db core && rm -r work, leaving only 19.7GB of reference files that are stored in the database directory db/.\n\nAlternatively, an already processed .tar.gz file (17.3GB, when unzipped it requires 19.7GB of space) of the required reference data can be downloaded directly from our servers, using the following lines of code:\n\n\n\nIf the user is interested in local imputation then the following command should also be run (in addition to the previous commands for the core database set up):\n\n\n\nThis command will download the imputation reference files and store them in a snpQT/db/impute directory. Downloading and processing the imputation data may take one to two hours or more, depending on the system and network. These reference files require an additional 30GB of storage. Alternatively, an already processed .tar.gz (13GB, when unzipped it requires 15GB of space) imputation reference file can be downloaded directly from our servers, using the following lines of code, and taking around 25 minutes:\n\n\n\nThe snpQT workflows generate many intermediate files that are not shown directly to the user, and are usually not needed by the user. Nextflow stores these in the snpQT/work/ directory by default. Due to the large size to which this directory can rapidly grow, it is recommended that the work folder be deleted after setting up the reference databases, using the command shown above. The same command can also be used to regularly clear the work/ folder as needed, such as after running multiple analyses using snpQT. However, while these intermediate files are retained, snpQT will remember previous work that it has done, such that it may automatically avoid needless repetition of previously completed work if asked to run a different stage of the pipeline, or to run again with tweaked parameters, on the same input data. When the work/ folder is deleted, all work for the analysis will need to be redone.\n\nAfter the download and set up of the database, analysis can then be done. A synthetic demonstration dataset is available with snpQT, which can be used to gain familiarity with the workflows and modules, while ensuring reproducible results identical to those shown in this section. The synthetic dataset is located within the data/ folder, and consists of a .vcf.gz file and three binary plink files (.bed, .bim and .fam). The dataset contains 6,517 randomised genotypes of chromosome 1, derived from 100 female samples having balanced binary phenotypes (i.e. 51 cases vs 49 controls). The chromosome positions, alleles and SNP IDs have been updated according to human 1,000 Genomes Project data (hg37).\n\nThe Human Genome Build Conversion workflow converts genomic files aligned in build 38 to build 37 (default mode) and vice versa, using Picard’s LiftoverVcf utility. snpQT assumes that your input genomic data are aligned to build 37, as some of the workflows are designed to accept this input. Despite that GRCh37 human reference genome is not the most recent one, it is the most frequently used build among current public reference genomic datasets (e.g. 1,000 Genomes data, Haplotype Reference Consortium panel), online imputation servers (e.g. Sanger Imputation Server) and available snp-array datasets, and for this reason snpQT has been designed to support GRCh37 (hg19) for most workflows. Hence, this workflow can be helpful for users with data aligned to build 38 to convert them to build 37, in order to run QC and population stratification. The workflow may also be helpful when a user has finished their main QC and wish to upload their data to an external imputation server that uses a reference panel aligned in b38 (i.e. TOPMed) or b37 (i.e. Haplotype Reference Concortium panel), or to run a local imputation using a reference panel which is aligned in another build.\n\nThe genomic build of the synthetic dataset (which is aligned to b37) can be converted to b38 by running the following code, with input files and options explained below:\n\n\n\nInput files:\n\n– ––vcf: This workflow requires a valid VCF file of human genomic data\n\n– ––fam: This workflow also requires an accompanying plink .fam file which should contain the same samples as the VCF file.\n\nsnpQT options:\n\n– ––convert_build: runs the build conversion workflow\n\n– ––input_build: defines the build of the input data [37/38 (default)]\n\n– ––output_build: defines the build of the output data [37 (default)/38]\n\n– ––mem [16 (default)] : assigns the memory size that the LiftoverVCF utility can use\n\n– ––results: specifies the directory where the output files are stored. To retain results from separate analyses, the name of the results folder should be changed between runs.\n\nNextflow options:\n\n– –resume: runs multiple jobs using cached files (so skipping processes which are not affected by new changes). When running a different stage of the pipeline on the same input data, this will cause snpQT to avoid needless repetition of work already done.\n\n– –profile conda can be replaced with –profile [docker/modules] depending on your installation and needs (e.g. whether local imputation is needed or not, HPC requirements).\n\nWhen this work is run successfully, a new folder will be created named convert_build_toy/ which contains a files/ subfolder which contains three binary plink files (the .fam file contains updated phenotype information) aligned to b38 and a .vcf.gz file for users who prefer this format for other purposes.\n\nsnpQT’s main QC workflow is divided into two distinct nextflow modules: Sample and Variant QC. Sample and Variant QC can be run using the parameter –-qc. The required input files are binary plink files which can be imported using the parameters –-bed, –-bim and –-fam, for .bed, .bim and .fam plink files, respectively. The main checks of Sample QC are listed below, with accompanying parameters and explanation:\n\nMissing variant call rate check: Remove very poor quality SNPs based on call rate (snpQT default threshold is 0.1). These SNPs will be removed anyway at the variant QC stage, and applying the filter here avoids unnecessary removal of samples that may otherwise be of good quality.\n\nMissing sample call rate check: Remove samples with lower than 98% call rate using the –-mind parameter (snpQT default threshold –-mind 0.02). The distribution for all samples using histograms and scatterplots is visualised before and after the applied threshold.\n\nCheck for sex discrepancies: Remove problematic samples for which (1) pedigree sex does not agree with the predicted sex based on sex chromosome homozygosity or (2) there is no sex phenotype using plink (default mode). This step can be skipped by setting the –-sexcheck false parameter.\n\nRemoval of non-autosomal SNPs: The default mode of snpQT is to keep the sex chromosomes. If the user wishes to remove the sex chromosomes, the –-keep_sex_chroms false parameter can be set.\n\nHeterozygosity check: Identify and remove heterozygosity outliers (samples that deviate more than 3 units of Standard Deviation from the mean heterozygosity). The distribution of the samples’ heterozygosity is visualised by a histogram and a scatterplot. Extreme heterozygosity implies inbreeding and/or DNA contamination. This step can be skipped using the –-heterozygosity false parameter.\n\nCheck for cryptic relatedness and duplicates: Check for cryptic pairs of relatives or duplicated samples using plink2’s relationship-based pruning. The pruning threshold can be changed using the --king_cutoff [0.125 (default)] parameter.\n\nRemoval of samples with a missing phenotype: Remove samples with missing phenotypes. As missing phenotype here we refer to phenotype status (i.e. case/control status, the last column in the plink .fam file). The default option in snpQT is to skip this step, but it can be performed using the parameter –-rm_missing_pheno true.\n\nThe second part of the main QC is Variant QC, which is again implemented using the --qc parameter. It is considered good practice to first filter low quality samples in order to reduce the risk of removing a potentially high-risk variant during Variant QC. For this reason, the population stratification workflow (if chosen to be run by the user, as explained in the next subsection), which is essentially a Sample QC step, is designed to run between Sample QC and Variant QC, as seen in Figure 1. The Variant QC module contains the following steps:\n\nMissing variant call rate check: Remove poor quality SNPs using the parameter --variant_geno (snpQT default threshold is --variant_geno 0.02).\n\nHardy-Weinberg equilibrium (HWE) deviation check: Remove SNPs that significantly deviate from the Hardy-Weinberg equilibrium (HWE) (snpQT default threshold is p-value <10e-7), indicating a genotyping error, and visualise the distribution of SNPs with extreme deviation. This threshold can be changed using the parameter --hwe.\n\nMinor Allele Frequency (MAF) check: Remove SNPs with low MAF (snpQT default threshold is 0.05) and visualise the MAF distribution. This threshold can be changed using the --maf parameter in snpQT. Rare SNPs (having a very low MAF) are usually considered as false-positives and need to be excluded from further analysis.\n\nMissingness in case/control status check: Remove SNPs with a statistically significant association of missingness (low call rate) and case/control status (snpQT default threshold is p-value <10e-7). The threshold can be changed using the parameter --missingness. This check can not be performed for quantitative data. If the user’s data are not binary, the --linear parameter can be used to skip this step.\n\nGenerate covariates using the first X Principal Components of each sample: Perform Principal Component Analysis and visualise the 2D and interactive 3D PCA plots annotating the samples by the phenotype status. If the GWAS workflow is called (using the parameter --gwas), use by default the first 3 Principal Components (PCs) to account for inner population structure. The number of PCs can be adjusted using the --pca_covars parameter which can take as input a number from 1 to 20, with 1 starting from the first Principal Component of the PCA. Prior to the PCA, snpQT keeps only independent markers performing variant pruning using PLINK. This behavior can be controlled using the parameter --indep_pairwise [\"50 5 0.2\" (default)].\n\nThe synthetic toy dataset does not contain sex chromosomes, so to avoid plink producing an error it is important to add --sexcheck false to skip the step which checks for sex discrepancies. Main QC on the toy dataset can be performed by running the following command:\n\n\n\nOn completion, the results_toy/ directory will now contain as many folders as the number of workflows that were run. Based on the example given, a results_toy/qc/ folder should be present, containing the following sub-folders and files (this structure will be similar for most other workflows):\n\nA bfiles/ folder including the binary plink files of the last step of the corresponding module\n\nA figures/ folder including all generated plots for the steps that have been run within this particular workflow, as well as log plots summarising the number of samples and variants in each step of the workflow\n\nA logs/ folder including two .txt files (sample_qc_log.txt and variant_qc_log.txt) summarising details about the numbers of samples, variants, and phenotypes for each step of Sample and Variant QC, as well as the working directory where the intermediate files for each process are stored, so that it is easier for the user to inspect the results\n\nTwo .html reports for Sample and Variant QC summarising all the \"before-and-after the threshold\" plots generated in each step, as well as a plot demonstrating the number of samples and variants in every step.\n\nIn Figure 2 and Figure 3, we show some examples of the output plots from the Sample and Variant QC workflows for the toy dataset. Figure 2 illustrates a sample call rate histogram and a scatterplot for the toy dataset, before and after the default threshold has been applied (indicated by a red line). Figure 3 shows one of the last processes of the Variant QC workflow, where Principal Component Analysis is performed on the clean dataset both for data exploration and for generation of covariates using the first X Principal Components, which can then be used in the GWAS workflow, to account for a potential inner population sub-structure.\n\nSample call rate for synthetic toy dataset shown as (a) a histogram and (b) a scatterplot, before and after applying the default threshold of 0.02% (red line). This synthetic randomised dataset was created for demonstration purposes, thus the sample call rate distribution may not closely resemble a real-world dataset.\n\nThe samples are annotated based on their phenotype (e.g. case/control status). The 3D PCA plot is available in an interactive environment incorporated into the .html reports. PCA plots are also provided in a 2D format for the first three Principal Components.\n\nThe aim of the Population Stratification workflow is to identify and then remove potential ethnic outliers, based on population structure, using the EBI’s latest release of a processed phased 1000 Genomes Project reference panel, aligned to human genome build 37. Population stratification is an essential step in QC analysis, since it minimises the possibility that the difference in the allele frequencies is caused by the different ancestry of the samples. The population stratification workflow requires the main QC workflow.\n\nDuring this workflow, internal processing of both the 1,000 Genomes data and of the user’s dataset are performed, and then the two datasets are merged, keeping only mutual SNPs shared by both. The internal processing consists of numerous QC steps, some of which can be tailored by the user, by passing the following parameters:\n\n--indep_pairwise [\"50 5 0.2\" (default)] : Control PLINK’s variant pruning process\n\n--variant_geno [0.02 (default), 0-1]: Remove poorly genotyped variants\n\nWhen both datasets are prepared and merged, snpQT creates a racefile labeling the race of each sample. User's samples are automatically labeled as \"OWN\". The race label for the 1,000 Genomes data can be controlled by the --racefile parameter, using super-population labels (e.g. EUR, AFR, AMR) by default or subpopulation labels using the --racefile [super (default), sub] parameter. When the racefile and the merged dataset are ready, EIGENSOFT's smartpca software is performed for automatic outlier removal. Smartpca takes a set of parameters, which are in the form of a file. snpQT provides the option to change this file according to the users' needs using the --parfile parfile.txt parameter. Lastly, the user can choose to infer eigenvectors based on a population subset list in smartpca using the parameter --racecode [\"\" (default), \"EUR\"/\"AFR\"/\"SAS\"].\n\nTo perform population stratification on the toy dataset the user can run the following command:\n\n\n\nAfter successful completion, a new sub-folder pop_strat/ will be created within the –-results directory, along with the previous qc/ folder. Since the -resume parameter was used, the Sample QC processes have been cached, making the pipeline run faster. As it was mentioned above, Population Stratification runs in between Sample and Variant QC, which means now that --pop_strat is combined with --qc the Variant QC, input files have changed and therefore, the corresponding processes will run again with the updated input. Within the pop_strat/ folder, the following are included:\n\nA bfiles/ folder including three binary plink files and a .log file coming from the last process of the --pop_strat workflow\n\nA figures/folder including six 2D plots for the first three Principal Components, two 3D plots in a .rds format for an interactive user experience for both before and after ethnic outlier removal using EIGEN-SOFT and lastly, two .log plots summarising the number of samples and variants in each step of the workflow\n\nA logs/ folder including a pop_strat_log.txt file summarising details about the numbers of samples, variants, and phenotypes for each step of the workflow, as well as the working directory where the intermediate files for each process are stored, so that it is easier for the user to inspect the results\n\nA popstrat_report.html report summarising all the aforementioned plots, as well as hosting an interactive environment for the 3D plots.\n\nFigure 4 shows the Principal Component Analysis (PCA) plot for the synthetic toy dataset. The PCA topology is quite artificial here, as this is a synthetic dataset made in plink2, containing only a few thousand genotypes of chromosome 1, which are subsequently pruned, leaving a few hundred independent SNPs merged with 1000 Genomes Project data. A more natural example of PCA plots resulting from real-world data is shown in the online tutorial for the ALS dataset.\n\nThe samples are annotated based on their ancestry, except for the user’s data which are labelled as \"OWN\". Two 3D PCA plots are available in an interactive environment incorporated in the .html reports, representing before and after ethnic outlier removal using EIGENSOFT. PCA plots are also provided in a 2D format for the first three Principal Components. Since the synthetic toy dataset is artificial and contains only a few hundred of randomised independent markers, it is located a large distance from the 1000 Genome data. For this reason, the before-and-after outlier removal PCA plots are identical, so only one is shown here.\n\nThis workflow performs both logistic and linear regression for binary and quantitative phenotypic traits, respectively, using the parameter --gwas. snpQT performs a logistic regression by default, but it is also designed to run linear regressions using the --linear parameter. These analyses can be performed with and without adjusted covariates to account for a fine-scale population structure. Covariates can be calculated at the end of the --qc workflow (preferably used with population stratification workflow) using the first X Principal Components of the generated PCA, using the --pca_covars [3 (default), 1-20] parameter; alternatively, covariates can be passed directly from the user as an argument with --covar_file [false (default), covar.txt]. The covar.txt file should follow the same format as a PLINK covariate file. The GWAS workflow requires the main QC workflow to run in advance. For a logistic regression analysis on the toy dataset, the user can run the following command (the following example assumes that the user wishes to run population stratification as well, although this is not obligatory):\n\n\n\nThe command above causes a total of 39 separate snpQT processes to run, and be completed in ~2 minutes on the development system. When GWAS has finished running successfully, a new gwas/ sub-folder will be created within the results_toy/ directory, along with the previous pop_strat/ and qc/ folders mentioned above. Within the gwas/ folder the following are included:\n\nA files/ folder including the plink2 Generalised Linear Regression results of GWAS analyses, both with and without adjusted covariates, accompanying log files and GWAS files with adjusted p-values for multiple-testing corrections.\n\nA figures/ folder including Quantile-Quantile (Q-Q) plots and Manhattan plots for the GWAS results, both with and without covariates, and log plots illustrating the number of samples and variants at each step.\n\nA logs/ folder including a gwas_log.txt file summarising details about the numbers of samples, variants, and phenotypes for each step of the corresponding workflow, as well as the working directory where the intermediate files for each process are stored, so that it is easier for the user to inspect the results.\n\nAn .html report summarising all the aforementioned plots.\n\nFigure 5 and Figure 6 show Q-Q and Manhattan plots, with and without covariate adjustment for the synthetic toy dataset, respectively.\n\nQ-Q (Quantile-Quantile) plots for the synthetic dataset both (a) with and (b) without covariate adjustment, with their accompanying lambda values. This synthetic randomised dataset was created for demonstration purposes using the default thresholds, thus the Q-Q distributions may not closely resemble a real-world clean dataset.\n\nManhattan plots for the synthetic dataset both (a) with and (b) without covariate adjustment. Each dot represents a variant located based on its genomic position (x-axis) and GWAS -log(p-value) (yaxis). The synthetic dataset at this stage contains 2,312 variants located in chromosome 1.\n\nThe Pre-Imputation workflow prepares a genomic dataset for imputation, including fixing issues such as flipping SNPs that are on the reverse strand, removing ambiguous and duplicated SNPs and fixing the reference allele. If the user wishes to run the Pre-imputation workflow independently (i.e. the user is not interested in local imputation) then it is required to combine the workflow with the main QC workflow (and only optionally with the Population Stratification workflow). When Pre-Imputation QC is run independently, the --pre_impute argument is used and it cannot be combined with the GWAS, Imputation and Post-Imputation workflows. To run Pre-Imputation QC on the synthetic dataset, the user can run the following command:\n\n\n\nPre-imputation workflow creates a preImputation/files/ directory, which contains a compressed VCF and an indexed VCF files which are ready for imputation\n\nsnpQT also offers an optional Imputation workflow, using the parameter –-impute, where the user can increase the number of markers of their genomic dataset, using EBI’s latest release of the phased 1,000 Genomes Project reference panel aligned to human genome build 37. When the --impute workflow is used, the Pre-Imputation and Post-Imputation workflows are called internally before and after phasing, and local imputation takes place, accordingly. As explained above, Pre-Imputation prepares the user’s dataset for phasing using shapeit4 and local imputation with impute5. When phasing and imputation per chromosome are finished, then the Post-Imputation workflow takes as input the imputed chromosomes, and filters out all poorly imputed variants, based on Info score and MAF. The user can alter these filters using --info [0.7 (default), 0-1] and --impute_maf [0.01 (default), 0-1] parameters, respectively. The Post-Imputation workflow also annotates missing SNP IDs and handles different categories of duplicated SNPs.\n\nTo run local imputation on the synthetic toy dataset the user can run the following command:\n\n\n\nWhen imputation is complete, separate preImputation/ and post_imputation/ folders are created. The post_imputation/ directory contains the following sub-folders:\n\nA bfiles/ folder including three binary plink imputed files and a .log file coming from the last process of the Post-Imputation workflow\n\nA figures/ folder including log plots illustrating the number of samples and variants at each step\n\nA logs/ folder including a post_impute_log.txt file summarising details about the numbers of samples, variants, phenotypes and the processes of the workflow\n\nDespite that the Post-Imputation workflow can be nested under the --impute workflow, it is also designed to run independently; as some users may prefer to run imputation on external online servers, or may have already imputed data and they wish to proceed only with a Post-Imputation QC. The accepted input files for Post-Imputation are a valid VCF file and an accompanying plink .fam file, which should both contain the same samples. To run Post-Imputation QC on the synthetic toy dataset, the user can run the following command:\n\n\n\nAs already explained above, the results directory contains a new post_imputation/ folder containing the same elements as in the Imputation workflow.\n\nLastly, snpQT provides a command-line help page which is continuously updated, using the parameter --help. We provide further information about the implemented snpQT processes, the synthetic toy dataset and the real-world ALS dataset results in the online documentation at https://snpqt.readthedocs.io/en/latest/.\n\n\nConclusions\n\nThe snpQT tool offers robust QC combined with scalability, reproducibility, flexibility and user-friendly design which can appeal to a broad spectrum of users. It is a stand-alone software, implemented as a modular nextflow DSL2 workflow. No additional coding nor manual installation/download of any data or other program are required apart from nextflow and Anaconda or Docker. We have designed environments of standard bioinformatics tools for each stage of the workflow, to ensure software version consistency and to improve user experience. The input for snpQT is a VCF file and/or binary plink files, formats which are widely used. The architecture of snpQT provides a thorough QC analysis (inspired and tested by 6,22,23), including parameters and generating plots, for both before and after the provided threshold for the majority of the steps. Outputs include interactive .html reports, summative .log files and graphs summarising all the results for easier inspection. For users who have limited experience with QC analysis, a thorough \"how-to\" guide and step-by-step tutorials are provided, using the demonstration dataset that is available with the tool, which can also be informative to users who wish to be newly acquainted with QC analysis.\n\n\nSoftware availability\n\nSource code available from: https://github.com/nebfield/snpQT\n\nArchived source code at time of publication:\n\nZenodo: nebfield/snpQT: v0.1.3 -Fluffy penguin, https://doi.org/10.5281/zenodo.508309324\n\nLicense: GNU v3.0\n\n\nData availability\n\nZenodo: snpQT reference data (Version 0.1), http://doi.org/10.5281/zenodo.491646925\n\nThis project contains the processed reference data required by snpQT to function. snpQT can download and process raw data from scratch to create reference data, as described in the installation section, or the data above can be downloaded and used to save time.\n\nZenodo: nebfield/snpQT: v0.1.3 -Fluffy penguin, https://doi.org/10.5281/zenodo.508309324\n\nThis project contains the synthetic dataset used in the Use Case section, which is distributed with the source code.\n\nNCBI dbGaP: Mega-GWAS ALS I. Accession number, phs000101.v5.p1: https://identifiers.org/dbgap:phs000101.v5.p1\n\nThis dataset is under restricted access. To access the dataset, access must be requested through the dbGaP authorised access portal (https://dbgap.ncbi.nlm.nih.gov/aa/wga.cgi?page=login).",
"appendix": "Author contributions\n\n\n\nConceptualisation, C.V., B.W., A.M. and W.D.; data curation, C.V.; GWAS workflow design, C.V. and A.M.; GWAS workflow implementation, C.V.; snpQT code implementation and nextflow architecture, B.W. and C.V.; review of code and testing, C.V. and B.W.; writing-original draft preparation, C.V.; writing-review and editing, C.V., B.W., A.M. and W.D.; supervision, W.D.; project administration, W.D. All authors have read and agreed to the published version of the manuscript.\n\n\nAcknowledgements\n\nWe would like to thank Dr. Priyank Shukla for helpful discussion, Dr. Apostolos Malatras for his assistance, and Peter Timlett for designing the snpQT logo.\n\n\nReferences\n\nVasilopoulou C, Morris AP, Giannakopoulos G, et al.: What Can Machine Learning Approaches in Genomics Tell Us about the Molecular Basis of Amyotrophic Lateral Sclerosis? J Pers Med. 2020; 10(4): 247. PubMed Abstract | Publisher Full Text | Free Full Text\n\nColeman JRI, Euesden J, Patel H, et al.: Quality control, imputation and analysis of genome-wide genotyping data from the Illumina HumanCoreExome microarray. Brief Funct Genomics. 2016; 15(4): 298–304. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTeo YY: Common statistical issues in genome-wide association studies: A review on power, data quality control, genotype calling and population structure. Curr Opin Lipidol. 2008; 19(2): 133–43. PubMed Abstract | Publisher Full Text\n\nBurt C, Munafò M: Has GWAS lost its status as a paragon of open science? PLoS Biol. 2021; 19(5): e3001242. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnderson CA, Pettersson FH, Clarke GM, et al.: Data quality control in genetic case-control association studies. Nat Protoc. 2010; 5(9): 1564–1573. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMarees AT, de Kluiver H, Stringer S, et al.: A tutorial on conducting genome-wide association studies: Quality control and statistical analysis. Int J Methods Psychiatr Res. 2018; 27(2): e1608. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEller RJ, Janga SC, Walsh S: Odyssey: A semi-automated pipeline for phasing, imputation, and analysis of genome-wide genetic data. BMC Bioinformatics. 2019; 20(1): 364. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSong Z, Gurinovich A, Federico A, et al.: nf-gwas-pipeline: A Nextflow Genome-Wide Association Study Pipeline. J Open Source Softw. 2021; 6(59): 2957. Publisher Full Text\n\ndi Tommaso P, Chatzou M, Floden EW, et al.: Nextflow enables reproducible computational workflows. Nat Biotechnol. 2017; 35(4): 316–319. PubMed Abstract | Publisher Full Text\n\nda Veiga Leprevost F, Grüning BA, Aflitos SA, et al.: BioContainers: an open-source and community-driven framework for software standardization. Bioinformatics. 2017; 33(16): 2580–2582. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarijo D, Kinnings S, Xie L, et al.: Quantifying Reproducibility in Computational Biology: The Case of the Tuberculosis Drugome. PLoS One. 2013; 8(11): e80278. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMerkel D: Docker: lightweight Linux containers for con-sistent development and deployment. Linux Journal. 2014; 2014(239): 2. Reference Source\n\n1000 Genomes Project Consortium; Auton A, Brooks LD, et al.: A global reference for human genetic variation. Nature. 2015; 526(7571): 68–74. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChang CC: 1000 Genomes phase 3, phased and anno-tated data for use in plink2.0 worked examples. GigaScience Database. 2018. Publisher Full Text\n\nPrice AL, Patterson NJ, Plenge RM, et al.: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006; 38(8): 904–909. PubMed Abstract | Publisher Full Text\n\nDelaneau O, Zagury JF, Robinson MR, et al.: Accurate, scalable and integrative haplotype estimation. Nat Commun. 2019; 10(1): 5436. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRubinacci S, Delaneau O, Marchini J: Genotype imputation using the Positional Burrows Wheeler Transform. PLoS Genet. 2020; 16(11): e1009049. PubMed Abstract | Publisher Full Text | Free Full Text\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. 2007; 81(3): 559–575. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChang CC, Chow CC, Tellier LC, et al.: Second-generation PLINK: rising to the challenge of larger and richer datasets. GigaScience. 2015; 4(1): 7. 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(2): giab008. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNicolas A, Kenna K, Renton AE, et al.: Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron. 2018; 97(6): 1268–1283.e6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVerma SS, de Andrade M, Tromp G, et al.: Imputation and quality control steps for combining multiple genome-wide datasets. Front Genet. 2014; 5: 370. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLaurie CC, Doheny KF, Mirel DB, et al.: Quality control and quality assurance in genotypic data for genome-wide association studies. Genet Epidemiol. 2011; 34(6): 591–602. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWingfield B, Vasilopoulou C, Morris AP, et al.: nebfield/snpqt: v0.1.2 -fluffy penguin. 2021. http://www.doi.org/10.5281/zenodo.4959322\n\nVasilopoulou, Wingfield, Morris: snpqt reference data. 2021. http://www.doi.org/10.5281/zenodo.4916469"
}
|
[
{
"id": "89658",
"date": "11 Aug 2021",
"name": "Andries T. Marees",
"expertise": [
"Reviewer Expertise GWAS",
"method development",
"statistics",
"addiction",
"psychiatry",
"socio-economic status"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 by Vasilopoulou et al. is well written and presents a potentially interesting software pipeline for genomic qc. Furthermore, the accompanying website provides a clear overview of all steps and options.\n\nMajor concerns:\n1A) The authors write: “The analyst may encounter incompatibility problems and installation difficulties as well as spending valuable time familiarizing themselves with a number of different tools that sometimes lack detailed documentation”.\nI agree with the authors that this is an issue the field is faced with and see the value snpQT can offer. Unfortunately, the snpQT installation difficulties (Anaconda/Docker/modules) are on par with many other packages. I strongly recommend looking into how you can make this process easier (if possible, aim for full copy-paste simplicity). Especially because the target audience is probably inexperienced analysts/researchers. I believe, based on my experience in providing tutorials/software tools that, unfortunately, 90% of potential users won’t make it past the current installation process.\n1B) A strong selling point of this paper is that all steps from QC, to imputation, to the results including figures, are all under one umbrella, which is great.\nHowever, many potential users will most likely use an HPC and have no root access for a docker installation. The authors write that this is needed for the imputation part as this is not possible with Anaconda. If the imputation might not be available for many users the question arises, what is the added benefit of this software pipeline? Clear protocols for all the separate steps (QC, imputation, association) are already widely available (and already in place for established groups).\nI am aware that the above problem can be solved using environment modules (as the authors write), but the current paper/website leaves the potential users on their own to figure the rest out. I am afraid that these hurdles will strongly limit adoption of this otherwise promising software package.\n\n2) Personally I do not like the defaults with the --qc command for example, and believe it is better for the user to specify input for the various qc steps. The default thresholds provided by the authors are not in all data sets per se the ideal choices (e.g., 3 PC as covariates or MAF 0.05). I see no benefit for the defaults but do see them causing potential negative outcomes - does snpQT provide the user with the flexibility to choose the order of the QC steps or is the sequence of steps hardcoded? (i.e., flexibility in order of the steps within and between the various workflow parts).\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": [
{
"c_id": "7368",
"date": "29 Nov 2021",
"name": "William Duddy",
"role": "Author Response",
"response": "We thank the reviewer for their time and very constructive comments. 1A) We apologise if the reviewer had problems installing snpQT, and we have taken further steps, detailed below, to make this as straightforward as possible. We would like to note in addition that, whereas a user may be faced with installation challenges and version choices for multiple separate tools if building their own ad-hoc analytical pipeline, snpQT requires only a single installation and compatible software versions are pre-selected. We have now simplified our Quickstart online documentation guide, aiming, as the reviewer suggested, for \"full copy-paste simplicity\" insofar as possible. We have updated our initial installation guides, adding further simple installation details about the provided profiles (Anaconda/Singularity/Docker/Modules) in a dedicated \"Profiles\" tab, and moving the more advanced installation details to a later subsection of the User Guide. Installation now contains only the necessary basic information for a new inexperienced user to get started with snpQT, including a subsection containing set up guidelines for users who wish to perform local imputation, and quick examples on how to run snpQT. Once their profile is created the user should not need to worry about any software inconsistencies, as the selected environments will combine specific software versions selected and tested for compatibility. In addition, environment setup has been streamlined: instead of having to wait for a large environment recipe to be solved before any process runs, the appropriate environments for each workflow combination are now created while each snpQT process is running. 1B) We thank the reviewer for the very positive comment. We agree that the need for root access had been a frustrating limitation. We have worked to overcome this, and now provide four different profile options including Anaconda, Singularity, Docker, and Environment Modules, to enable users to run the software in multiple environments, and now avoiding a requirement for root access to run on HPC. We provide two different options that enable the users to run snpQT on HPC, which are Singularity and Environment Modules. We apologise that our online documentation lacked some details on the profile installation, and we have now updated our installation guides (as mentioned above) and we further provide details and example code on how users who are interested in running their experiments on HPC can now submit to a SLURM queue. In general, we have worked to simplify the way snpQT sets an environment. We now provide two different types of profiles; the first type concerns the machine where snpQT is expected to run, i.e. a user working in a normal laptop would use -profile standard and in an HPC -profile cluster. The second type is responsible to set up successfully all the required libraries and software, assuming that the user has not installed anything except nextflow and the profile environment software of choice (e.g. Singularity, Anaconda, Docker). These two different types of profiles are expected to be combined according to the user’s needs and expectations. For instance, a user who would be interested to run their experiments in a HPC would use -profile cluster, singularity or -profile cluster,modules. Submission to a SLURM queue can be achieved by editing the cluster.config file in our “Profiles” tab in the online documentation at https://snpqt.readthedocs.io/en/latest/quickstart/profiles/ 2) We thank the reviewer for questioning the use of defaults – we had felt on balance that it would enhance user-friendliness to enable defaults while simultaneously providing the flexibility to change them, but we are fully aware that each analysis is unique so user needs and preferences can (and should) differ widely. To avoid these concerns, we have now removed defaults so that snpQT will not run when a necessary parameter is not specified. In addition, the reviewer’s comment prompted us to reflect that parameters specified through the command line can be at risk of mistaken or accidental misuse use through on-the-fly copy/pasting. To combat this risk, we have now implemented a parameter file that can be used in place of command line flags, and we now recommend this as the primary way to use snpQT. With respect to the wider query on flexibility to choose the order of QC steps, this consideration was a central concern in the design of snpQT. The pipeline is designed to offer multiple combinations of workflows (as shown in Figure 1), and the quality control steps are implemented with numerous user-modifiable thresholds. In fact, we have preserved, to the extent logical, all of the modifiable parameters of each of the external tools incorporated by the workflows, so that some 36 parameters are modifiable by the user (within the accepted range of values which is provided by the external tools). In Figure 1, we show how all 9 implemented workflows can be combined in different ways. As far as the processes are concerned, there is a specific order which they are expected to follow, based on previously established QC protocols; however, we have implemented special parameters which can be used to skip certain processes and adjust the pipeline to the user’s needs. We have adjusted the manuscript text in several places to further highlight the flexibility of snpQT."
}
]
},
{
"id": "91453",
"date": "26 Aug 2021",
"name": "Stephanie M. Gogarten",
"expertise": [
"Reviewer Expertise Human genetics",
"quality control",
"GWAS"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 snpQT software is a useful resource for researchers working on Genome-Wide Association Studies (GWAS). It bundles a wide collection of software together and provides a clearly defined workflow based on best practices in GWAS quality control. It will be particularly useful for beginning researchers as it provides a straightforward entry point to learning how to work with GWAS data. The software is open source and comes with extensive documentation and tutorials, all available on the web.\nThe manuscript is well written and clearly describes the use of the software and its benefits, with a few caveats as outlined below:\nMajor:\n1) The term \"racefile\" as an argument name is inappropriate and should be changed. Race refers to a social category that is correlated with, but not the same as, genetic ancestry, and using it in this way goes against current recommendations in the human genetics community (Brothers, Bennett and Cho 20211; Birney et al 20212). In fact, the allowed values in the \"racefile\" appear to be 1000 Genomes population labels, which are not races. A more appropriate term for this argument would be \"popfile\", with the associated argument \"racecode\" instead called \"popcode\".\n2) Similarly, the term \"ethnic outliers\" should also be changed, both in the manuscript and in the snpQT online tutorial. Ethnicity is also a social category and its use is not appropriate in this context. The outlier removal performed by EIGENSOFT does not rely on any labelling of race, ethnicity, or population, but is instead described in the original publication (Price et al 20063) as \"Outliers were defined as individuals whose ancestry was at least 6 standard deviations from the mean on one of the top ten inferred axes of variation.\" Outliers are defined with respect to mathematically inferred clusters, so using the term \"ethnic\" to describe outlier removal misrepresents the behavior of the underlying software. Replacing the term \"ethnic outliers\" with simply \"outliers\" would correct this problem, as the term is always presented in the context of the population structure workflow. \"PCA outliers\" would be another alternative.\nMinor:\n3) \"Dependency hell\" is a colloquial phrase that may be confusing to many readers. Please use a longer sentence in the abstract to more clearly describe the issue. The methods section already has such a description and the same text can be used in the abstract. Remove the words \"known as 'dependency hell'\" from the methods section, as it is unnecessary and the choice of words could potentially alienate some readers.\n4) The description of the installation process in the manuscript seems to be out of date when compared with the online tutorial. Although it is expected that software is updated after manuscript publication, during the publication and review process the manuscript should reflect the current operation of the software. Specifically:\nThe manuscript provides commands to download the development version of the software, while the tutorial recommends an alternative method to get the latest stable release. Links for tar.gz files with reference data are out of date. The manuscript references only Anaconda and Docker as options for running the software, while the tutorial recommends Singularity over Docker.\n\n5) The authors should consider changing the default behavior of the build conversion to be build 37 to 38. As a user, the behavior I would expect (and desire) would be converting to the most current build by default. The authors do provide rationale for their choice, citing that public reference panels are available in build 37. However, 1000 genomes data is currently available in build 38, so the reference dataset could be updated.\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? Yes",
"responses": [
{
"c_id": "7369",
"date": "29 Nov 2021",
"name": "William Duddy",
"role": "Author Response",
"response": "We thank the reviewer for noting this very important oversight, and apologise for the misuse of the terminology. We have updated our code, documentation and manuscript, changing the parameters' names from –racefile to –popfile, --racecode to –popcode. Again, we thank the reviewer for noting this very important oversight. Accordingly, we have removed the adjective \"ethnic\" from our online documentation and manuscript. As the reviewer suggested, we now refer to the excluded samples after population stratification as \"outliers\". We have changed the abstract from \"Dependency hell and reproducibility are recurrent challenges\" to \"Software incompatibilities, and inconsistencies across computing environments, are recurrent challenges, leading to poor reproducibility\". We also removed the term \"dependency hell\" from the methods. We apologise for this - we have been improving the installation procedure, as described in response to reviewer 1, and during this process inconsistencies arose between the manuscript and the documentation. We have now updated both the manuscript and the online documentation with our latest instructions. We made a decision early in the development of snpQT to focus on build 37, as this is still the most commonly used reference. As such, build 37 is the primary build for the current release that is described in the manuscript, and considerable effort has been expended to ensure that the tool functions well with this build. We are working to support build 38, but this is likely to be included in a future version of snpQT, and as such is beyond the scope of the current work."
}
]
},
{
"id": "92711",
"date": "01 Nov 2021",
"name": "Anna Ulrich",
"expertise": [
"Reviewer Expertise Statistical genetics",
"multi-omics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nVasilopoulou et al. presents a comprehensive and integrated workflow for the quality control (QC), assessment of population stratification, genome build conversion, imputation and genome-wide association (GWA) analysis of called genetic variants for those without much experience in bioinformatics. However, it seems counterintuitive to use the small synthetic dataset instead of the Amyotrophic Lateral Sclerosis (ALS) cohort (shown in the online tutorial) as a use case in the manuscript. Performance could be better demonstrated with a genome-wide dataset of a size more realistic for today`s GWA analyses. For example, the run time for the complete QC, population stratification and GWAS is presented for the synthetic dataset (~2 mins) which is not too informative for real datasets.\nIn addition, I would like to point out the following statements in the text which were unclear to me:\n“When this work is run successfully, a new folder will be created named convert_build_toy/ which contains a files/ subfolder which contains three binary plink files (the .fam file contains updated phenotype information) aligned to b38 and a .vcf.gz file for users who prefer this format for other purposes.” – The authors might have meant the updated .bim files here. It is unclear to me how the phenotype data file is updated when aligning genomic positions to a different build.\n“Remove problematic samples for which (1) pedigree sex does not agree with the predicted sex based on sex chromosome homozygosity or (2) there is no sex phenotype using plink (default mode).” – Instead of “there is no sex phenotype using plink” the authors could specify “there is no sex phenotype present in the .fam file”, as this might be more informative to those not too familiar with the PLINK.\n“Figure 3 shows one of the last processes of the Variant QC workflow, where Principal Component Analysis is performed on the clean dataset both for data exploration and for generation of covariates using the first X Principal Components, which can then be used in the GWAS workflow, to account for a potential inner population sub-structure.” – “generation of covariates using the first X Principal Components” would suggest that it is not the Principal Components (PC) themselves which are used as covariates in GWAS, but some other variable generated using PCs.\n“Pre-imputation workflow creates a preImputation/files/ directory, which contains a compressed VCF and an indexed VCF files which are ready for imputation.\" – The authors could specify here the imputation services/servers this output is compatible with (i.e. TopMed, HRC?).\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Partly",
"responses": [
{
"c_id": "7453",
"date": "29 Nov 2021",
"name": "William Duddy",
"role": "Author Response",
"response": "We thank the reviewer for their time and constructive comments. Regarding the use of the small synthetic dataset: The use case followed in the manuscript is intended to show how snpQT can be used. Since the ALS dataset requires an ethical process for access to it, we wished to provide a use case that users would be able to follow with minimal barriers – this is why we chose to use the synthetic dataset. However, we agree with the reviewer that it was not very relevant to refer to run time for this small synthetic dataset in the manuscript, and we have now removed reference to run time for the synthetic dataset in the new version of the manuscript. Furthermore, to give an indication of performance for datasets of more relevant size, we have now used nextflow’s built-in reporting functionality to generate performance metrics for two cohort sizes from the ALS dataset, and added this to the manuscript text: “On our development system, using the same workflows as in the example above (but including a sex discrepancy check and plotting, as well as a missing phenotype check, so that snpQT ran 45 processes in total), applied to the 2,000 case-control ALS cohort demonstrated in our online documentation and also to a 12,319 case-control ALS cohort (all the samples of dbGaP accession number: phs000101.v5.p1), snpQT completed in 4 minutes and in 3h 14m, respectively. Performance metrics for these two cohorts are provided (https://doi.org/10.5281/zenodo.5703398).” Regarding build conversion: We apologise for the ambiguity and thank the reviewer for spotting this. The phenotype information is not changed by the build conversion – the word ‘updated’ referred to the technical need to preserve phenotype information by updating the PLINK files that are generated during the build conversion process, in order to ensure consistency with downstream workflows. The required input files for the human genome build conversion workflow are a VCF and a .fam file. After the LiftOver process is complete, snpQT then creates 3 binary PLINK files, using the new VCF file that has been created during the LiftOver process. Although a .fam file is generated by PLINK at this stage, it is based on the VCF file and, as VCF files do not store any phenotype information, the phenotype column in the .fam file of the previously generated binary PLINK files would be -9 i.e. missing. For this reason, the user-provided .fam file is needed to update the PLINK files with the original phenotype information. In order to avoid confusion for readers, we have changed the text simply to, “When this work is run successfully, a new folder will be created named convert_build_toy/ which contains a files/ sub-folder with three binary PLINK files (with updated genomic information, and phenotypic information preserved).” Regarding sex phenotypes: We thank the reviewer for spotting this, and have changed the text as requested: \"Remove problematic samples for which (1) pedigree sex does not agree with the predicted sex based on sex chromosome homozygosity or (2) there is no sex phenotype present in the .fam file\" Regarding principal components: Thank-you for spotting this. The text now reads, \"Figure 3 shows one of the last processes of the Variant QC workflow, where Principal Component Analysis is performed on the clean dataset both for data exploration and the first X principal components are used as covariates in the GWAS workflow (if the user has not provided a separate covariate file), to account for a potential inner population sub-structure.\" Regarding imputation: The text now reads \"The Pre-Imputation workflow creates a preImputation/files/ directory, which contains a compressed VCF and indexed VCF files which are ready for phasing and imputation, compatible with the Sanger Imputation Server standards.”, and we have added similar explanation at the start of the Pre-Imputation, imputation & post-imputation section."
}
]
}
] | 1
|
https://f1000research.com/articles/10-567
|
https://f1000research.com/articles/10-468/v1
|
14 Jun 21
|
{
"type": "Research Article",
"title": "From frustration to enlightenment: experiences of student exchange program awardees in Taiwan",
"authors": [
"Wolter Parlindungan Silalahi",
"Friska Ria Sitorus"
],
"abstract": "Background: Studying abroad is one of the most exciting experiences for a college student who is running a student exchange program, as it creates opportunities to learn, work, solve problems, and ensure a secured life. However, Indonesians who are into student exchange programs face some difficulties in adjusting to their new environment. They experience awkwardness in the use of advanced equipment from technology and cultural aspects. This study investigates the experiences of two Indonesian students who participated for a semester at a Taiwanese university. It aims to explore the Indonesian student exchange program awardees’ experiences by examining both the obstacles and benefits of attending the Taiwanese university. Methods: This study used qualitative data analysis. Data were collected through a semi-structured interview, informal participant observations, and a set of open and closed-ended questions. Two Indonesian undergraduate students who belonged to the same major, year, and university were recruited to act as ambassadors. Results: The two students reported facing some problems but felt more independent and became more adaptable. They met with new people and explored new places, and learned much in terms of teaching pedagogy and personal development from the 21st-century classroom pedagogy, which was important for their future carrier in education. Aside from being able to feel the 21st-century classroom environment, they were able to learn the host language and culture, which enriched their insights. Five main findings emerged: departure and journey, difficulties in settling in, inability to use technology facilities, meeting new people and exploring new places, and 21st century classroom environment. Conclusions: Despite the challenges that are associated with being a student exchange awardee, there are vast opportunities for self-development and learning the ropes associated with teaching from the 21st-century classroom pedagogy.",
"keywords": [
"Experience",
"Qualitative Study",
"Student Exchange"
],
"content": "Introduction\n\nEducation has a lot of interesting opportunities for humans that can give us better chances to obtain good careers and well-paid jobs. These opportunities can help to build peace, prosperity, harmony, happiness, stability, self-esteem, and wisdom in individuals. Studying abroad is what many student aim to take part in because they can get to know how to appreciate and respect other people's culture and see it as a reflection of their own (Lai, 2018), increase their personal growth, awareness, self-efficacy (Edmonds, 2010), immerse themselves in a new language, make new friends with local or international students, and gain experience from being international students. To be part of student exchange is a priceless experience that comes with a lot of advantages such as an international learning exposure that leads to enhanced intercultural learning, global awareness, self-development, language acquisition, and many other positive long-term impacts (Giedt et al., 2015). On the other hand, there are lots of adjustments to be made, such as adjustment to homesickness, lack of adequate finance, adaptation problems, prejudice, and housing and transportation related problems (Crockett & Hays, 2011). Also, vocational, physical health, social, and academic issues can occur (Yi et al., 2003). Other adjustments include learning style, study habits, educational background, culture and language proficiency (Andrade, 2006), lack of understanding of local context (Park, 2010), and punctuality (Razack, 2002). However, the student exchange program can contribute to diversity and internationalization of classrooms, colleges, and communities and to the enhancement of mutual understanding and appreciation of the differences around the world. Cheney (2001) stated that international interaction could generate two specific benefits namely mastering of English or other foreign language, and increasing international friendships. In addition, having discussions with international students makes significant, positive effects on critical thinking and promotes friendship, and many campuses develop peer pairing programs to match those running student exchange programs with local students (Summers & Volet, 2008).\n\nBased on a study conducted by the International Educational Consultants Association, there were approximately 35,000 Indonesian students who studied abroad in 2019, for example, in Australia, United Kingdom (UK), Singapore, Europe, Canada, and Asia (Berita, 2020). Taiwan is one of the most highly educationally developed economies in the world (Guo, 2005, p. 134), and offers a lot of scholarships for undergraduate, master, doctor, double degree, and student exchange programs. Taiwanese universities are also highly favored by researchers.\n\nThis study aims to investigate the experiences of the awardees of student exchange programs. In Indonesia, student exchange candidates with Taiwan are elected based on reciprocal partnerships set up by Memorandum of Understanding signed by Taiwanese and Indonesian universities. It offers free tuition for only two students as awardees, and those who join the student exchange program have to support themselves. The case presented in this research was the first time for the Indonesian university (IU) to have a reciprocal partnership with a Taiwanese university and to send their awardees abroad. Therefore, this study focuses on the experiences of these two student exchange beneficiaries from Indonesia, who enrolled in the undergraduate program. This led to an investigation into the Indonesian exchange students' experiences at the Taiwanese university. This study is very important because it will benefit students in future who will study abroad as student exchange awardees, particularly for future students who have no previous foreign study experience background. It will also contribute to the education field of academicians, researchers, experts, or even the government, regarding the student exchange program, which affects life and study adjustment aspects.\n\n\nMethods\n\nTwo college students, with the pseudonyms P1 and P2, consented to participate in this descriptive qualitative study. Participants were recruited after the researchers knew the information from their home university that both of the participants were chosen to be the first batch of student exchange ambassadors to represent their home university. During the spring semester of 2020 (February to June 2020). Initially, they were elected as the first and second rank of hundreds of college students who took the student exchange written test and interview from the committee at their home university. However, despite their outstanding performances during the selection test from the committee, it was discovered that they did not have any experience regarding going abroad, which include experiences of the flight system, the process of check-in, and how to find the gates at the airport. It was therefore the first time in their lives to apply for passports and visas, with this study's authors as volunteers, to guide them during preparation for departure and to welcome them in Taiwan. The exchange was to a national university in the east coast county of Taiwan. They officially registered for the student exchange program for one semester in an English department, and attended several courses such as fundamental Chinese, English writing, reading contemporary, western English literature, and critical approach to literature. Those courses were taught in English; the students were used to studying in full Bahasa Indonesia in their home university, in the western part of Indonesia. The students' characteristics are shown in Table 1.\n\nData was gathered primarily through semi-structured interview questions (Table 2) that were administered to them after their exchange program. The purpose was to share their personal experiences in the Indonesian language for 30-60 minutes. The meeting was scheduled with participants, audio recorded, field notes made, and held in a location that was convenient to participants. Data were triangulated through an informal participant observation from P1 and P2.\n\nA set of open-ended questions was used to explore their experiences during the interview (Hsieh & Shannon, 2005). Close-ended questions regarding age, religion, and other privacy questions were also collected. A WhatsApp group was created to allow for follow-up questions which were sent via WhatsApp to the researchers and participants. During the interview participants answered the questions without pressure.\n\nAs the second author was a doctoral student at the same university with the participants, informal participants' observations were conducted by the researchers to see the participants' emotions during the exchange program while spending time with the two participants outside of the interview, on and off campus, for instance while going to the library, eating at the cafeteria, riding bicycles, window-shopping, or studying in the study room.\n\nThe interviews were transcribed into English. Subsequently, themes for each interview were created to develop thematic grouping. A summary form of the interview was created and provided to the participants in order to obtain their feedback before the themes was finalized (Creswell, 2013).\n\nThis study was approved by Tarutung State Christian Religion Institute (Protocol number H.0206/F1000R/RSF/XII/2020). After due consultation, consent letters were provided by the home university and Taiwanese university.\n\nBefore the interview was conducted, the researchers sought participants' willingness by asking them to fill out an informed consent sheet. It explained the objectives of the study, assuring confidentiality by using codes and pseudonyms prior to the interviews, and asking the participants to sign the informed consent form. After the data has been transcribed and analyzed qualitatively, the recorded data sheets were archived for confidentiality reason.\n\n\nResults and discussion\n\nFive major themes emerged: (1) Departure and journey; (2) Difficulties in settling in; (3) Inability to use technology facilities (4) Meeting new people and exploring new places; and (5) 21st-century classroom environment. These themes are discussed narratively in the following sections.\n\nFor the first time students were selected to be \"student exchange program ambassadors\" to represent their home university. Lecturers and staff were very excited because the university had succeeded in opening international doors, perhaps leading to an increase in the quality of their university through the international program. A week before the student's departure to Taiwan, the president of the university and staff gave an official \"send-off party\" at the home university. Motivational speeches were given, concluding with the tradition of giving the students tribe blankets called “ulos” as a symbol of blessings. At the time of departure, everyone, including the students' family members officially followed them to the airport in two of the university's official buses, a journey which took approximately three hours from the university to the airport. A printed banner on the bus explained that the students were being sent to Taiwan for student exchange programs.\n\nP1: “I felt emotional when a lot of people accompanied us to the airport and it also became a big spur for both of us to do our best at the Taiwanese university”.\n\nP2: “My parents and family members came with me to the airport for the send-off and we took permission from my younger brother's school, so he could accompany us”.\n\nFor the two students, it was the first time to fly by plane, so it was challenging for them to check in and transit at the airport. As they landed at Taiwan International Airport, they were confused about where to collect their luggage and ended up asking the airport employees for assistance. In addition, they did not have cash on them, so they tried to withdraw money at the airport's ATM machine, but this failed as their cards were not yet validated by their home bank for international transactions. This resulted in the students feeling sad and confused. They ended up borrowing money from an Indonesian student studying at the same campus with them. This student picked them up at the arrival hall, meaning that they could buy food and milk to sustain them until they reached their destination, approximately four hours from the airport.\n\nP1: “We didn't eat for seven hours even though we had bread, we couldn't eat it because we felt dizzy from the flight”.\n\nP2: “I did not know what to buy because it was my first time seeing the international food”.\n\nJenkins and Galloway (2009) investigated adjustment problems faced by international students studying in Taiwanese universities. Also Yi et al. (2003) found adjustment issues such as academic, physical health, financial, vocational, and personal/social issues in similar exchange programs.\n\nThe two students faced a lot of difficulties regarding understanding the local money because they did not change their Indonesian currency to Taiwanese currency when they were still in Indonesia; they thought that they would be able to use their ATM cards to get the Taiwanese currency, unfortunately, their cards were not identified. Upon reporting the case to the Indonesian local bank, but they were told that they have to wait for a couple of days. This led to both students being depressed and miserable as they did not know if there would be somebody to lend them money until their cards could be used. This culminated in P1 crying at the convenience store nearby their dormitory as she did not want to borrow money. P2 called her parents to ask that they send money urgently through her senior's ATM and asked her senior to borrow money in the interim. Therefore, due to P1's situation, they discussed their difficulties on the phone with one of their lecturers in Indonesia, and their lecturer was able to phoned their buddy to ask them to lend the students enough money to get by.\n\nEven though the two students belonged to different religions, they did not want to be separated from each other. Therefore, when P1 went to pray at church, P2 would accompany P1 to the church and wait for P1 in the lobby. When P2 went to pray at the Mushola, P1 would accompany P2 and wait. The other students asked P1 and P2 a lot of questions about Indonesia, for example, why Indonesian people like spicy food and how Indonesian people deal with their hot weather since theirs was a tropical country. Luckily, all the friends they met in Taiwan respected the religious backgrounds of both P1 and P2. For example, when they had to eat at a restaurant together with their international friends, everybody was really helpful to choose a vegetarian food for P2 since P2 is a Muslim and it is forbidden to eat pork. This friendly attitude is referred to as international relations, which means the ability of people from different countries to collaboratively work together so as to establish a good relationship (Knight & Wit, 1997).\n\nAfter living in Taiwan for one month, their home university asked P1 and P2 to take a photo in front of the logo of their university in Taiwan, so they could make a big banner in front of their home university stating that both of them had officially studied at the Taiwanese University as student exchange program ambassadors. Three months later, the IU campus advised them to make a short video about their learning process, environment and others in order to provide an overview of the study process in Taiwanese university so that their friends at IU could find out what their studies looked like. This was for promotional purposes to the public and at the same time, to inform the public that the IU is implementing the “goes international” campaign. This promotion can make both universities have a market branding and become highly reputable (Sakamoto & Chapman, 2012), and this promotion could create good reputation for them that will lead to a competitive advantage (knight, 2004). After a couple of weeks, they became comfortable with many things in Taiwan that make them interested more than ever in sharing their life experiences in their Taiwanese university.\n\nAt first, the students met with difficulties in getting water to drink at their dormitory, even though there were four dispensers in every corner of the floor; when they located them, they did not know how to use those dispensers, so they did not drink water that night. When they woke up the next morning, they had the bread that they brought from Indonesia for breakfast without drinking any water. They stayed hungry in the afternoon because they did not understand how to turn on the rice cooker so as to prepare lunch. After trying for four hours, P2 called their senior to teach them how to operate the electronic equipment in the dormitory area. Their first trial at cooking rice failed. Finally, they did not eat the rice, but ate more of the bread that they brought from Indonesia.\n\nP1: “We got confused and just felt awkward, and so we laughed at each other even though we were very hungry”.\n\nP2: “We were so grateful when our senior came to visit us and he brought us some food and drinks, we might have fainted if he did not”.\n\nThe two students were extremely pleased with the dormitory facilities and the condition of the rooms, which they described as comfortable, clean and safe. This made a great impression on the students, making them willing to stay for more than one semester.\n\nP1: “I was so sad when my room was separated from that of P2, but I still managed to be excited because I had a roommate who was a local student to be my new friend, unfortunately, I do not feel totally comfortable with my roommate because she always turns on the air conditioner while sleeping, and I get cold every night. I went to the manager of the dorm to change my room, but he refused me”.\n\nP2: “I do not have any specific problems with my roommate. I am a Muslim and have to pray five times every day, and she has no problem seeing me doing my habitual activities”.\n\nThe students were surprised to see that every student had bicycles which were parked properly in the parking lot, and after a short stay, their senior gave them a bicycle each. As at the first two weeks P1 used to hitch a ride with P2 because P1 was not good enough at riding a bicycle so she had to practice for about two weeks until P1 was able to ride herself.\n\nThe awardees felt awkward to explore the university facilities themselves, so their senior invited them to have a campus tour. This included visiting the library, which the senior left the students to explore by themselves. However, the students did not go anywhere as they felt awkward to go up to the next level of the floor, and instead they decided to sit and wait for the senior to come back and pick them up. In addition, the students did not know how to borrow books from the shelves or online through the library website. Their classmates helped them how to select and reserve books through the website. The library is usually open at 09:00 am to close at 22:00 pm, and most students come in the morning hours and stay until it is about to close. The library is very safe, meaning personal items can be left unattended.\n\nP1: “I saw a lot of students searching for books through the computers that are available on every floor. Many students copied their books by themselves using the photocopy machines that are available on every floor”.\n\nP2: “There are a lot computers provided in our library, we only sign in with our student id number and we can use unlimited materials, we also get 100 pieces of paper for free to print for every semester. This library provides a small room for individuals to study, and a big room for a group to have a discussion”.\n\nLiving in other countries, and exposure to other cultures generally creates goodwill and contributes to global peace and security (Guruz, 2008). Therefore, since these student exchange awardees were able to adapt to their environment, it is very likely that the Indonesian government or the education sector will be interested in hiring these two students who have the problem-solving ability to make decisions independently (Lai, 2018).\n\nThe cafeteria nearby the student's department provides a buffet, where food must be weighed before paying for it as payment is based on weight and this kind of payment system was very new for the student's to adapt. Even though hundreds of students come to this cafeteria, the students reported that everything was kept neat, clean and orderly.\n\nP1: “When I visited the buffet cafeteria alone, I was a bit nervous and I didn't know how to measure how much food I have already taken, finally, after I weighed my food, it was super expensive and I felt so worried about that, I wish I have taken just a little food”.\n\nP2: “Because I am a Muslim, I have to be careful to take own my food because beef and pork look alike on the stand”.\n\nMany restaurants in Taiwan open twice a day, including the restaurant near the student's college, which opens three hours per shift. The first shift is 11:00-14:00 pm, the second 17:00-20:00. Most of the local restaurants offer self-service, i.e. drinks, spoons, and sticks are gathered by the patrons and the patrons must clean their own tables. If people come late to the restaurant, they won't be served. All these rules are found in Taiwan and not in their home country Indonesia. The students reported that adjusting to local people's activities really helped them to more disciplined and organized.\n\nP1: “I could not find mineral water in all the restaurants that I visited, but there was always black tea, jasmine tea and soup. I was surprised that most of the students eat in the restaurants every day instead of cooking at dorm”.\n\nP2: “I didn't expect Taiwanese food to be so bland, the menu had spicy written in them but for me the meals were not spicy at all. I also discovered that most of the restaurants did not have menu written in English, so I had to order orally from the waiters with gestures and showing them the food picture from my cell phone at the same time. What I really love buying from the restaurants are the delicious soft drinks”.\n\nStudent exchange program awardees get the opportunity to make new friends with other international students and to also strike good friendship with the local students (Daly, 2007). They watch as many students do exercise at night even until mid-night and take showers after, they enjoy buying fried chicken pie and a big cup of Boba milk tea at night, to sleep so late at night and wake up at 12:00 am and most of them skip their breakfast and eat lunch later. If the students have to come to the class in the morning, they brought their breakfast to the classroom and they came to the class with free costumes such as short pants, with sandals.\n\nIn addition to that, they have a bus that always come based on their schedule. The bus is very convenient and the drivers are also friendly. The awardee used to say thank you after and smile getting off the bus. The students pay for their rides by tapping their student identity card to the monitor close to the driver.\n\nP1: “Most of the passengers always say thank you and goodbye to the driver. We can only stop at the official bus stops, we cannot stop just about anywhere we like and this is totally different from what happens in my own town”.\n\nP2: “Trains and buses are widely used and the system is extremely well organized. We used App for the bus schedule, and we used the website for the train schedule, and it really helped us to navigate our transportation here”.\n\nThey have an Indonesian students' community. At the beginning of the semester, this group of people got together in the auditorium to welcome the new students, they introduced themselves one after the other in front of their friends, revealing their personal profiles such as the name of their universities in Indonesia, their addresses, their majors and so forth and this is often the best moment for them to make more friends and to explore more about Taiwan. However, due to the COIVD-19 pandemic, many field trips from our university were cancelled. Due to welcome party cancelation, they found it difficult to get to know their fellow students from Indonesia so that their senior started inviting them to several activities outside the campus.\n\nP1: “We went to the river, lake and ocean together which was fantastic. We rode bicycles and explored the inside and outside of the college together. In addition, I began to have more friends to go to church with every Sunday; the church was located far away from my dorm”.\n\nP2: “There is always a pray day every Friday at the mosque located in the city, which I normally attend as a Muslim. It takes about thirty minutes from my dorm, after praying I used to get free Indonesian food for dinner and I am so happy because it helps me to save money”.\n\nThe lecturers the students received were from Professors, who are experts in their various fields. Most of them graduated from outside Taiwan. These lecturers taught them in English even though in the first week they were a little confused by a Taiwanese lecturer whose English pronunciation is unclear. Their lecturers implored them to be active in class, for example, to participate in collaborative learning that encourages students to be creative to solve problems and develop a relationship with each other; by collaborating and working effectively with others in order to make a lasting positive impact on individual student learning (Saner et al., 1994). The lecturers applied a 21st century teaching method in class, for example, a student centered method whereby students are used as facilitators to explain the materials to their peers through the learning by doing method. In the reading contemporary class, the student's reported the lecturer bringing stickers to class that were given to students who delivered some questions, ideas, responses to the lecturer. Before the class ended, the lecturer would use the remaining ten minutes to give conclusions that helped the students to understand more about the class. In the critical approach to literature class, the students reported the lecturer starting the class with an e-learning system and follow-up with discussions that required the participation of about 4-5 students per group.\n\nP1: “I felt very nervous, scared, and not confident because I never had classmates who came from various countries before. Fortunately, all the lecturers and classmates were very cool and friendly so that I became more comfortable”.\n\nP2: “I was initially not too shocked because there were a number of Indonesian students in the fundamental Chinese class, so I felt comfortable and not depressed. In another class, my Taiwanese friends were very friendly and helpful”.\n\nP1: “Our department is very big, but we never got lost on our way to the classroom”.\n\nThe students reported having good classmates; when they had assignments they used to have a discussion in the library, study room and café. When the class of semester was over, they had their own farewell party with their classmates. The students reported feeling very emotional at the end of the semester because they had to say goodbye to one another.\n\nThe classroom is one of the most important platforms for students to acquire knowledge acquisition and skills development (Kim et al., 2019). The students reported that their classroom facilities supported the learning process. These facilities included air conditioners, fans, projectors, comfortable seats, good lighting and other equipment, which made the learning environment to be very conducive and this situation is totally different at their home university. Therefore, all the activities in the classroom, including e-learning, really enhanced their 21st century skills which includes critical thinking, communication, collaboration, and creativity (Hadianto, 2019).\n\n\nConclusion\n\nThis qualitative study depicts the activities of two student exchange program awardees who were allowed to study abroad in Taiwan. It also examines the obstacles they faced during their one semester at the Taiwanese university. According to these awardees, the experience was a sure pathway to expand their friendship network to various countries in the world and with people of different backgrounds and cultural aspects. The student exchange awardees had a chance to introduce Indonesian culture to the foreigners that they met, through activities that were both inside and outside of the university. They also had the opportunity to meet some people in the Indonesian community in Taiwan, which formulated a network to work and discuss together, and to exchange experiences and knowledge among themselves. Moreover, they got a chance to meet with an Indonesian individual who is married to a Taiwanese individual; and this helped them to partake in the Halal food meant for Muslims.\n\nIn addition, the students had the opportunity to travel to several cities around Taiwan. It made them feel different when compared to their home country in terms of culture, weather, lifestyle, people, and transportation. Although it was not easy at first for them to live in Taiwan as strangers, but as time went by, they ended up adjusting to a whole new lifestyle altogether, in an unfamiliar environment, and to speak a new language which comprises both English and Chinese. They succeeded in completing the mission given to them to study for one semester at a Taiwanese university. Once back in Indonesia, the students were uncertain how to adjust the student experience to their old lives back home and they felt new to their old group of friends. They discovered that they had grown as ambassadors, and acquired knowledge about the 21st-century learning environment. In conclusion, they became independent, appreciative of their country, culture understanding, and they became more open to new ideas, assertive, and more confident in themselves.\n\nStudies conducted in recent times to investigate the international student exchange programs have increased significantly. However, this study did not investigate the student exchange program awardees' experiences in terms of motivation, cultural background, personality, attitude and so forth toward living and studying as student exchange awardees at the Taiwanese University. Therefore, for the sake of future research, this study suggests an in-depth research be done on other variables that relate to the international student exchange programs at the Taiwanese university.\n\n\nData availability\n\nFigshare: Raw Data Wolter, https://doi.org/10.6084/m9.figshare.14131646.v2 (Silalahi, 2021).\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nConsent\n\nWritten informed consent for publication of the anonymized interview transcript was obtained from the participants.",
"appendix": "References\n\nAndrade MS: International students in English speaking universities: Adjustment factors. J Res Int Edu . 2006: 131–154. Publisher Full Text\n\nBerita S: Retrieved April 22, 2020, from Minat Pelajar Indonesia Menuntut Ilmu di Luar Negeri Terus Meningkat. https://www.beritasatu.com/nasional/551247-minat-pelajar-indonesia-menuntut-ilmu-di-luarnegeri-terus-meningkat\n\nCheney RS: Intercultural business communication, internation students, and experiential learning. Business Communication Quarterly . 2001: 90–14. Publisher Full Text\n\nCreswell JW: Qualitative Inquiry and Research Design: Choosing Among Five Approaches . California, CA: SAGE Publicarion, Inc; 2013.\n\nCrockett SA, Hays DG: Understanding and Responding to the Career Counseling Needs of International College Students on U.S. Campuses. J College Counseling . 2011: 65–79. Publisher Full Text\n\nDaly AJ: Outbound student exchange at Australian and New Zealand universities: the effects of pre-departure decision-making, in country experiences and post sojourn outcomes . Brisbane: Griffith University; 2007.\n\nEdmonds ML: The Lived Experience of Nursing Students Who Study Abroad: A Qualitative Inquiry. J Stud Int Educ . 2010: 545–568.\n\nGiedt T, Gokcek G, Ghosh J: International Education in the 21stCentury:The Importance of Faculty in Developing Study AbroadResearch Opportunities. Interdisciplinary J Study Abroad . 2015: 167–186. Publisher Full Text\n\nGuo Y: Asia's educational edge: Current achievements in Japan, Korea, Taiwan, China, and India . Lanham, MD: Lexington Book; 2005.\n\nGuruz K: Higher education and international student mobility in the Global knowledge economy . New York: State University of New York Press; 2008.\n\nHadianto: The EFL Students' 21 Century Skill Practices through E- Learning Activities. Indonesian Res J Edu . 2019: 2580. Publisher Full Text\n\nHsieh HF, Shannon SE: Three Approaches to Qualitative Content Analysis. Qual Health Res . 2005: 1277–1288. PubMed Abstract | Publisher Full Text\n\nJenkins J, Galloway F: The adjustment problems faced by international and overseas Chinese students studying in Taiwan Universities: a comparison of student and faculty/staff perceptions. Pacific Education Rev . 2009: 159–168. Publisher Full Text\n\nKim S, Raza M, Seidman E: Improving 21st-century teaching skills: The key to effective 21st-century learners. Res Comparative & Int Edu . 2019: 9–117. Publisher Full Text\n\nknight J: Internationalization Remodeled: Definition, Approaches, and Rationales. J studies Int Edu . 2004: 5–31. Publisher Full Text\n\nKnight J, Wit HD: Internationalisation of higher education in Asia Pacific countries . Amsterdam: European Association for International Education; 1997.\n\nLai IC: Global world, global mind: Narratives of the University of Hong Kong Worldwide Exchange students. Transformation Higher Edu . 2018: 1–18. Publisher Full Text\n\nPark SJ: Reconsidering Korean culture and society and seeking self identity in the world: Short-term study abroad motivation and experiences. Comparative Korean Studies . 2010: 217–262.\n\nRazack N: A critical examination of international student exchanges. International Social Work . 2002: 251–265. Publisher Full Text\n\nSakamoto R, Chapman DW: Cross-border Partnerships in Higher Education: Strategies and issues . New York: Routledge; 2012.\n\nSaner H, McCaffrey D, Stecher B, et al.: The effects of working in pairs in science performance assessments. Educational Assessment . 1994: 325–338. Publisher Full Text\n\nSummers M, Volet S: Students' attitudes towards culturally mixed groups on international campuses: Impact of participation in diverse and non-diverse groups. Studies Higher Edu . 2008: 357–370. Publisher Full Text\n\nYi JK, Lin JG, Kishimoto Y: Utilization of counseling services by international students. J Instructional Psychol. 2003: 333–342."
}
|
[
{
"id": "87499",
"date": "16 Jun 2021",
"name": "Xuesong Gao",
"expertise": [
"Reviewer Expertise Language education"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript reports on a study that examined an underrepresented group of students in study abroad. It has some interesting insights for readers, but I do not think that the manuscript can be indexed in the current format. I suggest that the authors attend to the following issues before they resubmit their work for reconsideration.\nFirst of all, the manuscript requires substantial rewriting to improve the quality of writing. Just take the Abstract as an example: I do not understand whether a study abroad student is someone who is running a student exchange program. I also do not understand how an exchange program will ensure a secured life for its participants. Should the authors report how data were collected before talking about how data were analyzed? Can they elaborate on the problems the two students faced before talking about their feelings? Are the challenges associated with the participants or experienced by them? There are so many similar writing issues throughout the manuscript, which discourages this reader from making a positive recommendation.\n\nAs mentioned earlier, the Introduction section has a lot of writing issues. I hope that the authors can improve the quality of writing and reorganize it so that it can have a better argument development. I also suggest that the authors focus on developing an argument for the study. What do we know about study abroad students? What do we need to know about study abroad students? Since the study involved two Indonesian students in study abroad in Taiwan, the authors should highlight that previous research has focused on students in developed countries or English medium universities (or students from developed countries to other countries). I think that the study could potentially address an important void. See Li, J. & Han, H. (2020)1 and Song, Y. & Xia, J. (2020)2.\n\nThe manuscript needs research questions (or a research question) that are clearly motivated by the Introduction section. I think that the interview schedule can be included as an Appendix but needs to be described in the main text. More details on data analysis are needed. What did the authors do to enhance the quality of the analysis?\n\nThe results should be presented as answers to the research question. I believe that the authors should be more selective in choosing themes for inclusion. It is better to organize the presentation of findings into two groups: challenges and benefits. It is also important to develop sub-themes under the two major categories (challenges and benefits). For instance, under the category of challenges, the authors can present linguistic challenges, cultural challenges or social challenges, etc. Otherwise, I just found that the themes in the findings are not always relevant, for instance, departure and journey. We need findings that constitute significant insights into the two Indonesian students' experiences. The current findings as presented are highly descriptive and not sufficiently engaging.\n\nI suggest that the authors include a Discussion section or add some discussion to highlight in what sense the findings constitute important knowledge contributions to the field. It is not clear to this reader in what sense the study advances our understanding of study abroad students. Limitations should be presented before the Conclusion and can be presented as the directions for further research.\nI do hope the authors seriously consider my comments for revision. All the best wishes.\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": [
{
"c_id": "7463",
"date": "29 Nov 2021",
"name": "Wolter Parlindungan Silalahi",
"role": "Author Response",
"response": "Dear Prof Xuesong (Andy) Gao, We thank you most warmly for your suggestions to improve the quality of the writing. The writers have revised the paper regarding your suggestions as a reviewer as follows: In the background part of the abstract, the writers have organized the idea of the sentences based on your suggestions, from \"Studying abroad is one of the most exciting experiences for a college student who is running a student exchange program, as it creates opportunities to learn, work, solve problems, and ensure a secured life\", to \"This study investigates two Indonesian students who participated in a semester at a Taiwanese university. It aims to explore the Indonesian student exchange program awardees’ experiences by examining both the obstacles and benefits of attending the Taiwanese university.\" The introduction: we have revised the research question and the description of the participants' criteria. Previously, we didn't write these two points. The result: we have organized the themes and sub-theme based on your suggestions. Previously, we put the result and discussion in the same part. You suggested we separate them into different sections and we had revised it. We have put the \"limitations and future research\" before the conclusion as suggestions as follows \"Limitations should be presented before the Conclusion and can be presented as the directions for further research\"."
}
]
},
{
"id": "88855",
"date": "22 Jul 2021",
"name": "Anna Riana Suryanti Tambunan",
"expertise": [
"Reviewer Expertise TEFL",
"Intercultural Communication",
"English language and Literature",
"English Teaching and 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 study is fascinating to publish. I learned a lot from this article about the exchange experiences of Indonesian students studying in Taiwan. However, there are some things to consider, especially in terms of the language presented in this manuscript which is sometimes unclear. For example, in the sentence: \"Studying abroad is one of the most exciting experiences for a college student who is running a student exchange program, as it creates opportunities to learn, work, solve problems, and ensure a secured life,\" in the Abstract. In this sentence, the true meaning of studying abroad versus student exchange programs is not clear. The author may focus on only one program, for example, the student exchange program in Taiwan.\n\nIn the Introduction section, it is also necessary to elaborate on the issues related to the student exchange program related to student frustration. It is recommended that the research questions appear in the last paragraph of the Introduction section.\n\nThen in the Methods section, a detailed explanation of how to recruit participants, collect data, and analyze data should be given.\n\nIn the Discussion section, it is also necessary to add previous studies that support each finding. It would be better if it was elaborated according to the findings in the Discussion section.\n\nFinally, in the Conclusion section, there should be implications for this research.\n\nI hope my input will help the authors improve the article. Thank you.\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": "7464",
"date": "29 Nov 2021",
"name": "Wolter Parlindungan Silalahi",
"role": "Author Response",
"response": "Dear Prof Anna Riana Suryanti Tambunan, Thanks for submitting your review, we have read your suggestions for our paper and revised our study based on your suggestions as follows: The abstract: we have revised the election language presented in the manuscript. The introduction: the writer has elaborated on the issues related to the student exchange program related to student frustration and proposed a research question of this study. The methodology: the writers have revised the process of participants’ recruitment to participate in our study. Discussion: we have added previous studies that support our findings. Conclusion section: we have revised the implications for this research. Thank you Prof~"
}
]
},
{
"id": "90099",
"date": "23 Jul 2021",
"name": "Gregory Siy Ching",
"expertise": [
"Reviewer Expertise Study abroad",
"internationalization of higher education",
"research teaching nexus",
"academic identity"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 paper entitled \"From frustration to enlightenment: experiences of student exchange program awardees in Taiwan\" is an interesting study focusing on the study abroad experiences of two Indonesian students in Taiwan. However, as of the moment, the paper needs some reworking.\nThe Abstract can be improved. Participants were not clear. At first, two students were recruited as ambassadors - this is misleading. It should directly say there were two participants in the study (why was the term 'ambassadors' used - as later repeated in the Methods section) and this should be expanded.\nThe validity and reliability of the study might be affected since only two participants were interviewed. It would be hard to generalize the findings to all Indonesian students in Taiwan. However, the current study could be a starting point for a larger quantitative study, perhaps a survey generated from the current results.\nThe literature review should be expanded. There are also some studies done using a qualitative lens that the authors were not able to review. For instance: A case study on the international students’ social adaptability in Taiwan: A qualitative study by Lewis et al., 20121. Although it's not that new, the authors can still review it.\nIn general, the paper has potential but needs reworking.\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": "7465",
"date": "29 Nov 2021",
"name": "Wolter Parlindungan Silalahi",
"role": "Author Response",
"response": "Dear Prof Gregory Siy Ching, We are so thankful for your generous suggestion for this study. We had revised this paper based on your suggestions, as follows: The abstract: the writers had revised the participants' description instead of ambassador. Since only two participants were interviewed that affects the validity and reliability, based on your suggestion we agree that it could be a starting point for a larger quantitative study. The writer expanded the literature review in the introduction/background section. Thank you~"
}
]
}
] | 1
|
https://f1000research.com/articles/10-468
|
https://f1000research.com/articles/10-649/v1
|
26 Jul 21
|
{
"type": "Research Article",
"title": "Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial",
"authors": [
"Anwar Ebid",
"Mohamed El-boshy",
"Shamekh El-Shamy",
"Ali Thabet",
"Mohamed Abedalla",
"Tariq Ali",
"Mohamed El-boshy",
"Shamekh El-Shamy",
"Ali Thabet",
"Mohamed Abedalla",
"Tariq Ali"
],
"abstract": "Background: Osteoporosis is the most prevalent metabolic disease affecting bones. Objective: To investigate the long-term effect of pulsed electromagnetic field (PEMF) combined with exercise protocol on bone mineral density (BMD) and bone markers in men with osteopenia or osteoporosis. Methods: Ninety-five males with osteopenia or osteoporosis (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body–mass index (BMI), 26.08 ± 1.09 kg/m2) participated in the study, and they were randomly assigned to one of three groups: Group 1 received a full-body PEMF and exercise protocol (PEMF +EX), Group 2 received a placebo full-body PEMF and exercise protocol (PPEMF +EX), and Group 3 received a full-body PEMF alone (PEMF). PEMF was applied for the whole body using a full-body mat three times per week for 12 weeks, with an exercise protocol that includes flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises followed by whole-body vibration (WBV) training. Outcome measures include BMD of total hip and lumbar spine and bone markers [serum osteocalcin (s-OC), Serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), Serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), Parathyroid hormones (PTH), Bone-specific Alkaline Phosphatase (BSAP), and 25-hydroxy vitamin D (Vit D)]. Results: The BMD of total hip and lumbar spine was significantly increased post-treatment in all groups, and more so in Group 1 and Group 2 than Group 3. There was a significant difference in bone markers in all groups, more so in Group 1 and Group 2 than in Group 3. Conclusion: PEMF combined with exercise protocol exerts a potent role for treating OP, is more effective than exercise and PEMF alone for increasing BMD and enhancing bone formation, and suppresses bone-resorption markers after 12-weeks of treatment with the impact lasting up to 6 months.",
"keywords": [
"Pulsed electromagnetic field",
"Exercise protocol",
"bone mineral density",
"osteopenia",
"osteoporosis"
],
"content": "Introduction\n\nOsteoporosis (OP) is a systemic skeletal disease characterized by decreased bone mineral density, decreased bone quality, microarchitectural deterioration of bone tissue, and low bone mass, which causes discomfort, poor quality of life, increased bone fragility, and increased fracture risk, resulting in socio-economic burden, high morbidity and mortality, decreased functional mobility and increased attendant care and healthcare costs (WHO Report, 2003; Christenson et al., 2012).\n\nPharmacological therapies, such as bisphosphonates, hormone replacement, raloxifene, calcium, parathyroid hormone (PTH), vitamin D, calcitonin, testosterone, and anabolic steroids, have all been used to treat OP in recent years, but long-term use of antiosteoporosis drugs can cause gastrointestinal problems, infections, jaw osteonecrosis, hypocalcemia, atypical subtrochanteric femoral fractures, increased risk of certain cancers, and atrial fibrillation (Canalis et al., 2007; Body et al., 2012).\n\nBiophysical stimulus employing physical therapy modalities, such as pulsed electromagnetic fields (PEMFs), LASER, and physical exercise, has been offered as alternative treatments that are less expensive, non-invasive, effective, safe, and causes fewer side effects, and is highly recommended for clinical use (Wang et al., 2019). PEMFs are electromagnetic fields capable of producing biological currents in tissue and have unique biological effects. PEMFs also help patients with osteoporosis feel better by reducing pain, improving functional results and improving quality of life (QoL) (Liu et al., 2013; Wang et al., 2019).\n\nPEMFs may be one such effective therapy, and there is evidence that it has a positive impact on the treatment of various bone disorders, such as decreased bone mass, fresh fractures, non and delayed union, diabetic osteopenia, and osteonecrosis when compared with drug therapy (Liu et al., 2013), through a variety of mechanisms including mechanical stimulation, regulating the proliferation, activity, and mineralization of bone marrow mesenchymal stem cells (BMSCs), as well as osteoblast proliferation, differentiation, and activity, as well as osteoclastogenesis and osteoclast differentiation. PEMF therapy has gained extensive use due to its quick effects, ease of use, and lack of side effects (Liu et al., 2013; Wang et al., 2019; Zhang et al., 2017; Li et al., 2014).\n\nExercise training, weight-bearing exercise, and strength training have been linked to the maintenance of bone mineral density (BMD) by enhancing and increasing the differentiation and activities of osteoblasts, which has a direct impact on the production of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), 25-hydroxy vitamin D, and parathyroid hormones (PTH), which is more sensitive to exercise training and weight-bearing exercise (Yuan et al., 2016; Mohammad et al., 2020).\n\nPhysical activity and mechanical effort increase mechanical signals, such as fluid flow, anabolic effect on osseous tissue dynamic tension, upregulate the expression of osteogenic markers compression, stimulate resident osteocytes through fluid shifts in their canalicular network, and stimulate biochemical markers of bone formation and hydrostatic pressure. These mechanical signals enhance osteogenic differentiation while inhibiting adipogenic differentiation, which could be one of the reasons why exercise prevents osteoporosis and improves bone health (Maimoun and Sultan, 2009; Yuan et al., 2016).\n\nWhole-body vibration (WBV) produces high-frequency mechanical stimulation that is distributed throughout the entire body. It has been proposed as a unique non-pharmacological method for the treatment of musculoskeletal problems (Lau et al., 2011). WBV has been used as an alternate exercise strategy for bone and muscle stimulation. It has been demonstrated that increasing bone density via mechanical load and specific mechanical frequencies acting on the piezoelectric properties of bones can enhance osteogenesis, improve mechanical properties, accelerate fracture healing through angiogenesis, improve muscle function, increase BMD, reduce the risk of muscle power loss, improve muscle power, and help balance the musculoskeletal system (Lau et al., 2011; Wong et al., 2021; Wang et al., 2017; Fratini et al., 2016).\n\nTo our knowledge, no previous study has investigated the combined effect of PEMF and exercise protocol on BMD and bone markers in men. Therefore, this research is to investigate the long-term effects of PEMF alone or in combination with an exercise protocol on BMD and bone markers in males with osteopenia or osteoporosis.\n\n\nMethods\n\nThis was a three-measurement interval randomized placebo-controlled study. The Biomedical Research Ethical Committee of Umm Al-Qura University approved and considered this study ethically feasible (Approval number. HAPO-02-K-012-2021-540). The trial was also registered with the Clinical Trial Registry (Clinical Trials.gov ID: NCT04608162).\n\nThe G-power for Windows was used to calculate the appropriate sample size, with estimated power = 0.95 and α = 0.05. Using analysis of variance (ANOVA), with in-between interaction in three groups and three measurement intervals, the effect size was 0.30. In all therapy groups, a minimum of 92 patients was recommended as a sample size.\n\nThe study included 95 males over the age of 45 years (mean age, 51.26 ± 2.41 years; mean height, 176 ± 2.02 cm; mean weight, 83.08 ± 2.60 kg; mean body mass index (BMI), 26.08 ± 1.09 kg/m2). Initially, all participants were assessed for the recruitment criteria. A medical and psychological history, including height, weight, and BMI, as well as physical and laboratory exams, were part of the screening process. Every participant was assessed physically to see how physically active they were. The presence of any gait issues, muscular soreness, or joint pain was considered during the exam. Any supplemental therapies, special diets, or aerobic exercise programs would not be allowed throughout the study if participants underwent physical therapy or a change in their pharmacological therapy during the previous 3 months. Throughout the trial, participants were asked to continue with their normal daily routines and to avoid any systematic exercise training regimens. By dual-energy X-ray absorptiometry (DEXA), all patients were diagnosed with osteopenia or osteoporosis (T-scores<−1.5). The same assessor, who was blind to treatment, assessed all participants at pre-treatment, at the end of 12 weeks of treatment, and at 6 months after the trial ended. To control for diurnal variability, follow-up was done at the same time of day as the baseline and after the 12-week evaluation, if practicable. The study goals were discussed after the pre-treatment evaluation, and all participants gave written informed consent for their participation and the publication of their study results. The flow diagram of the study depicts all of the study’s steps (Figure 1).\n\nDiabetes mellitus, intraocular lenses, thrombosis history, cardiopulmonary conditions, severe vascular and renal disease, uncontrolled thyroid disease, cardiac pacemaker, uncontrolled hypertension, progressive neurological disease, chronic disabling arthritis, use of any medications that affect bone metabolism, severe hepatic diseases, presence of osteoporotic fracture, significant anemia, neuropsychiatric disorders (e.g., dementia), alcohol abuse, severe depression, panic disorder, bipolar disorder, or psychosis and BMI <19 kg/m2 or >31 kg/m2 were all excluded from the study.\n\nThe randomization method was carried out with the use of an online GraphPad Prism (RRID:SCR_002798; R is an open access alternative) that divided the patients into three groups. Group 1 received full-body PEMF and an exercise protocol (PEMF+EX), while Group 2 received a placebo full-body PEMF and an exercise protocol (PPEMF+EX), and Group 3 received full-body PEMF alone (PEMF). After the initial evaluation of the participants, randomization was carried out, and they were blinded to the treatment group randomization. The external evaluator and therapists were blinded to the participant’s group allocation.\n\nAn OsteoSys PRIMUS densitometer (OsteoSys, Seoul, Korea) was used to assess BMD in all patients at the lumbar spine (L2–L4) and total hip pre-treatment, after 12 weeks of treatment and at 6-months as a follow-up. The Middle East (ethnicity) reference database, provided by the manufacturer, was used to calculate T-scores for detecting osteopenia and osteoporosis. Machine calibration was performed daily before the assessments using spine phantoms provided by the manufacturers. All measurements were made by the same operator for all patients throughout the study period.\n\nSerum osteocalcin (s-OC), serum amino-terminal cross-linking telopeptide of type I collagen (s-NTX), serum carboxy-terminal cross-linking telopeptide of type I collagen (s-CTX), bone-specific alkaline phosphatase (BSAP), parathyroid hormones (PTH), and 25-hydroxy vitamin D (Vit D) were collected by vein puncture into vacationer tubes with no additive and processed to serum, which was stored at −20°C until needed for analysis. All samples were analyzed in triplicate.\n\nPEMF was applied to the whole body using a 68″×23″×1.5″ mat applicator and 8″×10″×2.5″ pillow applicator from Sedona Pro PEMF Systems, Portland Oregon USA Ltd). This mat generates a PEMF with a frequency range of 0.01–15,000 Hz, with sinusoidal, rectangular, multi-resonance, impulse, or sawtooth waveforms, the full-body maximum intensity is 30 gauss (3,000 microTesla) whereas the pillow is 101 gauss (10,000 microTesla). For a period of 12 weeks, each participant lay on the mat for 30 min/day, three times/week. The placebo intervention is identical to the actual intervention except that the PEMF device was not switched on. This method is particularly suitable for double-blind trials, as the application of PEMF therapy does not cause any feeling in the patient. The device used had a specially designed switch concealed at the back that enabled the independent researcher to interrupt the PEMF for the placebo group; the “on” sign and the parameters of PEMF therapy were displayed to all patients (placebo and PEMF groups) throughout the procedure.\n\nThe exercise protocol for each group consisted of three 60-min sessions per week for a total of 12 weeks, all of which were conducted in the exercise lab under the observation of the investigators. 40-min initial training exercises (flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises) were followed with WBV training exercise in each session. The initial training regimen was designed for beginning with a warm-up and gradually increased in intensity.\n\nFirst, stretching exercises for the upper and lower limbs, as well as the back and abdominal muscles, were given to the participants. Treadmill walking exercises involve a 20-min warm-up at the lowest speed, followed by 10 min at an intensity of 40–60% of the predetermined personalized maximal heart rate and a 5-min cool-down at the lowest speed.\n\nThe treadmill walking was immediately halted if the subject displayed any signs of weariness, discomfort, balance disturbance, heavy perspiration, chest pain, dyspnea, or leg cramps. Strengthening exercises for the back extensor, hip abductor, flexor, and extensor, and knee extensor were performed after a 5-min break. Each exercise was done in sets of ten and repeated three times.\n\nBack strengthening exercises were done on the bed against gravity, while hip strengthening activities were done in front of the wall bar in a weight-bearing position. Using a Total Gym gadget, a closed kinematic chain workout in the form of a leg press was conducted.\n\nThree sets of 10 maximum repetitions each of isotonic resistance workouts of the hip muscles were then done using a sandbag with varied weights according to patient tolerance. Under the guidance of the therapist, jumping into position and stair climbing was done.\n\nOn a Power Plate pro 5 vibration platform, WBV training consisted of a high frequency (30–40 Hz) vibration stimulus at a modest setting (2–4 mm peak to peak) (Performance Health Systems, LLC, Northbrook, IL, USA). Each subject was exposed to vibrations while squatting in a static position.\n\nFor all participants, the foot positions were standardized. According to the theory of progressive overload, the training intensity was raised by decreasing the rest periods or increasing the amplitude and/or frequency of the vibration. The vibration exposure began with one set of 30 s at 2 mm amplitude and 30 Hz, progressively increasing to a final exposure at a high amplitude of 35 Hz with two sets of 5 min each. They took part in a cool-down phase at the end of the program, which included relaxation and stretching exercises.\n\nParticipants in all groups were encouraged to walk for 30 min each day. All participants were given detailed workout descriptions, and they kept track of their exercise compliance. If any person missed four consecutive exercise sessions, they were removed from the study.\n\nAll participants had their age (years), height (cm), weight (kg), and BMI (kg/m2) measured, as well as BMD of the lumbar spine (L2–L4) and total hip. Bone markers such as s-OC, s-NTX, s-CTX, BSAP, PTH, and Vit D were also tested. Pre-treatment, 12-weeks post-treatment, and 6-month follow-up measurements were taken from all groups.\n\nG-Power 3.1 for Windows was used to calculate the estimated sample size based on the power analysis. One-way ANOVA was used to assess patient demographic data, such as age, weight, height, and BMI, using SPSS for Windows, version 16 (RRID:SCR_019096); JASP (RRID:SCR_015823) is an open-access alternative. ANOVA with a post hoc Bonferroni test was used to compare measurement intervals between treatment groups. Repeated measures ANOVA with post hoc Bonferroni test were used to measure baseline, after-treatment, and 6-month follow-up assessments in each group. For all tests, the level of significance was fixed at 0.05.\n\n\nResults\n\nFor this study, a total of 120 males were identified as potential participants (Figure 1). Of these participants, 25 were excluded (20 not meeting inclusion criteria, and five refused to participate). A total of 95 males participated in this study and were randomized into three groups. Between the three groups, there were no significant variations in mean age, weight, height, or BMI (Table 1). Following therapy, exercise compliance was 100% for all participants.\n\n** Non-significant differences in the same measurement interval among treatment groups (one-way ANOVA; p < 0.05).\n\nThere were significant differences between the three groups at measurement intervals with a higher significance in the PEMF+Ex group than PPEMF+Ex and PEMF groups. In the PPEMF+EX group, there were significant differences between pre-treatment and 12-week values and between 12-week and 6-month values, but insignificant changes between pre-treatment and 6-month values (Tables 2 and 3). Intergroup comparisons revealed significant differences between the 12-week and 6-month mean values (Table 4).\n\n* Significant difference in the same measurement interval among treatment groups (one-way ANOVA; p < 0.05).\n\n* Significant difference among the repeated measurement intervals in each treatment group (repeated measures ANOVA; p < 0.05).\n\n** Non-significant differences.\n\n* Significant difference in the same measurement interval among treatment groups (post hoc Bonferroni test; p < 0.05).\n\n** Non-significant differences.\n\n* Significant difference in the same measurement interval among treatment groups; p < 0.05).\n\n** Nonsignificant differences.\n\nIn all three groups, there were significant intragroup differences among the measurement intervals. The significance was higher in the PEMF+Ex group than PPEMF+Ex and PEMF groups. In the PEMF+EX group, there were significant differences between pre-treatment and 12-weeks or 6-months as follow-up values, but insignificant changes between 12-weeks and 6-months. In the PEMF group, there were significant differences between pre-treatment and 6- months and 12-weeks and 6-months values, but insignificant changes between pre-treatment and 12-weeks (Tables 2 and 3). Intergroup comparisons revealed significant differences in 12-weeks and 6-months mean values (Table 4).\n\nSerum s-OC revealed a significant decrease at 12-weeks in PEMF+EX and PPEMF+EX groups when compared with the pre-treatment values and PEMF group, but no significant difference in the PEMF group. At 12-weeks, there was no significant difference between the PEMF+EX and the PPEMF+EX groups. When comparing the PEMF+EX group with the PPEMF+Ex and PEMF groups at 6-months, there was a substantial decrease in the level of s-OC in the PEMF+EX group (Table 5). When compared with pre-treatment values and the PEMF group, the s-NTX and s-CTX in PEMF+EX and PPEMF+EX exhibited a substantial decrease at 12-weeks, while the PEMF group showed no significant difference. When comparing PEMF+EX with PPEMF+EX and PEMF groups at 12 weeks, there was a significant difference; furthermore, when comparing PPEMF+EX to the PEMF group at 12-weeks, there was a significant difference. When comparing the PEMF+EX group to the PPEMF+Ex and PEMF groups at 6-months, the level of s-NTX and s-CTX was significantly lower in the PEMF+EX group (Table 5).\n\n* Significant difference in each treatment group (one-way ANOVA; p < 0.05).\n\n** Non-significant differences.\n\nThe BSAP in all groups reduced significantly after 12-weeks as compared to pre-treatment levels and the PEMF group. When compared to PPEMF+EX and PEMF groups at 12 weeks, PEMF+EX showed a significant difference; additionally, PPEMF+EX showed a significant difference when compared to the PEMF group at 12 weeks. When comparing the PEMF+EX group to the PPEMF+Ex and PEMF groups at 6-months, the level of B-SAP was significantly lower in the PEMF+EX group. Within and between groups, there were no significant variations in serum PTH and 25(OH) VD levels (Table 5).\n\n\nDiscussion\n\nThe proposed mechanisms of PEMF’s impact on bone, particularly in OP, are unlikely to be detailed in the literature, and more research into the mechanism of action and effect on osteoporosis is needed. PEMF has recently gained popularity as a treatment option for musculoskeletal issues, such as pain, inflammation, tissue regeneration, osteopenia, osteoporosis, and bone healing. As a result, we investigated the impact of PEMF alone or in combination with exercise protocol on osteopenia or osteoporosis and bone markers. Our major findings demonstrate that PEMF, alone or in combination with an exercise protocol, has a significant influence on BMD of the hip and lumbar spine, bone-formation, and bone-resorption markers.\n\nPEMF has been shown to enhance osteogenesis, prevent bone loss, increase BMD, improve fracture healing, and enhance osteoblast activity, resulting in increased cell differentiation in both experimental and therapeutic settings (Sert et al., 2000; Shen and Zhao, 2010; Androjna et al., 2014; Liu et al., 2013). PEMF therapy also increased the levels of biomarkers of osteoblast-associated bone formation, such as serum bone-specific alkaline phosphatase (BSAP), serum osteocalcin (OC), and serum carboxy-terminal propeptide of type I collagen (PINP), while decreasing the levels of serum C-terminal telopeptide (CTX), which was independent of BMD change (Jing et al., 2014; Giordano et al., 2001; Spadaro et al., 2011).\n\nPEMFs’ biological activity could be linked to the amplification mechanisms that take place during transmembrane coupling (Ciombor and Aaron, 2005). Amplification is most likely to occur at transmembrane receptors. Several membrane receptors and pathways, including the PTH pathway, insulin, insulin-like growth factor (IGF-2), and calcitonin (Jiang et al., 2016), have been found to be affected by PEMFs in terms of ligand binding and distribution as well as activity. As a result, transmembrane signaling is modulated (Hu et al., 2020). PEMFs have a considerable anti-inflammatory and analgesic effect on the joint environment (Varani et al., 2017).\n\nIn multiple studies, PEMFs have been shown to considerably reduce pain and enhance the quality of life in individuals with primary OP (Spadaro et al., 2011). PEMFs can also considerably downregulate biomarkers associated with bone resorption as well as upregulate biomarkers associated with bone growth, as well as have also been confirmed to improve BMD in the distal radius, spine, and knees of patients with OP (Roozbeh et al., 2018).\n\nIn a recent analysis, various underlying molecular signaling pathways of PEMFs mechanism of action were summarized on bone repair, including Ca2+, Wnt/β-catenin, mitogen-activated protein kinase (MAPK), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β (Lohmann et al., 2003), bone morphogenetic proteins (BMP) (Aron et al., 2002), IGF, Notch, Prostaglandin E2 (PGE2) (Holmes, 2017), and cAMP/protein kinase A (PKA) (Miyamoto et al., 2019). Furthermore, it has been shown that the mammalian target of the rapamycin (mTOR) pathway is the underlying signaling mechanism of PEMFs implicated in bone formation (Fitzsimmons et al., 1992) and boosting the production of extracellular matrix (ECM) proteins and enabling tissue healing (Ciombor and Aaron, 2005).\n\nDespite the favorable effects of PEMFs on bone mineral density (BMD) in patients with OP, the results of some studies remain controversial, as a single-blind, randomized pilot trial found no significant improvement in BMD (Giordano et al., 2001). Furthermore, a randomized, sham-controlled trial found no long-term substantial favorable effects of PEMFs on BMD in patients with forearm disuse osteopenia (Spadaro et al., 2011). Similarly, following an 8-year follow-up (Tabrah et al., 1998), there were no further favorable effects of PEMFs (72 Hz, 10 h each day of 12 weeks) on BMD. The contradictory results could be attributable to the limited sample size of this research, as well as the fact that different groups used various clinical characteristics and strategies (Wang et al., 2019).\n\nIn this study, after 12-weeks of treatment and 6-months of follow-up, an exercise protocol significantly increased lumbar and total hip BMD, enhanced bone formation, and suppressed bone resorption markers in males with osteopenia or osteoporosis. The current study’s findings were in line with those of earlier clinical trials (Maddalozzo and Snow, 2000; Kukuljan et al., 2009; Almstedt et al., 2011; Bemben and Bemben, 2011; Kukuljan et al., 2011; Alayat et al., 2018) but not with those of other investigations (Huuskonen et al., 2001; Woo et al., 2007; Whiteford et al., 2010). The contrast between the current study findings and earlier studies could be explained by differences in study design, duration, age ranges, as well as exercise type and intensity (Huuskonen et al., 2001; Woo et al., 2007; Whiteford et al., 2010).\n\nExercise and strength training have been linked to bone mineral density (BMD) maintenance by increasing osteoblastic activity, which has a direct effect on OC production (bone remolding marker and osteoblast-specific protein) but also acts as an active hormone which responsible for the manner in which bone, adipose tissue, and muscle cross-communicate and how they impact glucose homeostasis in humans and has an important role in metabolic signaling in skeletal muscle and bone, and improves insulin sensitivity (Mohammad et al., 2020; Villareal et al., 2006).\n\nExercise has been found to alter calciotropic hormones, vitamin D, and parathormone (PTH), all of which are significant regulators of bone metabolism. In recent studies, a brief bout of exercise temporarily enhanced PTH secretion, which plays a variety of roles in bone turnover (Maimoun and Sultan, 2009), treatment of osteoporosis with an occasionally delivered PTH analog, on the other hand, has been demonstrated to boost bone production indicators and BMD (Neer et al., 2001).\n\nWBV exercise has been widely recommended for prevention and treatment of osteoporosis and increasing BMD, thereby improving bone mass, strength, and reducing bone destruction (Totosy de Zepetnek et al., 2009; Lau et al., 2011), and it appears to be a safe, non-invasive, non-pharmacological intervention and effective training method for maintaining or improving bone metabolism in a variety of group populations. Thus, the WBV modality may be an ideal approach to osteoporosis treatment for some specific populations (Bemben et al., 2010; Wong et al., 2021).\n\nMechanical signals, a major component of exercise, increase mesenchymal stem cells (MSC), activate mechanotransduction in bone, osteogenesis, proliferation, and reduce inflammatory marker levels when given in the form of low-intensity vibration (Bas et al., 2020). The direct transmissibility of vibratory signals to bone cells, resulting in osteogenic responses, is hypothesized by (Judex and Rubin, 2010) as a viable mechanism by which WBV training can generate anabolic or anti-catabolic responses in bone tissue. Rubin et al. (2004) found a significant difference in BMD change between the placebo and experimental groups after WBV training and conclude that WBV training can help to maintain and improve BMD (Rubin et al., 2004).\n\nRecently, there is growing evidence that exercise training leads to maintain and raised the level of undercarboxylated osteocalcin (uc-OCN), leptin (which plays an essential role in bone formation), and glucose homeostasis and adiponectin (which contribute to bone metabolism by increasing glucose utilization and fatty acid oxidation) (Mohammad et al., 2020; Levinger et al., 2017; Hiam et al., 2020).\n\nWhole-body vibration (WBV) alone or in combination with multi-component exercise programs of strength, aerobic, high impact, and/or weight-bearing training, as well as whole-body vibration (WBV) alone or in combination with exercise protocol, may help to improve functional mobility, QoL, and depressive symptoms in post-menopausal women, adults, and older populations. (Gomez-Cabello et al., 2012; Bolam et al., 2013; Sen et al., 2020). According to (Jepsen et al., 2019), adding WBV to teriparatide resulted in a significant increase in BMD in the lumbar spine at 12 months, as well as indices of bone turnover after 3 and 6 months.\n\n\nConclusions\n\nPEMF combined with exercise protocol was more effective than exercise and PEMF alone at increasing hip and lumbar BMD and have a beneficial effect on bone markers after 12-weeks of treatment, with effects lasting up to 6 months.\n\n\nRecommendation\n\nThe effects of such combinations should be investigated in other areas, such as the cervical or forearm, and for longer periods of time, as well as in osteoporosis-affected women.\n\n\nStudy strength and limitations\n\nAlthough there have been numerous studies evaluating the efficacy of PEMF either alone or with a combination of different exercise types in different groups of populations, there have been few studies evaluating the long-term efficacy of PEMF alone or combined with exercise protocol on male osteoporosis. The use of an exercise protocol in our prospective, randomized, controlled study allowed us to assess the long-term efficacy of the PEMF and exercise protocol compared with placebo PEMF and to compare the effects of the PEMF and exercise protocol to each other. In the literature review, there were no similar studies comparing PEMF and exercise protocol on BMD and bone markers in males. Another strength of this study was that the interventions were implemented as supervised group exercises. In the follow-up evaluations, in addition to measuring the BMD values, the use of various evaluation parameters, such as the determination of the bone turnover markers levels, can be listed as additional factors that strengthened our study. There were a few limitations to our study that should be noted when interpreting the data. For starters, our study’s follow-up time was just 6 months, which was insufficient to establish the efficacy of PEMF and existing exercise protocol on BMD or bone turnover markers. Previous research has revealed that it takes a long time for bone metabolism to produce an exercise response. Second, all study participants were instructed to maintain a well-balanced diet and engage in a regular exercise plan at home, which comprised 30 min of daily walking and tracking their exercise compliance. Because none of the participants reported any drawbacks, serious adverse events, or new-onset local pain, we regarded the home-prescribed exercise program to be a limiting factor in this study.",
"appendix": "Acknowledgments\n\nWe thank the Science and Technology Unit at Umm Al-Qura University for their continued logistics support. This work was funded by grant number 15-MED5406-10 from the National Science, Technology and Innovation Plan (MAARIFAH), the King Abdul-Aziz City for Science and Technology (KACST), Kingdom of Saudi Arabia.\n\n\nData availability\n\nFigshare: Underlying data for ‘Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial’.\n\nThe project contains the following underlying data:\n\n• Age, height and weight raw data: https://doi.org/10.6084/m9.figshare.14915805\n\n• BMD total hip and lumbar spine raw data: https://doi.org/10.6084/m9.figshare.14916057\n\n• Bone markers raw data: https://doi.org/10.6084/m9.figshare.14916078\n\nFigshare: Extended data for ‘Long-term effect of full-body pulsed electromagnetic field and exercise protocol in the treatment of men with osteopenia or osteoporosis: A randomized placebo-controlled trial’.\n\nThe project contains the following underlying data:\n\n• Flow chart of the study: https://doi.org/10.6084/m9.figshare.14915781\n\n• Tables: https://doi.org/10.6084/m9.figshare.14915790\n\n• CONSORT Checklist: https://doi.org/10.6084/m9.figshare.14916261v\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nReferences\n\nAaron RK, Wang S, Ciombor DM: Upregulation of basal TGFbeta1 levels by EMF coincident with chondrogenesis--implications for skeletal repair and tissue engineering. J Orthop Res. 2002; Mar; 20(2): 233–240. PubMed Abstract | Publisher Full Text\n\nAlayat SM, Abdel-Kafy EM, Thabet AA, et al.: Long-Term Effect of Pulsed Nd-YAG Laser Combined with Exercise on Bone Mineral Density in Men with Osteopenia or Osteoporosis: 1 Year of Follow-Up. Photomed Laser Surg. 2018 Feb; 36(2): 105–111. PubMed Abstract | Publisher Full Text\n\nAlmstedt HC, Canepa JA, Ramirez DA, et al.: Changes in bone mineral density in response to 24 weeks of resistance training in college-age men and women. J Strength Cond Res. 2011; 25: 1098–1103. PubMed Abstract | Publisher Full Text\n\nAndrojna C, Fort B, Zborowski M: Pulsed electromagnetic field treatment enhances healing callus biomechanical properties in an animal model of osteoporotic fracture. Bioelectromagnetics. 2014; 35(6): 396–405. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nJiang Y, Gou H, Wang S, et al.: Effect of pulsed electromagnetic field on bone formation and lipid metabolism of glucocorticoid-induced osteoporosis rats through canonical Wnt signaling pathway. Evid Based Complement Alternat Med. 2016: 4927035. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJing D, Cai J, Wu Y: Pulsed electromagnetic fields partially preserve bone mass, microarchitecture, and strength by promoting bone formation in hindlimb-suspended rats. J Bone Miner Res. 2014; 29(10): 2250–2261. PubMed Abstract | Publisher Full Text\n\nJudex S, Rubin CT: Is bone formation induced by high-frequency mechanical signals modulated by muscle activity? J Musculoskelet Neuronal Interact. 2010; 10(1): 3. PubMed Abstract | Free Full Text\n\nKukuljan S, Nowson CA, Bass SL, et al.: Effects of a multi-component exercise program and calcium-vitamin-D3-fortified milk on bone mineral density in older men: a randomised controlled trial. Osteoporos Int. 2009; 20: 1241–1251. PubMed Abstract | Publisher Full Text\n\nKukuljan S, Nowson CA, Sanders KM, et al.: Independent and combined effects of calcium-vitamin D3 and exercise on bone structure and strength in older men: an 18-month factorial design randomized controlled trial. J Clin Endocrinol Metab. 2011; 96: 955–963. PubMed Abstract | Publisher Full Text\n\nLau RW, Liao LR, Yu F, et al.: The effects of whole-body vibration therapy on bone mineral density and leg muscle strength in older adults: a systematic review and meta-analysis. Clin Rehabil. 2011; Nov; 25(11): 975–88. PubMed Abstract | Publisher Full Text\n\nLevinger I, Brennan-Speranza T, Zulli A, et al.: Multifaceted interaction of bone, muscle, lifestyle interventions and metabolic and cardiovascular disease: role of osteocalcin. Osteoporos Int. 2017; 28: 2265–2273. PubMed Abstract | Publisher Full Text\n\nLi JP, Chen S, Peng H: Pulsed electromagnetic fields protect the balance between adipogenesis and osteogenesis on steroid induced osteonecrosis of femoral head at the pre-collapse stage in rats. Bioelectromagnetics. 2014; 35(3): 170–180. PubMed Abstract | Publisher Full Text\n\nLiu HF, Yang L, He HC: Pulsed electromagnetic fields on post-menopausal osteoporosis in Southwest China: a randomized, active-controlled clinical trial. Bioelectromagnetics . 2013; 34(4): 323–332. PubMed Abstract | Publisher Full Text\n\nLohmann CH, Schwartz Z, Liu Y, et al.: Pulsed electromagnetic fields affect phenotype and connexin 43 protein expression in MLO-Y4 osteocyte-like cells and ROS 17/2.8 osteoblast-like cells. J Orthop Res. 2003; Mar; 21(2): 326–34. PubMed Abstract | Publisher Full Text\n\nMaddalozzo GF, Snow CM: High intensity resistance training: effects on bone in older men and women. Calcif Tissue Int. 2000; 66: 399–404. PubMed Abstract | Publisher Full Text\n\nMaimoun L, Sultan C: Effect of physical activity on calcium homeostasis and calciotropic hormones: a review. Calcif Tissue Int. 2009; 85(4): 277–286. PubMed Abstract | Publisher Full Text\n\nMiyamoto H, Sawaji Y, Iwaki T, et al.: Intermittent pulsed electromagnetic field stimulation activates the mTOR pathway and stimulates the proliferation of osteoblast-like cells. Bioelectromagnetics. 2019; Sep; 40(6): 412–421. PubMed Abstract | Publisher Full Text\n\nMohammad Rahimi GR, Bijeh N, Rashidlamir A: Effects of exercise training on serum preptin, undercarboxylated osteocalcin and high molecular weight adiponectin in adults with metabolic syndrome. Exp Physiol. 2020; Mar; 105(3): 449–459. PubMed Abstract | Publisher Full Text\n\nNeer RM, Arnaud CD, Zanchetta JR, et al.: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in post-menopausal women with osteoporosis. N Engl J Med . 2001; 344(19): 1434–1441. PubMed Abstract | Publisher Full Text\n\nPrevention and management of osteoporosis: World Health Organ Tech Rep Ser . 2003; 921: 1–164.\n\nRoozbeh N, Abdi F, Amraee A, et al.: Influence of Radiofrequency Electromagnetic Fields on the Fertility System: Protocol for a Systematic Review and Meta-Analysis. JMIR Res Protoc. 2018; Feb 8; 7(2): e33. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRubin C, Recker R, Cullen D, et al.: Prevention of post-menopausal bone loss by a low-magnitude, high-frequency mechanical stimuli: a clinical trial assessing compliance, efficacy, and safety. J Bone Min Res. 2004; 19(3): 343–351. PubMed Abstract | Publisher Full Text\n\nSen EI, Esmaeilzadeh S, Eskiyurt N: Effects of whole-body vibration and high impact exercises on the bone metabolism and functional mobility in post-menopausal women. J Bone Miner Metab. 2020; May; 38(3): 392–404. PubMed Abstract | Publisher Full Text\n\nSert C, Mustafa D, Duz MZ, et al.: The preventive effect on bone loss of 50-Hz, 1-mT electromagnetic field in ovariectomized rats. J Bone Miner Metab . 2000; 20(6): 345–349. PubMed Abstract | Publisher Full Text\n\nShen WW, Zhao JH: Pulsed electromagnetic fields stimulation affects BMD and local factor production of rats with disuse osteoporosis. Bioelectromagnetics. 2010; 31(2): 113–119. PubMed Abstract | Publisher Full Text\n\nSpadaro JA, Short WH, Sheehe PR, et al.: Electromagnetic effects on forearm disuse osteopenia: a randomized, double-blind, sham-controlled study. Bioelectromagnetics. 2011; May; 32(4): 273–82. PubMed Abstract | Publisher Full Text\n\nTabrah FL, Ross P, Hoffmeier M, et al.: Clinical report on long-term bone density after short-term EMF application. Bioelectromagnetics. 1998; 19(2): 75–78. PubMed Abstract | Publisher Full Text\n\nTotosy de Zepetnek JO, Giangregorio LM, Craven BC: Whole-body vibration as potential intervention for people with low bone mineral density and osteoporosis: a review. J Rehabil Res Dev. 2009; 46(4): 529–542. PubMed Abstract | Publisher Full Text\n\nVarani K, Vincenzi F, Ravani A, et al.: Adenosine Receptors as a Biological Pathway for the Anti-Inflammatory and Beneficial Effects of Low Frequency Low Energy Pulsed Electromagnetic Fields. Mediators Inflamm. 2017; 2017: 2740963. 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PubMed Abstract | Publisher Full Text\n\nZhang J, Xu H, Han Z: Pulsed electromagnetic field inhibits RANKL-dependent osteoclastic differentiation in RAW264.7 cells through the Ca (2+)-calcineurin-NFATc1 signaling pathway. Biochem Biophys Res Commun. 2017; 482(2): 289–295. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "90355",
"date": "09 Aug 2021",
"name": "Hesham Galal Mahran",
"expertise": [
"Reviewer Expertise Physical therapy for surgery"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an original research paper to evaluate the effect of full PEMF combined with exercise protocol on men with osteopenia or osteoporosis. The goal of this research is applicable. The title and topic are quite interesting for the journal scope. The paper is well-organized and easy to follow. Study design, methodology (materials and methods) are well described, data interpretation is appropriate and discussion is focused on the topic of the paper. The conclusion accounts for the target of the study. I really appreciate this excellent manuscript, but I have minor comments to be considered.\nIntroduction section:\n\nIn the 3rd paragraph, the LASER abbreviation must be defined first.\nMethods section:\n- Randomization\nAs the study was a double-blind study, please clarify who was blind to study; therapist and assessor or assessor and patients?\n-Full-body pulsed electromagnetic field (FBPEMF) therapy\nWhich waveform was employed in the PEMF application?\n-Exercise training protocol\nWhich type of exercise intensity was used in the study? Please clarify the distribution of 60 minutes between different exercise types within each session!\n\nExtended data:\nThe link to the CONSORT Checklist is incorrect, check it.\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": "7036",
"date": "14 Sep 2021",
"name": "Anwar Ebid",
"role": "Author Response",
"response": "Dear Prof. Hesham Mahran, Thank you very much for your review. The authors deeply appreciate the voluntary contribution of the review in the form of valuable comments that have helped us to improve our manuscript. Every effort has been made by the authors to revise the manuscript according to your comments. In response to your comments, we have uploaded a newer version of this article. Kindly review these new versions as the revised version of this article. Thank you. Regards, Authors Introduction section: In the 3rd paragraph, the LASER abbreviation must be defined first. Reply: Light amplification by stimulated emission of radiation (LASER), it was corrected in the introduction section. Methods section: - Randomization As the study was a double-blind study, please clarify who was blind to study; therapist and assessor or assessor and patients? Reply: All were blind to the study (assessor, therapist and patients) -Full-body pulsed electromagnetic field (FBPEMF) therapy Which waveform was employed in the PEMF application? Reply: “Sawtooth waveforms” In clinical applications sawtooth signal is one of the most famous pulsed magnetic field shapes, whose magnetic field changes rapidly. The rapid changes in signal strength can cause large current in the tissue. -Exercise training protocol Which type of exercise intensity was used in the study? Reply: “Moderate intensity” This according to the previous literature which recommend it for improving the BMD, muscle and bone strength and good tolerability by the patients Please clarify the distribution of 60 minutes between different exercise types within each session! Reply: Five-minute warm-up, 40 minutes initial training exercises (flexibility, aerobic exercise, strengthening, weight-bearing, and balance exercises), 10 minutes WBV and finally 5-minutes as cool-down. Extended data: The link to the CONSORT Checklist is incorrect, check it. Reply: The correct one is: https://doi.org/10.6084/m9.figshare.14916261"
}
]
}
] | 1
|
https://f1000research.com/articles/10-649
|
https://f1000research.com/articles/10-881/v1
|
02 Sep 21
|
{
"type": "Research Article",
"title": "Resource Description Framework reification for trustworthiness in knowledge graphs",
"authors": [
"Sini Govindapillai",
"Lay-Ki Soon",
"Su-Cheng Haw",
"Sini Govindapillai",
"Lay-Ki Soon"
],
"abstract": "Knowledge graph (KG) publishes machine-readable representation of knowledge on the Web. Structured data in the knowledge graph is published using Resource Description Framework (RDF) where knowledge is represented as a triple (subject, predicate, object). Due to the presence of erroneous, outdated or conflicting data in the knowledge graph, the quality of facts cannot be guaranteed. Therefore, the provenance of knowledge can assist in building up the trust of these knowledge graphs. In this paper, we have provided an analysis of popular, general knowledge graphs Wikidata and YAGO4 with regard to the representation of provenance and context data. Since RDF does not support metadata for providing provenance and contextualization, an alternate method, RDF reification is employed by most of the knowledge graphs. Trustworthiness of facts in knowledge graph can be enhanced by the addition of metadata like the source of information, location and time of the fact occurrence. Wikidata employs qualifiers to include metadata to facts, while YAGO4 collects metadata from Wikidata qualifiers. RDF reification increases the magnitude of data as several statements are required to represent a single fact. However, facts in Wikidata and YAGO4 can be fetched without using reification. Another limitation for applications that uses provenance data is that not all facts in these knowledge graphs are annotated with provenance data. Structured data in the knowledge graph is noisy. Therefore, the reliability of data in knowledge graphs can be increased by provenance data. To the best of our knowledge, this is the first paper that investigates the method and the extent of the addition of metadata of two prominent KGs, Wikidata and YAGO4.",
"keywords": [
"Wikidata",
"YAGO",
"RDF reification",
"Knowledge Graph",
"provenance data"
],
"content": "Introduction\n\nKnowledge regarding the real world entities in machine-readable format is furnished by Knowledge Graphs (KGs). These large-scale KGs provide both domain-dependent and domain-independent knowledge for many applications like entity linking, information retrieval and several other data mining tasks. KGs can be created by the extraction of structured knowledge from data sources like Wikipedia, collected by Artificial Intelligent (AI) projects, imported from other data sets, or by crowd-sourcing. Regardless of the methods followed, the presence of noise diminishes the quality of the KGs.1\n\nNoise can be due to outdated or conflicting information, erroneous facts, or facts that are not correct in a certain context. Trust in the data can be increased by providing additional information like the source of information or contextual information like the time or the location in which this fact was true or any other relevant additional information pertaining to a fact.2 This extra information would support the authenticity of the data, and in return, can help the machines to extract correct facts for critical applications. These facts can be classified as the provenance of knowledge and can contribute to the trust of these KGs.\n\nHowever, data in KGs are published using Resource Description Framework (RDF) where RDF encodes facts in the form of triples. RDF statement is an ordered set of the form (s, p, o) where s and o describe the subject and object entities and p describes the relationship between these two entities.\n\nRDF triple can be represented as:\n\n(s, p, o) ∈ (I ∪ B) × I × (I ∪ B ∪ L)\n\n\n\n• I is the set of Internationalized Resource Identifiers (IRIs), which identifies a unique resource on the Web\n\n• L is the set of RDF Literals,\n\n• B is the set of blank nodes that are anonymous and cannot be dereferenced globally.\n\nFigure 1 depicts examples of personal facts of the entity Donald Trump expressed as RDF triples. Some facts are eternal truth such as an individual’s parents, while some other facts can be true at a certain point in time. This figure shows that Donald Trump has three wives, which is partially correct. Donald Trump was married to three entities at different points in time. This example shows the importance of contextual data and the inadequacy of RDF in its expression.\n\nHowever, RDF data model does not support adding metadata to triples and therefore provenance data cannot be attached. Sikos and Philip3 describes different scales of provenance for datasets. In this paper, we focus on the provenance and contextualization of RDF data at the triple level. We first look at the existing approaches for integrating metadata into RDF. Next, we explore two popular KGs, namely Wikidata4,5 and YAGO6 to see how and to what extent they support meta information.\n\nTrustworthiness on the KG level is dependent on the trustworthiness of the facts at the basic level, which is the triple level. Contextual data restricts or gives meaning to a specific situation, location or time where this fact is true. Provenance data add source from which this triple is curated or imported. Therefore, we hypothesize that both contextual and provenance data adds trust to the fact that is described.\n\nIn order to encapsulate this additional information to RDF triple, RDF reification is used. In this section, we will explore some of the available methods for reifying RDF triples. These approaches include metadata of statements as triples in KGs. Additionally, some of the popular reification approaches standard reification, singleton property, n-ary relations and RDF* will be discussed.\n\nStandard reification7 annotates facts using RDF built-in vocabulary and the concept of blank nodes as described in RDF Primer. In standard reification, four triples are used for representing a fact. Blank nodes of type Statement together with properties subject, predicate and object are used for representing the triple. Additional provenance data can then be added to these triples using the same blank node.\n\nFor example, the fact Serena Williams is born in Saginaw can be represented as RDF statement (SerenaWilliams, birthPlace, Saginaw). The source of the triple is given as the book History of Tennis by Bud Collins. Standard reification employing blank node labelled _:x is used for reification in Table 1. Provenance information is added as the last row in the table using the same blank node _:x. Any number of metadata can be added with this blank node as the subject.\n\nHere for representing a single fact, four triples are needed. This will magnify the size of the KG by four times. At the same time, queries for retrieving these metadata facts will become complicated. This simple method of reification does not have formal semantics to link reified and original triples, and it is not commonly used.\n\nIn order to overcome issues with standard reification, singleton property8 was proposed. Singleton property provided formal semantics to RDF reification and the number of triples describing fact is reduced. This reification is based on the idea that the relation between two specific entities is unique. This unique statement-level property can be an instance of the general predicate using singletonPropertyOf property, which is a sub-property of rdf:type. This unique predicate is used to attach additional information to the fact like contextualization or provenance information.\n\nIn the example given in Table 2, birthplace_1 is an instance of singleton property describing the relation birthPlace between entities Serena Williams and Saginaw. Each of these relations has a unique IRI. Any number of metadata can be added to this fact with singleton property birthplace_1 as the subject. This will introduce a large number of unique predicates in the KG. This can be problematic for indexing techniques adopted by current triplestores.\n\nAnother alternative to achieve reification is the use of the n-ary relations.4,9 In this model, the subject has a relationship with some qualifiers and values. Resource node is used for this, but unlike standard reification, it is attached to the original triple.\n\nExample in Table 3 depicts n-ary relation of the triple (SerenaWilliams, birthPlace, Saginaw) where subject Serena Williams is related to a resource node, which cannot be dereferenced on the Web. This resource birthPlace_1 is related to the actual object Saginaw of the original triple. This is done using properties which are of statementProperty and valueProperty and are constructed from the property birthProperty of original triple. Here five triples are required to depict a fact and any number of complex meta-information can be attached to the resource node.\n\nAnother data model RDF*10 was introduced by Hartig in 2017. Unlike earlier approaches, which introduced metadata as triples, this data model follows embedded triple. The fact triple is enclosed within double brackets and is assigned as the subject or object of the triple as shown in Table 4. In the table, the embedded triple, <<s,p,o>> refers to <<Serena Williams, birthplace, Saginaw>>. Any number of metadata can be added as the predicate and object of the triple. RDF* is extended to have nested triples.\n\nRDF* data model is much more compact than other reification approaches and does not introduce any extra predicates like in singleton properties. It is also backward compatible with the RDF data model and other reification approaches. Although retrieving queries are simple compared to other approaches, various groups of annotations of the same fact (for example, the same incident happened at two different points in time) cannot be interpreted correctly. Frey et al. provide an alternative to overcome this by adding resource nodes for each annotation group.11\n\n\nMethods\n\nThe trustworthiness of a KG is categorized into knowledge graph level, statement level and whether the statement indicates it does not have value or the value is not known.7 In our research, we focus on trustworthiness defined at the statement level. Wikidata and YAGO provide statement-level provenance and contextual data, which is the focus of this paper and hence further explored in this section.\n\nWikidata is one of the largest KG in machine-readable format on the Web. This curated and crowd-sourced dataset has a rich set of entity information. Wikidata uses its own data model and data is inherently stored in JavaScript Object Notation (JSON) format in the BlazeGraph database. But in order to effortlessly query Wikidata like other KGs, Wikidata provides RDF dumps and has introduced Wikidata SPARQL query service for querying Wikidata in RDF form. A large number of facts in Wikidata are annotated with metadata and therefore, widely uses reification to describe the facts.12\n\nWikidata encodes facts in the form of item, label, description, alias and statement. Items and property-value pairs in statements are rather similar to the concept of representing facts as triple in RDF. Statements are annotated with qualifiers, references and ranks.\n\nWikidata employs qualifiers to annotate facts. Wikidata resolves the awkward interpretation of many wives in Figure 1 by attaching temporal information to supplement the facts as displayed in Figure 2. The most popular qualifier used is temporal data.\n\nThe source of the statements is referred by using predicates reference URL (P854), imported from (P143), stated in (P248), title (P1476) or publisher (P123). Wikidata references are optional and may be Wikidata items, links to websites, classical citations or datasets. More than one references are possible as depicted in Figure 3, where the references of the birthplace of American female tennis player Serena Williams is provided and serves as the provenance information.\n\nIf there are many statements involved for the same relations Wikidata provides ranks for filtering the result. Preferred, normal and deprecated are provided as ranks in the descending order of precedence.\n\nWikidata allows property-value pairs to represent two special cases, one is if a property has a value, which is unknown and another is if a property does not have a value. Some is employed to represent an unknown value and none is employed to represent no value. This increases the trustworthiness of Wikidata.\n\nWikidata employs n-ary relations to cater for RDF annotations.4,5 Each entity is linked to the statement node and the statement node is linked to the value nodes. Any number of references, contextualization data and ranks can be added to statement nodes. For applications that do not require the complexity of accessing these n-ary relations, data in plain RDF without annotations is provided by Wikidata. A simplified relation between subject and object is provided as RDF triples for top rank statements.\n\nWikidata uses the same predicate as part of primary relations and qualifiers. In Figure 4, the same predicate position held (P39) is used in primary relation (Stephen Hawking, position held (P39), Lucasian Professor of Mathematics) and as contextual information of the fact (Stephen Hawking, employer (P108), Gonville and Caius College). As we can see, here there is an inconsistency as to how to include the information of position held in a workplace.\n\nWikidata has more than a hundred and fifty qualifiers. Being a dynamic KG, qualifiers can keep getting added to the KG. Therefore Patel-Schneider13 states that if the number of qualifiers attached to a fact is more, it is not trivial work to infer the trustworthiness of a fact. Therefore, limiting the context information to specific needs might be the smarter way for balancing the complexity of inferring trustworthiness.\n\nYAGO4 employs RDF* data model to annotate facts in RDF format. YAGO4 is a combination of rich instance data from Wikidata and the ontology from schema.org. YAGO is constructed with very stringent measures to control noise. Facts which does not abide by these strict constraints are rejected. Semantic constraints like disjointness, domain and range restrictions, functional constraints on relations, cardinality constraint of objects are enforced on the dataset and has an accuracy of 95%. For the case in Figure 1, YAGO4 keeps only statements with the best rank from Wikidata, thus avoiding stale facts in KG.\n\nYAGO4 provides temporal information to the facts by employing nesting of triples using RDF* data model. RDF* provides SPARQL* for easy accessing data on the Web. YAGO4 provides temporal dimension using two general predicates startDate and endDate, which can be applied to any class.\n\nThe previous version, YAGO2,14,15 built from Wikipedia, GeoNames and WordNet is furnished with more contextualization and provenance data. YAGO2 employed a tuple type, sextuples, which is called SPOTLX. SPOTLX representation uses six tuples, with time, location and context added to the triple (s, p, o), which is of the form (Subject, Predicate, Object, Time, Location, conteXt).\n\n\nDiscussion\n\nBased on the investigation, Wikidata has better coverage of contextualization and provenance data of real world entities. For applications which is less susceptible to noise and more sensitive to specific contexts, the role of this meta information is really tremendous. YAGO4 provides coverage for temporal information. YAGO2 is more enriched with spatial and temporal facts and is provided with many predicates for including meta information.\n\nThe discussion of metadata in KGs is not complete without mentioning the downside. These provenance data come with a cost. The size of the KGs, which are already in humongous size, will further increase. This will depend on the approach used by each KG and the type and the number of provenance and contextualization data employed. The complexity of data retrieval is also another issue.\n\nIn order to reduce the effect of this, the data in KGs are provided without annotations, without employing any reification. Both Wikidata and YAGO4 are available in RDF format, without metadata information.\n\nIn another angle, for applications where provenance data is crucial, all facts in KGs are not furnished with annotations. Neverthless this issue is under constant improvement.\n\nThe investigation outcome paves the way for further research to apply provenance and contextualization information for identifying fully reliable and truthful facts from knowledge graphs.\n\n\nConclusions\n\nIn this paper, we have discussed RDF reification methods for annotating knowledge graphs with metadata. Two prominent knowledge graphs, namely Wikidata and YAGO4 were investigated. The method of incorporating metadata by these KGs and the extent of contextualization and provenance data supported by them are analyzed. The findings obtained will be further incorporated for the detection of errors in KG, in order to increase their trustworthiness.\n\n\nData availability\n\nThe data are taken from Wikidata and Yago.\n\n\nAuthor contributions\n\nSini Govndapillai did the conception of the work, data collection, data analysis and interpretation, drafting the article, and revision to the final version under the guidance of her supervisors, Lay-Ki Soon and Su-Cheng Haw. Su-Cheng Haw is the corresponding author for this paper.",
"appendix": "References\n\nPaulheim H: Knowledge Graph Refinement: A Survey of Approaches and Evaluation Methods. Semant. Web. 2017: 489–508. Publisher Full Text\n\nBienvenu M: Provenance for Web 2.0 Data.Publisher Full Text\n\nSikos LF, Philp D: Provenance-Aware Knowledge Representation: A Survey of Data Models and Contextualized Knowledge Graphs. Data Sci. Eng. 2020; 5(3): 293–316. Publisher Full Text\n\nErxleben F, Günther M, Krötzsch M, et al.: Introducing wikidata to the linked data web. Lect. Notes Comput. Sci. (including Subser. Lect. Notes Artif. Intell. Lect. Notes Bioinformatics). 2014; vol. 8796, pp. 50–65. Publisher Full Text\n\nMalyshev S, Krötzsch M, González L, et al.: Getting the Most Out of Wikidata: Semantic Technology Usage in Wikipedia’s Knowledge Graph. Proc. 17th Int. Semant. Web Conf. (ISWC 2018). 2018; vol. 11137, pp. 8–12.\n\nHartig O: Foundations of RDF* and SPARQL* (An Alternative Approach to Statement-Level Metadata in RDF). CEUR Workshop Proc. June, 2017. vol. 1963, no.\n\nManola F, Miller E, McBride B: RDF Primer. W3C Recommendation 10 February 2004. [Online]. Reference Source\n\nNguyen V, Bodenreider O, Sheth A: Don’t like RDF reification? Making statements about statements using singleton property. WWW 2014 - Proc. 23rd Int. Conf. World Wide Web. 2014; no. April, pp. 759–769. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHayes P, Welty C, Noy N, et al.: Defining N-ary Relations on the Semantic Web.Reference Source\n\nHartig O: RDF∗ and SPARQL∗: An alternative approach to annotate statements in RDF. Int. Semant. Web Conf. 2017.\n\nFrey J, Müller K, Hellmann S, et al.: Evaluation of metadata representations in RDF stores. Semant. Web. 2019; 10(2): 205–229. Publisher Full Text\n\nFärber M, Ell B, Menne C, et al.: Linked Data Quality of DBpedia, Freebase, OpenCyc, Wikidata, and YAGO. Semant. Web. 2017; 9: 77–129. Publisher Full Text\n\nPatel-Schneider PF: Contextualization via qualifiers. CEUR Workshop Proc. 2018; vol. 2317.\n\nHoffart J, Lewis-kelham E, Suchanek FM, et al.: YAGO2: Exploring and Querying World Knowledge in Time , Space, Context, and Many Languages. Time. 2011; 23(7): 229–232. Publisher Full Text\n\nHoffart J, Suchanek FM, Berberich K, et al.: YAGO2: A spatially and temporally enhanced knowledge base from Wikipedia. IJCAI Int. Jt. Conf. Artif. Intell. 2013; 3161–3165. Publisher Full Text"
}
|
[
{
"id": "93428",
"date": "06 Sep 2021",
"name": "Kok-Chin Khor",
"expertise": [
"Reviewer Expertise Data Mining",
"Computer Networks."
],
"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 provides an analysis on Wikidata and Yago4 related to provenance data and contextualisation. My comments are as follows:\nThe finding of comparing Wikidata and Yago4 can be stated in the Abstract section.\n\nA more detailed explanation on RDF is needed to help the readers to understand the semantic web representation. Please refer to [3].\n\nThe content in the Methods section is more towards analysis.\n\nThe Conclusion section, besides restating the research method and summarise your overall arguments, you may want to summarise your finding and reiterates the important parts for supporting your claim.\n\nAn error in Page 4, second paragraph: \"Additionally, some of the popular reification approaches standard reification, singleton property...\"\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "95305",
"date": "25 Oct 2021",
"name": "Weiguo Zheng",
"expertise": [
"Reviewer Expertise knowledge graphs"
],
"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: This paper focuses on RDF reification and introduces several approaches with examples. Then the author investigated the reification methods used by Wikidata and YAGO. However, there is no new method proposed in this paper, and the reification model, the query method and the ranking method are not well organized when analysing Wikidata and YAGO.\nStrong Points:\nThere are enough examples to make relevant approaches easy to understand. The examples of Donald Trump and Serena Williams are throughout the paper to make relevant approaches easy to understand.\n\nSeveral different methods from 2004 to 2017 are covered.\n\nWeak Points:\nThe structure of the abstract is not clear. For example, the analysis of YAGO4 and Wikidata is interspersed in the utility of provenance data.\n\nA specific definition of KG trustworthiness and RDF reification are needed.\n\nSome applications of trustworthiness need to be introduced to make RDF reification more meaningful.\n\nNo new method has been proposed in this paper. In the Methods section, the authors only analyse the methods described in the Introduction section used by Wikidata and YAGO.\n\nIn the sections of Wikidata and YAGO, the contents of the reification method, the query method and the ranking method are organized without clear structures.\n\nDetailed Comments:\nIn the abstract, “Therefore, the provenance of knowledge can assist in building up the trust of these knowledge graphs.” and “Therefore, the reliability of data in knowledge graphs can be increased by provenance data.” are repetitive.\n\nIn the Introduction section, “These facts can be classified as the provenance of knowledge and can contribute to the trust of these KGs.” is confusing due to the phrase of “facts”. In other parts of this paper the word “fact” refers to a triple in the KG.\n\n“Reification approaches” needs to be a section with the same level as “Introduction” and “Methods”.\n\nIn Wikidata section, “Wikidata uses the same predicate as part of primary relations and qualifiers.” needs more explanation to clarify the difference between predicate and primary relation.\n\nThe results from the Discussion section can be added to the Conclusions section.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-881
|
https://f1000research.com/articles/10-227/v1
|
22 Mar 21
|
{
"type": "Research Article",
"title": "Conversion of natural forests to farmlands and its associated woody species diversity and carbon stocks in a span of 33 years (1984 to 2016): in the case of southwestern Ethiopia",
"authors": [
"Tamiru Kefalew",
"Mulugeta Betemariyam",
"Motuma Tolera",
"Tamiru Kefalew",
"Motuma Tolera"
],
"abstract": "Background: Gura-Ferda forest is one of the Afromontane rainforests in the southwestern region of Ethiopia. However, since 1984, large parts of this forest have become increasingly disturbed and fragmented due to forest conversion into forest farm interface and farmlands. The study was conducted to assess changes of woody species diversity and carbon stock in association with the conversion of natural forest to forest farm interface and farmlands. Methods: Data were collected from natural forest, forest farm interface and farmland which are historically forest lands before 1984. A total of 90 nested plots (20m×20m for natural forest and forest farm interface; 50m*100m for farmland)) were established for inventory of woody species. Three 1m×1m subplots were established to collect litter and soil samples. A total of 180 soil samples were collected. The total carbon stocks were estimated by summing carbon stock in the biomass and soil (0-60 cm depth). Results: Results showed that Shannon-Wiener diversity (H’) in forest farm interface (H’ = 1.57) is relatively lower than that of natural forest (H’ = 3.33) but higher than farmland (H’ = 1.42). The total carbon stocks of natural forest were approximately 1.21 and 2.54 times higher than that of forest farm interface and farmland. Conclusion: Our study revealed that the changes of Natural Forest to Forest Farm Interface and Farmland have effects on the diversity of woody species and carbon stocks.",
"keywords": [
"Forest Farm Interface",
"Biomass Carbon",
"Soil Organic Carbon",
"Litter"
],
"content": "Introduction\n\nForests and forest management have changed greatly over the past two decades. In 1990, the world had 4.13 billion hectares (ha) of forests (31.6% of total land area of Earth). However, according to the Food and Agriculture Organization of the United Nations, by 2015 this area has decreased to 3.99 billion ha (30.6% of total land area of Earth) (FAO, 2015). This caused a net loss of 129 million ha of forests (natural and planted) from 1990 to 2015. However, the net annual rate of loss has reduced from 0.18% in the 1990 to 0.08% in 2015. The net annual natural forest loss between 1990 to 2000 was 8.5 million ha per year; however, from 2010 to 2015, natural forest decreased by a net of 6.6 million ha per year (8.8 million ha of loss and 2.2 million ha of gain). This resulted in a reduction of 697 million mega tons per year or about 2.5 gigaton (GT) of carbon dioxide (CO2) for the past 25 years (FAO, 2015). The world forest assessment in 2015 also indicated that world’s forests store an estimated 296 GT of carbon in both aboveground and belowground biomass (FAO, 2015).\n\nEthiopia has a wide range of ecological conditions ranging from the arid lowland in the East to high altitudes in the central high lands (Hurni, 1998). This wide range of ecological conditions coupled with the corresponding heterogeneous flora and fauna has made the country one of the internationally recognized major centers for biodiversity (Scholte, 2012). However, through time to time, there has been a dramatic decline in forested area in the country. Accordingly, from 1990 to 2000 and from 2000 to 2010, forest losses were estimated at 8.3 million ha and 5.2 million ha respectively (Eshetu, 2014). These days major parts of the remaining natural forests which harbor high biodiversity are located on steep slopes at high altitude and in the remote southern and southwestern parts of the country. These few remaining high forests are also threatened by anthropogenic activities and converted to agricultural and other land use systems (Abere, 2011). Similarly, other remaining natural forests have also been threatened by pressure from investors and changed to industrial plantation like coffee and tea (Abere, 2011; Moges et al., 2010). This reduction and conversion of natural forest to other land use systems in many parts of Ethiopia has led to the decline in number and distribution of many plant species, shortage of raw materials for wood processing industries and disturbance of ecosystem services (Lemenih & Kassa, 2014). Subsequently, it has resulted the expansion of forest farm interface in and around the forest ecosystem.\n\n“For this study forest farm interface is defined as a complex geographic and temporal mosaic landscape of integrated management and production practices that combine agriculture, forest and livestock land uses and formed from shifting of forest land uses by smallholder farmers and /or investors. The interface is not a discrete line separating farms and forests.” (CIFOR, 2017)\n\nFor the past five decades, the government of Ethiopia has attempted to reforest degraded forests. Hundreds of aid projects have been implemented in different parts of the country to reverse deforestation and forest degradation in the country. However, the success stories were below expectations and the problems are still immense. This resulted from the lack of effective management practices and quantification of the available forest resources. This insufficiency of scientific quantitative data brought lack of responsiveness for sound management of natural resources in the country.\n\nGura-Ferda forest is one of the Afromontane rainforests in the southwestern region of Ethiopia and grows at altitudes from 700 to 2,300 meter above sea level. This forest area is one of the areas in Ethiopia where traditional beliefs and ecological knowledge have assisted the conservation of forests up to now. During the past decades, especially since 1984, large parts of this forest have progressively been disturbed and fragmented due to forest conversion to settlements, agriculture, and industrial plantation (Schmitt et al., 2010). Nowadays, pressure produced by immigration and investors is increasing forest disturbance. However, there is no quantitative information on the change of species diversity and carbon stocks resulting from the conversion of natural forests to forest farm interface and farmlands. The overall objective of this study was, therefore, to analyze the woody species diversity and carbon stock change in association with the change of natural forests to forest farm interface and farmlands. The study hypothesized that, the conversion of natural forests to forest farm interface and farmlands affect the woody species diversity, biomass and soil organic carbon (SOC) stocks.\n\n\nMethods\n\nThe study was conducted at Gura-Ferda district of southwestern Ethiopia which is located at 603 km southwest of the capital city Addis Ababa (Figure 1). Geographically, it is positioned between 6°29’12” N and 7°13’22” N latitude and 34°52’23” E and 35°23’59” E longitude. The area coverage of this district is estimated to be 2565.42 km2. The annual average rainfall over the period of 1983–2012 was 1639.8 mm, with a maximum of 1946.3 mm and a minimum of 1289.8mm. The area receives a maximum rainfall in October and minimum rainfall in February. The average annual temperature is 23.4°C with a range from 16.1°C-30.6°C. The dominant soil type of the study area is nitisols with soil textural class loam to clay (Dewitte et al., 2013).\n\nAs the past data of the Gura-Ferda district specified, since 1984, there was a degradation of natural forest in the area (Table 1). The notable drivers of this forest area decrement were resettlement, crop investment and fuel wood. According to the office of Gura-Ferda district, in 1984, the populations of the district were 149. However, in 2016 they were increased to 45,028 (GFDAO, 2016). Moreover, during 2003/4 legal resettlement, massive deforestation of natural forest were accompanied for house construction of immigrates (Abere, 2011; Gessese, 2018). Next to resettlement, the taken up of forest by investors is other key drivers for the degradation and deforestation of natural forests in the area. According to (GFDAO, 2016), there were more than 30 investors who were involved in different agricultural investment especially coffee and rubber tree plantation. These investors had been used shrub land, natural forest, and grass lands for investment.\n\nSource (Authors Data)\n\n\nMethodology\n\nFor the purpose of this research both primary and secondary data were employed. Primary data were obtained through field survey of the study area. Secondary data used were satellite images and publications such as articles, data from district land administration offices and censuses results. Multi-sensor and multi-temporal Landsat images were downloaded from United States Geological Survey (USGS) (https://earthexplorer.usgs.gov) (Table 2). Accordingly, satellite images of 1984 and 2016 were used for this study. Images of the year 1984 were taken because it was the time when the government organized a resettlement program at the study area. Similarly, images from the year 2016 was selected because it was the time when recent agricultural systems were expanded and government was focused on commercial investments in the area. Since it is a time of free atmospheric cloud, satellite images in the months of December to January were used.\n\n** Panchromatic sharpened to 15m to favor visual interpretation\n\nBefore the resettlement program of 1984, all areas used for the sampling unit in this study time were covered by forest. However, nowadays, it is observed that the area has three discrete categories. These are: natural forest, forest farm interface and farmland (Figure 2; Figure 3).\n\nNatural forest (NF): a landform consisting of trees, shrubs and other vegetation that originally emerged on its own without the influence or direct intervention of man and found adjacent to FFI.\n\nForest-farm interface (FFI): a neither agriculture nor forest mosaic landscape of integrated management and production practices which is typically used by smallholder farmers/investors and found between natural forest and farmlands (find full definition in the introduction).\n\nFarmland (FL): an area which has been converted to intensive mono cropping with few/no scattered trees due to high disturbance and adjacent to FFI.\n\nField level data was collected from NF, FFI and FL which are adjacent to each other and historically forest land before 1984. With the help of a compass and Geographic Positioning System (GPS), three transects with a total of 30 plots (10 plots on each transect) were established for each land use system. Transect lines and samples plots were laid by a gap of 200m from each other (Figure 4). The sample plot size was determined based on expected density of woody species in each land use system (Tadesse et al., 2014; Tolera et al., 2008). Accordingly, for both NF and FFI a nested plot design of 400m2 with 25m2 and 1m2 size was used to collect vegetation data (tree, sapling and seedling respectively). In each of the quadrat (1m*1m), a number of all seedlings that have eight ≤ 50 cm and diameter at breast height (DBH) ≤ 2.5cm were recorded. Individuals attaining height > 50cm and DBH ≤ 2.5 cm were considered as sapling and counted. In the 400m2 sample plots, the diameter and height of all woody species ≥ 5cm DBH were measured. As per density and distribution of woody species is lower, plot size of 50 m x 100 m was used for FL (UNFCCC, 2015).\n\nDBH of sampled dead wood was measured following the techniques used by Pearson et al. (2005) and UNFCCC (2015). A complete list of woody species was made for each plot throughout the whole area and documented by local name. Species identification for common species was done in the field via different plant identification keys. However, for the less common species plant sample specimens were pressed and identified at the National Herbarium of Ethiopia, Addis Ababa University. Litter samples were collected from 1 m x 1 m subplot within the main plot. The collected fresh litter was weighed right on the site. Then the evenly mixed samples were taken to the laboratory and oven dried at 65ºC for 24 hours to determine dry to fresh weight ratio. Soil samples were collected from the sub-plots used for litter sampling. Two sets of soil samples were taken, one set for the determination of organic carbon fraction (%C), and one set for the determination of soil bulk density. A total of 90 soil samples (layers of 0–30 and 30–60 cm) were collected for %C analysis using soil auger. In addition, similar size of undisturbed soil samples were collected separately for determination of soil bulk density.\n\nDiversity analysis. Shannon-Wiener index (H`) was used to determine diversity of woody species of the study area. H` was determined through the analysis of two components of species diversity. These are the species richness (the number of species in the sample plots) and evenness of species (abundance distribution among species).\n\n\n\nWhere pi, is the proportion of individuals found in the ith species\n\nBeta diversity (β) which measures the change in the diversity of species among a set of land uses is determined using the formula provided by Whittaker (1972).\n\n\n\nWhere a, is the number of shared species in two land uses, and b and c are the numbers of species unique to each land use.\n\nAllometric equation developed by Chave et al. (2014) was used for estimating the aboveground biomass of woody species in NF (Table 3). Biomass of standing dead wood which has branches was also estimated using this allometric equation. This equation was selected since it was established for estimating the biomass of woody species in tropical natural forests. Moreover, this equation used diameter at breast height and wood density which was the most important biomass predictor variables. The biomass of woody species in FFI and FL was estimated using allometric equation developed by Kuyah et al. (2012a); Kuyah et al. (2012b) since it was developed for land use systems having more or less similar climatic properties as those in the current study area. Woody density was taken from the document of Ethiopia’s fForest reference level submission to the United Nation Framework Convention on Climate Change (UNFCCC) (EFRLS, 2016).\n\nAboveground biomass of standing dead wood which has no leaves was estimated following the procedure used by Pearson et al. (2005). The biomass of felled dead wood was estimated using allometric equation developed by Grais & Casarim (2013). The total biomass of the dead wood was estimated by summing up of the standing, logged and felled dead wood. Finally, estimated biomass of woody tree species in NF, FFI and FL were converted to carbon (C) stock using carbon fraction value of 0.5, 0.48, and 0.48 respectively (IPCC, 2006; Kuyah et al., 2012a). The loss on ignition method was used to estimate percentage of organic matter in the litter. The amount of C in the litter was estimated through multiplying of litter organic matter by 0.50 (Pearson et al., 2007).\n\nSoil organic carbon stock estimation. Soil analyses were undertaken at Wondo Genet College of Forestry and Natural Resources soil laboratory. The soil samples for bulk density were oven-dried at 105 °C for 48 hours. Bulk density was estimated by the core method (Blake & Hartge, 1986). The soil samples for %C were air –dried and analyzed using Walkley-Black method (Schnitzer, 1982). A SOC stock (Mg C ha-1) was calculated by multiplying of %C, bulk density (g/cm3) and soil depth (cm)).\n\nTotal carbon stocks. Total C stock (Mg C ha-1) was calculated by summing up of biomass C stocks (above-and-below) and SOC stocks.\n\nC stock of the three land uses were compared using one-way ANOVA and two-way ANOVA. All data were checked for normality prior to doing the analysis of variance using Kolmogorov-Smirnov test. The data were analyzed using Statistical Package for Social Science (SPSS version 20). All tests were conducted at 95% confidence level.\n\n\nResults\n\nA total of 59, 24 and 19 woody species belonging to 34 families were recorded and identified in the sample plots of Gura-Ferda NF, FFI, and FL respectively (Table 4). Among these woody species, Moraceae, Rubiaceae and Sapotaceae were the richest family all represented by six species (8.82%) of total floristic composition. The remaining families represented less than 3% of species each.\n\nThe overall mean H’, species richness and evenness of NF were 3.33, 59 and 0.82 respectively. FFI enriched with 24 woody species has an overall mean H’ of 1.57. The results of H’ and evenness indices indicated a difference in species diversity and evenness among the land uses. NF is relatively the most diversified one followed by FFI. Relatively, highest evenness was exhibited by NF followed by FFI (Table 4).\n\nSorensen’s similarity coefficient indicated the highest floristic similarity was found between NF and FFI (0.51) followed by FFI and FL (0.37). The magnitude of beta diversity indicates the change in woody species composition between adjacent land uses along the land use changes. The highest change in woody species diversity was observed between the changes from NF to FL (0.67) followed by FFI to FL (0.63) (Table 5). Cordia africana, Croton macrostachyus and Lepidotrichlea volkensi were some of common woody species in all land uses.\n\nThe basal area of woody species in NF (54.31±2.95 m2ha-1) was 2.3 and 4.1 times higher than FFI (26.66±2.28 m2ha-1) and FL (6.12±0.37 m2ha-1) respectively. The density of woody species ≥ 5cm DBH in the study area was 746±15.25 individuals per hectare for NF, 876±120 individuals per hectare for FFI and 158±6.9 individuals per hectare for FL.\n\nThe mean aboveground biomass (tree/shrub, dead wood and litter) C stocks of FFI (99.63± 9.72 Mg C ha-1) are significantly lower than the adjacent NF (134.40± 10.09 Mg C ha-1), but higher than that of FL (16.80± 1.18 Mg C ha-1). The mean aboveground biomass C stocks of NF were approximately 2.24 and 8.47 times higher than FFI and FL. The mean overall dead wood C stock of the study area was 2.3 ± 1.51 Mg C ha-1 for NF and 9 ± 2.56 Mg C ha-1 for FFI (Table 6). The mean litter biomass for aboveground biomass was 1.29 ±0.14 Mg C ha-1 for natural forest and 0.88 ±0.06 Mg C ha-1 for forest farm interface.\n\nDifferent letters show significant (p<0.05) different between Land Uses, and similar letters not significance differences\n\nA belowground biomass C stock in the NF was significantly higher (p< 0.001) than the belowground biomass C stocks of FFI and FL (Table 6). The mean belowground biomass C stocks in the NF, FFI and FL were 26.16±2.02 Mg C ha-1, 17.95±1.94 Mg C ha-1 and 3.36±0.23 Mg C ha-1 respectively. The total biomass C stocks in NF was by 7.73% and 38.84% higher than FFI and FL. Cash generating coffee ≥2.5 DBH shared 0.5% and 2.3% of the total biomass C stocks in NF and FFI respectively. The contribution of litter for total biomass C in both NF and FFI was 1%.\n\nWithin each land use, SOC stock was significantly higher (p<0.001) in the top layer (0–30cm) than in the lower layer (30–60 cm) (Table 7). The top layer stocked 57.84%, 54.76% and 56.98 of the total SOC in the NF, FFI and FL respectively. The total SOC stocks (0–60 cm depth) were significantly different among all land uses. SOC stock significantly differs along depths for all land uses. With respect to conversion of NF to FFI, 5.78% of SOC stocks (0–60 cm) were lost. Similarly, 21.82% of SOC stocks (0–60 cm) were lost in conversion of the NF to the FL.\n\nDifferent letters show significant (p<0.05) different between Land Uses, and similar letters not significance differences\n\nThe total C stock of the study area was calculated by summing up all the C value of each pool. Accordingly, the total C stock (Mg C ha-1) is significantly different among the three-land uses. The total C stock in NF was 382.97 ± 50.8 Mg C ha-1. While the total C stocks for FFI and FL were 315.68 ± 30.5 Mg C ha-1 and 150.76 ± 7.6 Mg C ha-1 respectively (Table 8). Of which, the SOC accounted for 58.07%, 62.75 and 86.63% for NF, FFI and FL, respectively. The total C stock of NF was approximately 1.21 and 2.54 times higher than that of FFI and FL.\n\nDifferent letters show significant (p<0.05) different among Land Uses\n\n\nDiscussion\n\nGura-Ferda forest is among the most degraded and deforested forest in southwestern region of Ethiopia. A change in NF to FFI and FL are the major threats to forest woody species diversity. In association with the conversion of natural forest to forest farm interface more than 17 species are lost. While, in connotation with the conversion of NF to FL, more than 33 species are lost. More specifically, Sapotaceae, Moraceae, and Rubiaceae which are the dominant families in NF of this study area are the most threatened families as a result of the conversion of NF to FFI and FL. Almost all woody species recorded in the FFI and FL were not planted rather they were the remnants of trees and shrubs during conversion of NF to FFI and FL.\n\nThe observed lowered H’ in FFI and FL in Gura-Ferda district is directly attributed by conversion of NF to coffee farms and indirectly by population growth, colonization of previously uncultivated land by subsistence crops and the expansion of settlements. As shown in Table (1), FFI which emerged after the resettlement program of 1984 accounts for 23.28% of the NF within 1984–2016-year interval. As reported by Gessese (2018), and GFDAO (2016) the main problem related to land use land cover change at Gura-Ferda district was agricultural investment, fuel wood collection, wood for house construction and farm implementation, wildfire, resettlement, land certification, poor governance within the district, and subsistence agricultural land expansion.\n\nAccording to a Gura-Ferda district land administration report, large areas of extra land were recorded for each farmer. The farmers had expanded their farmland into nearby forest, shrub/bush land and grass land and used those land uses for commercial crop production. Therefore, this increment of unregistered or unplanned farms and FL resulted from above mentioned drivers are the main causes for the loss of woody species diversity in the study area.\n\nThe main reason for the lower woody species diversity in FFI in relation to NF in the study area is due to the application of intensive thinning of different woody species in the system in order to reduce shading effect. (Gole, 2003) also reported that, managing forest for coffee production has resulted in significant changes in species diversity, composition and vegetation structure in coffee forests of southwestern Ethiopia. The number of woody species recorded in Gura-Ferda NF is comparable to the Komba-Daga moist evergreen forest in southwestern Ethiopia (62 woody species) (Geneme et al., 2015). For instance, the number of woody species recorded in the Gura-Ferda NF of the current study area is substantially higher than those reported for Agama tropical Afromontane forest of Ethiopia (39 woody species) (Addi et al., 2016). However, the number of woody species in the current studied NF is lower than the woody species recorded for Wondo Genet Afromontane forest in the central highlands of Ethiopia (72 woody species) (Kebede et al., 2013).\n\nOur results also indicated that, the woody species richness in FFI of the current study is comparatively lower than woody of species in agroforestry system of south-central and southern highlands of Ethiopia (Asfaw, 2003; Seta & Demissew, 2017). Since maximizing coffee production is the main goal, most of the native trees have been cleared by cultivators and few shade plant species are retained in highly populated coffee shrubs.\n\nThe study showed how C stocks in biomass and soils were varied across different land use systems. NF had higher biomass C stocks compared to FFI and that of the FL. Rajput et al. (2017) and Solomon et al. (2018) reported higher biomass C in forest land use system as compared to other land cover types in northwestern Himalaya and northern Ethiopia, respectively. From the studied land use systems of this area, most of the C was stocked in NF. FFI and FL biomass C stocks were 7.73% and 38.84% lower than the C stocks in the NF. The accumulation of high C stock in NF was attributed by the presence of diversified woody species in the NF in comparison with FFI and FL. Additionally, the NF has found to accumulate larger aboveground biomass in the litter compared with that of FFI. This result is in line with the result of Solomon et al. (2018) which stated that tree density, diversity and diameter have an effect on biomass C.\n\nCase studies have showed as different land use systems stocked different amounts of C in their biomass component. Accordingly, the biomass C stocks recorded in the NF of the current study area is substantially lower than the biomass C stocks of Adaba-Dodola community forest, southeastern Ethiopia (Bazezew et al., 2015). The biomass C stocks of NF of the current study area was approximately three times lower than the biomass C stocks reported for woody plants of Mount Zequalla Monastery in Ethiopia (Girma et al., 2014). Similarly, the biomass C stocks of FFI in this study was higher than that of the coffee based agroforestry system in Gera, Jimma Zone, South-West Ethiopia (Mohammed & Bekele, 2014). The difference in biomass C stocks might be due to various factors such as difference in diversity of trees (woody and non woody) of larger sizes, the used allometric equation, soil condition and climate factors. For instance, in the coffee based agroforestry system studied by Mohammed & Bekele (2014), trees aboveground biomass was determined using Brown et al. (1989) allometric equations. But, for this study, the generic equation developed by Chave et al. (2014) and Kuyah et al. (2012a) were used for woody tree species. The biomass C stocks of the FFI of the current study area was relatively equivalent with the total biomass C stocks of fruit coffee system of indigenous agroforestry systems of the south-eastern Rift Valley escarpment, Ethiopia (Negash & Starr, 2015).\n\nThe average mean above ground biomass C stock of the FFI was higher than the mean biomass C stocks of organic polyculture coffee, non-organic polyculture coffee and organic Inga species in Chiapas, Mexico (Soto-Pinto & Aguirre-Dávila, 2014). The variability among these systems in this respect might be because of differences in species composition, site characteristics, management practices, land holding sizes, ancillary factors (e.g. soil condition, climate, system age, land-use history), and adopted allometric model for biomass estimation (Montagnini & Nair, 2004).\n\nConcentrations of SOC decreased with an increment of depth in all NF, FFI and FL. The highest SOC stock in the NF might be attributed to the lower organic carbon turnover rate as a result of minimum soil disturbance in the system, and more litter fall inputs from different wood tree species. While in the FFI, common intensive management practices like cleaning, weeding, burning and relocation of biomass might influence accumulation of litter carbon. It was in agreement with results by Aticho (2013) who claimed the diminishing trend of SOC content with depth in his study in Kafa, Southwest Ethiopia. Yimer et al. (2015) also observed a declining trend in SOC concentration with depth in the Central Rift Valley area of Ethiopia.\n\nThe total SOC stocks at soil depth for the three land use systems in this study were within the range of SOC stocks reported for other similar systems in Ethiopia (Gebeyehu et al., 2017). The upper layer (0–30 cm depth) SOC stock of FFI in this study area was higher than the mean SOC (65.2 Mg C ha-1) of Nitisol soil under agroforestry systems in Ethiopia (Gebeyehu et al., 2017). The result of SOC in 0–30 systems cm depth in FFI was also higher than the 0–30 cm depth SOC recorded in Gununo watershed agroforestry practices (Bajigo et al., 2015), and 0–30 cm depth SOC (60.8 Mg C ha-1) of Indonesia homegarden agroforestry system (Roshetko et al., 2002).\n\nThe results indicate that 5.78 % and 21.82% of SOC stocks (0–60 cm) were lost in conversion of the NF to the FFI and FL respectively within 33 years. Another meta-analysis of Wei et al. (2014) found that SOC decreased by 44.5% following conversion from a NF to a crop field. Yimer et al. (2007) also found that SOC decreased by 30.9% after 15 years of deforestation in the Bale Mountains of Ethiopia.\n\n\nConclusion\n\nFFI in the southwestern part of Ethiopia plays an important role in maintaining more woody species and sinks of C. The higher contribution of NF to climate change mitigation is mainly due to the higher diversity and density of larger woody species in the system as compared to the adjacent FFI and FL. Trees in particular play substantial roles for enhancing biomass C stocks in forests and any other land use systems. However, the increment of FL found adjacent to the NF and FFI showed a lower role of biodiversity conservation and C stock. This shows that sustainability of the system is questionable. If the NF is not sustainably managed and certification of land is not carried out in the area, there will be expansion of FFI and FL which will cause further deforestation and forest degradation. Therefore, it needs to recognize FFI as part of climate change mitigation strategies, as it can also provide much benefit to the community and a potential to reduce pressure on adjacent NF.\n\n\nData availability\n\nZenodo: Conversion of Natural Forests to Farmlands and Its Associated Woody Species Diversity and Carbon Stocks in a Span of 33 Years (1984 To 2016): In the Case of Southwestern Ethiopia, http://doi.org/10.5281/zenodo.4601418 (Betemariyam et al., 2021).\n\nThis project contains the following underlying data:\n\nAverage DBH and Height per Plot.xlsx\n\nProcessed data of SOC.xlsx\n\nProcessed data of TBC.xlsx\n\nProcessed Data of Woody Species Diversity.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 acknowledge the logistic and technical support we got from Wondo Genet College of Forestry and Natural Resources Soil Laboratory, Hawassa University. We sincerely thank the farmers of the study area for their kindness and enthusiasm to talk to us and for allowing us to take measurements on their farms. Our gratitude goes to experts at National Herbarium of Ethiopia, Addis Ababa University, for their generous support on species identification that makes our research very fruitful.\n\n\nReferences\n\nAbere D: Impact of Resettlement on Woody Plant Species and Local Livelihood: The Case of Guraferda Woreda in Bench Maji Zone, South Western, Ethiopia. Addis Ababa University School of Graduate Studies Environmental Science Program, 2011. Reference Source\n\nAddi A, Soromessa T, Kelbessa E, et al.: Floristic composition and plant community types of Agama Forest, an “Afromontane Forest” in Southwest Ethiopia. J Ecol Nat Environ. 2016; 8(5): 55–69. 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}
|
[
{
"id": "83476",
"date": "04 Jun 2021",
"name": "Arshad Ali",
"expertise": [
"Reviewer Expertise My broad-scale research interests are in the area of forest or plant ecology",
"particularly related to multiple abiotic and biotic controls on ecosystem functions and 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\nI read your paper carefully, and found it an interesting idea to compare three land use types such as NF, FFI and FL. I found a very interesting hypothesis at the end of introduction, but unfortunately your experimental design and statistical analyses do not allow to test this hypothesis in a clear way.\nFor example, you selected plots with different sizes and hence it is hard to compare with ANOVA only or any other simple statistics. I suggest testing the direct and indirect effects of plot size, and land use types (i.e., three categories) on species diversity, structure and biomass using structural equation models or multiple linear mixed effect models. Otherwise, it is hard to understand results and hence hard to get right conclusions.\nWhy did you used different biomass equations for NF, FFI and FL? Is this not affecting the biomass estimation amongst three types?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7426",
"date": "29 Nov 2021",
"name": "Mulugeta Betemariyam",
"role": "Author Response",
"response": "Dear Arshad Ali We are grateful to the reviewer for insightful and constructive comments on our manuscript, \"Conversion of natural forests to farmlands and associated woody species diversity and carbon stocks in southwestern Ethiopia during 33 years (1984 to 2016).\" We have attempted to address all comments in this revised manuscript and believe that the manuscript, especially the language, has substantially improved. Track changes for changes made to the original version were added to the page where specific changes were required. Our responses to the specific comments are presented below. I read your paper carefully, and found it an interesting idea to compare three land use types such as NF, FFI and FL. I found a very interesting hypothesis at the end of introduction, but unfortunately your experimental design and statistical analyses do not allow to test this hypothesis in a clear way. For example, you selected plots with different sizes and hence it is hard to compare with ANOVA only or any other simple statistics. I suggest testing the direct and indirect effects of plot size, and land use types (i.e., three categories) on species diversity, structure and biomass using structural equation models or multiple linear mixed effect models. Otherwise, it is hard to understand results and hence hard to get right conclusions. In the statistical analysis section, we apologize for not explicitly expressing which types of statistical tests we utilized for the investigated parameters. We explicitly detailed how we test parameters in the revised manuscript. On comparison, the authors agreed that differences in sample sizes (plot size) affect carbon stocks, species richness, and structure. However, even if the sample size (plot size) for Farmland and other land uses for which comparison was made (NF, FFI) were different, the authors reached the comparison result after the individual plot size for each land use was converted to Ha (hectare) base, which the ANOVA can do for statistical differences. So, after similarizing the unit (ha) for each land use, we compared carbon stocks, diversity indices, and structural parameters among the three land uses following the ANOVA procedures. Why did you used different biomass equations for NF, FFI and FL? Is this not affecting the biomass estimation amongst three types? Many researchers have suggested that site conditions, management strategies, socioeconomic considerations, and farmer preferences could influence the distribution, diversity, and type of woody species (Tolera et al. 2008; Faye et al. 2011; IPCC, 2006; Chave et al. 2014; Kuyah et al., 2012). In our study area, 75 percent of the 70 different species identified do not have a specific allomnetric equation developed for them. As a result, we used an allometric equation developed for an agricultural landscape in Kenya (Kuyah et al., 2012), which has essentially similar bio-physical features to the research area for estimating the biomass of FFI and FL, and an allometric equation developed for natural forests in the tropical region by Chave et al. (2014) to estimate the biomass carbon stocks of natural forest."
}
]
},
{
"id": "92406",
"date": "20 Oct 2021",
"name": "Sigit D. Sasmito",
"expertise": [
"Reviewer Expertise Wetlands ecology and greenhouse gas monitoring"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript presents a set of assessments of tree species diversity and carbon stocks following land-use change. Such of this study is of interest broad audience in the context of land-based climate change mitigation strategies.\nI have a few suggestions below which may be used to improve the current manuscript.\nI’d suggest providing carbon stocks value across land-use change in the abstract’s result section.\n\nI’d drop the current first paragraph in the intro. It is too broad and you have to be direct to the Ethiopia case.\n\nSome references may be needed for the following statement “For the past five decades, the government of Ethiopia has attempted to reforest degraded forests.” and other few next sentences in this paragraph.\n\nTable 1: I didn’t see how the authors get the data presented in Table 1. What is the unit of the area data in 1984 and 2016?\n\nFor Tables 6,7 and 8: I’d suggest authors provide n sample size in addition to the current mean and SD. The soil C stocks are pretty high indeed. To support your soil carbon stocks numbers, I’d suggest providing the bulk density and %C (carbon content) in an additional table.\n\nFor the discussion section under carbon stocks: could you further explore whether soil erosion occurs following forest degradation? This erosion may lead to organic matter loss from the upper soil layer.\n\nTo test if the forest conversion or land-use change generates soil carbon loss, you may use both the fixed depth and mass balance approach. See the following paper for further information about two approaches: Gifford, R. M., & Roderick, M. L. (2003). Soil carbon stocks and bulk density: spatial or cumulative mass coordinates as a basis of expression?. Global Change Biology, 9(11), 1507-15141.\n\nIn the conclusion section, I’d suggest adding a few sentences describing how your study could support current literature on this topic and carbon monitoring in the context of climate change mitigation strategy in Ethiopia.\nGood luck!\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7427",
"date": "29 Nov 2021",
"name": "Mulugeta Betemariyam",
"role": "Author Response",
"response": "Dear Sigit D. Sasmito We are grateful for insightful and constructive comments on our manuscript, \"Conversion of natural forests to farmlands and associated woody species diversity and carbon stocks in southwestern Ethiopia during 33 years (1984 to 2016).\" We have attempted to address all comments in this revised manuscript and believe that the manuscript, especially the language, has substantially improved. Track changes for changes made to the original version were added to the page where specific changes were required. Our responses to the specific comments are presented below. I have a few suggestions below which may be used to improve the current manuscript. I’d suggest providing carbon stocks value across land-use change in the abstract’s result section Thank you for your comments; the carbon stock values have been added to the revised manuscript abstract. I’d drop the current first paragraph in the intro. It is too broad and you have to be direct to the Ethiopia case. Thank you for your constructive comment. We kindly revised accordingly. Some references may be needed for the following statement “For the past five decades, the government of Ethiopia has attempted to reforest degraded forests.” and other few next sentences in this paragraph. Thanks for the information; the suggested paragraph for removal from the introduction section has been removed. Table 1: I didn’t see how the authors get the data presented in Table 1. What is the unit of the area data in 1984 and 2016? Thank you for your input; in the amended manuscript, the technique for obtaining the data in table one, as well as the unit of the area shown in the table, are clearly defined. For Tables 6,7 and 8: I’d suggest authors provide n sample size in addition to the current mean and SD. The soil C stocks are pretty high indeed. To support your soil carbon stocks numbers, I’d suggest providing the bulk density and %C (carbon content) in an additional table. Thank you for your comment; the sample size has been put to the table's heading as recommended. For the discussion section under carbon stocks: could you further explore whether soil erosion occurs following forest degradation? This erosion may lead to organic matter loss from the upper soil layer. Thank you for your comment; the sample values of organic matter lost as a result of the conversion of natural forest to forest farm interface and farmland are mentioned in the amended manuscript's discussion section. To test if the forest conversion or land-use change generates soil carbon loss, you may use both the fixed depth and mass balance approach. See the following paper for further information about two approaches: Gifford, R. M., & Roderick, M. L. (2003). Soil carbon stocks and bulk density: spatial or cumulative mass coordinates as a basis of expression? Global Change Biology, 9(11), 1507-15141. Thank you for sharing us with the sources from which we can obtain additional information. In this study, we employed the fixed depth method to determine the soil organic carbon. As stated in the results section, there was no significant variation in bulk density among the land uses. The estimation of soil organic carbon by employing fixed depth is recommended by authors who were cited in our paper method section if the bulk density is not indicated as a significant difference. In the conclusion section, I’d suggest adding a few sentences describing how your study could support current literature on this topic and carbon monitoring in the context of climate change mitigation strategy in Ethiopia. Thank you for your suggestion. We include a statement in the conclusion section outlining how our research could contribute to current literature on the issue and carbon monitoring in the context of Ethiopia's climate change mitigation strategy."
}
]
}
] | 1
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https://f1000research.com/articles/10-227
|
https://f1000research.com/articles/10-766/v1
|
06 Aug 21
|
{
"type": "Research Article",
"title": "Boesenbergia pandurata application in Goldfish (Cyprinus carpio) Feed to Enhancing Fish Growth, Immunity System, and Resistance to Bacterial Infection",
"authors": [
"Esti Handayani Hardi",
"Gina Saptiani",
"Rudi Agung Nugroho",
"fadlul Rahman",
"Sulistyawati Sulistyawati",
"Widyaningsih Rahayu",
"Ali Supriansyah",
"Irawan Wijaya Kusuma",
"Gina Saptiani",
"Rudi Agung Nugroho",
"fadlul Rahman",
"Sulistyawati Sulistyawati",
"Widyaningsih Rahayu",
"Ali Supriansyah",
"Irawan Wijaya Kusuma"
],
"abstract": "Background: This study investigated how the inclusion of Boesenbergia pandurata extract (BPE) in goldfish feed affects fish growth, immunity, and resistance to infection by Aeromonas hydrophila and Pseudomonas fluorescens.\n\nMethods: Four fish feeds, were prepared by adding BPE at the concentrations of 0 (control), 2, 4, and 6 g kg-1, respectively, and 120 goldfish (Cyprinus carpio; initial weight 5 g) were separated into 12 boxes and fed with specific pellets and examined thrice. The experiment lasted 12 weeks, beginning with the different feeds, fish growth was measured at Weeks 4 and 8 after the feeding period. Moreover, a challenge test with pathogen bacteria to assay disease resistance was administered at Week 8 after the feeding period, and the survival rate and relative percentage of survival were quantified at Week 12.\n\nResults: At Week 8, the goldfish that were fed BPE-containing feeds were significantly heavier than the fish that received the control feed (pellet without BPE), and the highest weight gain, reaching 72.44 g, was obtained with Pellet 3; accordingly, the specific growth rate after BPE treatment (5.7%) was higher than that after control treatment. Conversely, the feed conversion ratio in the control group, 2.03, was higher than the ratios in the BPE groups, which were decreased to 0.55–0.90. Lastly, BPE treatment consistently enhanced the immunity parameters of goldfish (relative to control treatment) at weeks 4 and 8, and following BPE treatment, the rate of resistance against bacterial infection, 68.3%–77.0%, was higher than that after control treatment.\n\nConclusions: BPE addition in goldfish feed clearly produces a positive effect by enhancing fish growth, immunity, and resistance to infection by pathogenic bacteria, and 4 g kg-1 is the optimal BPE concentration in feed prepared for goldfish.",
"keywords": [
"Boesenbergia pandurata",
"Cyprinus carpio",
"Phytobiotics",
"Aeromonas hydrophila",
"Pseudomonas fluorescens."
],
"content": "Introduction\n\nOver the past few years, the use of antibiotics in aquaculture has attracted considerable research attention, and enhanced public awareness of the health and safety of fishery products has led to the insistence that all involved parties concurrently prioritize quality assurance and food safety in aquaculture production, whether for export purposes or domestic consumption.1 Moreover, increasing innovation in aquaculture methods, particularly in the technology used, has been accompanied by a drastic increase in the production. Antibiotics application in aquaculture have been identified as residual materials in fish products and have emerged as the main reason for the frequent rejection of fish products.2 Conversely, the use of plant extracts as one of the ingredients in fish feed to stimulate fish growth and immunity is highly recommended because the extracts produce no resistance effects as residual wastes nor pose any threat to the environment.3–9\n\nIn aquaculture, the use of fish feed prepared from plant extracts offers certain benefits, such as stimulation of growth and immunity, enhancement of digestion and absorption, and resistance to diseases, and also allows for effective control of water quality.10–20 Notably, all reported single extracts of fingerroot (Boesenbergia pandurata) have been found to exert a strong antibacterial effect (80% inhibition) against Aeromonas hydrophila and Pseudomonas fluorescens both in vitro and in vivo, and fish feed containing plant extracts as an additive has been widely developed in aquaculture.21–28 Moreover, addition of garlic in fish feed increased fish immunity,26 and inclusion of thymol carvacrol effectively enhanced the growth and health of rainbow trout fries.29 This study comprehensively describes the effectiveness of the inclusion of B. pandurata (crude) extract (BPE) in fish feed to stimulate growth, immunity, and resistance to A. hydrophila and P. fluorescens infection in goldfish (Cyprinus carpio).\n\n\nMethods\n\nTwelve aquariums (46 × 36 × 25.6 cm3) was used in this research with 25 L of water for 10 fish. There were four groups of different pellets and triplicates with the extracts added and a control. Each group used 10 goldfish, the fish were obtained from Rama Jaya Mahakam Company’s hatchery in Kutai Kartanegara regency, East Borneo, Indonesia, totalling 120 fish in this experiment.\n\nThe fish sample was collected using a fish sorting bucket of size 8 cm, fish that escaped from the 8 cm fish sorting bucket were collected. The fish species was goldfish (Cyprinus carpio), the fish sex was mixed between male and female, the developmental stage was larva size 8–9 cm, and the initial weight range was 5 ± 0.6 g.\n\nBefore the experiment, the goldfish were adapted to the natural environment for seven days and the fish were provided ad libitum access to commercial feed twice a day (at 8.00 a.m. and 4.00 p.m.). Moreover, the fish were first tested for infection by Aeromonas and Pseudomonas by incubating their isolated liver and kidneys with GSP (Himedia®) media; if the bacteria did not grow the fish were considered safe for use in the experiment, whereas if bacterial growth was constantly detected, the fish were soaked in 30% formalin for five minutes and the treatment was repeated for seven days until they were free from the bacteria, Aeromonas and Pseudomonas.\n\nThe method of Hardi et al.30 was used for B. pandurata extraction; the rhizome was cleaned to remove soil and then minced into pieces (0.3–0.5 cm) by using a chopper, and the chopped fingerroot was dried at 40–45 °C for 48 h in an oven. The dried fingerroot was continuously blended and soaked in 96% ethanol for 48–72 h at a 1:10 ratio (i.e. 1 kg of fingerroot powder was soaked in 10 L of ethanol), and the process was continued to extraction for 24 h until the BPE was obtained with a viscosity of 10–11.\n\nBPE was used in goldfish feed as per the method of Hoseinifar et al.,31 with the following four feed pellets being applied as treatments:\n\nPellet 1 (control diets with BPE 0 g kg−1 fish feed).\n\nPellet 2 (supplemented-control diets with 2 g kg−1 fish feed of B. pandurata).\n\nPellet 3 (supplemented-control diets with 4 g kg−1 fish feed of B. pandurata).\n\nPellet 4 (supplemented-control diets with 6 g kg−1 fish feed of B. pandurata).\n\nGoldfish feed was formulated as shown in Table 1.\n\nThe bacteria pathogen for challenges were A. hydrophila (EA-01) and P. fluorescens (EP-02) combination bacteria with bacterial density of 105 CFU mL−1 each bacteria and injection of as much as 0.1 mL were given to each fish. The bacteria were cultured in TSB (Merck®) medium for 24 h in 28–30 °C. Suspense bacteria was collected and centrifuged for 15 minutes in 7000 rpm and bacteria pellet was washing with sterile water twice, and then the bacteria suspense was counting density using TPC to measure 105 CFU mL−1, and bacteria had been properly prepared following the methods of Hardi et al. (2016).\n\nChallenge tests were carried out at week eight after feeding with different formulations, and mortality observations were checked from 24 hours after the first injection until week 12. The rate of resistance against both bacteria was measured using RPS (Amend, 1981). Eventually, the rate of protection against pathogen bacteria was also measured at week 12.\n\nThree parameters of water quality—temperature, pH, and dissolved oxygen (DO)—were measured (twice daily, in the morning and evening) using a multi-parameter checker, whereas total ammonia nitrogen was measured using a spectrophotometer.\n\nImmunological parameters were evaluated by quantifying total leukocyte (TL) using cells mm−3 numbers and by measuring lysozyme activity (LA) according to the method of Parry et al.32 (with the results expressed using the unit μg mL−1). Subsequently, phagocytosis activity (“index phagocytic,” IP) the results expressed using percentage and respiratory burst activity (RBA) were examined as per the method of Van Doan et al.,33 with a few modifications.\n\nGoldfish growth was measured according to the method of Hoseinifar et al.34 at Weeks 4 and 8 after the feeding period; growth was measured in terms of the following criteria: weight gain (WG), specific growth rate (SGR), and feed conversion ratio (FCR). These data were collected at 8 weeks after the feeding period:\n\nWG = final weight (g) – initial weight (g);\n\nSGR (%) = 100 × (ln final weight – ln initial weight)/duration of experiment;\n\nFCR = feed offered (dry weight)/weight gain (wet weight).\n\nThe challenge test was administered by using A. hydrophila (EA-01) and P. fluorescens (EP-02); the bacteria were appropriately prepared as per the method of Hardi et al.6,35 The test was administered at Week 8, with 10 goldfish being exposed to a specific treatment; the fish were infected with the combined bacteria by means of intermuscular injection (0.1 mL each fish) of 105 CFU mL−1 of the bacteria at a 1:1 ratio. Subsequently, fish mortality was monitored from 24 h after the first injection until week 12. The rate of resistance toward both bacteria was measured by using the relative percentage of survival (RPS) value, as defined in the Amend (1981) method. Lastly, the rate of protection against infection with the pathogenic bacteria was measured at Week 12.\n\nSR (%) = (final fish number/initial fish number) × 100;\n\nRPS = 1 − (test mortality/control mortality) × 100.\n\nThe obtained data were analyzed for statistical significance by using MINITAB® 17 computer program (Minitab, RRID:SCR_014483), followed by the DUNCAN test. The average scores calculated were considered significantly different at P < 0.05.\n\n\nResults\n\nGoldfish growth performance was measured at Weeks 4 and 8 after the feeding period. At Week 4, WG and SGR were significantly higher (P < 0.05) after all BPE treatments than after the control treatment (no BPE) (Table 2). The highest SGR and WG were recorded in the case of the goldfish that received fish feed containing BPE at 4 g kg−1, and these values at Week 8 were considerably different from those measured for goldfish exposed to the control and others treatments.\n\nAt Week 4, goldfish exposed to the control treatment grew by SGR 3.99–5.70 g; by contrast, treatment with BPE drastically enhanced growth, by 7.19–10.54 g in the case of the feed containing 4 g kg−1 BPE, and this was 2- or even 3-fold higher than that with the control treatment (Table 2). Moreover, consistent results were obtained at Week 8 after the third fish feeding, with the growth doubling relative to the initial weight and being markedly distinct from that measured after the control treatment. Furthermore, besides growth, feed efficiency also increased, as demonstrated by the FCR increase (relative to control) being substantially lower (0.55) at Week 8 in the case of goldfish that were fed Pellet 3 (BPE at 4 g kg−1), and this FCR value was also significantly different from those calculated after treatment with BPE at the two other concentrations (2 and 6 g kg−1), which produced roughly equal effects.\n\nNext, immunological parameters were measured at Weeks 4 and 8 after the feeding period (Table 3). Activity of Lysozymes (LA) in addition to control of feed-fish in BPE was significantly higher (P < 0.05) (Table 3). Compared with other formulas, the highest value was recorded in fish fed pellet 3 (4 g kg−1). No significant difference (P > 0.05) between fish fed 2 and 6 g kg−1 has been observed (Table 3). Similarly, in additional groups the activity of index phagocytic (PI), compared with the control of fed fish, was significantly higher (P < 0.05) (Table 3). Fish fed dietary pellets 3 showed the highest values (Table 3). In relation to the activity of respiratory burst (RBA), fish supplemented diets (P < 0.05) were significantly higher than the control. No significant difference (P > 0.05) between pellet 2 and pellet 4 was however observed. In comparison to controls after 8 weeks of feeding, and 12 weeks after challenges, significant (P < 0.05) differences in total leukocyte (TL) activity were observes in fish-feed supplements (Table 3).\n\nThe rate of survival and death and RPS were measured at Week 12 after completion of the challenge test. Unexpectedly, the results showed that treatment with BPE at all concentrations markedly increased the RPS, by >60%, relative to control, although BPE at 4 g kg−1 provided the maximal protection (99.56%) against A. hydrophila and P. fluorescens infection (Table 4).\n\nThe results of the experiment examining protection against pathogenic bacteria showed a significant increase in goldfish disease resistance, amounting to 68.3–77.0% following all BPE treatments, although no significant difference was measured between the distinct concentrations of BPE (P > 0.05); moreover, the highest RPS value (77.0%) was obtained with BPE used at 4 g kg−1 in the fish feed (Table 4). In conclusion, relative to Pellet 1, which did not contain BPE, all other pellets drastically increased the rate of survival after pathogenic bacterial infection.\n\nNo significant differences were present in the quality of water in the goldfish aquaculture media when BPE was included in fish feed. The temperature was set at 29 ± 0.2 °C, the DO was 7.6 ± 0.6 mg L−1, the pH range was 7.2 ± 0.5, and the total ammonia nitrogen was 0.69 ± 0.24 mg L−1.\n\n\nDiscussion\n\nPrebiotics prepared from plant extracts have been widely used in aquacultures. The results have shown that plant extracts added to feed enhance fish growth,36,37 maximize immunity,38 and strengthen disease resistance and thus reduce infection by pathogenic bacteria.39–43\n\nIn this study, we aimed to evaluate how BPE inclusion in fish feed affects goldfish growth, immunity, and disease resistance (i.e. resistance against infection by the bacteria A. hydrophila and P. fluorescens). The results comprehensively showed that BPE addition in feed exerted the positive effects of enhancing fish growth and strengthening the immune system. Similar results were reported by Hoseinifar et al.31,34,41 and Carbone & Faggio:44 Addition of the extract of medlar leaf (Mespilus germanica) consistently produced a large impact, with markedly enhanced performance being recorded in terms of growth, skin mucus levels, and serum concentrations of immune-response markers. Our study also showed increased growth of goldfish, particularly at Week 8, after consumption of feed containing BPE at 2, 4, and 6 g kg−1. Thus, BPE served as a growth-stimulating additive for the goldfish aquaculture here. Plant extracts included in fish feed have been reported to markedly increase WG, SGR, protein efficiency ratio, energy retention, feed efficiency, and protein retention.15,45–47 Moreover, champignon (Agaricus bisporus) powder extract included in fish feed effectively enhanced growth and acted as an immunostimulant in the case of goldfish fries.47 Our results here indicate that the growth, immune response, and disease resistance of goldfish were strongly influenced by the immunomodulatory effect of BPE.\n\nIn previous studies, BPE use at 400–900 ppm successfully strengthened the immune system and enhanced the disease resistance of Nile tilapia toward infection by A. hydrophila and P. fluorescens.10,48 Moreover, flavonoid and levamisole addition in feed potently intensified the antigen-phagocytosing effect of monocytes and macrophages,45 and inclusion of BPE alone or together with other extracts boosted leucocyte numbers and consistently accelerated pathogen elimination inside the body of Nile tilapia.4,6,11 Subsequently, BPE-containing vaccines were also found to increase the antibody levels and phagocytic index in Nile tilapia to enhance the immune system and produce accelerated and strengthened resistance against infection by pathogenic bacteria.4 An enhancement of monocyte and macrophage function in pathogen elimination, mucosal immune response, growth, and gene transcription is generally observed in fish that are fed plant-extract-containing fish feed formulated with peptin, oligosaccharides, and flavonoids,49,50 and the use of combinations of plant extracts in aquaculture is also well established. Moreover, addition of Ferula assafoetida extract to fish feed was shown to successfully enhance nonspecific immune-system response and growth in carp fish.51 The increased growth caused by fish feed-efficiency enhancement and FCR reduction in BPE-fed goldfish occurred because of the positive physiological impact that carbohydrates (oligosaccharides) and the essential nutrient pectin produced on the digestive system by reducing glucose absorbance52 and postponing gastric emptiness.53 Ho et al.54 and Naqash et al.55 reported that pectin and its derivatives are components that can potentially be used as prebiotics for aquaculture.\n\n\nConclusion\n\nBPE addition in fish feed provided to goldfish markedly enhances fish growth, feed efficiency, FCR, immunity, and resistance against infection by the bacteria A. hydrophila and P. fluorescens. Moreover, inclusion of 4 g kg−1 BPE in the feed more strongly affects the aforementioned parameters than does BPE added at other concentrations.\n\n\nEthical approval\n\nThe Commission of Ethical Research for Health, Medical Faculty of Mulawarman University, approved this study with the number LOA 04/KEPK-FK/1/2020. The application of B. pandurata, S. ferox, and Z. Zerumbet in freshwater fish feed to improve fish growth, immune system, and resistance to bacterial infection is the research theme. Esti Handayani Hardi of Mulawarman University's Faculty of Fisheries and Marine Science chaired this study. This study lasted six months (from January to June 2020). For a period of 12 weeks, a feed composition with extracts was tested to see how well the fish grew, how well their immune systems worked, and how well they were protected from infections.\n\n\nData availability\n\nOpen Science Framework, OSF 2021: Underlying data for ‘Boesenbergia pandurata application in goldfish (Cyprinus carpio) feed to enhance fish growth, immunity, and resistance to bacterial infection’. https://doi.org/10.17605/OSF.IO/827EN.56\n\nThis project contains the following underlying data:\n\n• Raw data of the growth Performa (Weight gain)\n\n• Raw data of the growth Performa (Specific growth rate)\n\n• Raw data of the growth Performa (Feed conversion ratio)\n\n• Raw data of the Immunological Parameters (Index phagocytic)\n\n• Raw data of the Immunological parameters (Total leukocyte)\n\n• Raw data of the Immunological parameters (Lysozyme activity)\n\n• Raw data of the Immunological parameters (Respiratory burst activity)\n\n• Raw data of the Survival Rate\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\nBoth the researchers and the writers thank Universitas Mulawarman, LPDP, for providing the funds to conduct this research. We are especially grateful to the students from the Faculty of Marine and Fisheries Science, Universitas Mulawarman, for their support and efforts in conducting this research.\n\n\nReferences\n\nDJPB RI: Direktur Jenderal Perikanan Budidaya No. Kep.35/DJ-PB/2012. Tata Cara Pengisian Formulir Data Teknis Obat Ikan. Direktur Jenderal Perikanan Budidaya Republik Indonesia.2012.\n\nCAC: Codex Alimentarius Commission. Code of Practice for Fish and Fishery Products. CAC/RCP 52-2003, Rev. 2010. 2010. Reference Source\n\nCheng LP, Hu QP: Antibacterial activities and mechanism of action of acetone extracts from Rabdosia rubescens. Aceh Int J Sci Technol. 2015; 4(1): 1–6. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nGiannenas I, et al.: Assessment of dietary supplementation with carvacrol or thymol containing feed additives on performance, intestinal microbiota and antioxidant status of rainbow trout (Oncorhynchus mykiss). Aquaculture. 2012; 350: 26–32. Publisher Full Text\n\nHassaan MS, Soltan MA: Evaluation of essential oil of fennel and garlic separately or combined with Bacillus licheniformis on the growth, feeding behaviour, hemato-biochemical indices of Oreochromis niloticus (L.) fry. J Aquaculture Res Devel. 2016. 7: p. 422–429. Publisher Full Text\n\nLee JY, Gao Y: Review of the application of garlic, Allium sativum, in aquaculture. J World Aquaculture Soc. 2012; 43(4): 447–458.\n\nPuvača N, et al.: Beneficial effects of phytoadditives in broiler nutrition. World's Poult Sci J. 2013; 69(1): 27–34. Publisher Full Text\n\nRamezanzadeh S, Kenari AA, Esmaeili M: Immunohematological parameters of rainbow trout (Oncorhynchus mykiss) fed supplemented diet with different forms of barberry root (Berberis vulgaris). Comparative Clin Pathol. 2020; 29(1): 177–187. Publisher Full Text\n\nAhmadifar E, Falahatkar B, Akrami R: Effects of dietary thymol-carvacrol on growth performance, hematological parameters and tissue composition of juvenile rainbow trout, Oncorhynchus mykiss. J Appl Ichthyol. 2011; 27(4): 1057–1060. Publisher Full Text\n\nHardi EH, et al.: Antibacterial activities of some Borneo plant extracts against pathogenic bacteria of Aeromonas hydrophila and Pseudomonas sp. AACL Bioflux. 2016; 9(3): 638–646.\n\nHoseinifar SH, Zoheiri F, Lazado CC: Dietary phytoimmunostimulant Persian hogweed (Heracleum persicum) has more remarkable impacts on skin mucus than on serum in common carp (Cyprinus carpio). Fish Shellfish Immunol. 2016; 59: 77–82. PubMed Abstract | Publisher Full Text\n\nParry RM Jr, Chandan RC, Shahani KM: A rapid and sensitive assay of muramidase. Proc Soc Exp Biol Med. 1965; 119(2): 384–386. PubMed Abstract | Publisher Full Text\n\nVan Doan H, et al.: Effects of Cordyceps militaris spent mushroom substrate and Lactobacillus plantarum on mucosal, serum immunology and growth performance of Nile tilapia (Oreochromis niloticus). Fish Shellfish Immunol. 2017; 70: 87–94. Publisher Full Text\n\nHoseinifar SH, et al.: Enrichment of common carp (Cyprinus carpio) diet with medlar (Mespilus germanica) leaf extract: Effects on skin mucosal immunity and growth performance. Fish Shellfish Immunol. 2017; 67: 346–352. PubMed Abstract | Publisher Full Text\n\nHardi EH, et al.: Antibacterial activity of Boesenbergia pandurata, Zingiber zerumbet and Solanum ferox extracts against Aeromonas hydrophila and Pseudomonas sp. Nusantara Biosci. 2016; 8(1): 18–21. Publisher Full Text\n\nKathia CM, et al.: Probiotics used in Biofloc system for fish and crustacean culture: A review. Int J Fisheries Aquatic Studies. 2017; 5(5): 120–125.\n\nRodrigues MS, et al.: Mannoprotein dietary supplementation for Pacific white shrimp raised in biofloc systems. Aquaculture. 2018; 488: 90–95. Publisher Full Text\n\nLara-Flores M, et al.: Use of the bacteria Streptococcus faecium and Lactobacillus acidophilus, and the yeast Saccharomyces cerevisiae as growth promoters in Nile tilapia (Oreochromis niloticus). Aquaculture. 2003; 216(1-4): 193–201. Publisher Full Text\n\nGatesoupe FJ: The effect of three strains of lactic bacteria on the production rate of rotifers, Brachionus plicatilis, and their dietary value for larval turbot, Scophthalmus maximus. Aquaculture. 1991; 96(3-4): 335–342. Publisher Full Text\n\nGildberg A, Mikkelsen H: Effects of supplementing the feed to Atlantic cod (Gadus morhua) fry with lactic acid bacteria and immuno-stimulating peptides during a challenge trial with Vibrio anguillarum. Aquaculture. 1998; 167(1-2): 103–113. Publisher Full Text\n\nHoseinifar SH, et al.: Effects of date palm fruit extracts on skin mucosal immunity, immune related genes expression and growth performance of common carp (Cyprinus carpio) fry. Fish Shellfish Immunol. 2015; 47(2): 706–711. PubMed Abstract | Publisher Full Text\n\nLi P, Gatlin D: Evaluation of the prebiotic GroBiotic®-A and brewers yeast as dietary supplements for sub-adult hybrid striped bass (Morone chrysops×M. saxatilis) challenged in situ with Mycobacterium marinum. Aquaculture. 2005; 248: 197–205. Publisher Full Text\n\nMohamed K, Fattah BA, Eid A: Evaluation of using some feed additives on growth performance and feed utilization of monosex Nile tilapia (Oreochromis niloticus) fingerlings. Agricultural Res J, Suez Canal University. 2007; 7(3): 49–54.\n\nCarbone D, Faggio C: Importance of prebiotics in aquaculture as immunostimulants. Effects on immune system of Sparus aurata and Dicentrarchus labrax. Fish Shellfish Immunol. 2016; 54: 172–178. Publisher Full Text\n\nAbd Elmonem A, Shalaby S, El-Dakar A: Response of red tilapia to different levels of some medicinal plants by-products black seed and roquette seed meals. Proc First Conf Egyptian Aquacultural Society. 2002. Publisher Full Text\n\nDawood MA, Koshio S: Recent advances in the role of probiotics and prebiotics in carp aquaculture: a review. Aquaculture. 2016; 454: 243–251. Publisher Full Text\n\nZou HK, et al.: Agaricus bisporus powder improved cutaneous mucosal and serum immune parameters and up-regulated intestinal cytokines gene expression in common carp (Cyprinus carpio) fingerlings. Fish Shellfish Immunol. 2016; 58: 380–386. PubMed Abstract | Publisher Full Text\n\nHardi EH, et al.: Immunomodulatory and antibacterial effects of Boesenbergia pandurata, Solanum ferox, and Zingiber zerumbet on tilapia, Oreochromis niloticus. AACL Bioflux. 2017; 10(2): 182–190.\n\nFaggio C, et al.: Cytotoxicity, haemolymphatic parameters, and oxidative stress following exposure to sub-lethal concentrations of quaternium-15 in Mytilus galloprovincialis. Aquatic Toxicol. 2016; 180: 258–265. PubMed Abstract | Publisher Full Text\n\nMiandare HK, et al.: The effects of galactooligosaccharide on systemic and mucosal immune response, growth performance and appetite related gene transcript in goldfish (Carassius auratus gibelio). Fish Shellfish Immunol. 2016; 55: 479–483. Publisher Full Text\n\nSafari R, et al.: The effects of dietary Myrtle (Myrtus communis) on skin mucus immune parameters and mRNA levels of growth, antioxidant and immune related genes in zebrafish (Danio rerio). Fish Shellfish Immunol. 2017; 66: 264–269. Publisher Full Text\n\nGrundy MM, et al.: Re-evaluation of the mechanisms of dietary fibre and implications for macronutrient bioaccessibility, digestion and postprandial metabolism. Br J Nutr. 2016; 116(5): 816–833. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchwartz SE, et al.: Sustained pectin ingestion delays gastric emptying. Gastroenterology. 1982; 83(4): 812–817. PubMed Abstract\n\nHo YY, Lin CM, Wu MC: Evaluation of the prebiotic effects of citrus pectin hydrolysate. J Food Drug Anal. 2017; 25(3): 550–558. PubMed Abstract | Publisher Full Text\n\nNaqash F, et al.: Emerging concepts in the nutraceutical and functional properties of pectin—A Review. Carbohydr Polym. 2017; 168: 227–239. PubMed Abstract | Publisher Full Text\n\nHardi EH, et al.: Boesenbergia pandurata application in goldfish (Cyprinus carpio) feed to enhance fish growth, immunity, and resistance to bacterial infection. OSF. 2021. Publisher Full Text"
}
|
[
{
"id": "95791",
"date": "22 Oct 2021",
"name": "Angela Mariana Lusiastuti",
"expertise": [
"Reviewer Expertise Fish Pathology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nI think this script is good, using herbs as an alternative to chemical drugs. Abstract, Introduction, Methods, and Results are good. The focus of the Discussion should be on BPE as an immunostimulant, not as a prebiotic. If you want to discuss prebiotics, you must include parameters related to the effects of prebiotics. For example prebiotic characteristics, prebiotics activity in the intestinal and other BPE performances as prebiotics such as digestive enzyme activity, short-chain fatty acid, or the diversity of the gut microbiome. If you want to compare research results with other people's research, it's best to use the same BPE or at least have the same active ingredients of BPE. not only compared with herbs that have different criteria. I think the reason for increased growth and FCR reduction is because of effects from BPE as immunostimulant not from the positive physiological impact that carbohydrates (oligosaccharides) and the essential nutrient pectin produced on the digestive system by reducing glucose absorbance, If you use this reason, you should have a proof that your feed formula contains carbohydrates (oligosaccharides) and the essential nutrient pectin (Table 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? 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": "7425",
"date": "15 Nov 2021",
"name": "Esti Handayani Hardi",
"role": "Author Response",
"response": "Thank you very much for the revision and response. In this research, I want to evaluate the effect of Boesenbergia pandurata Application in Goldfish (Cyprinus carpio) specifically on growth, immunity, and resistance to pathogens in general. By looking at the parameters WG, SGR, FCR, Immunological parameters, and SR. At the beginning of this research, separate extracts were made which were then mixed in feed and showed good results. Furthermore, the researchers made a feed formulation by adding BPE so that they could evaluate whether the effect was the same for carp or not. Whether its function as a prebiotic or as a growth stimulator mechanism has not yet been seen, but its effect on goldfish has been seen directly. The discussion presented tried to explore and evaluate several researchers regarding the opportunities for plant extracts as prebiotics. Initial tests showed that BPE showed carbohydrate content (Hardi et al., 2016)."
}
]
},
{
"id": "100290",
"date": "18 Nov 2021",
"name": "A. Abinawanto",
"expertise": [
"Reviewer Expertise Animal Physiology",
"Animal Genetics",
"Cell and Molecular Biology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe manuscript is quite good, generally. I made some corrections to the manuscript. These include species names being written in italic. In some tables should also add a “plus-minus mark” (±) following the average. In the Abstract, it should be explained the statistic analysis used in this study.\nMethods: The authors should specify the basis of choosing different concentration fish feed of B. pandurata as well as 4 and 8 weeks of observation?. The study lacks a specific hypothesis. Reference: #1, it should be translated into English.\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": "7471",
"date": "26 Nov 2021",
"name": "Esti Handayani Hardi",
"role": "Author Response",
"response": "Thank you for the review of my article, I made some revisions : Checking again the italics We have added more information and literature to make more clearly about the dose. the dose or concentration was using this research came from the research before (Hardi et al., 2016;2017;2018;2019). Revision in discussed chapter with adding the statistic results."
}
]
}
] | 1
|
https://f1000research.com/articles/10-766
|
https://f1000research.com/articles/10-1208/v1
|
26 Nov 21
|
{
"type": "Research Article",
"title": "Inequality and migration in Kenya: Investigating the subnational associations using census data",
"authors": [
"Mary Muyonga",
"Alfred Otieno",
"George Odipo",
"Alfred Otieno",
"George Odipo"
],
"abstract": "Background: Since the early 2000s, there has been an extensive debate on whether migration and inequality are interlinked, with varying conclusions arising from methodological as well as theoretical dispositions. The aim of this study is to contribute to this debate by exploring the nexus between several dimensions of inequalities and migration in Kenya. Methods: This study used the subnational(county) data on inequalities and migration in Kenya obtained from several reports. Four explanatory variables including access to water, electricity, composite index of County Human Development Index (County HDI) and County Gini were used. Our dependent variable was migration intensity, measured by the Revised Weighted Net Migration Rate. Correlation and spatial regression analysis were performed to model the relationship between migration and inequality.\n\nResults: Findings revealed that migration had a non-linear relationship with income inequality, such that a change in one unit of migration intensity results in a 567 negative change in County Gini. The County Gini had the highest explanatory power in our model, although counties with high HDI tend to have higher migration intensities. Migration intensities in the country were not randomly distributed as we found evidence of spatial clustering with two key emergent hotspots, a high-high in the lake region and a low-low in the coastal region. Regions with low migration intensities correspond with higher poverty, implying that structural factors may explain the migration intensities in the country.\n\nConclusions: The study highlights that the subnational income inequality reduces as migration intensifies. We conclude that migration has an equalizing effect on inequality as observed in some studies. Regions with high poverty tend to have lower migration intensity, implying that structural factors are important in influencing migration. Use of migration intensity and application of spatial analysis have improved our understanding of migration and inequality, and should be applied in future research.",
"keywords": [
"migration",
"inequality",
"subnational migration",
"migration intensity",
"spatial analysis",
"Geographically Weighted Regression",
"Kenya"
],
"content": "Introduction\n\nOne of the emerging research interests in the wake of the Sustainable Development Goals1 (SDGs) is to understand the nexus between migration and development outcomes. Goal 10 of the SDGs is specifically focused on addressing inequalities among countries, including those related to representations, migration, and development assistance. The importance of inequalities is captured in a United Nations Development Programme (UNDP) report that states that progress on the Millennium Development Goals was hampered by ‘unequal access to resources and distribution of power within and among countries’ (UNDP, 2005: 52). The growing inequalities within and between countries remains an important discourse in policy circles including the UN Commission on Population and Development Forty-Seventh Session (UN, 2013). Inequality is a multidimensional phenomenon and attracts interests of different disciplines including migration researchers (see Black et al., 2005)2. Inequalities, defined as the variations in wellbeing between people or groups of people, becomes an important explanatory factor in migration decision making process.\n\nMigration and inequality linkages are difficult to establish, although scholars have made attempts to understand such linkages. Black et al. (2005) observe that the relationship between migration and inequality is governed by access - who gets to migrate, where they migrate to – and the different opportunities that different types of migration streams offer. Whilst their study showed that the migration-inequality relationships vary across space and within and between regions, they also highlight the need to define both the types of migration and types of inequality being analyzed, as the different types of migration may have different effects on different dimensions of inequality. There are economic and social policy constraints affecting migrants as they move for better livelihoods as noted by Klugman (2009), depicting the complexity of human mobility and development. On one hand, inequalities experienced in household settings are a reflection and amplify the constrained opportunity structure (Melamed and Samman, 2013). On the other hand, while migration benefits the family members left behind, it can exacerbate inequalities as migrants tend to come from the better-off backgrounds to start with.\n\nGlobal scholarly work on migration and inequality as a causal relationship has led to inconclusive results, as some argue that inequality is a prerequisite for migration, while others hold that migration causes inequality. There is consensus that migration is a process that leads to social transformation resulting in changing social structures and creation of new social institutions (UNDP, 2009; de Haas, 2010; King, 2012). When it relates to inequality, migration results in increased opportunities, inequalities and at times, increased poverty, prompting de Haas to opine that ‘to understand society is to understand migration, and to understand migration is to better understand society’ (de Haas, 2014:16).\n\nScholars exploring the complex relationship between migration and inequality have mostly relied on econometric analysis of the effects that remittances, as a proxy measure that captures the contribution of migrants, and how that affects the household income and wealth status in the sending communities. Such remittances, especially in monetary form, improve the migrant receiving household welfare and could in fact improve their wealth status in the community. There are numerous studies on the effect that remittances have on income inequality globally (de Haas 2007, 2009; Ebeke and Le Goff, 2011), and a growing body of evidence from country case studies in Africa including Botswana, Burkina Faso, Egypt, Ethiopia, Ghana, Kenya, Nigeria and Somaliland (Plaza, et al., 2011; Muyonga, Odipo and Agwanda, 2020). The results of such studies have yielded conflicting findings, as some indicate that increased migration leads to higher inequality as remittances from migrants reduce income inequality between migrant and non-migrant households in areas of origin; while others find that remittances from migrants increase inequality in areas of destination. The conflicting findings in the effect that remittances have on income inequality are largely based on the methodological approach adopted in the respective studies (Adams, et al., 2008). The econometric approach is not without criticism, the method relies on point estimates of migration event3 which largely ignore the repeat movements across the life cycle, hence ignores the migration system. de Haas (2010) offers a framework for understanding the migration and inequality nexus, pointing out that migration is a social process, a normal process that occurs as societies develop, and inequality is an outcome of that process. Moreover, as societies change, migration processes transition into various forms, meaning that the effect of inequality may also vary. Thus, determination of the effects of migration on inequality requires that we consider migration as part of broader social process (Castels, 2010).\n\nSeveral studies in Kenya have explored the relationship between migration and inequality. The earlier studies considered inequality as a determinant of migration decision, with Wakajummah (1986) study showing that land inequality influenced the propensity to migrate among young males. In their study, Knowles and Anker (1981) consider the effects of remittances on income inequality, and find a weak effect of urban-rural remittances on income inequality. This led to their conclusion that the migration-inequality relationship depends on some intervening variables, including the educational level and income of the migrant, urban or rural residence of the migrant household, and the migrant household wealth status including assets owned and number of dependents. Different findings were observed by Hoddinott (1994) who finds that remittances increase income inequality between migrant and non-migrant households in rural areas. Reflecting on the perceived relationship between land inequality and the increase in migration propensity observed by Wakajummah (1986), a follow up study using data from the 2009 Kenya Migration Household Survey by the World Bank, shows that household predisposing factors influence migration decision making, and therefore, the effect of migration on inequality will depend on such household mitigating factors, hence land inequality is an outcome of other factors (Bang, et al., 2016). The observed effects of remittances are not similar for urban and rural areas, as noted by Oyvat and wa Githinji (2017), who found that in urban areas, migration results in the influx of migrant workers who may receive lower wages than natives in the urban areas resulting in increased income inequality in the urban areas; while in rural areas, the remittances received from migrants results in higher incomes for the migrant household resulting in improved economic wellbeing thereby increasing income inequality between migrant and non-migrant households. Thus, their study illuminated the mechanisms through which migration influences income inequality comparing urban and rural areas of Kenya.\n\nThe earlier studies conducted in Kenya have featured two main approaches, those that consider inequality as a determinant of migration, and others that consider inequality especially income inequality as an outcome of the migration process, but only in regard to the migrant areas of origin. This means that there are still many unknown aspects in understanding how migration as a process affects inequality. While aspects of the effect of inequalities on migration have been studied, they are limited to household analysis and individual migrant experiences. In addition, the effect of migration is measured using remittances sent by migrants, largely ignoring the effect of the wider process and the impact it has on population flows between sending and receiving areas. Moreover, beyond considering land inequality as a determinant for migration, there is little evidence of other dimensions of inequalities considered in earlier studies. Against this backdrop, our study seeks to investigate how migration as a demographic process is affected by inequalities.\n\nThe study sought to explore how the inequalities between counties (sub national administrative regions) in Kenya may be related to internal migration movements. This study builds upon works done on migration and inequality in Kenya but differs from previous studies in several ways. First, the study was not a deterministic but rather an exploratory study about how migration intensities change with shifting inequalities. Second, while previous analysis was based on individual migrant characteristics, the study conducted a macro analysis of county level migration and inequality patterns. Third, the study considered the effect of both income and non-income inequalities on migration. Lastly, the study focused on subnational analysis and adopted spatial analysis techniques to understand the effect of inequalities on migration in Kenya.\n\n\nData and methods\n\nMigration data was extracted from the 2009 Kenya Population and Housing Census micro data of the Kenya National Bureau of Statistics (KNBS) following a formal data request. The 2009 Population and Housing Census was conducted in August 2009, with the reference night being August 24/25. Data was collected for a period of one week, on all persons residing in Kenya on the census reference night (see Republic of Kenya, 2012). The unit of enumeration was the household unit and information were collected on type of household, access to social amenities, and demographic information on the household members including education, age, sex and occupation. Migration information was captured using the following variables: place of birth (P18), place of previous residence (P19), duration of residence (P20) and place of enumeration (P21) (Republic of Kenya, 2012:4). As information was collected on the persons who migrated at two points in time, at birth and at time of enumeration, there may be undercounts of migration transitions, as repeat movements and mortality of migrants are not captured.\n\nFor our study, we use two of the migration variables, namely place of birth (P18) and place of enumeration (P21) to generate information on lifetime migrants. Lifetime migrants were identified as persons whose place of birth was different from the place of enumeration at the time of the census. We derived the lifetime migration data from cross tabulating the place of birth by place of enumeration. The end result was a set of contingency flow for all the 47 counties showing in-migration and out-migration flows.\n\nThe next step in our analysis was generation of the migration intensity measure. Our dependent variable was migration intensity, a measure that captures both migration rates and impacts (Van Imhoff and Keilman, 1991; Rees et al., 2000; Bell et al., 2002; Liu, et al., 2011; Shi et al., 2020).\n\nFor each county, we generated net migration rates using the following formula\n\nThe Revised weighted migration rates, RNMi was calculated using the formula\n\nRNMi considers the proportion of migrants in the total population of a given area, therefore considering the undercounts or overcounts that would occur due to huge differences in total population. When in-migrants are larger than out-migrants, the RNMi gives a positive result while negative results imply that more migrants are leaving the area. Thus, the RNMi gives a useful indicator of the intensity of migration and the impact that has had on population redistribution in a given county. Thus, the Revised Weighted Net Migration Rate, gives us the proportional distribution of migrants in a given county as a weighted count of all in-migrants in the country.\n\nInequality was captured using four key indicators, namely the County Human Development Index (HDI), the County Gini, the proportional access to water and proportional access to electricity within the counties. The four indicators were readily available in different reports based on the 2009 Kenya Population and Housing Census data. The County Gini variable was extracted from the Kenya Inequality Study4 jointly conducted by the Kenya National Bureau of Statistics and Society for International Development using a hybrid dataset that combines household data from the 2009 Kenya Population and Housing Census with livelihood data from the 2005 Kenya Integrated Household Budget Survey data to estimate monetary and non-monetary measures of inequality in Kenya (KNBS and Society for International Development, 2013).\n\nThe County Gini was derived using the small area estimation technique that followed three key steps. First, data for 1999 Kenya Population and Housing Census was matched to the 2009 Kenya Population and Housing census through a process of matching the clusters of the enumeration areas in these censuses. The use of 1999 census data was necessitated so as to trace the Kenya Integrated Household Budget Survey household clusters, as these were based on the sampling frame used in the earlier census of 1999. The variables that are similar in the 2005/6 KIHBS and 2009 census were identified. Second, a regression model was applied to identify household characteristics and the comparable consumption patterns from the KIHBS survey data. The resultant regression equation was then used to estimate the daily consumption and expenditure patterns using the 2009 variables including household size and other characteristics (KNBS and SID, 2013:3). Finally, through a simulation process, household expenditures for the 2009 census households were inputted using the socio-economic variables estimated using the survey data. Thereafter, the Gini coefficient was computed using consumption expenditure values obtained from the small area techniques. The value of Gini ranges from 0 to 1, with 0 implying there is perfect equality in incomes while 1, implies there is perfect inequality in incomes. A summary table capturing the county level Gini Coefficients can be found in the report (see KNBS and SID, 2013:43).\n\nTwo non-income measures of inequality were used in the analysis, namely access to safe water sources, and use of electricity for lighting. Data on access to water and access to electricity was accessed from the Socio-Economic Atlas of Kenya report, which is based on deeper analysis of data from the 2009 Kenya Population and Housing Census data, and provides subnational analysis of county and sub-location level data (Wiesmann et al., 2014). Access to safe water sources was obtained from the 2009 census questionnaire, in which all households named their source of domestic water. The indicator of access to water captures the number of households with access to one or more water sources which may include piped, borehole, protected wells, protected springs or rainwater. The information is summarized by county giving the number and percentage of households with access to safe water (Wiesmann et al., 2014:64). In measuring the access to electricity, the study used data on the proportion of households using electricity as source of lighting. The data was extracted from the Socio-Economic Atlas of Kenya report (Wiesmann et al., 2014:78). We used this variable as a measure of the living standards of the household, as electricity distribution in the country is unequal. The variable captures the proportions of households in a given county who indicated that they use electricity as their main source of lighting.\n\nThe fourth variable, the County Human Development Index, County HDI was obtained directly from the 2009 Kenya National Human Development Report (UNDP Kenya, 2010). The report assesses the overall changes in the longer term, based on a composite measure of education and literacy rates, healthy living and access to social amenities, the gross domestic product and estimates of earned income by gender. From this report, we obtained estimates of the county HDI which were indicated by Province and district (see Annex 1.1, UNDP Kenya, 2010:77). To generate the values for the present-day counties, a matching process of district to county was employed and average measures used in situations where several districts made up one county, for example, in Nyanza Province, Bondo district and Siaya district are now part of one county, named Siaya County.\n\nTo determine the interrelationship between migration and inequality, the two key analytical techniques were employed, namely correlation and regression analysis using spatial analysis techniques using ArcGIS. While the normal correlation analysis could help to determine if a relationship exists between migration and inequality, and the strength of the relationship, spatial analysis helps to unveil the patterns of flows and their divergence and connectedness. Spatial analysis derives from Tobler’s First Law ‘Everything is related to everything else, but near things are more related than distant things’ (Tobler 1970: 234). It is a measure of relationship between contiguous spatial units and measures spatial dependence or spatial heterogeneity (Anselin, 1990).\n\nThe bivariate correlation analysis was conducted using SPSS 22 software. The outcome of the bivariate correlation analysis is the Pearson product-moment correlation, Pearson r (Pearson, 1909). Bivariate correlation assumes that variables are normally distributed but has been found to perform well when normalcy is violated or when one of the variables is discrete. The values of Pearson r range from −1 to 1, where −1 indicates there is perfect negative correlation between variables, 0 indicates there is no correlation between variables, while +1 indicates there is a perfect positive correlation between the variables, such that a rise in one variable leads to a rise in the other. The output of correlation analysis includes the Pearson r value and the significance of the correlation (2 tailed). An asterisk denotes that the correlation is significant at the 0.05 level, while double asterisk shows correlation is significant at 0.01 level.\n\nThe spatial analysis was done using ArcGIS 10.5 software to derive two measures of autocorrelation, the Global Moran I, and the local Moran also known as the local indicator of spatial autocorrelation (LISA) which conducts cluster and hot spot analysis (Anselin, 1995). The Global Moran I determine whether there may be unique patterns, such as incidences of clustering. The Global Moran’s I, tests for spatial randomness, thus testing the null hypothesis that the spatial autocorrelation of a variable is zero. If the null hypothesis is rejected, the variable is said to be spatially autocorrelated (Ord and Getis, 1995). The output of the analysis returns five values: the Moran’s Index, Expected Index, Variance, z-score, and p value. The value of Moran’s I range from -1 to 1, with -1, where the value 1 means there is perfect clustering of similar values, while 0 means there is no autocorrelation, hence any clusters arising are of dissimilar values. Thus, a positive value of Moran’s I indicates that the values being analyzed tend to cluster spatially, either as high values clustering together, or low values clustering together. A negative index implies that high values repel each other and tend to be near low values. The results also include spatially generated maps that show clustering of migration patterns, as well as areas with divergent characteristics, thus visually clarifies the effect of migration on inequality. A criticism of Moran’s I is that the measure is limited only to the strongest associated locations (Wartenberg, 1985). The local tests for spatial association (LISA) helps in spatial cluster identification and spatial filtering (Tiefelsdorf and Boots, 1995, 1997; Hepple, 1998). The formula for calculating LISA (Ii) is expressed in the works of (Anselin, 2017). The output of LISA is evidence of clusters, where regions with high or low values are identified based on their degree of statistical significance, based on the Getis-Ord statistic, Gi*(d) (Getis and Ord, 1992). The interpretation of z-scores for the Gi* statistic is quite different from the interpretation of z-scores in the Global Moran’s I. The interpretation of the Gi* Statistic is that a positive association denotes a clustering of high values, while negative association denotes a clustering of negative values. Comparatively, for the Moran’s I, positive value of Ii indicates spatial clustering of similar values while a negative value of Ii indicates a clustering of dissimilar values.\n\nRegression analysis was employed to determine the spatial relationship between the migration and inequality variables using two measures, the Ordinary Least Square regression (OLS) and Geographically Weighted Regression (GWR) tools in ArcGIS. The OLS regression analysis was employed to test if our model is effective in explaining the relationship between the variables. We conducted the Geographical Weighted Regression (GWR), which considers both geographical differences and spatial relationships in the data being analyzed. Geographically Weighted Regression fits a regression equation for all features in the data set using the dependent and explanatory variables, within similar neighborhoods. GWR builds on the OLS by allowing the relationship between the independent and dependent variables to vary by locality. The key assumption of GWR is that the strength and direction of the relationship between the dependent and independent variables is influenced and can be modified by contextual factors (Fotheringham et al., 2003). Several variables were included in the GWR regression equation. The dependent variable Y is migration intensity is measured by the Revised Weighted Net Migration Rate, that captures the temporal effect of migration on population distribution. The independent variables were the county-based measures of inequality including County Gini, County HDI, proportion of persons with access to power and proportion of population with access to water. The resultant equation was as follows:\n\nWhere, Y is the dependent variable and measures migration intensity, PWY is the autocorrelation factor, while the independent variables include the county inequality measures namely, County Gini, County HDI, proportion of persons with access to electricity in a given county, and proportion of population with access to water in a given county and B1, B2, … Bn are the coefficients to be estimated.\n\nThe OLS regression analysis yields an output that contains the following information: the OLS residuals, statistical results and diagnostics, a table of explanatory variables and their coefficients (called the OLS Summary Report) and a table of the regression diagnostics5. To interpret the results, we focus on the R-squared measures which shows how much change in the model is caused by the dependent variable, in our case, the migration intensity.\n\nWhile the OLS regression is useful in providing an indication of the model efficacy, it has limitations. First, it does not cater for the spatial effects. Second, when there two or more variables that can affect the dependent variable and also affect each other, OLS regression will not be able to counter this multicollinearity effect, thus, the analysis will show that variables which may otherwise be significant in the analysis, rendered statistically insignificant (Young, 2018; Shrestha, 2020).\n\nAs a result, we applied as second regression model, the Geographically Weighted Regression (GWR) to the data, to cater for multicollinearity. The output of the Geographical Weighted Regression Analysis comprises of five features. These include; fields for observed and predicted response values, condition number (cond), Local R2, explanatory variable coefficients, and standard errors generated by ArcGIS.6 The value called the condition number checks the level of local multicollinearity in the data. In case of strong evidence of multicollinearity, the results of the regression model will be unreliable, hence the variables being analyzed should not be larger than 30. The R Squared values indicate how well the model fits, and the values range from 0 to 1, indicating how well the model fits to the y values, thus a test of the fit of the model. Values closer to 0 has a poor fit. The output of the GWR analysis on ArcGIS produces a map of the Local R2 values, to show where predictions were good and where they were not.\n\nAn alternative open-source software that can be used for the spatial autocorrelation analysis is R, although this has been developed recently7. Migration intensities, inequality data and County HDI can be exported from MS Excel to R using the.csv format. The county spatial maps are generated using the shapefiles, that can be read in QGIS or R package8. Linear regression analysis can be done using R package using the command Im. For the spatial autocorrelation analysis, which checks for clustering of migration intensities, the migration intensities and county shapefiles can be read in R. The ArcGIS analysis used the ‘distance bands’ to determine the nearest neighbor or contiguous county. In R package, one can use the ‘contiguity neighborhood’ as the measure of the connectedness of the counties, and calculate the mean values of the neighboring units. While ArcGIS runs the spatial autocorrelation using a weighted index, W, that captures the average weighted measure (spatial lag) of contiguous units, using R package, one can calculate the Moran’s I using the moran.test function which gives you the Moran’s I value and the p-values. Further information on spatial analysis using R can be obtained from several research works (see Baddeley et al., 2016; Roger, et. al, 2013).\n\n\nResults\n\nCorrelation analysis was conducted between several inequality variables and migration intensity as the dependent variable using SPSS. The results are presented in Table 1 and indicate that migration has a significant positive relationship (p = 0.01) with access to electricity, and with county development, County HDI (p = 0.05).\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\nThese findings corroborate other studies that show that migrants tend to move to areas with better development indicators, and the access to electricity is a good predictor of development in this case. Thus, regions with higher development indicators exhibit higher incidences of migration.\n\nWe conducted spatial analysis of our model, with migration intensity as the dependent variable, and the four explanatory variables namely access to electricity, access to water, County Gini and County HDI. The purpose of this analysis was to provide evidence of spatial association between the variables, and the consistency of such association within the counties. The spatial analysis results from the ordinary least square regression (OLS) reveal several observations. First, the nature and direction of the relationship between the variables are captured using scatterplots and histograms as shown in Figure 1. The histograms show that the distribution of variables is not normal, with a left inclination, for the County Gini and access to power and a right inclination for the County HDI. The scatterplots show that the relationship between the variables and migration are non-linear. This corroborates literature findings implying that the relation between migration and inequality is curvilinear.\n\nTable 2 presents diagnostic results of our OLS model. The Multiple R-squared value shows that our model explains up to 21 percent of the changes in migration intensity. Owing to the complexity of the relationship, we opt to use the Adjusted R-squared results, which show this efficacy level declines to 14 percent. The low explanatory level of our model implies that there may be other variables that could explain the variations in migration intensity, but these were excluded in our model. Despite this, our model is statistically significant, indicated by the Joint Wald statistic (p < 0.05). Now that we have our model and the efficacy confirmed, the OLS regression also tested if the observations of the relationship between the variables were consistent across the counties. The Koenker (BP) statistic checks for stationarity, and the results show a p value of 0.005, confirming that there is no heteroscedasticity in our model. Finally, the OLS results also confirm that the relationship between migration and inequality is non-linear, with the Jarque-Bera statistic value of 285 (p < 0.001) confirming this.\n\nIn Table 3, the OLS results show the explanatory powers of each of the variables in the regression. The results show that the County HDI and County Gini, have higher explanatory powers, although they influence migration intensity in opposite direction. The County HDI has a positive influence on migration intensity, while the County Gini has a negative influence on migration intensity. The remaining two variables, access to electricity and access to water, have lower explanatory powers in the equation. However, only the County Gini gives a statistically significant relationship when robust statistics is considered. A unit change in migration intensity results in a negative change of up to 567 units in County Gini, showing an inverse relationship between the two variables. This finding confirms earlier observations by Kuznets (1971) and other scholars of the inverse relationship between migration and income inequality.\n\nThe data was subjected to Geographically Weighted Regression (GWR) analysis and the attributes used in the analysis are shown in Table 4. With the GWR, the efficacy of our model improves and the model explains up to 20 percent of the relationship between migration and the inequality variables, as shown by the R2 adjusted value. Just like the OLS model, the efficacy confirms that several other critical variables that could explain migration and inequality are missing in our model.\n\nThe GWR results provide a cold-to-hot rendered map of the standard residuals of the regression analysis. This map, shown in Figure 2, shows evidence of clustering of migration intensities in the country. For example, low migration intensities are found in Makueni, Machakos, Embu and Meru counties, respectively. Nairobi County has remarkably high migration intensity and is surrounded by regions with similarly high migration intensities, leading to a clustering of high-high migration. This may be because of the spillover effects of migration to Nairobi, hence migrants move to the next contiguous counties, as demonstrated by high intensities in Kajiado, Kiambu and Nakuru counties. In the western part of the country, there is a cluster of high migration in Vihiga County and similarly high migration in Migori County at the Kenya-Tanzania border. Comparatively, the coastal region shows evidence of low migration clustering in Mombasa and Kilifi counties, respectively.\n\nFollowing the observed clustering of migration intensities in the country, a spatial autocorrelation of the residuals was applied to the data to confirm if the results are random, or clustered. The results of the Global Moran’s I are presented in Figure 3. Our Global Moran Index gives a value 0.105452, z-score is 3.0785, while p value is 0.002, implying that the data is spatially clustered and not randomly distributed. The positive value of Moran’s I indicates that while the values are spatially clustered, positive values are clustered together and negative values are clustered together. This leads to the conclusion that migration intensity is spatially clustered, with neighboring regions recording similar values.\n\nThe results of the tests for identifying whether county migration is spatially clustered or not is presented in Figure 4 which provides evidence of hotspots. The spatial clusters of migration intensities of similar nature confirm the existence of two key migration hotspots in the country. There is a high migration hotspot in the lake basin region (comprising of Kisumu, Vihiga and Nandi counties) and a low migration hotspot in the coastal region (comprising of Mombasa, Kilifi and Kwale counties). The Getis-Ord Statistic GI* show a positive value indicating that migration intensities are clustered in these regions, with positive values together and negative values together.\n\nThese finding confirms the importance of spatial factors in explaining demographic phenomena. In this case, the clustering of high migration intensities in the lake basin region confirms the previous observations of the region as a reservoir of migrants, having higher outflow of migrants largely due to scarcity of opportunities in the region. In a review of inequalities in Kenya, data showed the marginalization of the western part of the country owing to political reasons (Ajulu, 2002) resulting in lower human development outcomes (Society for International Development, 2004, 2006). For the coastal region, migration intensities are low with most movements towards Mombasa, the second largest capital city, and the counties that reported highest intensities are largely poorly resourced regions with high levels of poverty (KNBS and SID, 2013).\n\n\nDiscussion\n\nThis paper sought to test the relationship between migration and inequality in Kenya using several Subnational (county) variables including migration intensity, access to water, access to electricity and Human Development Index (County HDI) and County Gini. We employed several tests including correlation and spatial regression techniques to make this determination. The former tests the general direction of the relationship between migration and different indicators of inequality, while the latter tests not just the association between the variables but checks for evidence of spatial relationships between the variables. The OLS results show that two measures of inequality, the County HDI and County Gini, have the highest explanatory powers for the changes in migration intensity. A statistically significant inverse relationship is also established for the County Gini and migration, such that a unit rise in migration intensity leads to a 567-unit decline in County Gini. This is a major contribution to the discourse on migration and inequality in Kenya.\n\nThe findings confirm that income is an important factor for migration, as indicated in earlier studies. These had shown that migrants tend to come from wealthier households, and that remittances sent by migrants increase income inequality between migrant and non-migrant households, as the migrant households receive remittances that increase their wealth status allowing them to invest in productive assets. While this may be true, our study did not test the family level dynamics, but rather the meso level intensities. Our findings show that regions that report higher migration intensities, which implies that they have higher proportion of migrants in the total population, report lower levels of income inequality. This may imply that migration has an equalizing effect as a compensation mechanism for poor households as observed in several studies elsewhere (Kuznets, 1955; Arslan and Taylor, 2012; Mezger and Beauchemin, 2015).\n\nOur spatial analysis shows that the migration intensities are not randomly spread in the country but cluster in specific geographic areas. The regions that have high migration intensity are clustered together, while those with low migration intensities are clustered together. As a result, Kenya has two key migration hotspots, a hotspot of high intensities at the lake basin region and a hotspot of low intensities at the coastal region. These results show that there are structural factors that may account for the variation of migration in the country and these underlying factors have an effect on the level of inequalities observed in the counties. We therefore concluse that spatial factors are important in understanding and interpreting the effects of migration on inequalities in Kenya.\n\nThe results of the GWR and OLS show that our model only partially explained the changes in the migration intensities in the country, thus the variables we chose to explain inequalities (County Gini, County HDI, access to water, access to electricity) may be insufficient in explaining the migration and inequality in the country. Our model only explained 20 percent of the variations, hence there may be other factors excluded as migration occurs as part of the wider social transformation system (Castels, 2010). Thus, for future research on migration and inequality, there may be need to consider the effect of other factors not included in this analysis.\n\nThe difference between our approach and that used by other scholars in previous studies was that we focused on the migration process measured by the level of intensity at the geographical level. The migration intensity measure, in our case, the Revised Weighted Net Migration Rate captures the overall effect of migration on population distribution, such that counties with high migration intensity are those with a higher proportion of internal migrants in the total population. The results of our analysis confirm that the counties with a higher proportion of migrants in their population tend to record significantly lower levels of income inequality. The 2009 migration intensities capture the changes that migration has on the receiving county populations, and the intensities were varied depending on the importance of migration to the county. For instance, our maps show a clustering of high migration intensities in Nairobi and surrounding counties, which is associated with higher development and economic opportunities, compared to the low intensities observed at the coast, a region associated with lower development.\n\nOf the four variables we selected as explanatory variables, only income inequality measured by County Gini proved to be statistically significant in explaining the changes in migration intensities observed in the counties. Our findings corroborate previous observations by other scholars that when migration increases, there is first a rise in income inequality in the sending areas, which falls as more people migrate (see Kuznets, 1955). Some researchers suggest that the rise and eventual fall of income inequality with increased migration occurs because migrants send remittances to the sending communities, so as more migrants increase, there will be little or no income inequality gaps between migrant and non-migrant households (Stark and Taylor, 1991; Faini and Venturini, 1993; Vogler and Rotte, 2000).\n\nWhile the migration intensities showed significant clustering, the inequality patterns measured by our four variables also depicted wide subnational variations. This may shed some light in the interpretation of our results. The regions with high income inequalities were mostly in the coastal region of Kenya especially in the counties of Tana River, Kwale and Kilifi. Coincidentally, these are also counties that experience high poverty levels (Kenya National Bureau of Statistics and Society for International Development, 2013). This may partly explain why the migration intensities at the coastal region are mainly low. The County Gini that is negatively associated with migration represents counties with higher income inequalities, some of which include the coastal region counties like Lamu, Kilifi, Kwale and Tana River, in Nyanza region including Siaya, Homa Bay, Kisii and Kisumu counties; in Busia County in Western Kenya and in Machakos County. The results imply that migration in Kenya is largely driven by the regional inequalities and corroborates previous scholarship (Rempel, 1971; Society for International Development, 2004, 2006; Oucho, 2007; KNBS and Society for International Development, 2013) on the wide inequalities in the country.\n\nUse of ArcGIS mapping enabled the visualization of migration intensities across the country, as well as mapping of the patterns of inequality. The results showed a north-south dichotomy in the patterns of inequality in the country, which may be traced to the country’s colonial legacy. The patterns of migration in the country were spatially clustered and not randomized events.\n\n\nConclusion and recommendation\n\nWe conclude that our findings support previous observations on the inverse relationship between migration and inequality, albeit using different variables (Bang, et al., 2016; Wakajummah, 1986). Using the ArcGIS and spatial analysis techniques, our results confirm that migration and inequality in Kenya have a spatial relationship, with migration patterns spatially distributed in response to the level of development in the country.\n\nWhile we set out to confirm if we can test the effect of other dimensions of inequality and their relationship with migration, our results confirm that income inequality remains a robust measure of inequality and is negatively associated with migration in Kenya. The association between lower migration intensity and higher County Gini could reflect the differential impact of background factors, including structural factors, that affect who migrates and where they migrate to. The low explanatory power of the variables we chose in our study however show that additional factors need to be considered in the analysis of migration and inequality, especially those that influence the County Gini outcomes.\n\nOur results confirm the importance of understanding not just the economic, but also the social and political contexts that affect mobility decisions. They point to the importance of a multi-layered analysis of migration and inequality in which structural and other factors are considered in the investigation. For example, we find that spatial factors remain important in explaining both migration and inequality in Kenya, as the patterns of migration and inequality show spatial variations.\n\nSeveral recommendations can be made from this study. First, spatial analysis resulted in improvement of our understanding of the migration patterns in the country, hence it should be applied in future migration studies to improve the understanding of the migration process. The GWR and OLS analysis showed that the factors used in the model only explain 20 percent of the variations in the relationship between migration and inequality. Thus, we can explore migration beyond the income lens. For future analysis, we recommend that a mixed method approach is adopted in understanding how migration correlates with non-income inequalities.\n\nA limitation of our study is the reliance on census data which only captures migration events without data on reasons for migration; therefore, it is difficult to determine individual level factors and confirm the migration history. Return migrants are also ignored in the analysis. While the data shows the overall impact of migration on the county, it was limited on the differential impacts within migrant households, migrant sending communities and the recipient communities.\n\n\nData availability\n\nThe internal migration dataset from the 2009 Kenya Population and Housing Census data is available from the Kenya National Bureau of Statistics (KNBS) and permission to obtain micro data can be obtained from their website. Access to the data requires registration and is granted for those who wish to use the data for legitimate research purpose. Alternatively, the micro data is available from Integrated Public Use Microdata Series (IPUMS) following user request from their registration page.\n\nInequality data was obtained from the Exploring Kenya Inequality National Report, published by the Kenya National Bureau of Standards (KNBS) and Society for International Development (2013). The report is available through this link: Exploring Kenya Inequality National Report - Kenya National Bureau of Statistics (knbs.or.ke).\n\nCounty Human Development Index data was obtained from the 2009 Kenya National Human Development Report that can be accessed here.\n\nAccess to electricity and access to water data was obtained from the Socio-Economic Atlas of Kenya (Wiesmann et al., 2014) which contains analysis of the 2009 Kenya Population and Housing Census data. This can be accessed here.\n\nA guide for using R program for spatial autocorrelation can be found here.",
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Geographical Analysis. 1985; 17(4): 263–283. Publisher Full Text\n\nWiesmann UM, Kiteme B, Mwangi Z: Socio-economic atlas of Kenya: Depicting the national population census by county and sub-location. Kenya National Bureau of Statistics, Centre for Training and Integrated Research in ASAL Development, Centre for Development and Environment; 2014.\n\nYoung DS: Handbook of regression methods. CRC Press; 2018.\n\n\nFootnotes\n\n1 Sustainable Development Goals are an Agenda with a specified Action Plan made of 17 Goals and 169 targets aimed at transforming the world by 2030. The SDGs build on to the Millennium Development Goals that were not achieved.\n\n2 Most studies specifically looked at the relationship between international migration and inequality. In fact, the paper makes a strong case for the use of multidimensional analysis of inequality not only focusing on income and wealth.\n\n3 Point estimates of migration events are captured through population census, which effectively measure the migration event at a fixed period referenced around the census date. It fails to capture any repeat movements that would have been made in the inter censal period, and thus is designated as a measure of events.\n\n4 The Kenya Inequality Study used the 2009 Kenya Population and Housing Census data and the 2005/6 Kenya Integrated Household Budget Survey, to generate estimates of poverty and inequality.\n\n5 The ArcGIS provides a tutorial on the interpretation of the spatial regression analysis, see https://pro.arcgis.com/en/pro-app/latest/tool-reference/spatial-statistics/how-ols-regression-works.htm\n\n6 https://desktop.arcgis.com/en/arcmap/10.3/tools/spatial-statistics-toolbox/interpreting-gwr-results.htm\n\n7 https://mgimond.github.io/Spatial/spatial-autocorrelation-in-r.html\n\n8 https://www.r-graph-gallery.com/168-load-a-shape-file-into-r.html"
}
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[
{
"id": "101215",
"date": "13 Dec 2021",
"name": "Abel Nzabona",
"expertise": [
"Reviewer Expertise Demographics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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:\nAuthors have a detailed introduction that delves into the subject matter. The section would be enriched if key concepts (such as intensity of migration, inequality e.t.c.) were operationally defined.\n\nData and methods:\nAuthors are using data collected some 12 years ago in the 2009 national census. The 2019 census is obviously more recent and would be expected to be the ideal choice. If there are reasons for not using it, let these be brought out to justify the use of the older dataset.\n\nIt is helpful to make solid and clear justification for other choices. These include selecting water and electricity as explanatory variables. Why not other socioeconomic variables but these two? Similarly, opting for lake basin and coastal areas requires explanation.\n\nAt the end of the section labelled 'analytical methods', there is a long paragraph about 'an alternative open-source software that can be used for the spatial autocorrelation analysis...' and this is in reference to 'R'. What is the point in disclosing possibilities in a section like this? This section is expected to touch on what 'was done and how' rather than what 'can be done and with what'.\n\nResults:\nUse of map displays is commendable as the results are presented in an interesting and elegant manner. Tables are used mainly for methodological results. It would be appreciated if they were similarly used for substantive results on migration-inequality nexus.\n\nRecommendations:\nRelevant methodological recommendations are made. However, less is done regarding policy implications and recommendations that emerge from substantive results. Authors need to re-visit this area.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? 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": "272038",
"date": "15 May 2024",
"name": "Nobuaki Hamaguchi",
"expertise": [
"Reviewer Expertise Spatial 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\nThe authors claim that there is a negative correlation between the intensity of the county-level migration in Kenya is explained by the degree of local inequality. They propose the revised weighted migration rates (RNMEi) as the measure of migration intensity, and test the statistical association with HDI, income inequality (Gini), access to electricity and water. They first run OLS but found problems of nonstationarity and spatial autocorrelation, which invalidate the OLS estimates. They proceed to estimate the Geographically Weighted Regression and found that OLS predictions of the migration intensity deviates systematically in the lake region and in the coastal region, suggesting the existence of some structural factors. Overall, I think this paper makes interesting contributions to the literature. It was nicely written and easy to follow. Having said that, I would like to leave some comments that might help the authors to make this article accessible to readers who are not familiar with the spatial data analysis.\n(1) Please provide a summary statistics table of the five variables (RNME, HDI, Gini, Electricity, Water).\n\n(2) I do not see any meaning of multiplying N (total number of counties) in calculation RNMi (page 5) because it multiplies the same N for all i. If it is necessary, please explain. It might be helpful if the authors could provide a choropleth map to show counties where RNME is negative (I-O<0) and positive (I-O>0).\n(3) In Conclusion (page 18), the authors point out that the model estimated in this paper has low explanatory power, suggesting influences of variables which are not included here. The authors could reflect what are possible candidates for such variables according to previous researches.\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/10-1208
|
https://f1000research.com/articles/10-1207/v1
|
26 Nov 21
|
{
"type": "Research Article",
"title": "Developing assessment criteria for operation control of local security health fund in the upper central area, Thailand",
"authors": [
"Prapot Boonmee",
"Pattapong Kessomboon",
"Supattarayan Thongjit",
"Prapot Boonmee",
"Supattarayan Thongjit"
],
"abstract": "Background: The government's support for public health care in Thailand is very important and necessary. Therefore, there must be a supervisory process for budgeting to create the most equality and fairness to all people. At present, the instruments used to monitor health fund performance cannot be comprehensively assessed for effectiveness such as planning, organizing, leading and controlling. To address this gap, we created the Assessment Criteria for Operation control of Local security health Fund (ACOLF) which evaluates old assessment criteria, review literature and experience as separate constructs. Methods: The ACOLF is a 42-item survey with 12 old assessment criteria, 26 review literature and four experience items rated on scale from 0-9. In an observational analytical study, the survey was administered to 406 general population participants working in a provincial office for local administration. Validity and reliability were evaluated by testing construct validity. Exploratory factor analysis was conducted to confirm the item of old assessment criteria, review literature and experience. Reliability of the questionnaires was tested using Cronbach’s alpha coefficient. Results: The ACOLF demonstrated convergent construct validity (KMO = 0.88 and Bartlett's Test; p value <0.001) and explaining 88.95% of the variance of this construct. There were seven factors involved and all factors consisted of a total of 41 variables observed by the weight of the composition of the observed variables ranged from 0.780 to 0.972 at the significance level of 0.05. The reliability of the assessment criteria was tested using Cronbach’s alpha coefficient, the total results was at 0.889. Conclusions: The ACOLF is a short, cover activity, valid, and reliable instrument for assessment operation control of local security health fund. Based on research findings the tool can be used to comprehensively assess the performance of local security health fund.",
"keywords": [
"Local Health Security Fund",
"Quality Criteria Assessment",
"indicators"
],
"content": "Introduction\n\nWorld Health Organization (WHO) attention to the policy of creating universal health insurance (Universal Coverage Scheme)1 and need for collaborative working was highlighted in the 1986 Ottawa Charter for Health Promotion. The health promotion demands coordinated action by all concerned: by governments, by health and other social and economic sectors, by nongovernmental and voluntary organizations, by local authorities, by industry and by the media. The recognition of the role those social determinants play in the health of the population makes it clear that health cannot be the responsibility of just one agency and, over the last three decades, collaboration has been an increasing focus of health promotion internationally.2 In 1997 the Jakarta Declaration identified partnerships for health and social development between different sectors as one of its five key priorities. It stressed the need to strengthen existing partnerships and urged the development of new partnerships3 (Jakarta 1997). These priorities were further highlighted in 2005 when the Bangkok Charter stated that “partnerships, alliances, networks and collaborations provide exciting and rewarding ways of bringing people and organizations together around common goals and joint actions to improve the health of populations”4 (WHO 2005).\n\nThailand’s policy on universal health coverage (UHC) has made good progress since its inception in 2002 by National Health Security Office Thailand (NHSO). Every Thai citizen is now entitled to essential health services at all life stages.5 The NHSO has a duty to support Coordinate and prescribe rules for local authorities to operate and administer the health insurance system at the local level as readily or appropriately to create health insurance for the population in each region. Well-coordinated district health systems enable individuals to seek care or referral at health units close to home.6\n\nThe NHSO is working with local governments to establish the Local Health Security Fund (LHF), with the key goal of increasing access to health promotion and disease prevention services in the community. There is a process by community participation in solving health problems that has been ongoing since 2006 to the present. Over the past 10 years, the local health insurance fund has been established and developed continuously. Therefore, the assessment and monitoring tools are very important for the Fund's development in order to know the factors affecting the coverage of health services such as education level, health, socioeconomic status.7 LHF Performance Assessment Emphasis is placed on work processes requiring the creation and development of LHF management evaluation criteria, which must be developed and improved to suit the current situation. In particular, the indicators can indicate that the fund management committee is effective and can reflect the level of strength and sustainability of the LHF.8\n\nHowever, the original LHF efficacy model did not cover all aspects of fund management and people still had insufficient access to local government services.9 Therefore, the development of an LHF operated and managed by the local government that can drive the health care of local people more efficiently and sustainably requires the development of an efficient and effective assessment tool to provide an overview of its operations.\n\nIn this research, it has been developed and designed to be used as a guideline to assess the quality of LHF management to be effective in the future.\n\n\nMethods\n\nCross-sectional analytical study.\n\nThe study was conducted in eight provinces in central areas of Thailand include Saraburi, Lop Buri, Sing Buri, Ang Thong, Phra Nakhon Si Ayutthaya, Pathum Thani, Nonthaburi and Nakhon Nayok. The subject answered question during a convenient time that did not disturb them from working. The study was conducted from January to December 2019.\n\nThe ACOLF is a 42-item survey with 12 old assessment criteria 26 review literature and four experience items rated on scale from 0-9. The content validity index (CVI) was tested by four experts, which is the primary method used to determine whether a test has content validity that purport to the same content domain and the results item content validity were between 0.76-1.0.\n\nWe collected data from a sample size involved in the local government organization, one representative at a time, using questions made up of three parts, totaling 42 item or a 42 item Observed Variable (OV) survey with 12 old assessment criteria, 26 review literature and four experience items rated on scale from 0-9. The questionnaire was developed to measure the factors Assessment Criteria for Operation control of Local security health Fund (ACOLF) dividing into 12 Latent Variable (LV): LV1 Fund Management. (Observe variable 2-4) LV2 Fund Allocation. LV3 Support for activities of the Fund. LV4 health benefits. LV5 Organizational Leadership. LV6 Assignment of people in the organization. LV7 Health Strategic Plan Formulation. LV8 Human Resource Development of the Fund. LV9 Health Network Potential Development. LV10 Database Management. LV11 Public Relations of the Fund. LV12 Monitoring and Evaluation. The content of the questionnaire was discussed with the experts in the field and then revised accordingly. Self-reported questionnaire bias may develop recall bias in data collection, which is eliminated by designing questionnaires to be easy to answer in accordance with the participants' regular work activities.\n\nSample size\n\nUsing the rule of sample size, in the factor analysis at least 300 for the Exploratory Factor Analysis (EFA).10 Purposive sampling was used to obtain data from a sample group that corresponds to the health fund management questionnaire, including representatives of the Health Security Fund Committee and representatives of health network partners from the public and public sectors. The consent to participate in the research was carried out by sending a questionnaire to the sample group and having the consenting person respond to the questionnaire back to the researcher. The study had 402 participants consisting of 23 local politicians, 343 government officers, 40 Public Health Technical Officers. The subjects were selected by a multi-stage sampling. The study was conducted in the upper central area, Thailand. Ethical permission (number HE 621205) was received from Khon Kaen University Ethics Committee for Human Research. The researcher was aware of the rights of participants and sufficient information was provided to the research participants before making a decision to participate and answering the questionnaire.\n\nStatistical methods\n\nA preliminary data analysis program using Microsoft Excel and EFA analysis was performed using SPSS Statistics for windows version 19, a copyright of Khon Kaen University. Double data entry was used to check for to data duplication and missing. EFA was performed to examine latent variables under the observation variables by grouping or combining variables that were related to one another. The relationship, both positive and negative, were used. Variables within the same element were highly correlated. Each component must have an Eigen value > 1, Factor loading > 0.5, and each group must have two observation variables, which would be appropriate for computation. If not, it would not be included in the model. The statistics used to describe subgroups were Kaiser-Meyer-Olkin (KMO) and Bartlett's test.\n\n\nResults\n\nData obtained from the questionnaire were analyzed by factorial analysis using EFA.23 Seven components were identified, each with Eigen value > 1, Factor loading> 0.5, Bartlett's test p-value <0.001, can explain the variance = 88.95%. The results are shown in Tables 1-2 and can be expressed as Factor loading in the Table 3.\n\nWhen analyzing by EFA, the latent factor was left with seven factors and the related observed variable was reduced to 41. The seven latent factors and their observation factor were as follows: LV1 Basic management has been component OV2-6 and factor loading were between 0.79-0.95. LV2 Service deliver for health care has been component OV7-11 and factor loading were between 0.78-0.85. LV3 Leadership and governance has been component OV12-17 and factor loading were between 0.78-0.88. LV4 Strategic planning has been component OV18-24 and factor loading were between 0.85-0.93. LV5 Human resource development has been component OV25-30 and factor loading were between 0.83-0.97. LV6 Health information system has been component OV31-37 and factor loading were between 0.79-0.95. LV7 Monitoring and evaluation has been component OV38-42 and factor loading were between 0.79-0.96.\n\nTo further test whether the variable in the study will can be used to analyze the causal relationship (Causal model) with the Structural Equation Modeling (SEM) method, the relationship between the two variables was tested to make sure that there was no Multicollinearity. Details of the relationship between observed variables are shown in Table 3.\n\nThe variables were both positive and correlated. The observed variables were positively correlated between 0.278 and 0.684, and the seven highest positive correlation coefficients were: LV2 and LV1 (r = 0.647, p-value <.01), LV4 and LV3 (r = 0.684, p-value <.01), LV6 and LV3 (r = 0.623, p-value <.01), LV7 and LV3 (r = 0.612, p-value <.01), LV6 and LV4 (r = 0.614, p-value <.01), LV7 and LV4 (r = 0.612, p-value <.01) and LV7 and LV6 (r = 0.659, p-value <.01). The couple with the least positive relationship were the observation which was made by LV5 and LV1 (r = 0.278, p-value <.05). When considering the correlation coefficients of the observed variables, it was found that none of the variables had a relationship greater than 0.85,11 which might cause linearity problems (Multicollinearity).\n\nTherefore, when considering the Pearson product moment correlation coefficient between variables, the value was not higher than the set value. It can be concluded that all variables do not have multiple linear states. The data in this set can be used to analyze the linear equation modeling (SEM).\n\nCronbach’s alpha was calculated for the ACOLF LV1-LV7 to measure the extent to which the items within the subscales correlated with each other and measured a similar construct. The five LV1 items had a Cronbach’s alpha of 0.86 and average inter-item covariance 232.48. The five LV2 items had a Cronbach’s alpha of 0.86 and average inter-item covariance of 234.04. The six LV3 items had a Cronbach’s alpha of 0.83 and average inter-item covariance of 234.52. The seven LV4 items had a Cronbach’s alpha of 0.83 and average inter-item covariance of 222.47. The six LV5 items had a Cronbach’s alpha of 0.86 and average inter-item covariance of 245.97. The seven LV6 items had a Cronbach’s alpha of 0.83 and average inter-item covariance of 227.73. The five LV7 items had a Cronbach’s alpha of 0.83 and average inter-item covariance of 240.34.\n\n\nDiscussion\n\nAnalysis of factors related to effective LHF management found that seven items were derived from the accompanying analysis. It was found that some factors were not variables for the implementation of local health insurance funds. The variables that the researcher chose to exclude variables from the statistic were values less than 0.5 out of the 1 variable (LV1). By collecting data from a sample group covering each size of LHF representatives in Thailand, both urban and rural communities, each category of the assessment had different assessment questions as follows.\n\nIn item 1 (LV1) Basic management was component OV2-6. which contains questions about fund management by carrying out activities in the development of the LHF in order to achieve its goals. A Case Study on Tacoma–Pierce County, Washington, in Assessing the Role of State and Local Public Health in Outreach and Enrollment for Expanded Coverage, found action by local governments in health care to obtain funding. Government sectors need to have good financial management or planning.12 A study of key factors for inefficient district health management practices in Ghana found inadequate planning in health management.13\n\nIn LV2 Service deliver for health care has been component OV7-11 is a measure of individual health care services. It is a measure of the effectiveness of LHF health services. Several studies have been conducted on the effectiveness of collaboration between government and local governments in evaluating public health promotion actions. Randomized controlled trials occurred in the Jerusalem region, Israel,14 to investigate the effectiveness of local government health services, measure illness-related absenteeism, handwashing behaviors before lunch and after using the bathroom. In 2008, a study in Copenhagen and Aarhus, Denmark15 measured Symptoms on the Scale for Assessment of Psychotic Symptoms and others to measure the effectiveness of local government health services. It was found that the knowledge and attitudes of the people towards the health services of the local government were measured.16,17\n\nLV3 Leadership and governance has been component OV12-17. It measures the part of organizational leaders in managing policies and managing funds for maximum efficiency. Several studies have found that the management or decision-making of a leader in health administration is extremely important. The study Assessing the Role of State and Local Public Health in Outreach and Enrollment for Expanded Coverage to determine Factors influencing the work efficiency of district health managers 12 found that one important factor was a narrow decision space that constrains the authority of health leaders. A 2007 study in Tanzania18 found that corporate leaders play a key role in managing the Community Health Fund.\n\nLV4 Strategic planning has been component OV18-24. This section assesses management planning to ensure that the Fund implements health activities in the best interests of the people. A Philippine Local Government Health Administration study found that lack of Strategic planning would result in less inequality and less access to local government health care systems among citizens.19,20\n\nLV5 Human resource development has been component OV25-30. A study by Bruzzese et al.21 in 2006 examined the management of asthma between schools, families, and primary care providers similar to health management with the participation of government or local residents. It was found that the potential development of personnel in the patient care network required training. Developing potential to have knowledge to be able to work effectively.\n\nLV6 Health information system has been component OV31-37. We believe that the provision of health information and information management will lead to the most efficient management of the LHF. A 2011 study by Florence et al.22 found that an information sharing partnership between health services, police, and local government in Cardiff, Wales, altered policing and other strategies to prevent violence based on information collected from patients treated in emergency departments after injury sustained in violence.\n\nLV7 Monitoring and evaluation has been component OV38-42. It is an important process to monitor the progress and results of LHF activities to ensure continuity and maximum efficiency. Kamuzara and Gilson (2007)18 study found that the influencing factors in the implementation of local health funds in Tanzania suggests that a lack of good management plans prevents the inability to assess or monitor the progress of implementation. This will affect future follow-up supervision.\n\n\nConclusions\n\nIn summary, the ACOLF is a 41-item survey rated on a sliding scale from 0-9, with 5 Basic management, 5 Service deliver for health care, 6 Leadership and governance, 7 Strategic planning, 6 Human resource development, 7 Health information system and 5 Monitoring and evaluation. The ACOLF subscales demonstrated convergent validity, internal consistency and reliability. The ACOLF is a concise, valid, and reliable instrument for evaluating local organization management differences in Basic management, Service delivers for health care, Leadership and governance, Strategic planning, Human resource development, Health information system and Monitoring and evaluation. This measure provides a new tool for ranking operation control of local security health fund in Thailand.\n\n\nAuthor roles\n\nBoonmee P.: Conceptualization, Data Curation, Formal Analysis, Methodology, Software, Writing – Original Draft Preparation; Kessomboon P.: Conceptualization, Methodology, Supervision, Writing – Review & Editing; Thongjit S.: Data Curation, Formal Analysis, Methodology, Visualization, Writing – Review & Editing.\n\n\nGrant information\n\nThis study was granted by Faculty of Medicine, Khon Kaen University, Thailand; IN 63202.\n\n\nData availability\n\nData Archiving and Networked Services: Developing Assessment Criteria for Operation Control of Local Security Health Fund in the Upper Central Area, Thailand, https://doi.org/10.17026/dans-245-3wxu.23\n\nThis project contains the following underlying data:\n\n‐ DATA_EFA prapot_F1000.dat\n\n‐ DATA_EFA prapot_F1000.dta\n\n‐ DATA_EFA prapot_F1000.sav\n\n‐ DATA_EFA prapot_F1000.sps\n\nThe name of data set shown is different in the file type so that it can be used in accordance with that program, for example file type “.sps” can be analyzed in the SPSS program.\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 participants, and the members of the faculty of medicine in Khon Kaen University for their support of this project.\n\n\nReferences\n\nWorld Health Organization: Ottawa Charter for Health Promotion: First International Conference on Health Promotion Ottawa.21 November 1986. Reference Source\n\nMarmot M: Social determinants of health inequalities. Lancet. 2005; 365: 1099–1104. Publisher Full Text\n\nWorld Health Organization: Jakarta Declaration. Jakarta: Fourth International Conference on Health Promotion.1997. Reference Source\n\nRissel C: The Bangkok Charter for Health Promotion in Globalized World. N. S. W. Public Health Bull. 2005. 2005; 16: 156–158. PubMed Abstract | Publisher Full Text\n\nSilverman R, Sakuma Y, Post L, et al.: Health access for all: Thailand’s universal coverage scheme. Glassman A, Temin M, editors. Millions saved: new cases of proven success in global health. 3rd ed.Washington: Center for Global Development; 2016; pp. 89–96. Reference Source\n\nNittayarumpong S: Evolution of primary health care in Thailand: what policies worked?. Health Policy Plan. 1990; 5(3): 246–254. Publisher Full Text\n\nSukartini T, Arifin H, Kurniawati Y, et al.: Factors Associated with National Health Insurance Coverage in Indonesia [version 1; peer review: awaiting peer review]. F1000Res. 2021; 10: 563. Publisher Full Text\n\nNational Health Security Office: 2014; Health Security Fund Operation Manual at Local or Local Level. Bangkok: National Health Security Office. Reference Source\n\nKhongthanachayopit S, Laohasiriwong W: Accessibility to health services among migrant workers in the Northeast of Thailand [version 1; peer review: 2 approved]. F1000Res. 2017; 6: 972. PubMed Abstract | Publisher Full Text\n\nHair JF (Jr), Black WC, Babin BJ, Anderson RE: Multivariate Data Analysis.2010; 120–130. PubMed Abstract Reference Source\n\nKline RB: Principles and Practice of Structural Equation Modeling. (2nd ed.).New York, Guilford. 2005. Publisher Full Text\n\nBharmal N, Williams MV, Martin LT, et al.: Assessing the Role of State and Local Public Health in Outreach and Enrollment for Expanded Coverage: A Case Study on Tacoma–Pierce County. Washington, Santa Monica, Calif.: RAND Corporation, RR-983-DHHS, 2016; As of August 23, 2021. Publisher Full Text Reference Source\n\nBonenberger M, Aikins M, Akweongo P, et al.: Factor Influencing the Work Efficiency of District Health Managers in Low-resource Setting: a Qualitative Study in Ghana. BMC Health Serv. Res. 2016; 16: 12. Publisher Full Text\n\nRosen L: Can a handwashing intervention make a difference? Results from a randomized controlled trial in Jerusalem preschools. Prev. Med. 2006; 42(1): 27–32. PubMed Abstract | Publisher Full Text\n\nBertelsen M, Jeppesen P, Petersen L, et al.: Five-year follow-up of a randomized multicenter trial of intensive early intervention vs. standard treatment for patients with a first episode of psychotic illness. Arch. Gen. Psychiatry. 2008; 65(7): 762–771. PubMed Abstract | Publisher Full Text\n\nTucker JS, Fitzmaurice AE, Imamura M, et al.: The effect of the national demonstration project Healthy Respect on teenage sexual health behaviour. Eur. J. Pub. Health. 2007; 17(1): 33–41. PubMed Abstract | Publisher Full Text\n\nSmylie L, Maticka-Tyndale E, Boyd DE-MA, et al.: Evaluation of a school-based sex education programme delivered to Grade Nine students in Canada. Sex Education. 2008; 8(1): 25–46. Publisher Full Text\n\nKamuzora P, Gilson L: Factors Influencing Implementation of the Community Health Fund in Tanzania. Health Policy Plan. 2007; 22(2): 95–102. PubMed Abstract | Publisher Full Text\n\nBossert TJ, Beauvais JC: Decentralization of Health Systems in Ghana, Zambia, Uganda and the Philippines: A Comparative Analysis of Decision Space. Health Policy Plan. 2002; 17: 14–31. PubMed Abstract | Publisher Full Text\n\nCapuno JJ, Quimbo SA, Kraft AD, et al.: The effects of term limits and yardstick competition on local government provision of health insurance and other public services: The Philippine case, UPSE Discussion Paper, No. 2012-01, University of the Philippines, School of Economics (UPSE), Quezon City2012; 1–44. Reference Source\n\nBruzzese J, Evans D, Wiesemann S, et al.: Using school staff to establish a preventive network of care to improve elementary school students’ control of asthma. J. Sch. Health. 2006; 76(6): 307–312. PubMed Abstract | Publisher Full Text\n\nFlorence C, Shepherd J, Brennan I, et al.: Effectiveness of anonymised information sharing and use inhealth service, police, and local government partnership forpreventing violence related injury: experimental study andtime series analysis. BMJ. 2011; 342: d3313. PubMed Abstract | Publisher Full Text\n\nDr. Thongjit S (Khon Kaen University): Developing assessment criteria for operation control of local security health fund in the upper central area, Thailand. DANS; 2021. Publisher Full Text"
}
|
[
{
"id": "115674",
"date": "05 Jan 2022",
"name": "Bhunyabhadh Chaimay",
"expertise": [
"Reviewer Expertise Public Health",
"Epidemiology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe comments are as follows;\nThe research title mentioned the specific areas in the upper central area, Thailand, but the introduction part does not mention that related to this area. In addition, the gap of knowledge of developing assessment criteria is not clear why to perform this.\n\nThe authors mentioned that this study is a cross-sectional analytic study. In my opinion, this is a survey study or descriptive study, and there is no comparison group as an analytic study. This should be reviewed correctly.\n\nThe sampling method should be clarified. The sampling method as mentioned in this study seems to be the purposive sampling method. It is due to having no details of the multi-stage sampling and sampling frame.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "140998",
"date": "05 Jul 2022",
"name": "Tintin Sukartini",
"expertise": [
"Reviewer Expertise Medical surgical nursing",
"tropical 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\nThank you to the authors for the excellent work in this article.\nThe authors have clearly stated the purpose of the study along with the novelty. The Assessment Criteria for Operation Control of Local Security Health Fund (ACOLF) was made to improve the old assessment criteria.\n\nIn the abstract, it would be better if the authors also mention the significant value of the statistical test.\n\nCurrent literature is a crucial aspect, it provides general and specific information about the problem, and also supports the authors' idea in delivering solutions. In this manuscript, from 23 references only a few articles are from the last five years. This could be because the authors want to give insight into the previous policy of operation control, so the authors used references from the last ten years, but it would be much better if the authors enrich the supporting idea with the newest sources.\n\nThe authors have clearly explained the method used. Explain it step by step beginning with the latent variables which become the focus of novelty.\n\nIn the sample size, they also explained how many participants participated in the study, consisting of different backgrounds, such as local politicians, government offices, and public technical officers. It would be much clearer for the readers the reason behind this selection. The authors may use inclusion and exclusion criteria to explain this part.\n\nThe authors already provide ethical permission which is a good point.\n\nThe assessment criteria that the authors try to develop may bring a good insight into the academic field, not only fixing the previous criteria, but the authors also improve new assessment with literature and experience item.\n\nThis study was a cross-sectional analytical study. The ACOLF was tested by four experts to check the validity of the instrument. It is recommended for the authors to also explain the responsibility of each expert and also what is the expert criteria for this study.\n\nThe authors have mentioned the content validity was between 0.76-1.0. It is a good point for the readers, if, in the future, the same study will be conducted, then this article could be one of the reliable references.\n\nThe bias in the questionnaire in data collection was eliminated by designing questionnaires to be easy to answer. The authors may add some explanation about this. Whether the method to collect the data using the online method, giving form directly to the participant, or something else? Also, if the participant was unable to answer the questionnaire, what did the authors do to handle it?\n\nThe authors have explained all the latent variables in the discussion and provided previous research to support the findings. It could be much improved by adding some of the authors' opinions in each latent variable explanation. Starting with the gap that is found in Thailand or comparing it with the 'status quo' or current situation.\n\nIn the conclusion, the authors have summarized each item from ACOLF. In the last sentence, the authors can add recommendations not only for the local security health fund in Thailand but also for other countries that may have similar problems.\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/10-1207
|
https://f1000research.com/articles/10-1206/v1
|
26 Nov 21
|
{
"type": "Research Article",
"title": "The job applicant reactions towards Patterned Behavior Description Interview (PBDI) and Mixed Situational and Patterned Behavior Description Interview (Mixed SPBDI)",
"authors": [
"Masyitah Mahadi"
],
"abstract": "Background: When applying for a job, applicant reactions are defined as the amount to which the applicants of the job regard the process of selection as impartial or unbiased. The questions for the structured interview can be future-oriented (Situational Interview) or past-oriented (Patterned Behaviour Description Interview). Past research on using SI or PBDI in selection process and their effects on applicant reactions showed that applicant reactions are highest towards PBDI. Methods: The aim of this study was to investigate the effect of combining PBDI and SI (mixed SPBDI) as interview questions, and to differentiate its effect with PBDI. This study involved 46 lecturers from the International Islamic University Malaysia (IIUM). This study used (a) mixed SPBDI, and PBDI as interview questions, and (b) Applicant Reaction Questionnaires which was based on the Organizational Justice theory. The interview was conducted in a transcript form. After the participants answered the interview transcripts, they answered the applicant reactions questionnaires. The data was then analysed and presented. Results: The results showed a significant difference between mixed SPBDI and PBDI, with the PBDI’s mean (M = 13.61; SD = 1.57) is significantly higher than the mixed SPBDI’s mean (M = 10.89; SD 1.91), t (46) = 7.22; p < 0.01. Specifically, applicants reacted more positively to PBDI interview content compared to the mixed SPBDI. Conclusion: This research had few limitations such as the interview being conducted in the form of transcript and not verbally as in real workplace context. It is also limited to studying the reactions in terms of only perceived fairness and no other elements such as organizational effectiveness or the decision making of the applicants. Nevertheless, this study has contributed to the theoretical and research development in applicant reactions, and to the practical application for organizations in Malaysia.",
"keywords": [
"Applicant reactions",
"Past Behavior Description Interview (PBDI)",
"Mixed SI PBDI (Mixed SPBDI)",
"selection process",
"structured interview content."
],
"content": "Introduction\n\nThe question that the organizations as well as researchers need to ask in general should not only be ‘have we selected the best applicant that can perform well in the job?’ but also ‘have we left a good impression for the best applicant to be interested to accept our job offer and is able to perform well?’.\n\nIn using interview for personnel recruitment and selection, it is important to choose the appropriate interview questions so that skillful people would want to work for that specific organization (Bauer, Truxillo & Paranto, 2004; Rynes, Barber & Varma, 2000). Hence, to some extent, interviews function not only as applicant screening and selection, but they also serve to attract applicants to the organization. If the interview causes a negative reaction such as perceived unfairness or lack of job-relatedness in the applicant, they might withdraw from the selection process, reject the employment offer, or take legal action (Rynes, Bretz & Gerhart, 1991). Hence, the usefulness of the interview process is reduced which then lead to a significant forfeit to organizations (Murphy, 1986).\n\nTwo common types of structured interview content are Situational Interview (SI) introduced by Latham (1989), which is future-oriented, and Patterned Behaviour Description Interview (PBDI) introduced by Janz (1982) which is past-oriented. Goal-setting theory (Locke & Latham, 1990) was used to develop SI (“What will you do if …”) with the assumption that goals or intentions are the instant predictor of the behavior of a person. On the other hand, PBDI (“What did you do when …”) is based on the empirical truism in which “past behaviour predicts future behaviour” (Janz, 1982). The conceptual framework of the present study is adapted from Rynes et al. (2000) as shown in Figure 1.\n\n\nLiterature review\n\nLatham and Finnegan (1993), Conway and Peneno (1999), Alias (2007), Abdullah (2009) and Mahadi, Alias and Ismail (2015) were among the first to study the applicants’ reactions to a structured interview content. These studies have shown mixed findings on SI and PBDI. There is a likelihood that the different findings were due to the different characteristics of the sample in each study (employees or students), different medium of interview (interview transcript, face-to-face or interview description), and distinguished applicant reaction’s construct studied (perceived predictive validity, practicality, perceived face validity, inclination to advocate the employer to other potential applicants, perceived procedural justice, affective reactions, and perceived content validity).\n\nThe first study about the effect of interview content on applicant reactions was done by Latham and Finnegan (1993). This study used students and employees as samples, interview descriptions as the interview medium, and practicality [in achieving applicants’ objectives] as applicant reaction. This study showed that PBDI led to more positive applicant reactions than SI among students, however no significant difference between these two variables among employees were found.\n\nThe second study was conducted by Conway and Peneno (1999) who used undergraduate students as study samples, face-to-face interview medium, and applicant reactions involving: (a) perception of predictive validity, (b) perception of face validity, (c) affective reactions, (d) procedural justice, and (e) inclination to advocate the employer to other potential applicants. The results showed applicants perceived SI as having greater perceived face validity as opposed to PBDI. However, SI and PBDI showed no significant difference with regards to perceived predictive validity, procedural justice, affective reactions, or inclination to advocate the employer to other potential applicants.\n\nThe third study was conducted by Alias (2007). This study used students as samples, two interview medium which were face-to-face and interview transcript, and applicant reactions based on perceived procedural justice. The findings showed that when utilizing face-to face interview, applicants gave more positive applicant reactions to SI than PBDI. Nonetheless, when utilizing interview transcript, applicants gave more positive reactions to PBDI than SI.\n\nMeanwhile, in the fourth study which was done by Abdullah (2009), SI and PBDI showed no significant difference in their effect on applicant reactions in terms of perceived procedural justice. This study used students as samples and interview transcript as interview medium.\n\nFinally, Mahadi, Alias and Ismail (2015) in their study on applicant reactions to SI and PBDI used employees as samples, interview transcript as medium, and perceived procedural justice as applicant reactions found that, employees reacted more positively to PBDI than SI.\n\nTaken together, though the past research showed mixed findings, applicant reactions were highest towards PBDI in general. This has led to the need to further examine the effect of different structured interview content. The objective of the current study is to examine the effect of a new variable which is the combination of SI and PBDI (mixed SPBDI) in comparison to PBDI on applicant reactions as measured by perceived procedural justice. It is hoped that this study will provide more evidence and support for the research development of applicant reactions towards interview content as it is still new. In this study, applicant reactions are operationally defined as the global scores of applicants received in the adapted Process Fairness Scale by Truxillo and Bauer’s (Bauer et al., 2004) which is based on the Organizational Justice theory. On the other hand, the interview content is operationally defined as the presentation of mixed SPBDI and PBDI using interview transcript. The hypothesis of the current study is non-directional as the mixed SPBDI and PBDI will lead to different effects on applicant reactions.\n\nThe researcher believes this study might provide valuable information to the development and implementation of structured interview in personnel selection. Based on the findings, it is hoped that an interview method that has a high validity and at the same time can lead to a positive applicant reaction can be proposed to other researchers as well as practitioners.\n\n\nMethods\n\nThis study involved 46 employees from the foundation center of International Islamic University Malaysia. It used materials comprised of (a) Interview Questions Mixed SPBDI and PBDI, and (b) Applicant Reactions Questionnaires based on perceived procedural justice as explained by Organizational Justice theory.\n\nThe study utilized job analysis for the job role of IIUM assistant lecturer in order to develop the interview questions. This usage of job analysis for interview questions was supported by Latham (1989). There are six job descriptions for the assistant lecturer: (i) teaching, (ii) assessing coursework and exam, (iii) invigilating exam, (iv) managing classroom, (v) preparing, and (vi) doing administrative matters. Through discussion with the subject matter experts (SMEs), tasks under teaching job descriptions were selected to be appraised through the job interview since it is the primary task, and it can be examined before the applicants have started their jobs. Meanwhile, the rest of the tasks can be evaluated by other types of assessment once applicants have started their jobs. The PBDI consisted of six questions which were past-oriented, while for the development of mixed SPBDI, the researcher selected three questions from SI which were future-oriented and three questions from PBDI, in total six questions. It was ensured that the mixed SPBDI questions did not ask the same criteria twice.\n\nSince the present study did not examine interview validity, there was no need to prepare the scoring guide for the interview. The focus of this study was on the answers given to the questionnaire about applicant reactions which was given after each interview session.\n\nThe applicant reaction was measured in terms of perceived procedural justice which indicated the extent applicants perceive the interview questions as being fair. As emphasized by Folger and Greenberg (1985), perceived procedural justice is part of applicant reactions that affects organizational decisions. The present study has adapted Truxillo and Bauer’s Process Fairness Scale (Bauer et al., 2004) for measuring the perceived procedural justice. This scale conveyed the highest reliability which was 0.96 and produced a global score for perceived procedural justice. This is considered as the suitable applicant reaction measurement as argued by Chan and Schmitt (2004) in which applicant reactions can be better predicted through a global score.\n\nThe questionnaire of applicant reactions involved three questions: (i) Overall, I believe that the interview process is fair, (ii) I feel good about the way the interview process works, and (iii) the interview process is fair to job applicants (Underlying data) (Mahadi, M.M., 2021). This questionnaire was based on a 5-point Likert Scale whose answer ranged from 1 (strongly disagree) to 5 (strongly agree). A positive applicant reaction was suggested when the mean score was higher and vice versa applied when the mean score was lower.\n\nThe study used within-subject (repeated-measure) design. The manipulation of the structured interview content as the independent variable was done at two levels: (1) SI, and (2) Mixed SPBDI. Using within-subject design, the possible extraneous variable was the practice effect. In order to control this practice effect, a counterbalancing technique was used in which the experimenter randomly assigned the participants to the possible orders of 1,2, and 2,1 experimental conditions.\n\nThis experiment was conducted in the same room. Prior to the experiment, participants were asked to fill in the informed consent form and explained the objective of the study as to differentiate the two types of content for the structured interview. They were not told about the real hypothesis of the study. Participants were given the interview transcript. After they read and answered the questions in each transcript of mixed SPBDI and PBDI, participants were instructed to response to the applicant reactions questionnaire. Lastly, they were debriefed in detail about the purpose of the experiment. The result was analyzed using t-test to test the significant difference between PBDI and mixed SPBDI.\n\n\nResults\n\nTable 1 represented the descriptive statistics for applicant reactions to PBDI and mixed SPBDI.\n\n** p < .01.\n\nThere was a significant difference between PBDI and mixed SPBDI, with PBDI’s mean (M = 13.61; SD = 1.57) significantly higher than mixed SPBDI’s mean (M = 10.89; SD 1.91), t (46) = 7.22; p < 0.01. Since perceived procedural justice is defined as the perception of fairness to the methods utilized (in this case the interview contents), which later affects decisions towards organizations (Folger and Greenberg, 1985), this finding shows that job applicants perceived PBDI as having a fairer method than mixed SPBDI.\n\n\nDiscussion\n\nBy using interview transcript as interview medium, employees as sample, and perceived procedural justice as applicant reactions, the result of the current study proved that job applicants reacted more favorably to PBDI than mixed SPBDI. This infers that the hypothesis of the present study is accepted, in which, the mixed SPBDI and PBDI will lead to different effects on applicant reactions. It is also worthwhile to highlight that the results also indicated that participants highly rated both PBDI and mixed SPBDI, where the means were 13.61 and 10.89, respectively. Both scores for PBDI and mixed SPBDI are above the average ratings (based on 7.5 as the average ratings in which the total maximum rating was 15 for the three questions in the scale). This indicates that both contents led to more than average positive applicant reactions.\n\nAlthough the previous research showed mixed- findings (Latham and Finnegan (1993), Conway and Peneno (1999), Alias (2007), Abdullah (2009), and Mahadi, Alias and Ismail (2015)) which may suggest that perhaps combining SI and PBDI in one interview session may be a good idea, the present study’s attempt to combine both SI and PBDI in one interview session did not lead to a more positive applicant reaction. The perceived procedural justice or perceived fairness to mixed SPBDI in the present study is lower than having only PBDI in one interview session. This means that in the case experienced workers are applying for a job, organizations can utilize PBDI instead of mixed SPBDI. The findings of the present study can lead to few assumptions. First, employees are more interested to be evaluated through their past experience instead of their future behavioral intention (Alias, 2007; Latham & Finnegan, 1993). Perhaps, they feel more confident answering about their work experience that can be evidence about their skills. Second, it also can be assumed here that when dealing with mixed SPBDI questions, perhaps applicants don’t feel comfortable with being asked about both their past and their future at the same time. Perhaps, mixed SPBDI indicated that the interviewer is not confident about applicants’ experience thus needs to ask about their future or vice versa.\n\nIn terms of the medium of the interview, the present study’s findings supported the suggestion made by Alias (2007), where if interview transcripts are to be utilized by the organizations (due to cost cutting or time saving), they should use PBDI instead of SI. Based on this study’s results, having mixed SI and PBDI questions in one interview session seems not necessary, and if organizations need to choose between PBDI and mixed SPBDI, they should choose PBDI. Hence, some assumptions can be made in terms of interview medium. First, perhaps through writing on paper, sharing of experience is more comfortable to applicants, which can lead to positive reactions. If the interview is done face-to-face, the findings of the present case study may be different. Second, participants feel better when asked to write their experience compared to when asked to write both their past experience and their future intention. In mixed SPBDI, participants may be confused on what to write to the mixture demand of the questions.\n\n\nConclusions\n\nIn summary, the current finding provides a better comprehension towards the contradicting findings in earlier empirical research between PBDI and SI. The mixed SPBDI is considered a new variable that has not been studied before. Based on this finding, using employees as sample, and interview transcript as medium, applicants still considered PBDI as having a more perceived fairness.\n\nIt is suggested that more studies are to be conducted by future research which can involve this new variable of mixed SPBDI in a different sample such as real job applicants, in other interview medium e.g. face-to-face, telephone or videoconferencing interview, in different construct of applicant reactions for instance as explained by Job Signal Theory in terms of perceived organizational attractiveness (Rynes, 1991), decision in accepting job offers or in self- withdrawing from the selection process (Ryan and Ployhart, 2000), and in qualitative researches to gather new data about the applicant reactions.\n\nIt is also worth noting that ratings towards interviews might be prone to cultural sensitivity. It is shown that in Malaysian context and among university academicians, applicants prefer PBDI than mixed SPBDI. This is not supported by some of the earlier studies done among job incumbents in United States (e.g Latham and Finnegan, 1993) but somehow it is similar to a Malaysian study conducted among students (e.g. Alias, 2007). Hence, more research is needed to study whether the result is influenced by geographical and job status background.\n\n\nData availability\n\nEASY (Data archiving and networked services): The Job Applicant Reactions Towards Patterned Behavior Description Interview (PBDI) and Mixed Situational Interview and Patterned Behavior Description Interview (Mixed SPBDI).\n\nhttps://doi.org/10.17026/dans-2xu-gbgt (Mahadi, M.M., 2021).\n\nThis project contains the following underlying data:\n\n• Data file 1. SPSS Data\n\n• Data file 2. Informed Consent Form\n\n• Data File 3. Transcripts and Questionnaires for PBDI and Mixed SPBDI\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CCO 1.0 Public Domain Dedication).\n\n\nConsent\n\nWritten informed consent for publication of the participants details and/or their responses was obtained from the participants.\n\n\nAuthor contributions\n\nMahadi, M. is the main author of this paper, hence the author contributes to the whole article.\n\n\nEthical approval number\n\nApproval Number: EA1192021 Multimedia University Malaysia.",
"appendix": "References\n\nAbdullah S: The effects of different types of interview content (PBDI and SI) on applicants’ reactions. Unpublished dissertation. International Islamic University Malaysia.2009.\n\nAlias A: Pengaruh focus temuduga dan kandungan temuduga berstruktur ke atas reaksi pemohon. Unpublished dissertation. University Kebangsaan Malaysia (UKM), Malaysia.2007.\n\nBauer TN, Truxillo DM, Paronto ME: The measurement of applicant reactions to selection. Thomas JC, editor. Comprehensive handbook of psychological assessment. New Jersey: John Wiley & Sons, Inc.; 2004; 482–506.\n\nChan D, Schmitt N: An agenda for future research on applicant reactions to selection procedures: A construct oriented approach. Int. J. Sel. Assess. 2004; 12: 9–23. Publisher Full Text\n\nConway JM, Peneno GM: Comparing structured interview question types: Construct validity and applicant reactions. J. Bus. Psychol. 1999; 13: 485–506. Publisher Full Text\n\nFolger R, Greenberg J: Procedural justice: An interpretive analysis of personnel systems. Res. Pers. Hum. Resour. Manag. 1985; 3: 141–183.\n\nJanz T: Initial comparisons of patterned behavior description interviews versus unsructured interviews. J. Appl. Psychol. 1982; 67: 577–580. Publisher Full Text\n\nLatham GP: The reliability, validity, and practicality of the situational interview. Eder RW, Ferris GR, editors. The employment interview: Theory, research, and practice. Newbury Park, CA: Sage Publications, Inc.; 1989; (pp. 169–182).\n\nLatham GP, Finnegan BJ: Perceived practicality of unstructured, patterned, and situational interviews. Schuler H, Farr JL, Smith M, editors. Personnel selection and assessment: Individual and organizational perspectives. Hillsdale, NJ: Lawrence Erlbaum Associates; 1993; (pp. 41–56).\n\nLocke EA, Latham GP: A theory of goal-setting and task performance. London: Prentice Hall; 1990.\n\nMahadi, M. M (Multimedia University Malaysia): The Job Applicant Reactions Towards Patterned Behaviour Description Interview (PBDI) and Mixed Situational Interview (Mixed SI) and Patterned Behaviour Description Interview (Mixed SPBDI). DANS. 2021. Publisher Full Text\n\nMahadi M, Alias A, Ismail IS: The Effects of Situational Interview (SI) and Patterned Behavior Description Interview (PBDI) on Applicant Reactions. Aust. J. Basic Appl. Sci. 2015; 9(28): 219–224.\n\nMurphy KR: When your top choice turns you down: Effect of rejected offer to utility of selection tests. Psychol. Bull. 1986; 99: 13–18.\n\nRyan AM, Ployhart RE: Applicants’ perceptions of selection procedures and decisions: A critical review and agenda for the future. J. Manag. 2000; 26(3): 565–606. Publisher Full Text\n\nRynes SL: Recruitment, job-choice, and post-hire consequences. Dunnette MD, Hough LM, editors. Handbook of industrial and organizational psychology. 2nd ed.Palo Alto, CA: Consulting Psychologists Press; 1991; Vol. 2. : pp. 399–444.\n\nRynes SL, Barber AE, Varma GH: Research on the employment interview: Usefulness for practice and recommendations for future research. Cooper CL, Locke EA, editors. Industrial and organizational psychology: Linking theory with practice. Oxford, United Kingdom: Blackwell Publishers Ltd.; 2000; 250–277.\n\nRynes SL, Bretz RD Jr, Gerhart B: The importance of recruitment in job choice: A new way of looking. Pers. Psychol. 1991; 44: 487–521."
}
|
[
{
"id": "101913",
"date": "21 Dec 2021",
"name": "Fahd Mohammed Obad Al-Shaghdari",
"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\nAbstract\nToo much detail in the Abstract and unnecessary information was included, such as the background section.\n\nThe Author may need to remove the background section from the abstract and put the research objective and the problem statement instead.\n\nGenerally, in writing the Abstract, the Author should briefly highlight the objective of the study, problem statement, methodology, findings and Implications.\n\nIntroduction Part\nIts recommended to start with one or two paragraphs writing about the background of the topic.\n\nThe Author may need to add the significance of this study in the last part of the introduction section.\nLiterature Review section\nIn the Research Conceptual Framework, the Author has mentioned the Organizational Justice theory, however, the Author didn’t explain how this theory related to the variables included in this study.\n\nI recommend moving the following quoted yo the the last paragraph in the introduction part: \"The researcher believes this study might provide valuable information to the development and implementation of structured interview in personnel selection. Based on the findings, it is hoped that an interview method that has a high validity and at the same time can lead to a positive applicant reaction can be proposed to other researchers as well as practitioners.\"\nMethods:\nThe Author may have to provide some details about the unit of analysis selected such as (their educational background, and their current roles in the organization). Also should explain how these selected lecturers are fit to be selected as the sample size in this study.\n\nAlso, the Author need to explain the type of sampling they have applied in this study and justify the choice.\n\nThe Author needs to justify the choice of 46 employees only as the unit of analysis in this study? Is that enough?\n\nAs there are three main types of t-test, the Author may need to explain which type of t-test they have performed and justify their choice.\n\nThe Author is also recommended to develop the null hypothesis and the alternative hypothesis based on the provided conceptual framework\nDiscussion Part\n\nVery Good.\nReferences\nIn general, the list of reference need some improvements, due to that it’s recommended if the author can cite few more articles from the last 5 years onward.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "241400",
"date": "27 May 2024",
"name": "Fadzilah Salim",
"expertise": [
"Reviewer Expertise Education",
"Mathematics Education",
"Mathematical Modeling"
],
"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\nABSTRACT If the written abstract is following the guidelines of the journal article, then it should be okay. Otherwise, usually the abstract will be a summary of the whole article which is written in one paragraph and does not exceed 200 words.\nINTRODUCTION SECTION - Author did not state the problem statement and the purpose of the study. - It is also good if the last paragraph briefly outline the sections that this article will be covering so that it will help the reader to have a sense of coherence and organization of the article.\nLITERATURE REVIEW SECTION - There is no recent research studies (the last 5 years) was cited. - The last two paragraphs in this section is about the current study by the author, not about the previous related research. Thus, those two paragraphs should be re-looked again or taken out as certain statements can be put in the Introduction section and the Conclusion section. - Need more information on Organizational Justice Theory since I believed the design of questionnaires in the Methodology Section is based on this theory.\nMETHODOLOGY SECTION - Need more clarification on the sample chosen in the study. Why only 46 samples? Is it a random or non-random sampling?\n\n- Is this 46 samples enough to represent the whole population? Or this study is only to represent IIUM organization only? - It is also good to mention why t-test is used to analyze so that the readers with no statistics background can also understand.\nREFERENCES - Lack of the recent research studies.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1206
|
https://f1000research.com/articles/10-1097/v1
|
29 Oct 21
|
{
"type": "Case Report",
"title": "Case Report: Portal cavernoma secondary to multiple liver hydatidosis: A rare cause of cataclysmic haemorrhage in a young adult",
"authors": [
"Alia Zouaghi",
"Nawel Bellil",
"Khalaf Ben Abdallah",
"Dhafer Hadded",
"Haithem Zaafouri",
"Mona Cherif",
"Anis Ben Maamer",
"Alia Zouaghi",
"Nawel Bellil",
"Dhafer Hadded",
"Haithem Zaafouri",
"Mona Cherif",
"Anis Ben Maamer"
],
"abstract": "Clinical presentation of liver hydatidosis can vary from asymptomatic forms to lethal complications. We report a rare case of a 27-year-old male from a rural Tunisian region who presented with large-abundance haematemesis, haemodynamic instability, and marked biological signs of hypersplenism. Endoscopy showed bleeding esophageal varicose veins that were ligated. Abdominal ultrasound concluded the presence of three type CE2 hydatic liver cysts causing portal cavernoma with signs of portal hypertension. Despite resuscitation, the patient died of massive rebleeding leading to haemorrhagic shock. Hepatic hydatid cyst should be considered as an indirect cause of gastrointestinal bleeding in endemic countries. Early abdominal ultrasound in varicose haemorrhage is essential in orienting the diagnosis.",
"keywords": [
"Case report",
"portal cavernoma",
"variceal bleeding",
"hydatidosis"
],
"content": "Introduction\n\nEchinococcosis liver hydatidosis is endemic in the Maghreb countries. Vascular complications are exceedingly rare,1 however, its manifestations can be critical. The clinical presentation depends on the cyst’s segment localization. Compression or invasion of the hydatic cyst in the portal vein can lead to portal vein thrombosis or extrahepatic portal vein obstruction (EPVHO).2 This can rarely lead to cavernous transformation and portal hypertension explaining the origin of symptoms. Prognosis is generally good. Cataclysmic presentations have not been described in the literature.\n\n\nCase presentation\n\nA 27-year-old male patient, from a rural area of Tunisia, without any medical history, presented to the Habib Thameur Hospital emergency room with massive upper gastrointestinal bleeding. On admission (day one) in August 2020, physical examination revealed diffuse mucocutaneous pallor, lesions of old scarifications in the left upper limb, a Glasgow Coma Score (GCS) of 15/15, tachycardia of 105 bpm, hypotension of 80/50 mmHg without signs of peripheral hypoperfusion. Abdominal examination revealed slight epigastric tenderness and splenomegaly without hepatomegaly or skin signs of hepatocellular failure. The rectal digital examination came back stained with melena.\n\nLaboratory investigation showed signs of hypersplenism including decreased count of white blood count of 2870 cells/mm3, thrombocytopenia of 46,000 cells/mm3, and normochromic normocytic anemia of 5.6 g/dL. Minor signs of hepatocellular insufficiency were also displayed including a low rate of prothrombin ratio of 60% and hypocholesterolemia of 2.87 mmol/L. He had neither cholestasis nor cytolysis. Albuminemia was normal at the value of 36 g/L. Acute kidney failure was noted (urea of 11.6 mmol/L) with a normal blood ionogram. Viral hepatitis screening was negative.\n\nOn day two, the patient was stabilized following fluid resuscitation and blood transfusion of two red blood cell concentrates. He was put on a proton-pump inhibitor (omeprazole) and octreotide. Upper gastroduodenoscopy showed the presence of oesophageal varices with massive active bleeding, moderate hypertensive gastropathy and gastric varicose veins (Figure 1). Four elastics with a first kit of ligature were put in place but did not allow the control of bleeding. Five supplementary elastics in a second ligature kit allowed a reduction in bleeding but without total control of the haemorrhage.\n\nAn abdominal ultrasound concluded the presence of multiple multiloculated cystic formations evoking hydatic cysts type CE2 of the WHO classification of segments I, IV, and V with the largest cyst measuring 40 mm (Figures 2a and 2b). A portal cavernoma with a dilated splenic vein and splenomegaly of 22 cm was described. Hepatic veins were permeable with a normal caliber.\n\nAfter a week, the patient had a cataclysmic re-bleeding causing refractory hemorrhagic shock and disseminated intravenous coagulation leading to death.\n\n\nDiscussion\n\nHepatic hydatid cyst can invade or compress the portal vein and results in EPVHO. Portal cavernoma is the outcome of chronic portal vein obstruction. It results in the creation of collateral circulation.4\n\nAs soon as portal hypertension is established, blood can run hepatopetal or hepatofugal from the liver through portosystemic collaterals. This leads to the development of gastroesophageal or ectopic rectal variceal bleeding which represents the most typical symptomatic presentation as in our case.5 According to a prospective study by Noronha et al., (2016), 71% of patients with chronic EPVHO showed gastroesophageal varices in endoscopy.5\n\nEPVHO is an uncommon entity in adults. Indeed, the incidence of having EPVHO for the general population does not exceed 1% with a very low mortality rate.6 Hepatic hydatid cyst can results in EPVHO whether by compressing or directly invading the portal vein1,7 Computerized tomography (CT) can help indicate the mechanism of thrombosis. Venous compressions are among the rarest complications of hydatid liver cysts even in endemic countries as shown in Table 1. Size and perivascular topography are two essential elements for its occurrence (tunisiechirurgicale.com).\n\nFrom a pathophysiological point of view, EPVHO is the consequence of the ‘Virchow’s Triad’: the extrinsic chronic compression of the vascular wall by the hydatic cysts decreases the blood flow rate thus creating endothelial injuries. This can lead to the formation of a bland thrombus.\n\nTo our knowledge, few cases of hepatic hydatidosis revealed by portal hypertension have been reported in the medical literature since the publication of the first case in 1990.8–10 In a large Spanish cohort of 506 patients followed over 20 years, only two patients presented portal hypertension and variceal haemorrhage.11 This demonstrates how seldomly described is this complication in the literature.\n\nOur case offers an unusual presentation. The portal vein thrombosis and the cavernous transformation remained undiagnosed until hematemesis due to varices rupture. Our young patient had no history of inflammatory bowel diseases, pancreatitis, cirrhosis, neoplastic condition or coagulopathy to explain the cavernoma. The only convincing cause was the compression of the hydatid cysts respectively in segments I, IV, and V of the portal vein leading to chronic thrombosis. The minor biological signs of hepatocellular insufficiency were probably secondary to the chronic evolution of the cavernoma, but the ultrasound did not show any signs of chronic hepatopathy. Ultrasound was an indispensable tool to orienting diagnosis as proved in the literature.12 In this particular case, our patient's prognosis was poor, unlike previous ones.\n\nWe summarize in Table 2 different cases of hepatic hydatid cyst causing portal cavernoma. The mean age was 58.2 years old. No signs of gastrointestinal bleeding were reported before diagnosis. Portal thromboses were mainly secondary to direct compression or invasion of the portal vein. The outcome was generally positive in all cases unlike ours. Treatment was generally based on surgery and the drug albendazole.\n\nOur case illustrates the importance of considering non-cirrhotic portal hypertension secondary to liver hydatidosis especially in young patients in endemic countries. Urgent therapy and diagnostic investigations should be pursued simultaneously to ensure on-time intervention. Our case lacks abdominal computed tomography or magnetic resonance imaging which could have given a more accurate demonstration of the thrombosis mechanism. Our patient could have been a candidate for transjugular intrahepatic portosystemic shunt.\n\n\nConclusion\n\nLiver hydatidosis remains a public health issue in Tunisia because of its high morbidity and, exceptionally, possible mortality. Our case highlights an unusual presentation due to the young age, symptomatic portal cavernoma, and unfortunate death of the patient. It shows the importance of considering hepatic hydatid cyst as a cause of portal hypertension and portal cavernoma on presentation of gastrointestinal bleeding. Early abdominal ultrasound has a valuable contribution to orienting diagnosis, especially in endemic countries.\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’s family.",
"appendix": "References\n\nGrosso G, Gruttadauria S, Biondi A, et al.: Worldwide epidemiology of liver hydatidosis including the Mediterranean area. World J. Gastroenterol. 2012; 18: 1425–37. Baishideng Publishing Group Inc. Publisher Full Text\n\nMacpherson CNL, Vuitton DA, Gharbi HA, et al.:International classification of ultrasound images in cystic echinococcosis for application in clinical and field epidemiological settings. Acta Tropica. Elsevier;2003; p. 253–61\n\nHerek D, Sungurtekin U: Magnetic Resonance Imaging of a Liver Hydatid Cyst Invading the Portal Vein and Causing Portal Cavernomatosis. Ochsner J. 2015; 15(4): 479–80. Free Full Text PubMed Abstract |\n\nIntagliata NM, Caldwell SH, Tripodi A: Diagnosis, Development, and Treatment of Portal Vein Thrombosis in Patients With and Without Cirrhosis. Gastroenterology. W.B. Saunders;2019; Vol. 156. : p. 1582–1599.\n\nNoronha Ferreira C, Seijo S, Plessier A, et al.: Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis. Hepatology. 2016 May 1 [cited 2021 Jan 17]; 63(5): 1640–50. PubMed Abstract | Publisher Full Text\n\nAgeno W, Dentali F, Pomero F, et al.: Incidence rates and case fatality rates of portal vein thrombosis and Budd-Chiari syndrome. Thromb. Haemost. 2017 Apr 3 [cited 2021 Jan 17]; 117(4): 794–800. PubMed Abstract | Publisher Full Text\n\nGreco S, Cannella R, Giambelluca D, et al.: Complications of hepatic echinococcosis: multimodality imaging approach. Insights Imaging. Springer;2019; Vol. 10. : p. 1–12\n\nSalah JM, Habib BHKM, Radhouane T, et al.: Sténose digestive haute due à un kyste hydatique du foie. La tunisie medicale. 2015; 93(3): 129–130.\n\nEddeghai S, Eddoukani I, Diffaa A, et al.: Kyste hydatique du foie: À propos d’un mode de révélation exceptionnel. Pan Afr. Med. J. 2014 [cited 2021 Jan 17]; 18: 1937–8688. Publisher Full Text\n\nHafi Z: Les complications vasculaires du kyste hydatique du foie à propos de 10 cas. Thèse, faculté de médecine de Tunis.1996.\n\nPapadimitriou J, Kannas D, Papadimitriou L: Portal hypertension due to hydatid disease of the liver. J. R. Soc. Med. 1990; 83: 120–121. Publisher Full Text\n\nBotezatu C, Mastalier B, Patrascu T: Hepatic hydatid cyst - diagnose and treatment algorithm. J Med Life. 2018 Jul 1 [cited 2021 Jan 17]; 11(3): 203–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nErtan G, Ulus S, Kilicarslan R, et al.: Hydatid disease of the liver with portal vein invasion mimicking portal vein thrombosis. Arab J Gastroenterol. 2019; 20(1): 50–2. PubMed Abstract | Publisher Full Text\n\nKirmizi S, Kayaalp C, Yilmaz S: Hydatid liver cyst causing portal vein thrombosis and cavernous transformation: A case report and literature review. Gastroenterol Hepatol from Bed to Bench. 2016 Sep 1 [cited 2021 Jan 17]; 9(4): 331–4. PubMed Abstract | Free Full Text\n\nMoisan FR, Galindo JL, Jarufe NP: An unusual cause of portal cavernomatosis IMAGES IN HEPATOLOGY CASE REPORT.2012; Vol. 11.\n\nColovic RB, Grubor NM, Colic MU, et al.: Portal cavernoma caused by a calcified hydatid cyst of the liver (case report). Eur. J. Gastroenterol. Hepatol. 2008 Mar [cited 2021 Jan 17]; 20(3): 237–9. PubMed Abstract | Publisher Full Text\n\nKayacetin E, Hidayetoglu T: Hydatid cyst of the liver causing a cavernous transformation in the portal vein and complicated by intrabiliary and intraperitoneal rupture. J. Gastroenterol. Hepatol. 2004 Oct 1 [cited 2021 Jan 17]; 19(10): 1223–4. Publisher Full Text PubMed Abstract |"
}
|
[
{
"id": "98522",
"date": "03 Nov 2021",
"name": "Souheil Zayet",
"expertise": [
"Reviewer Expertise Specialist in Infectious 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 submission is an observation of a patient with a rare presentation of portal cavernoma related to multiple liver hydatidosis.\nThis original document is well treated in its entirety and is of academic and scientific interest, although limited due to the incidence of the disease, but both necessary and useful to understand the infectious mechanisms and the care options. Personally, I find very enriching the approach of the authors and the way they described this case, associated with quality references. I believe the content is substantially acceptable. However as the article is intended for surgery/infectious diseases specialists and needed some minor revisions:\nIn the title: ‘Portal cavernoma related to multiple liver hydatidosis: A rare case of fatal cataclysmic haemorrhage’ is more appropriate.\nIn the Abstract: Correct ‘We report herein a rare case of a 27-year-old Tunisian male a rural region’. ‘Biological data’ instead signs.\nIn the Introduction: Add a reference with the Echinococcosis liver hydatidosis’ prevalence in the Maghreb countries. Please check the English of this sentence ‘Prognosis is generally good’. Please avoid jargon and relaxed language.\nIn the Observation: You can define gastrointestinal as ‘GI’ and used it in the whole text. Please precise the native region ‘rural area’ of patient to emphasize epidemiological link. Delete the name of your affiliation or institution in the text. Correct beats per minute; avoid abbreviations. Use ‘enlarged spleen’ instead splenomegaly. Define all normal ranges in laboratory investigations in the text. Replaced normal ionogram with ‘normal electrolytes’. What is ‘Viral hepatitis screening’; it means serology; if yes, precise all serology and rt-PCR included. He was put on a proton-pump inhibitor?? Please changed it (the patient was treated or a treatment was started/began). To retain the diagnosis, hydatidosis serology (or other microbiological testing) was done ? If not, precise it and discuss this point in the discussion part).\nIn the Discussion: Replace symptomatic presentation with ‘clinical feature’. Replace ‘offer’ with highlighted. Deleted CT as abbreviation, used once in the text. Please add a reference when you explain pathophysiology of EPVHO. Please check this sentence ‘The outcome was generally positive in all cases unlike ours’. Surgery technique was not detailed; (you can do it in 1-2 sentences.\nIn the conclusion: Avoid unfortunate; change it (lethal or fatal form). Add ‘in endemic low-middle income countries’.\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": "7455",
"date": "08 Dec 2021",
"name": "Khalaf Ben Abdallah",
"role": "Author Response",
"response": "Thank you for your valuable comments. Your remarks were gladly taken into consideration. Needed changes were adressed. When it comes to surgical treatment, there is no consensus on the right way to treat liver hydatidosis with portal cavernoma. Conservative approaches were reported due to the high risk of intraoperative bleeding. Surgical shunt can be an effective way to treat induced portal hypertension, but, it can only be performed in expert centers."
}
]
},
{
"id": "98517",
"date": "16 Nov 2021",
"name": "Khaoula Chabbouh",
"expertise": [
"Reviewer Expertise Gastro-enterology"
],
"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 case as it illustrates a rare complication of Echinococcosis liver hydatidosis which is still endemic in the Maghreb countries.\nHowever, some remarks should be mentioned:\nThe diagnosis was based on abdominal ultrasound findings only. Authors did not perform abdominal computed tomography or magnetic resonance imaging.\n\nGiven the young age of the patient, a thrombophilia assessment could have been requested.\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/10-1097
|
https://f1000research.com/articles/10-511/v1
|
29 Jun 21
|
{
"type": "Research Article",
"title": "Refining the content and design of an alcohol reduction app, Drink Less, to improve its usability and effectiveness: a mixed methods approach",
"authors": [
"Claire Garnett",
"Olga Perski",
"Susan Michie",
"Robert West",
"Matt Field",
"Eileen Kaner",
"Marcus R. Munafò",
"Felix Greaves",
"Matthew Hickman",
"Robyn Burton",
"Jamie Brown",
"Olga Perski",
"Susan Michie",
"Robert West",
"Matt Field",
"Eileen Kaner",
"Marcus R. Munafò",
"Felix Greaves",
"Matthew Hickman",
"Robyn Burton",
"Jamie Brown"
],
"abstract": "Background: Digital interventions have the potential to reduce alcohol consumption, although evidence on the effectiveness of apps is lacking. Drink Less is a popular, evidence-informed app with good usability, putting it in a strong position to be improved upon prior to conducting a confirmatory evaluation. This paper describes the process of refining Drink Less to improve its usability and likely effectiveness. Methods: The refinement consisted of three phases and involved qualitative and quantitative (mixed) methods: i) identifying changes to app content, based on findings from an initial evaluation of Drink Less, an updated review of digital alcohol interventions and a content analysis of user feedback; ii) designing new app modules with public input and a consultation with app developers and researchers; and iii) improving the app’s usability through user testing. Results: As a result of the updated review of digital alcohol interventions and user feedback analysis in Phase 1, three new modules: ‘Behaviour Substitution’, ‘Information about Antecedents’ and ‘Insights’, were added to the app. One existing module – ‘Identity Change’ – was removed based on the initial evaluation of Drink Less. Phases 2 and 3 resulted in changes to existing features, such as improving the navigational structure and onboarding process, and clarifying how to edit drinks and goals. Conclusions: A mixed methods approach was used to refine the content and design of Drink Less, providing insights into how to improve its usability and likely effectiveness. Drink Less is now ready for a confirmatory evaluation.",
"keywords": [
"smartphone app",
"development",
"refinement",
"alcohol",
"digital",
"behaviour change",
"Drink Less app"
],
"content": "Introduction\n\nDigital interventions have much promise in supporting health-related behaviour change; those for alcohol have been found to be effective at reducing hazardous and harmful alcohol consumption (Kaner et al., 2017; Riper et al., 2018). Digital interventions include websites, wearable devices, and smartphone apps. Apps have the advantage of being available to deliver support when and where needed, with smartphones being the most important device used to access the internet in the United Kingdom (UK) in 2020 (Ofcom; Critical Research, 2020). However, the majority of the alcohol-related apps available have been developed without reference to scientific evidence or theory (Crane et al., 2015), and evidence on the effectiveness of apps to reduce alcohol consumption is lacking. A recent Cochrane evidence review (Kaner et al., 2017) found that digital interventions may reduce alcohol consumption when compared with a control (i.e. screening, assessment, printed or onscreen health or alcohol-related information). However, only one of the 42 randomised controlled trials (RCTs) evaluated a smartphone app, and this study was conducted among university students in Sweden, not in a general population sample (Gajecki et al., 2014). Therefore, despite the availability of hundreds of alcohol-related apps in commercial app stores, none so far have been evaluated in an RCT among the general population of adult drinkers in the UK. The lack of current evidence on the effectiveness of alcohol reduction apps highlights the need for a robust evaluation strategy of an evidence- and theory-informed alcohol reduction app.\n\nDigital interventions tend to have multiple components, which pose a number of issues relating to initial evaluation with a RCT. These issues include understanding which components are driving intervention effectiveness, building in the ability to refine the intervention over time, making timely decisions about what components to retain in the intervention, and updating the intervention to keep pace with the rate of change of software. The Multiphase Optimisation Strategy (MOST) is an experimental approach for efficiently and systematically developing and optimising multi-component interventions within pre-specified constraints, such as financial (Collins et al., 2005, 2007, 2011, 2014). MOST can be simplified into a three-step process of: screening (efficient identification of intervention components for inclusion in the ‘first draft’ of the intervention); refining (fine-tuning of the selected components in the ‘first draft’); and confirming (evaluating the ‘final draft’ of the intervention in a standard RCT) (Collins et al., 2007). The initial screening and refining steps allow researchers to understand the effects of the individual intervention components and create an optimal intervention. MOST recognises that RCTs are the gold standard for assessing the effectiveness of an intervention as a package in its ‘final draft’, though highlights the importance of this being the last step after the intervention has been refined through experimentation. By following MOST, researchers are likely to avoid the (typically very slow) cycle of intervention – RCT – post hoc analyses – revision of intervention – RCT.\n\nDrink Less is a freely available, evidence- and theory-informed app that aims to help the general population of people who are hazardous or harmful drinkers to reduce their alcohol consumption (“Drink Less on iTunes store,” n.d.; Garnett et al., 2019a). Drink Less was guided by MOST (Collins et al., 2005, 2007) and the first screening step was conducted between 2014 and 2016. The screening involved a systematic and transparent development process (Garnett et al., 2019a) involving users across a range of socioeconomic groups (Crane et al., 2017), and a randomised factorial screening trial (Crane et al., 2018). The aim of the screening trial was to identify the individual components, or combinations of components, within the multi-component intervention that affect change and to screen out the ineffective ones (Collins et al., 2014). The screening trial found no clear evidence for simple main effects but did find evidence that two-way combinations of certain components resulted in greater reductions in alcohol consumption, and there was an overall decline in weekly alcohol consumption among all trial users of 3.8 standard UK units (Crane et al., 2018). Furthermore, Drink Less appears to have favourable usability amongst its users: the app was launched in May 2016 and has since been downloaded by over 62,000 unique users and has an average 4.3/5 star rating (as of January 2021) in the Apple App Store.\n\nSince Drink Less is a popular, evidence-informed app (Crane et al., 2018; Garnett et al., 2019a), a confirmatory evaluation is warranted. To ensure the evaluation was of optimal content and design, it was refined in line with the second step of MOST. This ‘refining’ step was important to fine-tune the selected components from the first version and ensure the app was in an optimal state prior to conducting a resource-intensive confirmatory evaluation. This refinement process is typically based on experimentation of the intervention (Collins et al., 2011); however, other study designs may also be used. Here, we describe the three-phase, mixed methods process of refining the Drink Less app to improve its usability and likely effectiveness across socioeconomic groups, in preparation for its evaluation in an RCT.\n\n\nMethods\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics approval was granted by the University College London’s Research Ethics Committee under the “The optimisation and implementation of interventions to change behaviours related to health and quality of life” project (CEHP/2016/556).\n\nThe refinement of the app consisted of three phases and involved a combination of qualitative and quantitative (mixed) methods: (i) identifying changes to the content of the app, (ii) design and translation of new content into app modules, and (iii) improving the usability of the app. The refinement began in January 2018 and the project ended in July 2019. The final version of the app (v2) was launched in January 2020. Figure 1 shows an overview of the process of refining the Drink Less app.\n\nThe development of the Drink Less app used the COM-B model of behaviour, which posits that behaviour results from interactions between ‘capability’, ‘opportunity’ and ‘motivation’, to provide an overarching theoretical structure (Michie et al., 2014). The original version of Drink Less consisted of six modules: (i) Goal Setting; (ii) Self-Monitoring and Feedback; (iii) Normative Feedback; (iv) Cognitive Bias Retraining; (v) Action Planning; and (vi) Identity Change (details of these modules are reported in full elsewhere (Garnett et al., 2019a)).\n\nUser input was included in every phase of the refinement process, which is important for digital interventions as they commonly have low rates of engagement and high rates of attrition (Eysenbach, 2005; Helander et al., 2014). User input helps to ensure that a digital intervention has engaging content, and good acceptability and usability. We followed the principles of user-centred design, a systematic method of app development that focuses on the relevance, needs, and preferences of the user at every stage of the development process (Mccurdie et al., 2012).\n\nPriority changes to the content of the app were identified based on findings from the randomised factorial screening trial of Drink Less (Crane et al., 2018), an update of a review of digital alcohol interventions (Kaner et al., 2017), and a content analysis of user feedback.\n\nFindings from the randomised factorial screening trial\n\nThe randomised factorial screening trial of Drink Less with 672 excessive drinkers found that certain combinations of intervention modules produced modest improvements in alcohol-related outcomes after four weeks, though no clear evidence for main effects (published in full elsewhere (Crane et al., 2018)). Bayes factors are a measure of strength of evidence and can distinguish between two interpretations of a non-significant result: i) support for the null hypothesis of ‘no effect’ and ii) data are insensitive to detect an effect (Dienes, 2014; Jeffreys, 1961). Bayes factors also allow researchers to ‘top-up’ their results from one trial with additional data collected (Rouder, 2014). In the factorial trial, Bayes factors showed the data to be insensitive so an update was conducted to analyse additional trial outcome data collected through extended recruitment (published in full elsewhere (Garnett et al., 2019b)). After the required sample size was reached (n = 672), additional data from new participants (n = 1914) were collected over five months (available in Underlying data: https://osf.io/nad4e) Bayes factors with a half-normal distribution and priors set to the point estimates from the initial 672 participants were calculated.\n\nUpdate of review of digital alcohol interventions\n\nA Cochrane evidence review on the effectiveness of digital alcohol interventions found that ‘Behaviour substitution’ (prompt substitution of drinking with a neutral behaviour) was associated with intervention effectiveness (Garnett et al., 2018b; Kaner et al., 2017) and worthy of inclusion in the next version of Drink Less. However, as the field of research on digital interventions is expanding rapidly, an update of the meta-regression on the behaviour change techniques (BCTs) associated with intervention effectiveness in the Cochrane systematic review on the personalised digital interventions for reducing excessive alcohol consumption was conducted. The same search strategy, inclusion criteria, and procedure as in the published Cochrane evidence review (Kaner et al., 2017) was used with the search strategy run on 7th March 2018 from the date of the last search (March 2017). Studies were RCTs with the outcome measure of quantity of alcohol consumption and participants were community-dwelling individuals who were identified as hazardous or harmful drinkers. The intervention had to target alcohol consumption of related problems in the drinker and be delivered through a digital device. A total of 12 new studies met the inclusion criteria, and were added to the 42 trials from the published Cochrane review, and were coded for BCTs using an established and reliable method – the BCT Taxonomy v1 with 93 distinct BCTs (Michie et al., 2013). Meta-regressions were conducted to assess the association of the BCTs with intervention effectiveness. Effect sizes were based on a random effects model where each unstandardized effect was the mean difference between the digital intervention and control (expressed in grams of alcohol consumed per week, at the longest follow-up time point). Independent associations were investigated with an adjusted meta-regression analysis where all of the BCTs that had a meaningful association (defined as a regression coefficient, B>23 (Kaner et al., 2007)) with intervention effectiveness in the unadjusted models were included. The BCTs of ‘Information about antecedents’ (B = −58.09, 95% CI = −91.29, −24.88) and ‘Credible source’ (B = −32.82, 95% CI = −58.15, −7.49) were independently associated with the effectiveness of digital interventions to reduce alcohol consumption.\n\nThe ‘Credible source’ (present communication from a credible source in favour of or against the behavior) was already present in Drink Less. Therefore, this update concluded that ‘Information about Antecedents’ (which provides information about social and environmental situations and events, emotions, and cognitions that reliably predict drinking) should be added to the refined version of Drink Less. A short report on the update is available as Extended data (https://osf.io/azpc2/)https://osf.io/mc8yz/.\n\nContent analysis of user feedback\n\nUser feedback typically contains positive and negative feedback on content, functionality, and quality of an app (Khalid et al., 2015; Vasa et al., 2012). This feedback can help to identify key areas for change to improve the app’s usability and acceptability and provide a rich source of information to support app development from a user perspective (Mudambi and Schuff, 2010).\n\nUser feedback on Drink Less from 18th May 2016 (when the app was launched) until 28th November 2018 (when the latest analysis of user feedback was conducted) was anonymised and collated (n = 480). The feedback was received via the Apple App Store user reviews (n = 116) and via email to the Drink Less support email address (n = 364). Content analysis was used to identify and report the key themes within the data (Braun and Clarke, 2006), as well as to quantify the data in terms of the frequency of different themes (Vaismoradi et al., 2013). The initial set of categories was selected according to categories used to classify users’ reviews for software maintenance and evolution (Panichella et al., 2015). These are: 1) Information seeking (sentences related to attempts to obtain information or help from other users or from developers); 2) Information giving (sentences that inform or update users or developers about an aspect related to the app); 3) Feature request (sentences expressing ideas, suggestions or needs for improving or enhancing the app or its functionalities); and 4) Problem discovery (sentences describing issues with the app). Sub-themes within these categories were then generated inductively from the data, and the user feedback was coded against these initial sub-themes in an iterative process. Each case of user feedback could be coded multiple times. The most common category was ‘Information giving’ (35.1%, with the majority providing overall positive feedback on the app), followed by ‘Feature request’ (32.0%), then ‘Problem discovery’ (14.5%), ‘Information seeking’ (14.1%) and ‘Other’ (4.4%). The most frequent requests for changes to existing features were “changes to add drinks feature”, “ability to update normative feedback data”, “calendar to start on Monday”. Common new features requested were having an android version, international availability and a running total for units. The most common sub-themes in ‘Problem discovery’ were “Clocks changing” and “Bug with drinks data when time zone changes”. In the ‘Information seeking’ category, how to navigate to the mood diary and edit existing drinks entries were the most common sub-themes. A number of the sub-themes in this category were related to clarification on how to edit entries (e.g. mood diary, ABV, cost, volume) and navigation (e.g. drinking calendar). The content analysis of user feedback identified a list of high priority changes (e.g. changes to add drinks feature; ability to update normative feedback data; calendar to start on Monday; fix bugs with drinks data when time zone changes) that should be made to the existing app modules to improve the design and functionality of the app to refine it in terms of acceptability and usability. The full report of the user feedback analysis is available in Extended data (https://osf.io/vdmsk/).\n\nPhase 2 involved public input on paper prototypes (rough drawings of the user interface). This was considered alongside the feasibility of development and through consultation with app developers, designers and digital behaviour change researchers.\n\nDesign principles\n\nAs with the original development of Drink Less (Garnett et al., 2019a), a number of design principles were followed to translate the new content of the app into modules that were coherent and appealing to use (Garnett et al., 2019a). This included: a visually appealing and professionally designed app (Garnett et al., 2015; Perski et al., 2016; Ubhi et al., 2015); easy to use, intuitive and consistent navigation (Ubhi et al., 2015); credibility of the information presented (Perski et al., 2016; Ubhi et al., 2015); and minimal text, free of scientific jargon (Ubhi et al., 2015).\n\nPaper prototypes\n\nNew app content was first proposed as a series of paper wireframe prototypes with multiple design options (available as Extended data: https://osf.io/mu7sw/) created by two members of the research team (CG and OP). The creation of paper prototypes for new modules was informed by how the new content had been implemented in other digital interventions (Garnett et al., 2018b) and health-related apps. The paper prototypes differed in their design and functionality, whilst remaining consistent with the design principles.\n\nPublic involvement through an Alcohol Discussion Group\n\nA meeting was held in November 2018 with the UK Centre for Tobacco and Alcohol Studies (UKCTAS) Alcohol Discussion Group, a public involvement group comprising approximately 20 people who consumed alcohol and lived locally to Stirling, Scotland. Two researchers (CG and OP) facilitated the meeting; neither had established a relationship with the public involvement group prior to the meeting. CG has a MSc in Research Methods in Psychology and has previously facilitated a workshop, and OP is a mixed-methods researcher and has conducted several interviews, focus groups and workshops as part of her doctoral and post-doctoral work. The meeting lasted two hours and the aim was to get input, comments and advice from this stakeholder group on various research materials, such as the content of the app and the paper prototypes for the new modules. A brief overview of the app and the research conducted to date was presented and then a group discussion was had about the new app features and how they could be designed in the app, along with general feedback on the app and upcoming research priorities. Notes were taken by CG and OP to summarise the group discussion with no direct quotes taken. Verbal permission was given by the UKCTAS Alcohol Discussion Group to take an audio recording of the session solely for the purpose of informing the summary notes (these summary notes are provided in Underlying data: https://osf.io/9ca37/).\n\nConsultation with app designers, developers and researchers\n\nApp designers, developers and researchers with expertise in digital behaviour change interventions who were known to the research team were emailed and invited to take part in an online consultation on the quality and feasibility of the paper prototypes (e.g., the relative cost of different options). The aim was to identify the most favourable option for the more complicated changes arising from Phase 1. In Round 1, a total of 13 app designers, developers and researchers completed an online survey and nine completed the survey in Round 2. The survey instruments for each survey round are provided in Extended data (Round 1: https://osf.io/w3tx8/ , Round 2: https://osf.io/4xa73/) and the results for each survey are provided in Underlying data (Round 1: https://osf.io/jxvns/, Round 2: https://osf.io/vt3ub/). Written informed consent was obtained for participation and publication of anonymised data.\n\nThe final decisions were based on the preference of the majority and discussions with the app developer to assess ease of development, including cost. This informed the final app briefs provided to the developer for the refined version of the app, ready for user testing in Phase 3.\n\nPhase 3 involved user testing of the refined version of Drink Less and further internal bug testing.\n\nUser testing of the resulting refined version from Phase 1 and 2\n\nThe aim was to refine the usability and acceptability of the updated Drink Less app to inform changes to Drink Less. A think-aloud study was conducted using a person-based approach to elicit and observe user reactions among novice users of the updated app (version 2.0), and paper prototype designs for the ‘Insights’ module (Yardley et al., 2015). A semi-structured interview was conducted after the think-aloud procedure with questions on: (i) participants’ expectations of the app, (ii) desired improvements or changes, and (iii) acceptability of the app (Sekhon et al., 2017). The briefing interview guide, ‘think aloud interview’ guide, and semi-structured interview guide are provided in a brief report of the study (see Extended data: https://osf.io/wzvt8/).\n\nParticipants were recruited from London, Bristol, Sheffield and Newcastle using ‘Call for Participants’, social media and an online classified and social community website and approached via email. Participants had to be aged 18 and over, have an Alcohol Use Disorder Identification Test (AUDIT) score of 8 or more (indicative of excessive drinking (Babor et al., 2001)), and be interested in using an app to support health-related behaviour change. Purposive sampling was used to ensure participants of low socioeconomic status (SES) were adequately represented. This is critical to ensure that digital interventions at the very least do not exacerbate health inequalities, and hopefully reduce them. Including people from low SES groups in the development of the digital smoking cessation intervention, StopAdvisor, resulted in the intervention being more effective for those from low (in comparison with those from high) SES groups (Brown et al., 2012). This highlights the importance of having input from users from low SES groups to maximise the acceptability and usability of the app across the social spectrum.\n\nThere were 18 participants that took part, which met the threshold required for a usability test to detect all of the usability problems. Half of participants (n = 9) were either: unemployed; employed in a routine or manual occupation; or had no post-16 educational qualifications. No-one refused to participate or dropped out. The mean age of the whole sample was 33 years old (range: 19 to 65) and 44% were female (n = 8). The mean interview length was 52 minutes (range: 28 to 81). Data were collected in private rooms within university buildings (University College London, Bristol University, University of Sheffield, and Newcastle University) with no-one else present besides the participant and researcher. Data were collected between 4th April and 22nd May 2019.\n\nParticipants were briefed on the purpose of the study and understood that it was a research project for CG. No relationship with the participants was established prior to study commencement. Ethical approval had been granted, participants reviewed the participant information sheet prior to giving their written informed consent for participation in the study, and for their anonymised data to be used in future research. Participants were compensated £20 in vouchers for their time. CG (female, Research Fellow, PhD) conducted the interviews and had training as part of a MSc in Research Methods in Psychology. CG was part of the team that developed Drink Less which was a potential source of bias.\n\nInterviews were semi-structured and follow-up questions were allowed. The interview guide was pilot tested with members of the research group (who read through and provided feedback on the guide) with no resulting changes. No repeat interviews were carried out. Interviews were audio recorded, transcribed verbatim and analysed (by CG) using content analysis, thus enabling us to quantify the data in terms of the frequency of different themes [19]. No field notes were made and transcripts were not returned to participants for comment or correction. The initial set of themes were selected deductively, based on those used previously to classify users’ reviews for software maintenance and evolution (see section on ‘content analysis of user feedback’) [21]. Sub-themes within these categories were then generated inductively from the data. NVivo version 11 (Taguette is a freely available alternative) and Microsoft Word were used to manage the data. Transcripts were coded against these initial sub-themes in an iterative process that led to new sub-themes being identified or existing sub-themes being amended to accurately capture the essence of the data.\n\nThis study found that the ‘information giving’ theme had five sub-themes: positive feedback on the app; easy to use; difficulty with navigation; reactions to normative feedback, and concerns about the game. The ‘information seeking’ theme had six sub-themes: how do I do this; how to I find this; what are the drinking guidelines; why should I trust this data; what is this trying to tell me, and what’s in a drink. There were also nine major feature requests and four problems discovered by participants that all required changes to be made to the app. Participants did not provide feedback on the findings. Participant quotations to illustrate the themes are provided in Extended data (https://osf.io/wzvt8/). Participants generally had positive feedback on the app and found it easy to use, though a number of issues were identified in terms of novice use of the app resulting in changes to Drink Less to ensure the refined version of the app has good usability among users from a range of socioeconomic backgrounds.\n\nTesting for bugs\n\nTesting for bugs was an extensive and iterative process. Screens that required user input were tested with dummy data and the app was thoroughly examined for programming bugs before being released. Informal testing was performed by members of the research team. Testing included the app’s text, design and functionality, the registration process, and the fidelity of data storage.\n\n\nResults\n\nA number of key changes were made to the content and design of the Drink Less app to improve its likely effectiveness and usability, including adding new modules, removing existing ones and making changes to improve existing modules. Example screenshots from the Drink Less app of some of these changes are shown in Figure 2.\n\nTable 1 reports how the three phases of the refinement process relate to changes to the app modules. The full content of the refined version of Drink Less is available in Extended data (https://osf.io/akqy9/).\n\n* Changes not implemented due to budget restrictions.\n\nThe ‘Behaviour Substitution’ module was added as it was found to be associated with the effectiveness of digital alcohol interventions in the Cochrane Review (Garnett et al., 2018b) (Phase 1). The module design was based on existing interventions and how other apps had implemented a similar concept (Phase 2). The module received positive feedback in user testing, though users wanted clearer instructions on how to add an alternative plan and why to make one, and a longer list of options to choose from (Phase 3). The final ‘Behaviour Substitution’ module, labelled ‘Drinking Alternatives’ in the app, prompts users to make an alternative plan within the drinking calendar on the app (e.g., go for a walk, watch a film, have a soft drink). Users can choose from a list of options or write their own, and set a reminder if they wish to. See Figure 2 and Supplementary Figure 1 (see Extended data (https://osf.io/5y7pc/) for screenshots).\n\nThe ‘Information about Antecedents’ module was added as it was found to be associated with effectiveness of digital alcohol interventions in the update of the evidence review (Phase 1). The module design was based on existing interventions and the implementation of this concept in other apps (Phase 2). The final design was chosen based on development costs and simplicity for the user. Public input through an Alcohol Discussion Group suggested the wording ‘cues’ rather than ‘triggers’ (Phase 2). Users requested further details explaining the module’s purpose and how it related to other modules (Phase 3). The final ‘Information about Antecedents’ module, labelled ‘Your Drinking Cues’ in the app, prompts users to identify the situations and events, or feelings that occur before drinking. Users can select from a list of drinking cues and add their own. Users are then prompted to make a plan for how to deal with these drinking cues and signposts the ‘Action Planning’ module. See Figure 2 and Supplementary Figure 2 (see Extended data (https://osf.io/5y7pc/) for screenshots).\n\nA common new feature requested in user feedback was a running total for the units of alcohol consumed (Phase 1). Public input included asking for a more detailed summary of weekly and/or monthly feedback (Phase 2). Designs for this new module were based on how other apps had presented similar modules alongside a consultation with app designers, developers, and researchers (Phase 2). During user testing, users provided positive feedback on the ‘Insights’ module and preferred the design as bar graphs (Phase 3). The final ‘Insights’ module, labelled ‘Insights’ in the app, consists of one screen with three sections: My Last Week, My Average Week, and Lifetime Totals. My Last Week and Lifetime Totals showing the total number of units, money spent, calories consumed, and alcohol-free days as well as a summary of their goals. My Average Week shows their average week in terms of units, calories, cost, and alcohol free days over different user-selected time periods: one month, three months, six months, one year, lifetime, with a graphical representation of their weekly units and alcohol free days. See Figure 2 and Supplementary Figure 3 (Extended data: https://osf.io/5y7pc/) for screenshots of the ‘Insights’ module.\n\nThe Bayes factor analysis of additional trial outcome data (Phase 1) indicated that there was support for the null hypothesis that the ‘Identity Change’ module – helping users foster a change from seeing being a “drinker” as a key part of their identity – had no effect on past week alcohol consumption (Garnett et al., 2019b). These findings, alongside results from analysing user feedback (Phase 1) and usage data indicating users very rarely viewed these screens, guided the decision to remove the module. There were many screens within the module that may have meant it was too complex to use, and it may be that, had the intervention content been implemented differently in the app, it would have been more popular with users.\n\nThe ‘Normative Feedback’ module provides feedback on how their own drinking compares with the norms for alcohol consumption and alerts them to any discrepancy. A high-priority change identified from the content analysis of the user feedback was to include the ability for users to update the normative feedback they received (Phase 1). App designers, developers, and researchers were consulted on the best way to implement this change and to illustrate the various user scores (Phase 2). The final design was a new home screen for the module with a dial widget that showed both their original (in grey) and latest (in black) normative feedback. Users could re-take a three-item survey (the AUDIT-C) every 28 days via a link on the Dashboard named “See how your drinking has changed”. Users then saw normative feedback that was tailored to their latest score as well as being able to see any of their previous feedback by tapping on the relevant date under ‘Drinking Review History’ on the main home screen for the module. See Figure 2 and Supplementary Figure 4 (Extended data: https://osf.io/5y7pc/) for the final designs.\n\nDuring the user testing, some users wanted further clarification about the meaning of the feedback they received from the AUDIT and the Normative Feedback (Phase 3). Therefore, changes to the text on these screens were made to clarify their meaning (see Supplementary Figure 5, Extended data: https://osf.io/5y7pc/).\n\nThe ‘Self-Monitoring and Feedback’ module prompts users to record their alcohol consumption and provides feedback on their consumption, the consequences of consumption, and progress against goals. The content analysis of user feedback found that a high priority change was for the Drinking Calendar week to start on a Monday, instead of a Sunday, to match up with the weekly goals (Phase 1); this was implemented immediately prior to Phase 2. User feedback also showed that users struggled with how to edit or delete an existing drink entry (Phase 1). The consultation with app designers, developers and researchers in Phase 2 resulted in adding an ‘Edit’ button in the top menu bar that mirrors the ‘delete’ widget in iOS (i.e., shows a little red circle which, if tapped, shows the ‘delete’ button from the right), and adding the option to delete the entry, instead of save, when users were editing it. See Supplementary Figure 6 (Extended data: https://osf.io/5y7pc/) for screenshots.\n\nDuring the user testing, many users did not realise that they could edit the default settings when adding a drink and that there were drop-down lists (Phase 3). Therefore, an arrow was added to indicate that the user could edit these fields. The content analysis of user feedback identified that users wanted the ability to customise volumes when adding a drink (Phase 1). The final design selected during the consultation of app designers, developers, researchers (Phase 2) still had a default start value and a drop-down list of common options but with ‘Custom’ at the end allowing users to type in the exact volume in ml (see Figure 2 and Supplementary Figure 7, Extended data: https://osf.io/5y7pc/, for screenshots).\n\nThe user testing found that users were unsure of how to add a mood diary for the first time and wanted more guidance on how to use this part of the app (Phase 3). An overlay was added for the Dashboard indicating how to add a mood diary and further text was added to the ‘Your hangover and you’ screen, which appears before any entries are made, and explains how to add one (see Supplementary Figure 8, Extended data: https://osf.io/5y7pc/). Other changes from the user testing included highlighting the links to the ‘units infographic’ in bold and to include the typical calories alongside the units in the infographic (Phase 3).\n\nThe ‘Goal Setting’ module allows users to set a weekly goal in terms of units, calories, cost and alcohol-free days. In the user testing, users often did not realise that they could change the type of goal they were setting or choose from a drop-down list; therefore, an arrow was added to indicate that users could choose the type of goal (Phase 3). Users also wanted a link to the drinking guidelines from the ‘Set a goal’ screen as they did not understand why the default was ‘14’ for the units goal. Text explaining this was added (Phase 3). See Supplementary Figure 9 (Extended data: https://osf.io/5y7pc/) for screenshots.\n\nThe ‘Cognitive Bias Re-training’ module aims to change approach biases to alcohol stimuli through an approach-avoidance style game in which users must avoid alcohol-related pictures and approach non-alcohol-related pictures. Two changes were made to this module; the first was as a result of the content analysis of user feedback (Phase 1) and the public input from an Alcohol Discussion Group (Phase 2) in which users did not want the game to be promoting other unhealthy drinks as an alternative to alcohol. Therefore, we removed any non-alcohol-related pictures that involved sugary and/or fizzy drinks from the game. The second change arose from the user testing and involved re-ordering the instructions, so the demonstration screens were shown first and then the text screen was last and made briefer (Phase 3). See Supplementary Figure 10 (Extended data: https://osf.io/5y7pc/) for screenshots of these changes.\n\nDuring user testing, users requested a link to the Drinking guidelines screen under ‘Useful Links’ on the Dashboard (the main landing page of the app) and that the ‘We suggest’ list was updated to reflect the new app modules (Phase 3). See Supplementary Figure 11 (Extended data: https://osf.io/5y7pc/) for screenshots. An issue for many users during user testing was the navigational structure as some users were confused how to find different modules and by the names of the modules (Phase 3). Therefore, to improve the navigational structure, the navigation tab bar (at the bottom of the screen) was changed to include the app modules visited more frequently; the ‘Calendar’ replaced the ‘Game’ which was moved to the original ‘Progress’ screen (renamed ‘Activities’ to highlight the difference from the Dashboard).\n\nUsers needed more guidance on how to use the app during onboarding (first time use of the app and set-up) during the user testing (Phase 3). The original onboarding process on the Dashboard involved three steps (set a goal; add drinks; explore) but there was no clear link between the steps or how to find those steps again, resulting in users getting confused and lost on the app. Therefore, the three-step onboarding process on the Dashboard was removed and integrated into the app in different ways to provide more guidance to users. The ‘set a goal’ step was moved to the end of registration in a step-by-step wizard so that all users could choose to set a goal by the time they reach the Dashboard. Then on arriving at the Dashboard, a number of overlays take the users through how to perform the key functions on the app: add a drink; view your drinking calendar; view the graph on the Dashboard; enter your mood diary. See Figure 2 and Supplementary Figure 12 (Extended data: https://osf.io/5y7pc/) for screenshots of these changes.\n\nThe content analysis of user feedback highlighted a key change to make in terms of making the app accessible for individuals with red-green colour blindness (Phase 1). The original design of the app meant that individuals with red-green colour blindness could not differentiate between these colours on the calendar or Dashboard graphs. On the recommendation of a user, we gave each of the colours a texture (e.g., red = ‘hash’, orange = ‘diagonal’) so that any user could understand the colour scheme of the app (see Figure 2 and Supplementary Figure 13, Extended data: https://osf.io/5y7pc/). Finally, changes were made to the ‘Help’ section of the app to update the information provided to users as this was out of date from the first version of the app (e.g., NHS websites, where to find further support).\n\n\nDiscussion\n\nDrink Less is a standalone app for people in the UK who are seeking support to reduce their alcohol consumption. To the authors’ knowledge, this is the first alcohol reduction app that has been refined, following its original development, using a systematic and iterative process based on evidence and user input. The refinement resulted in a number of major changes to the app including the addition of three modules – ‘Behaviour Substitution’, ‘Information about Antecedents’ and ‘Insights’ – and the removal of the ‘Identity Change’ module. In response to user feedback and user testing there were a number of changes conducted within existing modules to improve the app’s usability and acceptability, and improvements were made to the navigational structure and onboarding process. The refinement of the Drink Less app continues to follow MOST for developing and evaluating complex behavioural interventions, and the refined version of the app is now ready for a confirmatory evaluation in an RCT (Garnett et al., 2021b).\n\nDrink Less is the first alcohol reduction app aimed at the general population of people who are hazardous or harmful drinkers to have reported a systematic and transparent approach to its development, screening and refinement. Transparency with both the process and content of the intervention is important for the replication of interventions (de Bruin et al., 2021). This paper follows on from the original development paper of Drink Less (Garnett et al., 2019a) by reporting the processes and resulting content from refining the app in the next stage in MOST. By refining the app and releasing an updated version, the app has avoided issues of poor user experience and early app abandonment, and not been left to ‘rot’ in the app store, as is the case for many apps developed by academics (Larsen et al., 2016).\n\nOne of the strengths of this refinement process was that it drew on empirical evidence and user input to improve the usability and likely effectiveness of the app. The user input – both from novice users (during the user testing) and experienced users (through the user feedback received) – was critical to improve the app’s usability, which is important for longer-term user engagement. Therefore, it is likely that the refined version of Drink Less has been further improved in terms of likely effectiveness at reducing alcohol consumption and that users will find it usable and acceptable. This places the Drink Less app in a strong position to be evaluated in an RCT, the next step in MOST, which will advance the limited evidence base in this field.\n\nAnother strength of this study is the mixed methods approach and the triangulation of different sources of evidence to refine Drink Less. For example, the user testing with novice users identified navigation issues with the onboarding process, which were not identified in the analysis of existing user feedback. Users who have difficulty with navigation during the onboarding process in a real-world setting may disengage with the app completely and not provide feedback. The user feedback is unlikely to have a social confirmation bias as it came from a real-world setting, though it may be that user reviews are polarised and therefore not necessarily representative of the majority of users.\n\nThe refinement of Drink Less continues to be in line with the Open Science principles of making materials, data, results and publications freely available (Munafò, 2016), which is important for efficient scientific progress and to reduce trial wastage. The content of the refined version of the app is described in Extended data (https://osf.io/akqy9/) and this paper may provide a helpful template to other researchers refining health-related digital interventions.\n\nThere are some limitations with this process of refining Drink Less. First, we could not know what changes would arise from the process in advance of applying for funding and were limited by a fixed budget that we estimated in advance. The fixed budget was a key factor in how many changes could be implemented which meant we had to prioritise the changes and therefore that not every improvement that arose throughout the process, such as tailored reminders, could be implemented. Changes arising from the randomised factorial screening trial and the update of the evidence review (in Phase 1) – the addition and removal of modules – were all implemented to improve the likely effectiveness of the app. However, the implementation of some modules was adapted and simplified to keep the cost of development within budget. Changes to the app that arose from the user feedback (Phase 1), public input from an Alcohol Discussion Group (Phase 2), and user testing (Phase 3) were prioritised based on importance to the users (judged on how frequently the suggested change occurred) and balanced with the development cost of making that change, as well as consideration of how many other changes could be made. We acknowledge that the decisions made in prioritising changes by the research team was subjective and that another team may have made different decisions based on the same information.\n\nCost was a major factor in the decisions made when refining the Drink Less app and this is often an issue with the development of digital interventions where an interdisciplinary team with varying expertise is required. Our research budget covered researcher salaries and development costs for a professional app developer and designer. Another way of working is to have an in-house developer which can remove limitations on what changes can be made. However, there is still the cost of the developer’s salary to cover and therefore this may only be good value for money when the team is working on multiple digital interventions. It is also worth noting that development costs are likely to change over time and also depend on the intervention itself. Therefore, the costs associated with the changes made in the refinement process of Drink Less are likely to differ if replicated with a different intervention.\n\nAnother limitation is that there is not a universal end point to follow when refining a digital intervention and one could continue to iterate indefinitely. Whilst the refinement process has finished, we will continue to collect and monitor the user feedback we receive to identify changes that can be made to improve Drink Less.\n\nThe refined version of Drink Less will be evaluated in an RCT funded by the National Institute for Health Research (NIHR127651; registered on ISRCTN on 29th April 2020 https://doi.org/10.1186/ISRCTN64052601). The trial will evaluate whether the digital offer of Drink Less (compared with the recommendation to view the NHS alcohol advice webpage) reduces alcohol consumption over the previous week at a six-month follow-up. This will be the largest RCT of a digital alcohol intervention and the first of an alcohol reduction app for the general population in the UK. There is currently little evidence regarding the effectiveness of apps and this research will start to build a robust evidence base on the effectiveness and cost-effectiveness of health-related apps. Drink Less is also collecting user engagement and behavioural data of value in understanding its theoretical mechanisms of action (Garnett et al., 2018a), which can help inform future behaviour change interventions.\n\n\nConclusions\n\nThe alcohol reduction app Drink Less has been systematically developed and refined based on evidence and theory. A mixed methods approach was used to refine Drink Less, following its original development (Garnett et al., 2019a), which provided insights into how to improve the likely effectiveness of the intervention whilst also providing users with what they want from the intervention, which is critical for longer-term engagement. This meant the app was not left to ‘rot’ in the app store, as is the case for many apps developed by academics (Larsen et al., 2016) and issues of poor user engagement were avoided. The three-phase refinement process involved adding three new modules to Drink Less (‘Behaviour Substitution’, ‘Information about Antecedents’ and ‘Insights’) as well as a number of changes to existing modules to improve its likely effectiveness, and its acceptability and usability to users. Drink Less is now ready for evaluation in an RCT to assess its effectiveness and cost-effectiveness at reducing hazardous and harmful alcohol consumption. Drink Less is a freely available intervention to people wanting support to reduce their drinking, which, if found to be effective, could be widely recommended resulting in important implications for public health.\n\n\nData availability\n\nOpen Science Framework: Drink Less/Refinement of Drink Less app. https://osf.io/8tqv6 (Garnett et al., 2021a).\n\nThis project contains the following underlying data:\n\n- UKCTAS Alcohol Discussion Group - summary notes.docx (summary notes from the PPI Alcohol Discussion Group, https://osf.io/9ca37/).\n\n- Consultation survey data – Round 1.xlsx (https://osf.io/jxvns/).\n\n- Consultation survey data – Round 2.xlsx (https://osf.io/vt3ub/).\n\n- Drink Less_extended trial outcomes dataset.sav (additional trial outcome data from the randomised factorial screening trial, https://osf.io/nad4e)\n\nThe user feedback data used for content analysis (Phase 1) cannot be made available publicly as consent was not gained from users to share the user feedback data. Interested parties should contact the corresponding author, Claire Garnett (c.garnett@ucl.ac.uk), for a restricted route of access to the user feedback data after signing a data access agreement confirming the data will be held securely and that no further research will be conducted using this data.\n\nAudio recordings for the PPI Alcohol Discussion Group (Phase 2) cannot be provided as consent was not gained from participants for this purpose. The audio recordings were taken for the sole purpose of informing the summary notes written (provided in Underlying data).\n\nAudio recordings and transcripts for the user testing interviews (Phase 3) cannot be made available publicly as consent was not gained from participants for this purpose. Participants did provide consent for their anonymised data to be used by others for future research and interested parties should contact the corresponding author, Claire Garnett (c.garnett@ucl.ac.uk), to apply for access to the transcripts for further research after signing a data request form.\n\nOpen Science Framework: Drink Less/Refinement of Drink Less app. https://doi.org/10.17605/OSF.IO/8TQV6 (Garnett et al., 2021a).\n\nThis project contains the following extended data:\n\n- Report on rapid update of Cochrane systematic review on digital alcohol reduction interventions.docx (https://osf.io/azpc2/)\n\n- User feedback content analysis - report - Nov 2018.docx (https://osf.io/vdmsk/)\n\n- App wireframes_handout to UKCTAS Alcohol Discussion Group.pdf (https://osf.io/mu7sw/)\n\n- Round 1 consultation survey.pdf (https://osf.io/w3tx8/)\n\n- Round 2 consultation survey.pdf (https://osf.io/4xa73/)\n\n- User testing brief report_OSF.docx (https://osf.io/wzvt8/)\n\n- Content of Drink Less app (version 2.0.7).pdf (https://osf.io/akqy9/)\n\n- Supplementary Figures.pdf (https://osf.io/5y7pc/)\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\n\n\n- Software available from: https://apps.apple.com/gb/app/drink-less/id1020579244\n\n- Source code available from: https://github.com/UCL-Centre-for-Behaviour-Change/DrinkLess-public\n\n- Archived source code at time of publication: http://doi.org/10.5281/zenodo.4721332 (Pointryogi & UCL-Centre-for-Behaviour-Change, 2021).\n\nLicense: GNU Affero General Public License version 3 (AGPL-3.0)",
"appendix": "Acknowledgements\n\nWe would like to thank Dr Dave Crane for his important role in the development and factorial screening trial of the Drink Less app.\n\n\nReferences\n\nBabor T, Higgins J, Saunders J, et al.: AUDIT: the alcohol use disorders identification test guidelines for use in primary care. 2nd ed. World Health Organisation; 2001.\n\nBraun V, Clarke V: Using thematic analysis in psychology. Qual. Res. Psychol. 2006; 3: 77–101. Publisher Full Text\n\nBrown J, Michie S, Geraghty AWA, et al.: A pilot study of Stop Advisor: A theory-based interactive internet-based smoking cessation intervention aimed across the social spectrum. Addict. Behav. 2012; 37: 1365–1370. PubMed Abstract | Publisher Full Text\n\nCollins LM, Baker TB, Mermelstein RJ, et al.: The multiphase optimization strategy for engineering effective tobacco use interventions. Ann. Behav. Med. 2011; 41: 208–226. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCollins LM, Murphy SA, Nair VN, et al.: A strategy for optimizing and evaluating behavioral interventions. Ann. Behav. Med. 2005; 30: 65–73. PubMed Abstract | Publisher Full Text\n\nCollins LM, Murphy SA, Strecher V: The multiphase optimization strategy (MOST) and the sequential multiple assignment randomized trial (SMART): new methods for more potent eHealth interventions. Am. J. Prev. Med. 2007; 32: S112–S118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCollins LM, Trail JB, Kugler KC, et al.: Evaluating individual intervention components: making decisions based on the results of a factorial screening experiment. Transl. Behav. Med. 2014; 4: 238–251. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCrane D, Garnett C, Brown J, et al.: Factors influencing usability of a smartphone app to reduce excessive alcohol consumption: Think aloud and interview studies. Front. Public Heal. 2017; 5: 1–19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCrane D, Garnett C, Brown J, et al.: Behavior change techniques in popular alcohol reduction apps: content analysis. J. Med. Internet Res. 2015; 17: e118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCrane D, Garnett C, Michie S, et al.: A smartphone app to reduce excessive alcohol consumption: Identifying the effectiveness of intervention components in a factorial randomised control trial. Sci. Rep. 2018; 8: 4384. PubMed Abstract | Publisher Full Text | Free Full Text\n\nde Bruin M, Black N, Javornik N, et al.: Underreporting of the active content of behavioural interventions: A systematic review and meta-analysis of randomized trials of smoking cessation interventions. Health Psychol. Rev. 2021; 1–33. PubMed Abstract | Publisher Full Text\n\nDienes Z: Using Bayes to get the most out of non-significant results. Front. Psychol. 2014; 5: 781. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDrink Less on iTunes store [WWW Document]: n.d. (accessed 10.5.16). Reference Source\n\nEysenbach G: The law of attrition. J. Med. Internet Res. 2005; 7: e11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGajecki M, Berman AH, Sinadinovic K, et al.: Mobile phone brief intervention applications for risky alcohol use among university students: a randomized controlled study. Addict. Sci. Clin. Pract. 2014; 9: 11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Crane D, Brown J, et al.: Reported Theory Use by Digital Interventions for Hazardous and Harmful Alcohol Consumption, and Association With Effectiveness: Meta-Regression. JMIR. 2018a; 20: e69. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Crane D, Brown J, et al.: Behavior Change Techniques Used in Digital Behavior Change Interventions to Reduce Excessive Alcohol Consumption: A Meta-regression. Ann. Behav. Med. 2018b; 52: 530–543. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Crane D, West R, et al.: The development of Drink Less: an alcohol reduction smartphone app for individuals who drink excessively. Transl. Behav. Med. 2019a; 9: 296–307. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Crane D, West R, et al.: Identification of Behavior Change Techniques and Engagement Strategies to Design a Smartphone App to Reduce Alcohol Consumption Using a Formal Consensus Method. JMIR mHealth uHealth. 2015; 3: e73. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Michie S, West R, et al.: Updating the evidence on the effectiveness of the alcohol reduction app, Drink Less: using Bayes factors to analyse trial datasets supplemented with extended recruitment. F1000Res. 2019b; 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarnett C, Oldham M, Angus C, et al.: Evaluating the effectiveness of the smartphone app, Drink Less, compared with the NHS alcohol advice webpage, for the reduction of alcohol consumption among hazardous and harmful adult drinkers in the UK at 6-month follow-up: protocol for a randomised con. Addiction add. 2021b; 15287. PubMed Abstract | Publisher Full Text\n\nGarnett C, Michie S, West R, et al.: Refinement of Drink Less App. 2021a, April 26. Publisher Full Text\n\nHelander E, Kaipainen K, Korhonen I, et al.: Factors related to sustained use of a free mobile app for dietary self-monitoring with photography and peer feedback: retrospective cohort study. J. Med. Internet Res. 2014; 16: e109. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJeffreys H: The Theory of Probability. 3rd ed. Oxford University Press; 1961.\n\nKaner EFS, Beyer FR, Garnett C, et al.: Personalised digital interventions for reducing hazardous and harmful alcohol consumption in community-dwelling populations. Cochrane Database Syst. Rev. 2017. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKaner E, Dickinson H, Beyer F, et al.: Effectiveness of brief alcohol interventions in primary care populations (Review). Cochrane Libr; 2007.\n\nKhalid H, Shihab E, Nagappan M, et al.: What do mobile app users complain about? IEEE Software. 2015. Publisher Full Text\n\nLarsen ME, Nicholas J, Christensen H: Quantifying App Store Dynamics: Longitudinal Tracking of Mental Health Apps. JMIR mHealth uHealth . 2016; 4: e96. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMccurdie T, Taneva S, Casselman M, et al.: mHealth consumer apps: The Case for User-Centered Design. Biomed Instrum Technol. 2012: S49–S56. PubMed Abstract | Publisher Full Text\n\nMichie S, Atkins L, West R: The Behaviour Change Wheel - A Guide To Designing Interventions. 1st ed. London: Silverback Publishing; 2014.\n\nMichie S, Richardson M, Johnston M, et al.: The behavior change technique taxonomy (v1) of 93 hierarchically clustered techniques: building an international consensus for the reporting of behavior change interventions. Ann. Behav. Med. 2013; 46: 81–95. PubMed Abstract | Publisher Full Text\n\nMudambi SM, Schuff D: What Makes a Helpful Online Review? A Study of Customer Reviews on Amazon.com, MIS Quarterly.2010. Publisher Full Text\n\nMunafò MR: Opening up addiction science. Addiction. 2016; 111: 387–388. PubMed Abstract | Publisher Full Text\n\nOfcom; Critical Research: Devices used to access the internet UK 2020 [WWW Document].Statista; 2020. (accessed 1.11.21). Reference Source\n\nPanichella S, Di Sorbo A, Guzman E, et al.: How can i improve my app? Classifying user reviews for software maintenance and evolution. IEEE 31st Int. Conf. Softw. Maint. Evol. ICSME 2015 - Proc. 2015; 281–290. Publisher Full Text\n\nPerski O, Blandford A, West R, et al.: Conceptualising engagement with digital behaviour change interventions: a systematic review using principles from critical interpretive synthesis. Transl. Behav. Med. 2016; 7: 254–267. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPointryogi, & UCL-Centre-for-Behaviour-Change: UCL-Centre-for-Behaviour-Change/DrinkLess-public: v2.0.11 of the Drink Less app (Version v2.0.11). Zenodo. 2021, April 26. Publisher Full Text\n\nRiper H, Hoogendoorn A, Cuijpers P, et al.: Effectiveness and treatment moderators of internet interventions for adult problem drinking: An individual patient data meta- analysis of 19 randomised controlled trials. PLOS Med. 2018; 15: e1002714. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRouder JN: Optional stopping: No problem for Bayesians. Psychon. Bull. Rev. 2014; 21: 301–308. PubMed Abstract | Publisher Full Text\n\nSekhon M, Cartwright M, Francis JJ: Acceptability of healthcare interventions: an overview of reviews and development of a theoretical framework. BMC Health Serv. Res. 2017; 17: 88. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUbhi HK, Michie S, Kotz D, et al.: Characterising smoking cessation smartphone applications in terms of behaviour change techniques, engagement and ease-of-use features. Transl. Behav. Med. 2015; 6: 410–417. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVaismoradi M, Turunen H, Bondas T: Content analysis and thematic analysis: Implications for conducting a qualitative descriptive study. Nurs. Heal. Sci. 2013; 15: 398–405. PubMed Abstract | Publisher Full Text\n\nVasa R, Hoon L, Mouzakis K, et al.: A Preliminary Analysis of Mobile App User Reviews. Proc. 24th Aust. Comput. Interact. Conf. ACM; 2012; 241–244. Publisher Full Text\n\nYardley L, Ainsworth B, Arden-Close E, et al.: The person-based approach to enhancing the acceptability and feasibility of interventions. Pilot Feasibility Stud. 2015; 1: 37. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "88560",
"date": "15 Jul 2021",
"name": "Andre Bedendo",
"expertise": [
"Reviewer Expertise Alcohol use and digital interventions"
],
"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 describes the process of refining the app Drink Less, designed to help hazardous or harmful UK drinkers to reduce alcohol consumption. The manuscript is well-written and provides a detailed description of the updating process of the app, an aspect that is often vaguely described or absent in scientific literature of drug digital interventions. This is the main contribution of the study to the field and it is highly appreciated the efforts of the authors in documenting and summarising the app revising/updating process.\nThe authors used a three-phase process to refine the app: identified changes to be made, updated the app, and tested the refined version. A mixed-methods approach was utilised and included a factorial randomised trial, content analysis of user feedback, expert consultation, public involvement group, Cochrane systematic review, semi-structured interviews, etc. The manuscript also presents multiple information as supporting files (e.g. data, user’s feedbacks, app prototypes, etc.). The study did not present a typical discussion section with results being discussed in light of other research, but the authors commented on various strengths and limitations. Finally, the overall quality of the manuscript is good, and I provide below some minor comments aiming at contributing to the study.\n\nIt is not clear in the manuscript if the results of the randomised factorial trial after the additional data collection are available. Did the additional data change the results observed among the 672 participants? If this information is available, it would be relevant to include it in the manuscript.\n\nHow the authors defined that the number of 18 participants was sufficient for Phase 3? Also, were participants guided to use all app features or were they free to use during the thinking aloud?\n\nHaving a table showing the modules that were present in the first version of the app, in the revised version would facilitate reading and provide a good summary to readers. If possible, also include the behaviour change techniques of each module.\n\nConsidering that major changes occurred in the new iteration of the app, how comparable the two versions of the app are?\n\nAs highlighted by the authors, engagement is a major issue on digital interventions. Therefore, including details on the engagement of the previous version of the app will be of value as well as to have the authors comment on the potential impact of the inclusion of more modules on the user engagement.\n\nThe authors highlighted that budget limitations played an important role during the app refinement. However, do authors perceive any limitations regarding the methods used? Similarly, in the future studies section, the authors focused on the presentation of the future RCT evaluation of the app. However, are there any broader recommendations for future studies that also develop and evaluate?\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7482",
"date": "25 Nov 2021",
"name": "Claire Garnett",
"role": "Author Response",
"response": "The paper describes the process of refining the app Drink Less, designed to help hazardous or harmful UK drinkers to reduce alcohol consumption. The manuscript is well-written and provides a detailed description of the updating process of the app, an aspect that is often vaguely described or absent in scientific literature of drug digital interventions. This is the main contribution of the study to the field and it is highly appreciated the efforts of the authors in documenting and summarizing the app revising/updating process. The authors used a three-phase process to refine the app: identified changes to be made, updated the app, and tested the refined version. A mixed-methods approach was utilized and included a factorial randomized trial, content analysis of user feedback, expert consultation, public involvement group, Cochrane systematic review, semi-structured interviews, etc. The manuscript also presents multiple information as supporting files (e.g. data, user’s feedbacks, app prototypes, etc.). The study did not present a typical discussion section with results being discussed in light of other research, but the authors commented on various strengths and limitations. Finally, the overall quality of the manuscript is good, and I provide below some minor comments aiming at contributing to the study. Response: Thank you for your helpful and thorough comments. We have addressed each of them below. It is not clear in the manuscript if the results of the randomised factorial trial after the additional data collection are available. Did the additional data change the results observed among the 672 participants? If this information is available, it would be relevant to include it in the manuscript. Response: We have clarified that on page 8: “In the factorial trial, Bayes factors showed the data to be insensitive to detect a main effect (d=0.22) of individual modules so an update was conducted to analyse additional trial outcome data collected through extended recruitment. This update is published in full elsewhere (Garnett et al., 2019b).” How the authors defined that the number of 18 participants was sufficient for Phase 3? Also, were participants guided to use all app features or were they free to use during the thinking aloud? Response: We have clarified the sample size and added details on the think-aloud procedure on pages 14 and 15, respectively: “There were 18 participants that took part, which met the threshold recommended for a usability test to detect most of the usability problems (Nielsen, 1994).” “Participants were set four tasks (e.g. set a goal) before being asked to browse the app (see Extended data (https://osf.io/wzvt8/)).” Having a table showing the modules that were present in the first version of the app, in the revised version would facilitate reading and provide a good summary to readers. If possible, also include the behaviour change techniques of each module. Response: This is an excellent suggestion and we have created a supplementary table and referred to this on page 16 of the manuscript: “Supplementary Table 1 provides a summary of the modules and the relevant BCTs for each module, along with whether the modules were present in the original and/or revised version of the app (see Extended data: https://osf.io/c3s6j/).” Considering that major changes occurred in the new iteration of the app, how comparable the two versions of the app are? As highlighted by the authors, engagement is a major issue on digital interventions. Therefore, including details on the engagement of the previous version of the app will be of value as well as to have the authors comment on the potential impact of the inclusion of more modules on the user engagement. Response: These are both good points and we have now addressed them in the discussion on page 30: “Whilst a lot of the core features, navigational structure and module content remain in the refined version, a number of major changes were made to the original version of the app meaning that the overall content of the original and refined versions of the app are not entirely comparable. A previous study has investigated engagement with the original version of the app (Bell et al., 2020) though no research has yet been conducted on engagement with the refined version of the app. It is an empirical question as to whether engagement with the app has changed as a result of the refined version of the app being released and a question to consider for future research.” The authors highlighted that budget limitations played an important role during the app refinement. However, do authors perceive any limitations regarding the methods used? Similarly, in the future studies section, the authors focused on the presentation of the future RCT evaluation of the app. However, are there any broader recommendations for future studies that also develop and evaluate? Response: This is an excellent point and we’ve added another paragraph on p28 on the limitations with the individual methods used: “There were also some limitations with the methods used to identify the changes to the content of the app. The study analysing the data from the extended randomised factorial screening trial with Bayes factors was unable to use the intention-to-treat approach because there was an extremely low follow-up rate (13%) (Garnett et al., 2019b). In this case, the intention-to-treat approach would have meant no change in the great majority of the sample. A limitation of the update of the review of digital alcohol interventions is that there was infrequent use of many behaviour change techniques meaning the possible effects of most behaviour change techniques could not be evaluated. The reviews included in the content analysis of user feedback may be polarised with views at one end of the spectrum (extremely positive or extremely negative) being more likely than users who were indifferent about the app. Therefore, these reviews are not necessarily representative of the majority of app users. In terms of improving the usability of the app, the interviewer was part of the team that developed Drink Less, which was a potential source of bias.” It is difficult to provide very broad recommendations for future studies as it will depend on the digital intervention and the aim of the evaluation. We have added a sentence highlighting some resources for deciding on the most appropriate evaluation approach on p29: “RCTs are important for evaluation of effectiveness and cost-effectiveness of digital health interventions, though are best undertaken when the intervention is stable and can be implemented with high fidelity (Murray et al., 2016 ), as is the case here. However, there are many considerations and approaches to the development and evaluation of digital health interventions, depending on the aim or research question (Murray et al., 2016) and there are resources available to help people choose the most appropriate evaluation approach Public Health England, 2021).”"
}
]
},
{
"id": "92034",
"date": "09 Sep 2021",
"name": "Maria Lucia O. Souza Formigoni",
"expertise": [
"Reviewer Expertise brief interventions and virtual interventions"
],
"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\nAlthough there are several applications (app) to reduce the consumption of cigarettes or alcohol, many were developed based on clinical principles, not always supported by a solid theoretical basis. This is not the case with this manuscript, in which the authors clearly support the choice of tools included in the application and describe in a very detailed way all the steps of refinement of the application carried out. The language is clear and precise and several details of the procedures are made available to the reader in the form of supplementary material, which makes it an excellent source of reference for the area. Despite this, the article could benefit from the inclusion of some details such as:\nWhat was the criterion used to determine the sample size (n=18) of the 3rd phase of the study? Was it pre-determined or the authors use another criterion such as “theoretical saturation”?\n\nIf the authors have data on the app's adherence to the use of the preliminary version and the updated version, it would be appropriate to include and compare them, as well as to include this point in the discussion.\n\nThe authors could include more explicitly in the discussion the changes they intended to make and that were not possible due to budget limitations, as well as the criteria adopted for inclusion of changes: they were the most accessible, or the most important from the point of view theoretical or the most frequently requested by users? What are the possible impacts of these decisions? This aspect, as well as the fact that one of the authors was the interviewer, which is considered a bias in the methodology, should appear at the end of the manuscript among the limitations of the study.\nThe discussion could be further developed, both in relation to the theoretical bases that motivated the changes and in relation to the criticisms made by users. The removal of the “identity change” module and the inclusion of \"Information about antecedents\", “Behavior substitution” and “Insights” should be more deeply addressed in the discussion, considering the theoretical aspects involved.\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": "7483",
"date": "25 Nov 2021",
"name": "Claire Garnett",
"role": "Author Response",
"response": "Although there are several applications (app) to reduce the consumption of cigarettes or alcohol, many were developed based on clinical principles, not always supported by a solid theoretical basis. This is not the case with this manuscript, in which the authors clearly support the choice of tools included in the application and describe in a very detailed way all the steps of refinement of the application carried out. The language is clear and precise and several details of the procedures are made available to the reader in the form of supplementary material, which makes it an excellent source of reference for the area. Response: Thank you for your positive review and helpful comments which we’ve addressed below. Despite this, the article could benefit from the inclusion of some details such. What was the criterion used to determine the sample size (n=18) of the 3rd phase of the study? Was it pre-determined or the authors use another criterion such as “theoretical saturation”? Response: A sample size of 16 participants is recommended for a usability test to detect most of the usability problems (Nielsen, 1994). We have clarified about the sample size on page 14: “There were 18 participants that took part, which met the threshold recommended for a usability test to detect most of the usability problems (Nielsen, 1994).” If the authors have data on the app's adherence to the use of the preliminary version and the updated version, it would be appropriate to include and compare them, as well as to include this point in the discussion. Response: A previous study investigated engagement with the original version of the app and we have now included this in the discussion on page 27 along with highlighting that future research should consider comparing engagement between the original and refined version of the app: “A number of major changes were made to the original version of the app meaning that the overall content of the original and refined versions of the app are not directly comparable. A previous study has investigated engagement with the original version of the app (Bell et al., 2020) though no research has yet been conducted on engagement with the refined version of the app. It is an empirical question as to whether engagement with the app has changed as a result of the refined version of the app being released and a question to consider for future research.” The authors could include more explicitly in the discussion the changes they intended to make and that were not possible due to budget limitations, as well as the criteria adopted for inclusion of changes: they were the most accessible, or the most important from the point of view theoretical or the most frequently requested by users? What are the possible impacts of these decisions? This aspect, as well as the fact that one of the authors was the interviewer, which is considered a bias in the methodology, should appear at the end of the manuscript among the limitations of the study. Response: Thank you, we have added a more detailed discussion of the limitations including clarifying about which changes were not possible due to budget restrictions on p27 and p28: “The fixed budget was a key factor in how many changes could be implemented, which meant we had to prioritise the changes and not every improvement identified, such as tailored reminders, could be implemented (see Table 1 for the changes not implemented due to budget restrictions). Changes arising from the randomised factorial screening trial and the update of the evidence review (in Phase 1) – the addition and removal of modules – were all implemented to improve the likely effectiveness of the app. However, the implementation of some modules was adapted and simplified to keep the cost of development within budget. Changes to the app that arose from the user feedback (Phase 1), public input from an Alcohol Discussion Group (Phase 2), and user testing (Phase 3) were prioritised based on importance to the users (judged on how frequently the suggested change occurred) and balanced with the development cost of making that change, as well as consideration of how many other changes could be made.” “There were also some limitations with the methods used to identify the changes to the content of the app. The study analysing the data from the extended randomised factorial screening trial with Bayes factors was unable to use the intention-to-treat approach because there was an extremely low follow-up rate (13%) (Garnett et al., 2019b). In this case, the intention-to-treat approach would have meant no change in the great majority of the sample. A limitation of the update of the review of digital alcohol interventions is that there was infrequent use of many behaviour change techniques meaning the possible effects of most behaviour change techniques could not be evaluated. The reviews included in the content analysis of user feedback may be polarised with views at one end of the spectrum (extremely positive or extremely negative) being more likely than users who were indifferent about the app. Therefore, these reviews are not necessarily representative of the majority of app users. In terms of improving the usability of the app, the interviewer was part of the team that developed Drink Less, which was a potential source of bias.” The discussion could be further developed, both in relation to the theoretical bases that motivated the changes and in relation to the criticisms made by users. The removal of the “identity change” module and the inclusion of \"Information about antecedents\", “Behavior substitution” and “Insights” should be more deeply addressed in the discussion, considering the theoretical aspects involved. Response: We have developed our discussion further around these areas, in particular on p25: “The refinement resulted in a number of major changes to the app including the addition of three modules – ‘Behaviour Substitution’, ‘Information about Antecedents’ and ‘Insights’ – and the removal of the ‘Identity Change’ module. ‘Behaviour Substitution’ and ‘Information about Antecedents’ are both behaviour change techniques that were identified from the review of digital alcohol interventions, and users provided feedback on how they were implemented during the user testing. The ‘Identity Change’ module was removed from the app based on the findings from the factorial screening trial which showed there was support for no effect of the module (Crane et al., 2018; Garnett et al., 2019b). These findings, alongside user feedback and usage data on the most frequently visited screens, guided the decision to remove the Identity Change module.”"
}
]
}
] | 1
|
https://f1000research.com/articles/10-511
|
https://f1000research.com/articles/10-342/v1
|
05 May 21
|
{
"type": "Research Article",
"title": "Design of a soft sensing technique for measuring pitch and yaw angular positions for a Twin Rotor MIMO System",
"authors": [
"Sneha Nayak",
"Sravani Vemulapalli",
"Santhosh Krishnan Venkata",
"Meghana Shankar",
"Sneha Nayak",
"Sravani Vemulapalli",
"Meghana Shankar"
],
"abstract": "Background: This paper presents a soft sensor design technique for estimation of pitch and yaw angular positions of a Twin Rotor MIMO System (TRMS). The objective of the proposed work was to calculate the value of pitch and yaw angular positions using a stochastic estimation technique. Methods: Measurements from optical sensors were used to measure fan blade rotations per minute (RPM). The Kalman filter, which is a stochastic estimator, was used in the proposed system and its results were compared with those of the Luenberger observer and neural network. The Twin Rotor MIMO System is a nonlinear system with significant cross coupling between its rotors. Results: The estimators were designed for the decoupled system and were applied in real life to the coupled TRMS. The convergence of estimation to the actual values was checked on a practical setup. The Kalman filter estimators were evaluated for various inputs and disturbances, and the results were corroborated in real time. Conclusion: From the proposed work it was seen that the Kalman filter had at least Integral Absolute Error (IAE), Integral Square Error (ISE), Integral Time Absolute Error (ITAE) as compared to the neural network and the Luenberger based observer.",
"keywords": [
"Kalman filter",
"Twin Rotor MIMO system",
"analytical redundancy",
"neural network",
"Luenberger observer",
"soft sensing"
],
"content": "Introduction\n\nStudy of aerospace systems has always been a subject of interest by many researchers, engineers, and technical students. However, it is practically very difficult to analyse these aerospace systems, so a replica is designed to understand the behaviour of the actual systems. One such system, which replicates the behaviour of a helicopter system, is a TRMS. The TRMS has two of the three movements of a helicopter, pitch angle and yaw angle.1 The TRMS position is controlled by the rotor speed. The two input variables to the TRMS are voltage to the main rotor and tail rotor, and the outputs are the pitch and yaw angle as shown in Figure 1. Excitation to these motors is given by a controller based on a set point given by user. Desired control action can be achieved only by accurate measurements of pitch and yaw.\n\nSeveral researchers have reported work on computing the yaw and pitch positions using different techniques.1–5 Different algorithms are incorporated to maintain and retain the stability of the TRMS. Controllers like Proportional Integral Derivative (PID), fuzzy PID, sliding mode controller, fuzzy sliding mode controllers and estimators like Luenberger and Kalman are incorporated on the TRMS.2 Rahideh and Shaheed3 discussed the design of a model predictive controller for a TRMS. The controller is simulated based on the state model using motor armature current and angular speed as inputs. Jahed and Farrokhi4 discussed the design of a fuzzy based robust control for a TRMS using angular speed given by tachometer in a simulation platform, and Tao et al.5 discussed the fuzzy sliding and integral sliding controller design for a TRMS. In Rohith,6 a new control law was proposed for the design of sliding motor controllers, which mitigate the chattering problem with the gain variation and thereby guarantees faster system response and robustness. Design of an auto tuning based PID controller with fractional-order reference model approximation for a DC rotor in a TRMS model is discussed in Alagoz et al.7 The data regarding the process variable is derived from the angular position of pitch and yaw. In Patel and Janardhanan,8 a tuning method based on the Moore Skelboe Algorithm for a PID controller was presented. This was effective in finding the optimal PID values for the given initial range and applicable for some of the higher-order Linear Time Invariant (LTI) systems as well as for all first and second order linear time invariant systems. Further the method was effective in stabilizing unstable systems. Halim and Ismail9 presented a PID controller tuning using tree physiology optimization, which was based on the tree growth concept whose simulation results showed better results compared to other tuning methods in Single Input Single Output (SISO) and MIMO problems. Rao et al.,10 reported design of an observer using robust PID controller logic with H∞ observer to obtain the stable output in TRMS with sensor and actuator failure. Netto et al.,11 reported an Adaptive PID controller to cancel the effect of cross coupling between the tail rotor and main rotor when operating simultaneously in a TRMS. Adaptive linear quadratic regulator design for stable system operating at a single reference point with six tail and main rotors is reported by Faisal and Omar Waleed.12 Ghellab et al.,13 reported an adaptive radial basis function neural network with a dynamic terminal sliding mode control with cross coupling between tail and main subsystem for tracking the set point in the presence of wind gust and other external disturbance.\n\nIn Sleimi et al.14 a linear time-varying controller was designed using a differential flatness property leading to a two Degree of Freedom (DOF) controller for which the system must be in canonical controllable form with no need to define its dynamics. In Panda et al.15 the proposed control strategy used an adaptive back stepping controller implemented on a Twin Rotor Multi Input Multi Output System. It provided an explicit relationship between the saturation bound of the input signal and upper bounds of tracking errors, uncertainties, and disturbances. Mondal and Dey16 presented the development of a two DOF control system design providing an additional degree of freedom depending on the nature of the plant and loop compensators. The design methodology can be implemented for integer as well as non-integer order plants with better tracking and loop robustness.\n\nNeural network based controller design using model inversion control for a twin rotor MIMO system was reported in Rahideh et al.17 Design of a differential evolution based neural network model to control the TRMS with data of angular positions was reported by Subudhi and Jena.18 Pratap and Purwar,19 reported implementation of a neuro-adaptive robust back stepping controller for TRMS. Many researchers have worked on the TRMS, but the design technique of most controllers is based on the data received from the sensor. If the sensor data is erroneous the complete system fails. To overcome the above problem, this paper attempts to design a soft sensor or observer for computing the actual yaw and pitch data to the controller. In order to start the design of a soft sensor it is essential to understand the TRMS model.\n\nThe TRMS dynamics are given in Rahideh et al.,20 Sun and Song21 and Ahmad et al.22 It was found that the system was a nonlinear and coupled one with considerable error in the measurements. The method based on the Kalman filter is considered as it provides for updating the estimates based on errors, and also takes into account the process and the measurement noise uncertainties to give out the best estimate. Model dynamics of the system are known and are used for estimation. The Kalman filter is widely used as a state estimator and is used in various fields. For example, the Kalman filter is used to estimate track soil parameters,23 for tracking objects in videos based on color features and mean shift,24 for estimation of flow rate and isolation of occurrence of fault,25 for estimation of wind speed and comparison with the estimation from Takagi-Sugeno observers.26\n\nThe TRMS is a prototype device used to understand the dynamics of a helicopter system. It consists of two rotor fans to operate the device in two Degrees of Freedom (2-DoF). For controlling/stabilizing the system performance based on a desired set point, it is essential to sense the actual pitch and yaw positions. The presence of faults during data transmission to the controller lead to the controller failing to take the desired action and thus the system destabilizes. Hence, a technique is proposed with the objective of designing an estimator so that it can be used in case of any contingencies. The Kalman filter technique is used to design the estimators for estimating the pitch and yaw position of the TRMS. In order to verify the effectiveness of the algorithm, it is applied to the system in real life and compared with the actual trajectory of the response. The performance of the designed Kalman filter for estimating angular pitch and yaw information is compared with the Luenberger observer and neural network estimator to evaluate its performance. The outline of the work carried out is shown in Figure 2.\n\n\nMethods\n\nThe twin rotor MIMO system is a prototype of a helicopter propeller system. It is shown in Figure 3. The system was a non-linear MIMO system with significant cross-coupling. The angle of attack of the rotors was fixed and the aerodynamic forces were controlled by varying the speed of the motors. Significant cross-coupling was observed between the actions of the rotors, with each rotor influencing both angle positions. Two propellers were driven by DC motors controlled by their supply voltages. The measured signals were positioned on the beam in the space i.e. two position angles which are measured by rotary optical encoders mounted on each of the rotor shafts. The measured output was obtained from the rotary optical encoders. It was calibrated for the inertial axis using the loop up table approach.19, 20\n\nThe TRMS has two modes of operation, namely, 1-DOF control and 2-DOF control. In 1-DOF control, the pitch and the yaw are controlled individually and independently, whereas in 2-DOF control the pitch and the yaw are controlled simultaneously in a coupled system. The block diagram of the proposed scheme is shown in Figure 4. Here the coupled TRMS was controlled by two separate PID controllers for the pitch and the yaw respectively. The controllers were tuned to maintain the angles at the desired positions or set point, except in the event of some contingency such that the pitch or the yaw failed to maintain the desired position. The transient output of the sensors was used to design an estimator to find the angles where models were generated using a system identification process. A decoupled pitch and yaw model was used for designing the estimator. In this case pitch and yaw angles were independently calculated using the Kalman filter.\n\nThe Kalman filter is developed from the Bayesian filter. It was initially used to extract the signal from the noisy output data of sensors, and/or actuators.27–29 Over time, it has been used as a state estimator also. It is a stochastic estimator and requires explicit modeling of the process noise and the measurement noise in addition to the system model. The Kalman filter estimation is a two-step process. Initially it generates an estimate from the knowledge of the system dynamics, which is embedded in the system model along with the noise model. This is called the apriori estimate. Once the measurement output is available, the apriori estimate is updated to the posteriori estimate. The second stage involves the Kalman gain which is altered in every step based on an optimization problem. The Kalman gain was the main feature of this estimator and it decided if the estimate derived much of its information from the measurement output or the system dynamics. Hence, the Kalman gain was also updated on every step such that the error between the actual output and the estimate was reduced i.e. the residue reduced to zero. The noise covariance matrix was also updated at each step based on the error. Here the Markovian model was used where the state was said to be Markovian but the measurement was usually not Markovian. Also, we considered the process noise and measurement noise as Gaussian and they were not correlated with each other. It is also called the Gauss-Markov model. This allows nonlinearity. The mean was assumed to be zero for both measurement and process noises. Covariance was chosen in this case such that the covariance of measurement noise was slightly less than the covariance of the process noise. In general, the probability distribution of the state is given by equation (1)\n\nwhere pXk+1was determined by pWkwhich was the probability distribution of the process noise. The system state Xk was modeled as a linear combination of the previous states along with the input U and the process noise W, as given in equation (2)\n\nFor the considered TRMS, the matrices for the decoupled pitch model were found to be:\n\nThe matrices for the decoupled yaw model were found to be:\n\n\n\nThe measurement obtained was modeled as a linear combination of the system states and measurement noise V as in equation (5)\n\nIn the TRMS model, the measured output i.e. pitch and yaw, were related to states directly through output matrices S i.e. Hp=Sp, Hy=Sy. Hence for pitch, Hp=0.01660.41942.454. For Yaw,Hy=0.0010.03360.4065. Let Q and R be processed noise covariance and measurement noise covariance respectively. The apriori error covariance P is given by equation (6).\n\nOnce the measurement was obtained, the Kalman gain was computed and the apriori state estimates and the apriori error covariance were updated as follows:\n\nKalman gain:\n\nThe posteriori estimate:\n\nThe posteriori error covariance\n\nHere Xk̂ was the estimate of the state at k given the measurement at k and the apriori estimate Xk at time k. Also, it should be noted that the Kalman filter was a one step ahead predictor. The noise covariance matrices R and Q were the most complex matrices to compute, therefore the idea was to start with an initial estimate of identity matrices for both R and Q and to change them based on the convergence between the actual and the estimated outputs. The Kalman filter estimated the states. However, the objective was to estimate the pitch and the yaw which were the output of the TRMS. Hence, the output was obtained from equation (10).\n\nand the output residue (error) was given by equation (11)\n\nError,\n\nwhere Y′k was the actual value of pitch and yaw\n\nThe Kalman filter provided a stochastic method of estimation, whereas the Luenberger observer and neural network provided a deterministic method of estimation of the states. The estimation of yaw and pitch carried out with these deterministic methods had a poorer performance due to their inability to incorporate uncertainties that emerge inherently in any real systems, such as the uncertainties due to modeling errors or sensor output errors. However, these estimates can be feasible if the error margin is not very stringent.\n\nLuenberger based observers are widely used for numerous applications and modified according to the type of the system.27 The extended Luenberger observer and adaptive Luenberger observer are the latest class of these observers.27 The Luenberger observer is used for estimation of battery charge for electric vehicles,30 flux in motor drives,31 motorcycle dynamics,32 sensor-less speed estimation.33 The scheme of this observer is shown in Figure 5. The following were the expressions for the observer design from Figure 5.\n\nAssume a plant:\n\nState equations of the observer:\n\nFrom equation 17, it is understood that if the eigenvalues were all negative, the estimated state vector error, ex, would decay to zero. The design then consisted of solving for the values of L to yield a desired characteristic equation.\n\nThen the selection of eigenvalues for the observer was carried out to achieve a required closed loop response. These eigenvalues determined a characteristic equation that was made equal to equation 19 to solve for L. The poles for the observer for both pitch and yaw were chosen to be at -1, -2, and -3.\n\nThe Luenberger gain L for pitch was:\n\nThe Luenberger gain L for yaw was:\n\nThe estimation based on the neural network was based on a time series correlation between the input and the output, also called the targets. This assumed a black body model, where the dynamics of the system were not explicitly parameterized and the forecasting was done only from the input output relationship of the system. Here the neural network was trained to replicate the behavior of the system by using the given set of input output pair of data. The Levenberg-Marquardt algorithm with a back-propagation network having one hidden layer with a size of 10 neurons, which was used to predict the output i.e. the pitch and the yaw from the input. The neural network used for the present work is shown in Figure 6. The ‘nftool’ of MATLAB version R2014a,34 provided the platform to train the neural network and this was used in the current work. The regression graph for the trained neural network is shown in Figure 7 for pitch and Figure 8 for yaw systems.\n\n\nResults\n\nA soft sensor for computing the yaw and pitch in TRMS using three different techniques, a neural network, Kalman filter, and a Luenberger observer, was designed. It was subjected to tests in real life. Tests were conducted by applying input and disturbance. The response of the proposed sensing system using the Luenberger observer is represented in Figures 9-12. The output obtained for the Kalman filter is shown in Figures 13 and 14. Similarly, the output obtained from the neural network is shown in Figures 15 and 16. From the responses it was found that the proposed sensing technique was able to track the pitch and yaw positions accurately in a practical system. The performance measures IAE, ISE, and ITAE were used to quantitatively compare the outputs obtained from the Luenberger observer, Kalman filter, and neural network estimator. The results of these for the pitch and yaw measurement are shown in Figures 17 and 18, respectively. This method provided a way to classify the errors that occurred in different stages of the system operation and provided a means to judge the accuracy of estimation. The estimator having the highest number of errors was not accurate. The steady state of the system occurred at around time = 50 seconds, and the errors at that instant for all the estimators were tabulated for pitch and yaw measurements in Table 1.35\n\n\nDiscussion and Conclusions\n\nTwin rotor multi input systems are fundamental for any aerial system, analysis of any property on the TRMS makes it important when designing any system further. The TRMS contains a motor system along with a sensor system for testing. Sensors are an integral part of the TRMS for providing actual information to the controller. Failure of the sensors would lead to errors in control action and thus lead to system failure. An attempt was made in this work to design an observer-based system, which would function accurately even with sensor faults. The effectiveness of the Kalman filter algorithm for estimation of pitch and yaw angular positions was verified in real life on the TRMS with external disturbances. The estimate was updated at every sampling time to predict the yaw and pitch for angular positions for the given input and measurement data. The performance of the Kalman filter was compared with that of the neural network and Luenberger observer. From the results of IAE, ISE, and ITAE, the error was least when using the Kalman filter followed by the Luenberger observer and lastly, the neural network. Hence, the estimation by the Kalman filter was more accurate during both transient and steady states.\n\n\nData Availability\n\nOpen Science Framework: Extended data for ‘Design of a soft sensing technique for measuring pitch and yaw angular positions for a Twin Rotor MIMI System’, https://doi.org/10.17605/OSF.IO/52V9D.35\n\nThis project contains the following extended data:\n\n• Supplementary Video 1: Experimental model of a soft sensor design technique for estimation of pitch and yaw angular positions of a Twin Rotor MIMO System (TRMS)\n\n• Supplementary Data 1: Simulink file used to carry out the real time experimentation of TRMS system.\n\nData are available under the terms of Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nSilva A, Caminhas W, Lemos A, et al.: Real-time nonlinear modeling of a twin rotor MIMO system using evolving neuro-fuzzy network. IEEE Symposium on Computational Intelligence in Control and Automation (CICA). 2014: 1–8. Publisher Full Text\n\nEzekiel DM, Samikannu R, Matsebe O: Pitch and Yaw Angular Motions (Rotations) Control of the 1-DOF and 2-DOF TRMS: A Survey. Archives of Computational Methods in Engineering. 2020: 1–10. Publisher Full Text\n\nRahideh A, Hasan Shaheed M: Stable model predictive control for a nonlinear system. J Franklin Institute. 2011;384: 1983–2004. Publisher Full Text\n\nMaryam J, Mohammed F: Robust adaptive fuzzy control of twin rotor MIMO system. Jr. of Soft Computing. 2013; 17: 1847–1860. Publisher Full Text\n\nTao C-W, Taur J-S, Chang Y-H, et al.: A novel fuzzy-sliding and fuzzy-integral sliding controller for the Twin-Rotor Multi-Input-Multi-Output system. IEEE Transactions on fuzzy system. 2010; 18(5): 893–904. Publisher Full Text\n\nRohith G: Fractional power rate reaching law for augmented sliding mode performance. J Franklin Institute. 2021; 358(1): 856–876. Publisher Full Text\n\nAlagoz BB, Abdullah A, Celaleddin Y: Auto-tuning PID controller according to fractional-order reference model approximation for DC rotor control. Mechatronics J. 2013; 23: 789–797. Publisher Full Text\n\nPatel P, Janardhanan S: Near Optimal PID Controller Tuning: Interval Arithmetic Approach. IFAC-PapersOnLine. 2020; 53(1): 246–251. Publisher Full Text\n\nHalim AH, Ismail, et al.: Tree physiology optimization on SISO and MIMO PID control tuning. Neural Computing and Applications. 2019; 31(11): 7571–7581. Publisher Full Text\n\nRao VS, George VI, Kamath S, et al.: Reliable robust PID controller design for TRMS. 11th Asian Control Conference (ASCC). 2017: 565–569. Publisher Full Text\n\nNetto W, Lakhani R, Sundaram SM: Design and performance comparison of different adaptive control schemes for pitch angle control in a Twin-Rotor-MIMO-System. Int J Elec Comp Eng. 2019; 9(5): 2088–8708. Publisher Full Text\n\nFaisal RF, Abdulwahhab OW: Design of an Adaptive Linear Quadratic Regulator for a Twin Rotor Aerodynamic System. J Control, Automation Electrical Syst. 2021; 32: 404–415. Publisher Full Text\n\nGhellab MZ, Zeghlache S, Djerioui A, et al.: Experimental validation of adaptive RBFNN global fast dynamic terminal sliding mode control for twin rotor MIMO system against wind effects. Measurement. 2021; 168: 108472. Publisher Full Text\n\nSleimi M, Abdallah MB, Ayadi M: Discrete-Time Flatness-Based Control Design for LTV MIMO Systems. Arab J Sci Eng. 2019; 44(3): 2389–2398. Publisher Full Text\n\nPanda M, Peyada NK, Ghosh A: Saturated Adaptive Backstepping Control of Uncertain Nonlinear Systems with Validation using Twin Rotor System. J Franklin Institute. 2020; 357(18): 13477–13510. Publisher Full Text\n\nMondal R, Dey J: Fractional order (FO) two degree of freedom (2-DOF) control of linear time invariant (LTI) plants. ISA Trans. 2020; 96: 352–366. PubMed Abstract | Publisher Full Text\n\nRahideh A, Bajodah AH, Shaheed MH: Real time adaptive nonlinear model inversion control of a twin rotor MIMO system using neural networks. Eng App Artifi Intell. 2012; 25: 1289–1297. 10.1016/j.engappai.2011.12.006\n\nSubudhi B, Jena D: A differential evolution based neural network approach to nonlinear system identification. Applied soft computing. 2011; 11: 861–871. Publisher Full Text\n\nPratap B, Purwar S: Real-time implementation of neuro adaptive observer-based robust back stepping controller for twin rotor control system. J Control Auto Elec Syst. 2014; 25: 137–150. Publisher Full Text\n\nRahideh A, Shaheed MH, Huijberts HJC: Dynamic modelling of a TRMS using analytical and empirical approaches. Control Eng. Practice. 2008; 16: 241–259. Publisher Full Text\n\nSun T, Song YG: Study on a method for unmanned helicopter flight dynamics model identification. Acta Aeronaut Astronaut Sin. 2007; 28: 14–18. Publisher Full Text\n\nAhmad SM, Shaheed MH, Chipper AJ, et al.: Non-linear modeling of a one- degree-of-freedom twin-rotor multi-input multi-output system using radial basis function networks. J Aero eng. 2002; 216(4): 197–208. Publisher Full Text\n\nYao Y, Cheng K, Zhou Z-J, et al.: A novel method for estimating the track-soil parameters based on Kalman and improved strong tracking filters. ISA Trans. 2015; 59: 450–456. PubMed Abstract | Publisher Full Text\n\nMazinan AH, Amir-Latifi A: Applying mean shift, motion information and Kalman filtering approaches to object tracking. ISA Trans. 2012; 51: 485–497. PubMed Abstract | Publisher Full Text\n\nNanditha N, Santhosh KV: Sensor fault isolation in a liquid flow process using Kalman filter. Automatic Control Computer Sciences. 2019; 53(4): 310–319. Publisher Full Text\n\nGauterin E, Kammerer P, Kühn M, et al.: Effective wind speed estimation: Comparison between Kalman Filter and Takagi-Sugeno Observer Techniques. ISA Trans. 2016; 62: 60–72. PubMed Abstract | Publisher Full Text\n\nTangirala AK: Principles of system identification Theory and Practice. CRC Press;2014.\n\nDan S: Optimal state estimation: kalman, H infinity, and Nonlinear Approaches.Wiley Publishers; 2006.\n\nSimon Haykin S: Kalman Filtering and Neural Networks. John Wiley & Sons Inc;2001.\n\nHu X, Sun F, Zou Y: Estimation of state of charge of a lithium-ion battery pack for electric vehicles using an adaptive Luenberger observer. Energies. 2010; 3(9): 1586–1603. Publisher Full Text\n\nOrlowska-Kowalska T: Application of extended Luenberger observer for flux and rotor time-constant estimation in induction motor drives. IEE Proceedings D (Control Theory and Applications). 1989; 136(6): 324–330.\n\nDamon P-M, Dabladji H, Ichalal D, et al.: Estimation of lateral motorcycle dynamics and rider action with luenberger observer. IEEE 19th International Conference on Intelligent Transportation Systems (ITSC). 2016: 2392–2397. Publisher Full Text\n\nYou J, Wu W, Wang Y: An adaptive luenberger observer for speed-sensorless estimation of induction machines. Annual American Control Conference (ACC). 2018: 307–312. Publisher Full Text\n\nThe Math Works, Inc., MATLAB: Version R2014a. The Math Works, Inc., Natich, MA.2020. Reference Source\n\nSanthosh KV, Sneha Nayak, Sravani V, et al.: TRMS. OSF. 2021. Publisher Full Text"
}
|
[
{
"id": "92431",
"date": "16 Sep 2021",
"name": "Abuabiah Mohammad",
"expertise": [
"Reviewer Expertise Control",
"system identification",
"mechatronics systems",
"automotive"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nContribution: The paper addresses the problem of estimation pitch and yaw angular positions of a Twin Rotor MIMO System (TRMS) using the soft-sensor technique. In particular, the authors propose an estimation to calculate the value of pitch and yaw angular positions using Kalman filter, Luenberger observer and neural network. More specifically, measurements from optical sensors were used to measure fan blade rotations per minute (RPM), and then Kalman filter estimators were evaluated for various inputs and disturbances. Finally, different experimental results have been presented to compare Kalman filter estimation with those of the Luenberger observer and neural network. The results show that the Kelman filter has the least IAE, ISE and ITAE as compared to the two other mentioned methods.\nGeneral Evaluation: The submitted paper has some novelty in the field of soft sensing techniques using the Kelman filter approach for the Twin Rotor MIMO system. Although the paper suffers from a lack of deep analysis and comparison with other previous works, it is the reviewer opinion that the presented approach is of some interest since it provides an approach for estimating TRMS using Kalman filter in a comparison with Luenberger observer and neural network approach.\nAll considered, it is my opinion that the paper deserves the merit to be considered for publication, provided that the comments reported below are properly taken into account by the authors.\nComments: The paper in general is organized. However, the authors are invited to take into account the following comments in order to improve the quality of the contribution.\n1) It is my opinion that the literature review is not satisfactory. Although the authors mentioned some of the previous methods related to the topic, they didn't provide a full literature overview of the proposed problem and more specifically to model estimation of the TRMS system. The authors are advised to add e.g., the work of A. Tastemirov et al. (2017)1, R. Maiti et al. (2018)2, S. Miah et al. (2019)3, etc. and to provide a discussion on the comparison between such works and the proposed approach.\n\n2) It is not clear on which basis the poles for the observer for both pitch and yaw were chosen to be at -1, -2, and -3. The authors are advised to add more details about the chosen values and how these can affect the accuracy of the obtained model.\n3) The matrices for the decoupled pitch and yaw models in Equations 3 and 4 are exactly the same; which is strange. The authors are advised to re-check again the values and discuss more the founded model. Moreover, the Sy matrix is not clear, there should be spaces between each column.\n\n4) R and Q matrices computation was missing or not well discussed. The authors are advised to explain more the procedure they used to compute R and Q and how this leads to equation 10.\n\n5) An explanation of Fig. 2 is missing. The authors are advised to comprehensively discuss the outline of this paper. Furthermore, it suggested removing any literature that is out of the scope of the provided topic (e.g., 23 - 26).\n\n6) The authors stated the following \"The estimator having the highest number of errors was not accurate\" on page 11. However, it is not so clear and it is suggested to re-write it in a better way.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7433",
"date": "20 Jan 2022",
"name": "Santhosh Venkata",
"role": "Author Response",
"response": "1) It is my opinion that the literature review is not satisfactory. Although the authors mentioned some of the previous methods related to the topic, they didn't provide a full literature overview of the proposed problem and more specifically to model estimation of the TRMS system. The authors are advised to add e.g., the work of A. Tastemirov et al. (2017)1, R. Maiti et al. (2018)2, S. Miah et al. (2019)3, etc. and to provide a discussion on the comparison between such works and the proposed approach. Response: Thank you for the suggestion, we have included recent and relevant publications in the literature review. 2) It is not clear on which basis the poles for the observer for both pitch and yaw were chosen to be at -1, -2, and -3. The authors are advised to add more details about the chosen values and how these can affect the accuracy of the obtained model. Response: Any observer design aims to drive the error between the outputs of the plant and observer to zero. The error function is multiplied with the gain which enhances the convergence of the estimates to the true states. A high gain leads to fast convergence but too high causes a peaking phenomenon. By choosing the eigenvalues of the observer on the left half of the s-plane, the error dynamics can be controlled appropriately. For computation, poles are considered by multiplying by at least 10 times to the poles of the system. 3) The matrices for the decoupled pitch and yaw models in Equations 3 and 4 are exactly the same; which is strange. The authors are advised to re-check again the values and discuss more the founded model. Moreover, the Sy matrix is not clear, there should be spaces between each column. Response: The decoupled pitch model was found to be: Fp=-1.4389-3.1862 1.67060.0803-4.9874 -29.1821-0.0376 0.0474 -5.5737; Gp=100 Sp=0.0166 0.4194 2.454; D=0 (3) The matrices for the decoupled yaw model were found to be: Fy=-1.38-1.6456-14.76110.9244-2.5724-31.1124-0.01960.3346-8.0476; Gy=100 Sy=0.001 0.0336 0.4065; D=0 (4) Both the equations were rechecked. Sorry for the representation, Fy is a 3x3 matrix, Gy is 3x1 and Sy is a 1x3 matrix. 4) R and Q matrices computation was missing or not well discussed. The authors are advised to explain more the procedure they used to compute R and Q and how this leads to equation 10. Response: the noise covariance matrices R and Q are the most complex matrices to compute, therefore the idea is to start with an initial estimate of identity matrices for both R and Q and to change it based on the convergence between the actual and the estimated outputs. 5) An explanation of Fig. 2 is missing. The authors are advised to comprehensively discuss the outline of this paper. Furthermore, it suggested removing any literature that is out of the scope of the provided topic (e.g., 23 - 26). Response: Thank you for the suggestion, we have added an explanation for Figure 2 and removed the literature as suggested. 6) The authors stated the following \"The estimator having the highest number of errors was not accurate\" on page 11. However, it is not so clear and it is suggested to re-write it in a better way. Response: Sorry for that, we have revised the paragraph so, as to prove improvement to the work."
}
]
},
{
"id": "92429",
"date": "21 Sep 2021",
"name": "Sudhakar Kumarasamy",
"expertise": [
"Reviewer Expertise Solar energy",
"Energy modelling",
"Energy systems"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nNayak et al., have carried out a study of soft sensing technique for measuring pitch and yaw angular positions for a Twin Rotor MIMO System. The research result is interesting. However some suggestions are provided to improve the quality and presentation of the study:\nPlease maintain consistency in the use of Terminologies. For instance , is it MIMO or MIMI?\n\nSome sentences are difficult to read or incomplete (e.g. \"Twin rotor multi input systems are fundamental for any aerial system, analysis of any property on the TRMS makes it important when designing any system further; It was subjected to tests in real life\"). Sentence structure and rephrasing is needed.\n\nProvide list of Abbreviations: TRMS, MIMO, MIMI IAE, ISE, and ITAE.\n\nInstead of Comparative graphs, it may be mentioned as Comparative results.\n\nDistinguish the various soft sensing technique in terms of the stochastic methods? Which among the studied are stochastic and deterministic?\n\nThe Luenberger observer based system, Kalman filter algorithm and gain, and neural network model using Levenberg-Marquardt algorithm and gain.\n\nThe various gain values and the noise covariance may be compared in a tabular format.\n\nThe transient, steady states, 1-DOF control and 2-DOF control may be explained a bit clearly in the methodology and results section.\n\nPlease provide the technical details of the TRMS containing the Twin Rotor motor system and the sensor system.\n\nThe neural network regression model results for both pitch and yaw control may be introduced under the results section.\n\nWhat is the major contribution of this study? The soft sensing technique designed and tested for the senor motor by the authors is useful for other applications? Please elaborate on those aspects.\n\nWhat are the major limitations and future scope of the study.\n\nThe conclusion lacks significant numbers to support the major outcome of the study.\n\nList down the key conclusion on the various numerical values obtained from the study.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? 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": "7434",
"date": "25 Nov 2021",
"name": "Santhosh Venkata",
"role": "Author Response",
"response": "Reviewer 2: Comments: Nayak et al., have carried out a study of a soft sensing technique for measuring pitch and yaw angular positions for a Twin Rotor MIMO System. The research result is interesting. However, some suggestions are provided to improve the quality and presentation of the study: Please maintain consistency in the use of Terminologies. For instance, is it MIMO or MIMI? Response: Sorry for the mistake, we have consistently used MIMO, in the revised article. Some sentences are difficult to read or incomplete (e.g. \"Twin rotor multi-input systems are fundamental for any aerial system, analysis of any property on the TRMS makes it important when designing any system further; It was subjected to tests in real life\"). Sentence structure and rephrasing are needed. Response: Sorry for the mistake, the sentence is rephrased. Provide a list of Abbreviations: TRMS, MIMO, MIMI IAE, ISE, and ITAE. Response: As suggested a table for abbreviation is provided. Instead of Comparative graphs, it may be mentioned as Comparative results. Response: As suggested the comparative graphs is changed to comparative results Distinguish the various soft sensing technique in terms of the stochastic methods? Which among the studied are stochastic and deterministic? Response: As suggested we have added details about the sensing technique. The Luenberger observer-based system, Kalman filter algorithm and gain, and neural network model using Levenberg-Marquardt algorithm and gain. The various gain values and the noise covariance may be compared in a tabular format. Response: As suggested a comparative analysis of various system gains is provided in the revised version. The transient, steady states, 1-DOF control, and 2-DOF control may be explained a bit clearer in the methodology and results section. Response: As suggested details are presented in the results section Please provide the technical details of the TRMS containing the Twin Rotor motor system and the sensor system. Response: Thank you for the suggestion, we have included details of the TRMS. The neural network regression model results for both pitch and yaw control may be introduced under the results section. Response: As suggested results of both pitch and yaw are moved to results sections. What is the major contribution of this study? The soft sensing technique designed and tested for the senor motor by the authors is useful for other applications? Please elaborate on those aspects. Response: As suggested details are included in the conclusion. What are the major limitations and future scope of the study? Response: As suggested details are included in the conclusions. The conclusion lacks significant numbers to support the major outcome of the study. Response: As suggested, outcomes are included in the conclusion List down the key conclusion on the various numerical values obtained from the study. Response: As suggested, numerical values are included in the conclusion."
}
]
}
] | 1
|
https://f1000research.com/articles/10-342
|
https://f1000research.com/articles/10-1197/v1
|
24 Nov 21
|
{
"type": "Research Article",
"title": "Comparing the first and second waves of COVID-19 in a tertiary university hospital in Barcelona",
"authors": [
"Yolima Cossio",
"Marta-Beatriz Aller",
"Maria José Abadias",
"Jose-Manuel Domínguez",
"Maria-Soledad Romea",
"Maria-Àngels Barba",
"Maria-Isabel Rodríguez",
"Antonio Roman",
"Albert Salazar",
"Marta-Beatriz Aller",
"Maria José Abadias",
"Jose-Manuel Domínguez",
"Maria-Soledad Romea",
"Maria-Àngels Barba",
"Maria-Isabel Rodríguez",
"Antonio Roman",
"Albert Salazar"
],
"abstract": "Background:\nHospitals have constituted the limiting resource of the healthcare systems for the management of the COVID-19 pandemic. As the pandemic progressed, knowledge of the disease improved, and healthcare systems were expected to be more adapted to provide a more efficient response. The objective of this research was to compare the flow of COVID-19 patients in emergency rooms and hospital wards, between the pandemic's first and second waves at the University Hospital of Vall d’Hebron (Barcelona, Spain), and to compare the profiles, severity and mortality of COVID-19 patients between the two waves. Methods:\nA retrospective observational analysis of COVID-19 patients attending the hospital from February 24 to April 26, 2020 (first wave) and from July 24, 2020, to May 18, 2021 (second wave) was carried out. We analysed the data of the electronic medical records on patient demographics, comorbidity, severity, and mortality. Results: The daily number of COVID-19 patients entering the emergency rooms (ER) dropped by 65% during the second wave compared to the first wave. During the second wave, patients entering the ER were significantly younger (61 against 63 years old p<0.001) and less severely affected (39% against 48% with a triage level of resuscitation or emergency; p<0.001). ER mortality declined during the second wave (1% against 2%; p<0.000). The daily number of hospitalised COVID-19 patients dropped by 75% during the second wave. Those hospitalised during the second wave were more severely affected (20% against 10%; p<0.001) and were referred to the intensive care unit (ICU) more frequently (21% against 15%; p<0.001). Inpatient mortality showed no significant difference between the two waves. Conclusions: Changes in the flow, severity and mortality of COVID-19 patients entering this tertiary hospital during the two waves may reflect a better adaptation of the health care system and the improvement of knowledge on the disease.",
"keywords": [
"covid-19",
"hospital management",
"tertiary hospital"
],
"content": "Introduction\n\nThe COVID-19 pandemic has challenged healthcare systems around the world.1 Hospitals with the capacity to undertake critical patients in intensive care units (ICUs) have constituted the limiting resource of the healthcare systems for the management of the pandemic. ICUs possess essential equipment such as mechanical ventilators and monitoring devices that have enabled the provision of vital support to COVID-19 patients developing a severe form of the disease.2 As a consequence, hospitals, especially tertiary ones, have had to reorganize their activity to make available the largest number of beds for treating COVID-19 patients, including ICU beds, to manage the progressive surge in demand, while trying to maintain essential hospital services.3\n\nAs many other countries, Spain has been seriously affected by the COVID-19 pandemic, and a significant number of confirmed cases and deaths have been reported. The first case of COVID-19 was confirmed on January 31 in La Gomera in the Canary Islands. Six weeks later, on March 14, Spain declared a state of emergency and imposed rigorous lockdown measures to the population,4 that enabled a sustained decrease in the accumulated incidence of COVID-19 in the population.5,6 After the end of the first pandemic wave, the measures to contain the disease were relaxed during the summer, and the incidence of cases began to rise slowly in some Spanish regions such as Catalonia, starting the second wave.\n\nAlthough we do not have conclusive data about a potential increase of aggressiveness of the virus, both the virus and our knowledge of the disease have evolved over time, as well as the adaptation of health systems to cope with the pandemic. We could therefore expect differences in the number, severity and outcomes of patients admitted in healthcare services, including tertiary hospitals. Several studies pointed out differences in the epidemiological and clinical behaviour of the pandemic waves in terms of severity, transmission and dissemination of the virus.7,8 Incidence levels showed different patterns between waves, with the number of cases being higher in the second wave in comparison to the first one, probably as a consequence of the shortage of diagnostic testing in the first wave, causing declared numbers underestimating real numbers.8 Moreover, the second wave showed a behaviour of multiple peaks that may reflect the mobility of the population,9 while the incidence decrease may be connected to an increase in containment measures.9,10 There have been significant improvements in the clinical knowledge of the disease that may have affected the flow of hospitalized patients, as well as their severity and outcome. These include a better approach to treatment,11,12 and a better understanding of prognostic factors13 that may have served to optimize treatment, and resource management strategies in the care of COVID-19 patients. Finally, the adaptation of healthcare systems may have also modified the profile and flow of patients entering the hospitals. In Catalonia, there has been a progressive adaptation of health services to better allocate patients according to the complexity of care needed.14 While in the first wave COVID-19 care was mainly hospital-centered, with scarce territorial coordination, there has been a progressive increase in coordination between healthcare levels, including the definition of clear roles and care protocols for the primary care.15 In addition, key strategies have been implemented to protect vulnerable groups, such as the systematic COVID-19 screening in nursing homes16 and vaccination campaigns.17\n\nTertiary hospitals are expected to treat complex patients requiring a more specialized care. During the first wave, hospitals have been the first contact with the healthcare system for many COVID-19 patients, almost resulting in its collapse. As the pandemic progressed, knowledge of the disease improved and healthcare systems adapted to provide a more efficient response. As a consequence, tertiary hospitals might have mainly received the most severe COVID-19 cases. However, few data are available to analyse how the profile and severity of COVID-19 patients entering tertiary hospitals has evolved over time. The aim of this study was to compare the flow, profile, severity and mortality of COVID-19 patients, during the first and second waves of the pandemic at the University Hospital of Vall d’Hebron (Barcelona).\n\n\nMethods\n\nThis study was approved by the Clinical Research Ethics Committee at the Hospital Universitari Vall d’Hebron from Barcelona (Spain), in session Number 497 on 30 July 2021. No consent from the participants was required for this study since this is a retrospective research study based on anonymous and de-identified data.\n\nThis retrospective, exploratory, observational analysis compared demographic, clinical and outcome data of COVID-19 patients attending the Vall d’Hebron University Hospital (HUVH), from February 24 to April 26, 2020 (first wave) and from July 24, 2020 to May 18, 2021 (second wave). The HUVH is a 1,100-bed university hospital in Barcelona, the second largest hospital in Spain, and is part of the Catalan Public Healthcare System, which provides universal coverage to the population. The hospital works in close coordination with other healthcare organisations in the region, including one secondary care hospital, three intermediate care centres and 19 primary care centres. The HUVH hosts over 7,500 healthcare professionals and covers a population of about 450,000 people.\n\nWaves have been defined based on the 14-day cumulative incidence (CI) in Catalonia, which is published by the Catalan Health Department, and is defined as the total number of confirmed cases in the prior 14 days/100,000 population. A CI value equal to or lower than 150 has been set to define the boundaries of the waves, as this value was considered the threshold for a high-risk situation in Spain according to the health authorities.19 We defined February 24, 2020 as the start date of the first wave, when the first case of COVID-19 was reported in Catalonia (Figure 1). The peak of CI during the first wave was on April 1, with a value of 281.26, and the end of the first wave was on April 26, when the CI fell below 150 (147.85). The second wave started on July 24, when the CI exceeded 150 (153.4), reached its peak on October 31 (840.27), and ended on May 18, when the CI fell below 150 (146.89). Data was extracted and frozen on August 16, 2021.\n\nThe orange dashed line shows the cumulative incidence threshold that has been defined as a very high-risk situation in Spain. The blue dashed line represents the two waves of the pandemic in Catalonia according to the criteria defined in the article.\n\nThe study included 8,684 distinct COVID-19 patients who attended the emergency rooms (ER) and/or were hospitalised. Cases were identified using the ICD-10-CM diagnostic codes recorded in the hospital-discharge data: B34.2 and B97.29 (from February 2020) and ICD-10 code U07.1 (from July 1, 2020). Discharge diagnoses of hospitalised patients were registered by specialised coders. To guarantee that we were analysing and comparing data from patients affected by the COVID-19 disease, we only included: i) patients whose primary diagnosis was COVID-19 or, ii) patients with a secondary COVID-19 diagnosis following a first diagnosis of a respiratory system disease (ICD-10-CM code starting by J), or who were described with a Diagnosis Related Groups (DRG) 137 (Infections in major lung inflammations) or 139 (other pneumonia). The selection criteria for the patients attending the ER was to have a confirmed COVID-19 diagnosis, regardless of whether it was a primary or secondary diagnosis.\n\nTo compare the inpatient and emergency flow activity of the HUVH between waves, we created an indicator measuring the total daily number of patients entering the hospital. To compare the characteristics of COVID-19 patients who entered the hospital emergency department and/or were hospitalized, we used data on patient demographics (sex and age) and comorbidity (the adjusted morbidity groups [GMA]). GMA is a validated morbidity measurement developed and adapted to the Spanish Healthcare System that classifies the population into seven morbidity groups, taking into account the typology of their diseases (acute, chronic, or oncological), and in the case of chronic disease, identifying whether it is a single or a multimorbidity. Two additional groups refer to pregnant/childbirth women and populations without previous pathologies.20,21\n\nTo compare the severity of patients attending the ER, we included the type of emergency as defined by the structured triage system for emergency services implemented in Catalonia, which is based on the Australian-Canadian triage systems, and divides the emergencies into five groups: resuscitation, emergent, urgent, less urgent and non-urgent.22 The severity of hospitalised patients’ state was analysed according to the following variables: first, the severity of the episode, as measured by the weight of the diagnosis-related groups (APR- DRG, version 36) and its severity. Changes in the DRG weights of COVID-19-related diagnosis occurred in July 2020, due to 1) the use of the U07.1 diagnosis code for COVID-19, 2) the number of patients accessing the ICU and 3) the overall length of stay (LOS) during the hospitalization and the ICU-specific LOS. Finally, to compare the mortality rates between the two waves, we included three variables: overall mortality during the hospitalization, three-day mortality and mortality of patients who entered the ICU.\n\nData was obtained from the electronic medical records and extracted using structured query language (SQL), to create and anonymized database. The data collection period was defined as per the hospital admission date and only discharged patients’ data was included.\n\nContinuous variables were reported as mean and standard deviation (SD), and median and interquartile range (IQR). Categorical variables were presented as frequency rates and percentages. Continuous variables were compared using the Mann-Whitney U-test, while comparisons of categorical variables were performed using Chi square tests. All analyses were performed using STATA 13.0 (STATA Corp.). A p-value lower than 0.05 was considered as statistically significant.\n\n\nResults\n\nA 65% drop in the daily number of COVID-19 patients entering the ER was observed during the second wave compared to the first wave (17.5 against 49.8 patients per day on average, respectively). The distribution of ER admissions is shown in Figure 2. During the second wave, patients entering the ER were significantly younger (median age of 61 against 63) (Table 1). No significant difference was observed in the percentage of women entering the ER (47.0% and 47.6% during the second and first waves, respectively). During the second wave, patients entering the ER were less severely affected (39.1% against 48.5%, with a triage level of resuscitation or emergency), and the ER mortality significantly declined from 2.3% to 1.2%.\n\nIQR = interquartile range; GMA = adjusted mortality group. Bold p-values represent statistically significant values.\n\nA 75% drop in daily hospitalised COVID-19 patients was observed during the second wave compared to the first wave (7.9 against 32.0 mean patients per day, respectively). The distribution of hospital admissions is shown in Figure 2. No significant differences were found when comparing the median age (Table 2); however, patients older than 80 represented a lower percentage among hospitalised patients during the second wave in comparison to the first wave (8.2% against 11.6%), while patients younger than 18 represented a higher percentage during the second wave (2.7% against 1.7%). The percentage of hospitalized women was significantly lower during the second compared to the first wave (38.8% against 43.9%). In terms of basal morbidity, the most significant difference between waves was found in the population with acute pathologies, which increased during the second wave (5.6% against 2.1%).\n\nIQR = interquartile range. Bold p-values represent statistically significant values.\n\nThe median severity of the hospitalizations significantly increased during the second wave, with those patients hospitalised during the second wave being more severely affected (20.2% had the highest DGR severity score compared to 10.0% during the first wave) and were admitted more frequently to the ICU (20.6% against 15.3%). The median length of stay significantly increased during the second wave (6.6 against 5.9 days during the first wave) while the median ICU length of stay was significantly lower during the second wave (9.8 against 15.2 days during the first wave). Finally, there were no significant differences in inpatient nor in ICU mortality between waves, although the three-day-mortality rate was significantly lower during the second wave (2.1% against 3.1% during the first wave).\n\n\nDiscussion\n\nThe study shows differences in the flow and characteristics of hospitalized patients between the first and second waves of the COVID-19 pandemic at the HUVH. While the daily flow of patients entering the hospital during the second wave was lower, hospitalized patients were more severely affected, and a higher proportion were admitted to the ICU. However, during the second wave, we did not observe any increase of the overall mortality among hospitalized patients, despite the increase in severity.\n\nThe lower daily flow of COVID-19 patients entering the hospital during the second wave contrasts with the increased incidence officially reported in the population during this period.18 This result reflects the adaptation of the health system to tackle the pandemic, with a greater involvement of other healthcare levels in the diagnosis and management of COVID-19 patients.14 During the first wave, hospitals were challenged with the need to simultaneously provide healthcare to a high number of COVID-19 patients, with hospitals centralizing most of the healthcare activity, and reaching a situation close to the collapse. However, the second wave benefited from a more experienced management and the redistribution of the responsibilities at various levels, stratifying patients and referring them to hospitals only upon need.15,23 In addition, during the first wave, there was a limited availability of real-time diagnostic tests in primary care, and the diagnosis of COVID-19 was mainly conducted in hospitals, especially on symptomatic patients.24 Conversely, during the second wave, population screenings were conducted and a rapid diagnosis of COVID-19 was performed mainly at the primary care level. These adaptations of the healthcare system during the second wave may have led to a lower daily flow of patients requiring hospitalization.\n\nThe severity of COVID-19 patients entering the ER and getting hospitalized differed between waves. COVID-19 patients entering the ER during the second wave were less severely ill, whilst the opposite was observed in hospitalizations. The lack of clinical knowledge on the disease and the messages communicated to the population about hospital collapse during the first wave may have contributed to these differences, as well as significant improvements in the coordination of health services produced during the second wave. Regarding the severity of cases in the ER, we measured this parameter according to the structured triage system implemented in Catalonia.22 It is therefore possible that during the first wave, the lack of knowledge of the disease by the personnel responsible for ER triage led to registering patients with a higher level of urgency. During the first wave the population was encouraged to stay at home. This, added to the population’s fear of infection, may have resulted in people being more likely to seek emergency care only when there was a more severe presentation of the disease, with almost no alternatives to seeking care outside of hospitals. Regarding the severity of hospitalised patients, other factors may be contributing to the observed differences, probably related to the adaptation of the healthcare system. In fact, the higher percentage of COVID-19 patients requiring ICU care and being categorised with the highest degree of severity at discharge, may be reflecting the participation of other healthcare levels in the management of COVID-19 that was observed during the second wave14,23; this may have resulted in a better stratification of the patients referred to the hospital, depending on the severity of their symptoms. An increased knowledge on prognostic factors may have also affected the severity of hospitalised patients. While during the first wave any patient with a radiologically-diagnosed pneumonia was hospitalised, during the second wave the hospital implemented protocols to hospitalize patients with a COVID-19 diagnostic according to their prognostic factors. Finally, the observed differences are not expected to be caused by differences in the virus, as new strains of the SARS-CoV-2 virus were detected late in Spain.25\n\nIn addition to differences in the severity of patients entering the hospital between waves, we observed differences in these patients’ profiles in terms of age, sex and comorbidities. First, younger patients were admitted into the ER during the second wave, which is consistent with the lower severity reported in this period. In addition, during the second wave a lower percentage of COVID-19 patients older than 80 and patients without any described comorbidity were hospitalised. The large number of older patients coming from nursing homes during the first wave, most of which presenting a severe condition, together with actions to improve the protection of this population after the first wave26 and their prompt vaccination around mid-January 2021,27 could explain the differences in age distribution between the two waves. Finally, a lower percentage of women were hospitalized during the second wave compared to the first one. As previously described, being male correlates with a more severe COVID-19 profile.28 The increased severity in the hospitalized patients observed during the second wave is correlated with the lower percentage of hospitalized women.\n\nFinally, we did not observe any increase of the overall mortality during the second wave, despite the greater severity of hospitalised patients. Significant improvements in the clinical knowledge of the disease may contribute to explain this result. A large number of drugs have been tested from the start of the pandemic around the world in order to identify effective therapeutic alternatives.29 This led to the identification of a few safe and effective therapeutic approaches in severe cases of the disease, including anticoagulant therapy and corticosteroids.11,12\n\nThis study has some limitations, as it used a limited number of parameters for the analysis. Further analysis including the type of treatments received during the hospitalization, or more detailed information on previous conditions would help gain a better understanding of the differences in the profiles of COVID-19 patients admitted between the pandemic phases, as well as differences in hospital management strategies.\n\n\nConclusions\n\nThis comparative study shows a less intensive activity in the second wave of the COVID-19 pandemic in both the ER frequentation and hospitalizations, but more severe profiles of patients receiving inpatient care compared to the first wave. Although severity in hospitalised patients increased over time, no significant differences were observed in the overall mortality rate during the hospitalization. The results may be reflecting a better adaptation of the overall healthcare system, including a better adaptation and coordination of the healthcare services, better understanding of prognostic factors and treatment, and the success of the different strategies to protect more vulnerable populations, including vaccination and protection of the elderly in nursing homes. These results may be helpful to improve current knowledge on the evolution of the pandemics in a tertiary hospital, the most limiting resource in the healthcare system, and may shed light on the adaptation processes of the healthcare systems and their results for incoming waves.\n\n\nData availability\n\nDRYAD: Comparing the first and second waves of COVID-19 in a tertiary university hospital in Barcelona, https://doi.org/10.5061/dryad.0k6djhb1d.30\n\nThis project contains the following underlying data:\n\n- Files_manuscript_COVID12Waves_20210910_.xlsx, that includes: 1) table describing the number of hospital admissions by day and the 14 days accumulated incidence in Catalonia; 2) table describing the profile of patients accessing emergency care, the type of emergency and mortality; and 3) table with data describing the profile of hospitalised patients, and details on their length of stay, UCI stay, severity, and mortality.\n\n- Readme_COVID12Waves.xlsx (a detailed description of variables included in the files).\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 want to acknowledge Dr. Pascal Kahlem and Pau Berenguer Molins from Scientific Network Management S.L. (Spain) for their support in the elaboration of the manuscript. The authors would also like to thank all the Vall d’Hebron staff for the effort, understanding and dedication they have had in these difficult times.\n\n\nReferences\n\nHaldane V, De Foo C, Abdalla SM, et al.: Health systems resilience in managing the COVID-19 pandemic: lessons from 28 countries. Nat. Med. 2021; 27: 964–980. 2021. Publisher Full Text\n\nOECD/European Union: Health at a Glance: Europe 2020: State of Health in the EU Cycle. Paris: OECD Publishing; 2020. Publisher Full Text\n\nWorld Health Organization: Maintaining essential health services: operational guidance for the COVID-19 context. World Health Organization; 2020. Published 2020. Accessed October 29, 2021. 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}
|
[
{
"id": "143967",
"date": "13 Jul 2022",
"name": "Guglielmo Mantica",
"expertise": [
"Reviewer Expertise Urology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting manuscript about the difference between ED admissions between first and second wave at a hospital in Barcelona, Spain. The abstract and introduction are well written. Methods are well designed and clear.\n\nHere some minor concerns:\n“The study included 8,684 distinct COVID-19 patients who attended the emergency rooms (ER) and/or were hospitalised.” This is already a result. Please move it to the correct section.\n\nPlease specify in the methods if in your hospital there have been differences/changes in COVID swab tests during the two different waves (type of diagnostic test) since this might lead to differences in the correct identification of patients.\n\nPlease expand and declare all limitations.\n\nSome authors found differences between admissions during the first and second waves also for Non Covid patients (doi: 10.1016/j.ajem.2020.11.046.). Do you have any data available from your hospital? Otherwise just make a comment in the discussion session.\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": "143966",
"date": "03 Aug 2022",
"name": "Andri Frediansyah",
"expertise": [
"Reviewer Expertise Pharmacology and Microbiology"
],
"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\nCossio et al. investigated the flow of COVID-19 patients in emergency rooms and hospital wards in Barcelona, Spain, between the first and second waves of the pandemic. Additionally, they compared the severity and mortality profiles of COVID-19 patients from the two waves. The entire manuscript is well-written, and the methodology is well-executed. Therefore, I suggest indexing after the following minor revisions:\nPlease define ICD-10-CM in the introductory paragraphs.\n\nPlease include some hospital-improved strategies as the hospital also improves its facilities after the first wave.\n\nPlease include the limitations of the study.\n\nPlease specify the hospital's COVID-testing procedures.\n\nSome of the references listed below may be useful for discussing 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/10-1197
|
https://f1000research.com/articles/10-123/v1
|
17 Feb 21
|
{
"type": "Research Article",
"title": "Molecular study of sapovirus in acute gastroenteritis in children: a cross-sectional study",
"authors": [
"Maysaa El Sayed Zaki",
"Raghdaa Shrief",
"Rasha H. Hassan",
"Raghdaa Shrief",
"Rasha H. Hassan"
],
"abstract": "Background: Sapovirus has emerged as a viral cause of acute gastroenteritis. However, there are insufficient data about the presence of this virus among children with acute gastroenteritis. The present study aimed to evaluate the presence of sapovirus in children with acute gastroenteritis by reverse transcriptase-polymerase chain reaction (RT-PCR). Methods: A cross-sectional study enrolled 100 children patients with acute gastroenteritis from outpatient clinics with excluded bacterial pathogens and parasitic infestation. A stool sample was collected from each child for laboratory examination. Each stool sample was subjected to study by direct microscopic examination, study for rotavirus by enzyme-linked immunoassay (ELISA) and the remaining sample was subjected to RNA extraction and RT- PCR for sapovirus. Results: The most frequently detected virus was rotavirus by ELISA (25%). RT-PCR detected sapovirus in 7% of the stool samples. The children with sapovirus were all from rural regions and presented mainly during the winter season in Egypt (42.9%). The main presenting symptoms were fever (71.4%) and vomiting (57.1%). None of the children with sapovirus had dehydration. Rotavirus was significantly associated with sapovirus infections in 5 patients (71.4%, P=0.01). There was an insignificant difference between symptoms of gastroenteritis in children with sapovirus and children with gastroenteritis without sapovirus as regards vomiting (P=0.7), fever (P=0.46), and abdominal pain (P=0.69). Conclusion: The present study highlights the emergence of sapovirus as a frequent pathogen associated with acute gastroenteritis in children. There is a need for a national survey program for the study of sapovirus among other pathogens associated with acute gastroenteritis for better management of such infection.",
"keywords": [
"sapovirus"
],
"content": "Introduction\n\nSapovirus is a single strand non enveloped RNA virus that belongs to the Caliciviridae family1–4. The length of its genome is 7.1 to 7.7 kb, and its polyadenylated 3’ terminal is responsible for viral replication, while its 5’ terminal is associated with viral translation through production of VPg5,6. The viral genome consists of two to three open reading frames5. There are 15 genotypes of the virus with only four genotypes that can infect humans, namely GI, GII, GIV and GV)2,5,7,8.\n\nThe laboratory methods for detection of sapovirus include enzyme-linked immunosorbent assay, electron microscopy, reverse transcription-polymerase chain reaction (RT-PCR) and next-generation sequencing3. The sensitivity and specificity of RT-PCR are good and can be used for routine identification of the virus3. The primers used for the amplification of the virus depend upon the use of a segment from VP1 encoding gene compared to the RdRp region3,9. The classification of sapovirus depends upon complete sequence analysis of VP16,10,11.\n\nSapovirus infection is associated with viral gastroenteritis, especially in children below five with, around two million deaths around the world, and sapovirus causing viral gastroenteritis represents the second common cause of death12. The common symptoms are vomiting and diarrhoea5. The transmission of sapovirus occurs via ingestion of contaminated food and water and also by direct contact with affected individuals13,14. The infection occurs both sporadically and as an outbreak2,9. Treatment is symptomatic to prevent the aggravation of the disease3,9, and prevention of the infection depends mainly upon access to clean drinking water and food15.\n\nThere are data available about sapovirus infection in different countries such as Peru16 Iran17 and Ethiopia18. However, to our best of knowledge, there are no available reports about this in Egypt. Therefore, the present study aimed to evaluate the presence of sapovirus in children with acute gastroenteritis by RT-PCR.\n\n\nMethods\n\nThe present study was a cross-sectional study that enrolled 100 children patients (sample size calculated by a statistician) with acute gastroenteritis from outpatient clinics from Mansoura Children’s Hospital, Mansoura, Egypt within the previous 48 hours with excluded bacterial pathogens and parasitic infestation by microbiological culture and microscopic examination to exclude parasites. The study was carried out from January 2019 till February 2020.\n\nThe procedures followed were approved by the Mansoura Faculty of Medicine, Egypt ethical committee on human experimentation (R.20.11.1053) and were carried out in accordance with the Helsinki Declaration of 1975, as revised in 1983. Written informed consent was obtained from the parents of the included children.\n\nEach child was subjected to full medical history by asking the parents about the residence area and age of the child, which was then followed by clinical examination. A stool sample was collected from each child for laboratory examination.\n\nEach stool sample was subjected to study by direct microscopic examination, study for rotavirus by ELISA Ridascreen® (R-Biopharm AG- An der Neuen Bergstraße 1764297 Darmstadt, Germany), and the remaining samples was subjected to RNA extraction and RT-PVR for sapovirus.\n\nELISA for rotavirus. The kit is ELISA for qualitative detection for rotavirus in the stool sample. The kit used monoclonal antibodies in a sandwich-type method. The monoclonal antibody is directed to the protein of the six viral genes (VP6), and it is used for the coating of the wells of the microplate. The VP6 is a group-specific antigen present in all rotaviruses genotypes. In brief, the stool suspension was prepared using ready to use stool diluent (protein-buffered NaCl solution). A total of 1 ml of the diluent was added to 100 microliter of the stool and homogenized the suspension by aspiration into and ejection from a disposable pipette or, alternatively, blending in a Vortex mixer. The suspension was allowed to stand for a short period of time (10 minutes) for the coarse stool particles to settle, and the clarified supernatant of the stool suspension was used directly in the test.\n\nThe control supplied with the kit were added to the wells of a microplate with biotinylated monoclonal anti-rotavirus antibodies and incubated at room temperature for one hour. The wells were washed with the supplied wash buffer after incubation and streptavidin poly-peroxidase conjugate was added before a second incubation was performed for a half-hour at room temperature. After a second wash, the substrate of the enzyme was added leading to a colour change of colourless to blue if the test is positive. The samples were then incubated at room temperature for 15 minutes. A stop reagent was added, changing the colour from blue to yellow. The colour intensity was proportional to the concentration of rotavirus present in the stool samples in comparison with a control, and was measured at 450 nm using a microplate ELISA reader (Statfax Chromate 4300).\n\nExtraction of RNA and complementary DNA preparation. The stool samples were subjected to the extraction of RNA of sapovirus using QIAamp Viral RNA kit (Qiagen). The extraction was performed according to the instructions supplied by the manufacturer.\n\nComplementary DNA (cDNA) was generated by adding 100 nanograms of the extracted RNA to 32.5 µl prepared mixture composed of 1 µl hexamers primers (Fermentas, Latvia), 4 µl of 5 × buffer, 0.5 µl of Ribolock RNase inhibitor, 2 µl of dNTP mixture composed of 10 mM each of dNTP, 200 units of reverse transcriptase enzyme and 19 µ1 of RNase free water (Fermentas, Latvia). The RT assay was performed at 42°C for one hour.\n\nPCR for sapovirus. The amplification process was carried out using previously reported primers with nucleotide sequences of primers as follows: SLV5317 forward 5’-CGGRCYTCAAAVSTACCBCCCCA-3’; SLV5317 reverse 5’- CTCGCCACCTACRAWGCBTGGTT-3’19.\n\nThe amplification mixture used was ready to use Qiagen Taq PCR Master Mix Kit mixture (Cat No./ID: 201443) with 5 µl of cDNA added to a 20 µl PCR mix. The amplification procedures were performed using the following conditions: denaturation at 94°C for 5 minutes, then 35 cycles composed of 94°C for 45 seconds- 55°C for 45 seconds and 72°C for 1 minute, then final extension of 7 minutes at 72°C (MiniAmp Thermal Cycler, Applied Biosystem).\n\n. PCR products were visualised under UV illumination after electrophoresis on a 1% agarose gel stained with ethidium bromide. The estimated amplified fragment size for sapovirus was 434 bp19.\n\nData were analysed with SPSS 22 (SPSS Inc, Chicago, Illinois, USA). Qualitative values were calculated as numbers and percentages. The use of the chi-square test performed comparisons, and the P-value was considered significant if it was <0.05.\n\n\nResults\n\nThe study included 100 children with acute gastroenteritis manifested by diarrhoea associated predominately with fever (56%), vomiting (47%), abdominal pain (42%). A minority had dehydration (11%). Their mean age± SD was 53.33± 11.71 months. Most cases presented in the spring season (34%) followed by winter (24%). Demographics of the children are shown in Table 1.\n\nThe most frequently detected virus was rotavirus by ELISA (25%). RT-PCR detected sapovirus in 7% of the stool samples.\n\nThe children with sapovirus were all from rural regions (Belkas, Dekrnes, Aga) and presented mainly during the winter season in Egypt (42.9%). The main presenting symptoms were fever (71.4%) and vomiting (57.1%). None of the children with sapovirus had dehydration. Rotavirus was significantly associated with sapovirus infections in 5 patients (71.4%, P=0.01). There was an insignificant difference between symptoms of gastroenteritis in children with sapovirus and children with gastroenteritis without sapovirus as regards vomiting (P=0.7), fever (P=0.46), abdominal pain (P=0.69) (Table 2).\n\n\nDiscussion\n\nViral pathogens represent a significant aetiology for acute gastroenteritis. These infections are usually self-limited in developed countries while it may lead to mortality in underdeveloped countries, especially in children13.\n\nThe present study included 100 children with acute gastroenteritis manifested by diarrhoea with the majority experiencing fever (56%), vomiting (47%), and abdominal pain (42%). A minority had dehydration (11%). These are common symptoms of viral gastroenteritis. These patients usually present to outpatient clinics and do not require hospital admission except for dehydration20.\n\nThe proper management of children with acute gastroenteritis relies upon appropriate and robust diagnosis of the aetiology. In the present study, the most frequently detected virus was rotavirus by ELISA (25%). Previous meta-analysis study revealed that rotavirus is associated with acute gastroenteritis in 31.5% of children and 25.7% in the general population14. Previous studies in Africa reported that the prevalence of rotavirus infections ranged from 22.73% up to 30%21,22. A previous study from Egypt reported that the prevalence of rotavirus was 31% among children with acute gastroenteritis23.\n\nThe study of sapovirus as an emerging pathogen associated with acute gastroenteritis has gained importance in recent years. Research has been facilitated by the emergence of the molecular techniques in laboratory diagnosis16,24,25. In the present study, sapovirus was detected among 7% of children with acute gastroenteritis by RT-PCR. A previous meta-analysis study reported that the prevalence of sapovirus was 6.5% with a remarkable difference in the presence of sapovirus between low income and high-income countries26. Another study reported a lower prevalence of sapovirus 4.6% (10/219)27. Previous studies reported the prevalence of 3% up to 17% of sapovirus in acute gastroenteritis in children with gastroenteritis in high and low-income countries, respectively16,24,25. The variation of the prevalence rates reported may be due to the variation of the climate, environment, socio-economic factors, and cultural practices beside the difference of the used method of diagnoses.\n\nThe management of sapovirus depends mainly upon oral rehydration solution and zinc supplementation28. The risk factors for sapovirus infection are not fully understood. The prevention of sapovirus infection depends mainly upon efficient hand hygiene practice, environmental disinfection, proper sewage disposal, and limited contact with ill individuals. There is an argument about the role of improvement of water sanitation in the prevention of sapovirus as it is a common pathogen in both high and low-income countries. However, as it is transmitted by contaminated water and food29, increasing food and water sanitation will reduce the burden of the infection.\n\nThe use of new molecular technologies for sapovirus detection in different samples from patients, food and environment, is mandatory to recognize the mode of sapovirus transmission. Infection at a young age may predispose to durable immunity. Therefore, the development of a vaccine toward this virus may reduce the burden of this infection30.\n\nIn the present study, there was an insignificant difference between the clinical presentation of sapovirus positive and sapovirus negative children. The clinical symptoms associated with acute gastroenteritis usually include diarrhoea, vomiting, and fever, making laboratory diagnosis essential for appropriate management. Therefore, there is a need for a national survey program to improve the monitoring of the circulation of the new virus such as sapovirus alongside other pathogens associated with gastroenteritis to improve the control measures30.\n\n\nConclusions\n\nThe present study highlights the emergence of sapovirus as a frequent pathogen associated with acute gastroenteritis in children. There is a need for a national survey program for the study of sapovirus among other pathogens association with acute gastroenteritis for better management of such infection.\n\n\nData availability\n\nFigshare: Molecular study of sapovirus in acute gastroenteritis in children: a cross-sectional study, https://doi.org/10.6084/m9.figshare.13574933.v131\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nLauritsen KT, Hansen MS, Johnsen CK, et al.: Repeated examination of natural sapovirus infections in pig litters raised under experimental conditions. Acta Vet Scand. 2015; 57: 60. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu X, Jahuira H, Gilman RH, et al.: Etiological Role and Repeated Infections of Sapovirus among Children Aged Less than 2 Years in a Cohort Study in a Peri-urban Community of Peru. J Clin Microbiol. 2016; 54(6): 1598–1604. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOka T, Wang Q, Katayama K, et al.: Comprehensive review of human sapoviruses. Clin Microbiol Rev. 2015; 28(1): 32–53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMakhaola K, Moyo S, Kebaabetswe LP: Distribution and Genetic Variability of Sapoviruses in Africa. Viruses. 2020; 12(5): 490. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi J, Shen Q, Zhang W, et al.: Genomic organization and recombination analysis of a porcine sapovirus identified from a piglet with diarrhea in China. Virol J. 2017; 14(1): 57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVinjé J, Estes MK, Esteves P, et al.: ICTV Virus Taxonomy Profile: Caliciviridae. J Gen Virol. 2019; 100(11): 1469–1470. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOka T, Lu Z, Phan T, et al.: Genetic Characterization and Classification of Human and Animal Sapoviruses. PLoS One. 2016; 11(5): e0156373. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVarela MF, Rivadulla E, Lema A, et al.: Human Sapovirus among Outpatients with Acute Gastroenteritis in Spain: A One-Year Study. Viruses. 2019; 11(2): 144. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu X, Yamamoto D, Saito M, et al.: Molecular detection and characterization of sapovirus in hospitalized children with acute gastroenteritis in the Philippines. J Clin Virol. 2015; 68: 83–88. PubMed Abstract | Publisher Full Text\n\nHansman GS, Oka T, Sakon N, et al.: Antigenic diversity of human sapoviruses. Emerg Infect Dis. 2007; 13(10): 1519–1525. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHarada S, Tokuoka E, Kiyota N, et al.: Phylogenetic analysis of the nonstructural and structural protein encoding region sequences, indicating successive appearance of genomically diverse sapovirus strains from gastroenteritis patients. Jpn J Infect Dis. 2013; 66(5): 454–457. PubMed Abstract | Publisher Full Text\n\nKebede Fufa W, Berhe Gebremedhin G, Gebregergs GB, et al.: Assessment of Poor Home Management Practice of Diarrhea and Associated Factors among Caregivers of Under-Five Years Children in Urban and Rural Residents of Doba Woreda, Ethiopia: Comparative Cross-Sectional Study. Int J Pediatr. 2019; 2019: 8345245. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShane AL, Mody RK, Crump JA, et al.: 2017 Infectious Diseases Society of America Clinical Practice Guidelines for the Diagnosis and Management of Infectious Diarrhea. Clin Infect Dis. 2017; 65(12): e45–e80. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOjobor CD, Olovo CV, Onah LO, et al.: Prevalence and associated factors to rotavirus infection in children less than 5 years in Enugu State, Nigeria. VirusDis. 2020; 31(3): 1–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVarela MF, Ouardani I, Kato T, et al.: Sapovirus in Wastewater Treatment Plants in Tunisia: Prevalence, Removal, and Genetic Characterization. Appl Environ Microbiol. 2018; 84(6): e02093–17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSánchez GJ, Mayta H, Pajuelo MJ, et al.: Epidemiology of Sapovirus Infections in a Birth Cohort in Peru. Clin Infect Dis. 2018; 66(12): 1858–1863. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRomani S, Azimzadeh P, Mohebbi SR, et al.: Prevalence of sapovirus infection among infant and adult patients with acute gastroenteritis in Tehran, Iran. Gastroenterol Hepatol Bed Bench. 2012; 5(1): 43–8. PubMed Abstract | Free Full Text\n\nGelaw A, Pietsch C, Mann P, et al.: Molecular detection and characterisation of sapoviruses and noroviruses in outpatient children with diarrhoea in Northwest Ethiopia. Epidemiol Infect. 2019; 147: e218. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSvraka S, Vennema H, van der Veer B, et al.: Epidemiology and genotype analysis of emerging sapovirus-associated infections across Europe. J Clin Microbiol. 2010; 48(6): 2191–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStuempfig ND, Seroy J: Viral Gastroenteritis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020 [Updated 2020 Jun 25]. Reference Source\n\nDjeneba O, Damintoti K, Denise I, et al.: Prevalence of rotavirus, adenovirus and enteric parasites among pediatric patients attending Saint Camille Medical Centre in Ouagadougou. Pak J Biol Sci. 2007; 10(23): 4266–70. PubMed Abstract | Publisher Full Text\n\nMwenda JM, Ntoto KM, Abebe A, et al.: Burden and epidemiology of rotavirus diarrhea in selected African countries: preliminary results from the African Rotavirus Surveillance Network. J Infect Dis. 2010; 202 Suppl: S5–11. PubMed Abstract | Publisher Full Text\n\nKamal Allayeh A, Mostafa El-Baz R, Mohamed Saeed N, et al.: Detection and Genotyping of Viral Gastroenteritis in Hospitalised Children Below Five Years Old in Cairo, Egypt. Arch Pediatr Infect Dis. 2018; 6(3): e60288. Publisher Full Text\n\nDiez-Valcarce M, Castro CJ, Marine RL, et al.: Genetic diversity of human sapovirus across the Americas. J Clin Virol. 2018; 104: 65–72. PubMed Abstract | Publisher Full Text\n\nHassan F, Kanwar N, Harrison CJ, et al.: Viral Etiology of Acute Gastroenteritis in <2-Year-Old US Children in the Post-Rotavirus Vaccine Era. J Pediatric Infect Dis Soc. 2019; 8(5): 414–421. PubMed Abstract | Publisher Full Text\n\nMagwalivha M, Kabue JP, Traore AN, et al.: Prevalence of Human Sapovirus in Low and Middle Income Countries. Adv Virol. 2018; 2018: 5986549, 12 pages. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPortal TM, Reymão TKA, Quinderé Neto GA, et al.: Detection and genotyping of enteric viruses in hospitalized children with acute gastroenteritis in Belém, Brazil: Occurrence of adenovirus viremia by species F, types 40/41. J Med Virol. 2019; 91(3): 378–384. PubMed Abstract | Publisher Full Text\n\nKobayashi S, Fujiwara N, Yasui Y, et al.: A foodborne outbreak of sapovirus linked to catered box lunches in Japan. Arch Virol. 2012; 157(10): 1995–1997. PubMed Abstract | Publisher Full Text\n\nRockx B, De Wit M, Vennema H, et al.: Natural history of human calicivirus infection: a prospective cohort study. Clin Infect Dis. 2002; 35(3): 246–53. PubMed Abstract | Publisher Full Text\n\nBecker-Dreps S, Bucardo F, Vinjé J: Sapovirus: an important cause of acute gastroenteritis in children. Lancet Child Adolesc Health. 2019; 3(11): 758–759. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZaki M, Shrief R, Hassan R: Molecular study of sapovirus in acute gastroenteritis in children: a cross-sectional study. figshare. Dataset. 2021. http://www.doi.org/10.6084/m9.figshare.13574933.v1"
}
|
[
{
"id": "83889",
"date": "12 May 2021",
"name": "Marta Diez Valcarce",
"expertise": [
"Reviewer Expertise Molecular epidemiology of calicivurs"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 titled 'Molecular study of sapovirus in acute gastroenteritis in children: a cross-sectional study' by El Sayed Zaki et al. includes some very interesting data on the prevalence of sapovirus in Egypt.\nOverall, the article is well presented but there are a few minor comments that I would like to make, and also some edits that I consider necessary for clarity and accuracy.\nIn the abstract section, results paragraph, I think it could be informative which months are considered winter season in Egypt, as this varies in different parts of the world.\n\nIn the introduction I would suggest to write the family Caliciviridae in italics. Also, and that is a major edit that need to be done, the sapovirus genus contains or can be divided into 15 genogroups, not genotypes.\n\nI am not sure what the authors mean when they say that the primers used depend upon the use of a segment from VP1 encoding gene compared to the RdRp region. I am not aware of any comparison made between the capsid and the polymerase for classification of sapovirus. In some cases, both regions are sequenced to give a more accurate classification, but not compared. Maybe the authors could rewrite this sentences so they are clearer.\n\nThe third paragraph of the introduction mentioned a reference but I think the authors misinterpreted the findings of that work. What the article said is that globally, diarrhea is the second cause of mortality and the most common cause of illness in children younger than 5, and that it causes approximately 2 million deaths per year. But that is diarrhea, from any cause, not only sapovirus. Please correct.\n\nIn the methods section, under the stool samples paragraph the acronym for the molecular detection method used is incorrect, it should read RT-PCR and not RT-PVR.\n\nAlso in the methods section, when the mentioned the Ridascreen method to detect rotavirus, I think they should refer to the method as a semiquantitative one, since as they mentioned, the color intensity is proportional to the concentration of rotavirus present compared with the control.\n\nI also suggest to rewrite the part in which they explain how the kit uses monoclonal antibodies that specifically react with the VP6 protein (not the protein of the six viral genes, please correct).\n\nIn the statistical analysis paragraph, if results were expressed as numbers and percentages, those are quantitative values, not qualitative. Please correct.\n\nIn the discussion section, the fifth paragraph, I suggest to replace the word 'management' for 'treatment'. Also, I would rewrite the sentence and instead of using the word 'argument', I would say something like: There are conflicting/contradictory opinions about the role of water sanitation improvement in the prevention of sapovirus …\n\nI suggest to replace the expression 'an insignificant difference' for 'no significant difference', throughout the manuscript. Similarly, I also suggest to just mention acute gastroenteritis with all the letters once, with the acronym AGE between brackets, and from then on just use AGE throughout the article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? 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": "6673",
"date": "24 May 2021",
"name": "Maysaa El Zaki",
"role": "Author Response",
"response": "Dear Dr. Diez Valcarce, Thanks for your valuable comments. I have made all the required corrections. Best Regards."
}
]
}
] | 1
|
https://f1000research.com/articles/10-123
|
https://f1000research.com/articles/10-101/v1
|
11 Feb 21
|
{
"type": "Research Article",
"title": "Platelet count can predict the grade of esophageal varices in cirrhotic patients: a cross-sectional study",
"authors": [
"Anum Afsar",
"Muhammad Nadeem",
"Syed Asim Ali Shah",
"Huma Hussain",
"Aysha Rani",
"Sadaf Ghaffar",
"Anum Afsar",
"Syed Asim Ali Shah",
"Huma Hussain",
"Aysha Rani",
"Sadaf Ghaffar"
],
"abstract": "Background: Bleeding from esophageal varices is a life-threatening complication in cirrhosis. Screening endoscopy is recommended in cirrhotic patients to identify patients at risk of variceal hemorrhage, but this is an invasive procedure and has limitations. Therefore, thrombocytopenia has been proposed to predict the existence and grade of esophageal varices. The aim of the current study was to determine a correlation between platelet count and grades of esophageal varices in patients with liver cirrhosis. Methods: This cross-sectional study was conducted at the POF Hospital, Wah Cantt from 1st October, 2017 to 30th May, 2018. Newly diagnosed cases of cirrhosis having varices of any grade on endoscopy were included. Endoscopic findings of patients were standardized using Paquet grading system. On the basis of platelet count, patients were divided into four subgroups. Platelet count groups were correlated with grading of esophageal varices using Spearman rank correlations. Chi Square test was used to see association between the platelet count and grade of esophageal varices. Results: 110 patients were included in the study, 55.5% (n=61) were male. Mean age of the patients was 59.89±9.01 years. Platelet count was <50,000/uL in 35.5% patients, 50,000-99,000/uL in 26.4%, 100,000-150000 in 12.7%, and >150,000/uL in 25.5% patients. Grade I esophageal varices were found in 23.6% of patients, whereas grade II, III and IV were found in 24.5%, 33.6% and 18.2% of patients, respectively. Mean platelet count was 213884.62/mm3 in patients with grade I varices, whereas it was 119518.52/mm3, 58386.49/mm3 and 21600.00/mm3 in patients with grade II, III and IV varices, respectively (p=<0.0001). A significant negative correlation between platelet count and grades of esophageal varices was found (p<0.001). Conclusion: Platelet count can predict the grade of esophageal varices in cirrhotic patients. There is significant negative correlation between platelet count and grades of esophageal varices.",
"keywords": [
"Cirrhosis",
"Platelet",
"Varices"
],
"content": "Introduction\n\nPortal hypertension is a common complication of liver cirrhosis which can lead to esophageal varices that may rupture and bleed1. Bleeding from esophageal varices is life threatening and comprises 10% of all cases of upper gastrointestinal (GI) bleeding2. Esophageal varices are present in approximately one third of patients at diagnosis of cirrhosis and incidence increases to 90% in 10 years3. The rate of progression from small to large varices is estimated to be 8–10% per year and the annual rate of esophageal hemorrhage is 5% for small varices and 15% for large varices3,4. Screening endoscopy is therefore recommended for early detection of esophageal varices and grading of varices in cirrhotic patients to identify patients with risk of variceal hemorrhage and administer prophylactic treatment if required5. Screening endoscopy is however an invasive procedure and has limitations6.\n\nDiagnosis and grading varices by endoscopy is operator dependent. This approach also places a heavy burden upon endoscopy units and repeated testing over time may affect patient compliance, and endoscopic screening also increases the associated health care costs7. Due to these problems regarding endoscopy, some noninvasive means have been proposed for prediction of esophageal varices and their grades in order to restrict endoscopy to the population with high risk of variceal bleeding7. Various clinical and biochemical predictors have been studied to predict the existence and grade of esophageal varices in cirrhotic patients8.\n\nThrombocytopenia (platelet count <150,000 /uL) is one such predicator. It is found in approximately 64–76% of patients with portal hypertension and cirrhosis9. The pathogenesis of thrombocytopenia in cirrhosis is multi-factorial and includes decreased thrombopoietin production, sequestration of platelets in spleen and direct myelosuppression due to hepatitis C virus10. As thrombocytopenia and esophageal varices are common findings in cirrhosis, and portal hypertension is associated with both of these findings, some studies have been conducted to see the relation of thrombocytopenia as a non-invasive marker with grades of esophageal varices10,11. It was found in different studies that platelet count was inversely correlated with grades of esophageal varices11. Large esophageal varices also appeared to have a lower platelet count in a study conducted at Shanghai East Hospital4\n\nIn resource poor developing countries, endoscopy of every cirrhotic patient to grade the esophageal varices to select the patients for prophylactic therapy is not possible due to the limited number of endoscopes and endoscopists in government hospitals. We need to identify non-invasive and reliable markers to predict the grades of esophageal varices in our population in Pakistan, so that endoscopists can select the patients at increased risk of bleeding for endoscopy on priority basis. Therefore, we conducted this study to determine correlation between platelet count and grades of esophageal varices in our population and thus assess the possibility of using platelet count to predict the grades of esophageal varices.\n\n\nMethods\n\nThis cross-sectional descriptive study was conducted at the Department of Medicine, POF Hospital, Wah Cantt, Pakistan from 1st October, 2017 to 30th May, 2018. Newly diagnosed cases of cirrhosis having varices of any grade on endoscopy, irrespective of the cause of cirrhosis, with or without ascites and splenomegaly, from 18 to 70 years were included in the study. Diagnosis of cirrhosis was made using data obtained from clinical findings, laboratory investigations and ultrasonographic findings of the liver. Patients with hematological disorders, portal vein thrombosis, on B-blocker prophylactic therapy and those who had undergone endoscopic band ligation or sclerotherapy were excluded.\n\nThe sample size calculated was 110 using sample size calculator n = (Z2 × P × (1 - P))/d2 for cross sectional studies, taking a confidence level 95%. In total, 110 patients were included by consecutive sampling.\n\nInformed written consent was taken from patient or relative wherever relevant (consent was taken from relatives in patients with hepatic encephalopathy). Ethical approval was obtained from POF Hospital Research Ethics Committee before the start of the study (vide letter no. POFH/ERC/99053/03).\n\nEndoscopy was performed by the same endoscopist using the Olympus GIF type Q260 endoscope. All patients were kept NPO for 8 hours before endoscopy and the endoscopic findings of the patients were standardized using the Paquet grading system for esophageal varices dividing esophageal varices by grades I to IV12. Blood samples of all patients were taken by the staff nurse before endoscopy and sent to the laboratory of POF Hospital on the same day to calculate platelet count. Platelet count was calculated by automatic hematology analyzer (Sysmex XN-1000) and confirmed by manual method (small volume of whole blood was treated with RBC lysing reagent ammonium oxalate, was put in hemocytometer and platelet counting was done by hematologist using phase contrast light microscopy). All details including demographic details, endoscopic findings and platelet count were obtained from medical records of the selected patients. On the basis of platelet count, patients were divided into four subgroups: group 1,platelet count <50,000/uL; group 2,platelet count 50,000–99000 /uL; group 3,platelet count 100,000–150,000/uL; and group 4,normal platelet count >150,000/uL.\n\nAll data was entered and analyzed using SPSS version 19.0. Mean and standard deviation was calculated for quantitative data, such as age. Frequency and percentage was calculated for gender, platelet count and grade of esophageal varices. Platelet count group was correlated with grading of esophageal varices using Spearman rank correlations. Chi square test was used to calculate the association between platelet count and grade of esophageal varices. P-value ≤0.05 was considered significant.\n\n\nResults\n\nA total of 110 patients were included in the study, 55.5% (n=61) were male and 44.5% (n=49) were female. Mean age of the patients was 59.89±9.01 years. Platelet count was <50,000 /uL in 35.5% (n=39) of patients, 50,000–99,000/uL in 26.4% (n=29), 100,000–150000 in 12.7% (n=14), and >150,000/uL in 25.5% (n=28) patients. Grade I esophageal varices were found in 23.6% (n=26) patients, whereas grade II, grade III and grade IV were found in 24.5% (n=27), 33.6 (n=37) and 18.2% (n=20) of patients, respectively.\n\nA significant association was found between the platelet count groups and grades of esophageal varices; groups with lower platelet counts had high-grade varices, while groups with higher platelet counts had low-grade varices (Table 1).\n\nSpearman’s correlation showed a significant negative correlation between platelet count and grades of esophageal varices (Table 2).\n\nMean platelet count was also significantly lower in patients with grade IV varices as compared to patients with grade I varices (p=0.0001; Table 3).\n\n\nDiscussion\n\nOur results showed that there is a significant negative correlation between the platelet count and grades of esophageal varices. Patients with a lower platelet count had varices of higher grades. In group 1 patients (platelet count <50,000//uL; n=39), 18 and 16 patients were found to have grade IV and grade III varices, respectively, as compared to only 2 and 3 patients having grade I and II varices, respectively. In contrast, in group 4 patients (platelet count >150,000/uL; n=28), 22 patients had grade I varices and no patients had grade III or IV varices. This suggests that platelet count can be used as a predictor of grades of esophageal varices without frequent upper GI endoscopy.\n\nIn our study, 55.5% (n=61) patients were male and 44.5% (n=49) were female. Studies have shown that the incidence of cirrhosis is lower in females as compared to males due to slower progression of fibrosis13. In a study conducted in Taiwan, 71% cirrhotic patients were male14. These findings are consistent with our findings of male predominance. Another study also supports our findings, as it shows that men had a higher incidence of cirrhosis in all age groups as compared to women of the same age group15. A local study also showed that 64% of cirrhosis patients were men16.\n\nMean age in our study was 59.89±9 years. Although cirrhosis of the liver can develop at any age, it is usually common in old age with a higher mean age of incidence15. Mean age was found to be 40.5 years in cirrhosis patients in a study conducted by Devrajani et al.16. This is comparable with our results. A study conducted in China showed a mean age of 50.29±7.03 years in cirrhosis patients17, which is similar to a mean age of 54.39±7.46 years in a study conducted by Abd-Elsalam et al.10, almost the same mean age as found in our study.\n\nA significant inverse correlation was found between platelet count and grades of esophageal varices in our study. Lower platelet count was associated with high varices and vice versa. Platelet count is low in advanced cirrhosis; similarly, large varices are associated with advance cirrhosis. Many studies conducted previously to see the relationship of platelet count with esophageal varices concluded that lower platelet count is associated with large varices. For example, a study conducted by Abbasi et al. shows that platelet count is inversely related with esophageal varices, supporting our findings11. Similarly, a study conducted in India also had the same results; lower platelet count was significantly associated with large varices18.\n\nMean platelet count was significantly lower in patients with grade III (58386.49±34188.43mm3) and IV (21600.00±16161.68mm3) esophageal varices as compared to grade I (213884.62±86434.86mm3) and II (119518.52±68027.91mm3) varices in our study. These results are comparable with a study conducted in Egypt, where platelet count was significantly lower in patients with grades II and III (165.2±13.0 and 60.3±14.1 mm3, respectively) than in patients with grade I (100.5±19.8mm3)19. According to these findings, platelet count can be used to identify patients who may have large varices and need prophylactic endoscopic treatment to prevent upper GI bleeding rather than doing endoscopy in every patient with cirrhosis. Platelet count is not only noninvasive, it is also inexpensive, resource effective, does not need special expertise, and is easily available.\n\nOur study has some limitations: it was a single center study including all patients of cirrhosis irrespective of the cause; we only used platelet count to predict the grade of varices, some studies have shown that platelet count and spleen size ratio is more accurate in predicting the size and grade of varices. In future, multicentre studies with specific cause of cirrhosis and using platelet count and spleen size ratio are suggested.\n\n\nConclusion\n\nThere is significant negative correlation between platelet count and grades of esophageal varices. Low platelet count is associated with higher grades of esophageal varices. This suggest that platelet count can be used as a predictor to predict the grade of esophageal varices.\n\n\nData availability\n\nFigshare: Platelet count can predict the grade of esophageal varices in cirrhotic patients, https://doi.org/10.6084/m9.figshare.13379939.v120.\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nTsochatzis EA, Bosch J, Burroughs AK: Liver cirrhosis. Lancet. 2014; 383(9930): 1749–61. PubMed Abstract | Publisher Full Text\n\nAshkenazi E, Kovalev Y, Zuckerman E: Evaluation and treatment of esophageal varices in the cirrhotic patient. Isr Med Assoc J. 2013; 15(2): 109–15. PubMed Abstract\n\nMeseeha M, Attia M: Esophageal varices. [Updated 2020 Aug 10]. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2020. Reference Source\n\nGulamhusein AF, Kamath PS: The epidemiology and pathogenesis of gastrointestinal varices. Techniques in Gastrointestinal Endoscopy. 2017; 19(2): 62–68. Publisher Full Text\n\nGrgurević I, Jukić I, Sokol S, et al.: Low specificity of platelet to spleen ratio for noninvasive prediction and characterization of esophageal varices in patients with alcoholic liver cirrhosis. Acta Med Croatica. 2014; 68(4–5): 353–60. PubMed Abstract\n\nChiodi D, Hernández N, Saona G, et al.: [Noninvasive diagnosis of esophageal varices in cirrhotic patients]. Acta Gastroenterol Latinoam. 2014; 44(2): 108–13. PubMed Abstract\n\nRye K, Scott R, Mortimore G, et al.: Towards Noninvasive Detection of Oesophageal Varices. Int J Hepatol. 2012; 2012: 343591. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCherian JV, Deepak N, Ponnusamy RP, et al.: Non-invasive Predictors of Esophageal Varices. Saudi J Gastroenterol. 2011; 17(1): 64–68. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSheikh M, Raoufi R, Atla P, et al.: Prevalence of Cirrhosis in Patients with Thrombocytopenia Who Receive Bone Marrow Biopsy. Saudi J Gastroenterol. 2012; 18(4): 257–262. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbd-Elsalm S, Habba E, Elkhalawany W, et al.: Correlation of platelets count with endoscopic findings in a cohort of Egyptian patients with liver cirrhosis. Medicine (Baltimore). 2016; 95(23): e3853. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbbasi A, Butt N, Bhutto A, et al.: Correlation of Thrombocytopenia with Grading of Esophageal Varices in Chronic Liver Disease Patients. J Coll Physicians Surg Pak. 2010; 20(6): 369–72. PubMed Abstract\n\nPhilips CA, Sahney A: Oesophageal and gastric varices: historical aspects, classification and grading: everything in one place. Gastroenterol Rep (Oxf). 2016; 4(3): 186–95. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThomas DL, Astemborski J, Rai RM, et al.: The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000; 284(4): 450–56. PubMed Abstract | Publisher Full Text\n\nHung TH, Liang CM, Hsu CN, et al.: Association between complicated liver cirrhosis and the risk of hepatocellular carcinoma in Taiwan. PLoS One. 2017; 12(7): e0181858. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVaz J, Eriksson B, Strömberg U, et al.: Incidence, aetiology and related comorbidities of cirrhosis: a Swedish population-based cohort study. BMC Gastroenterol. 2020; 20(1): 84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDevrajani BR, Soomro AA, Attra KM, et al.: Variceal bleeding and its dependence on portal vein size in liver cirrhotic patients. World Journal of Medical Sciences. 2009; 4(1): 50–53. Reference Source\n\nWei FF, Zhang X, Xu Z, et al.: New Markers to Explore Spontaneous Bacterial Peritonitis. J Mol Biomark Diagn. 2014; 5(6): 200. Publisher Full Text\n\nPriyadarshi BP, Khan IK, Kumar V, et al.: Study the association between platelets count and grades of oesophageal varies in patients of cirrhosis of liver with portal hypertension. Int J Adv Med. 2020; 7(4): 603–07. Publisher Full Text\n\nEl-Din Nouh MA, El-Momen Ali KA, Badaway AM, et al.: Correlation of thrombocytopenia with grading of esophageal varices in chronic liver disease patients. Menoufia Med J. 2018; 31(2): 588–93. Reference Source\n\nAfsar A, Nadeem M, Sha SAA, et al.: Platelet count can predict the grade of esophageal varices in cirrhotic patients. figshare. Dataset. 2020. http://www.doi.org/10.6084/m9.figshare.13379939.v1"
}
|
[
{
"id": "87611",
"date": "30 Jun 2021",
"name": "Muhammad Asim Anwar",
"expertise": [
"Reviewer Expertise internal medicine/gastroenterology/hepatology"
],
"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 cross sectional of the platelet count predictability of esophageal varix is important study for those countries where the availability of the endoscopy services are few and the burden of disease is high. You can also schedule the endoscopy procedure where the predictability of high grade varix is high. Methodology is fine and the results are also presented well. In the discussion authors should also give some details of other non invasive methods like platelet spleen index. In conclusion there is significant negative correlation between platelet count and grade of varix\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7422",
"date": "24 Nov 2021",
"name": "Muhammad Nadeem",
"role": "Author Response",
"response": "We would like to thank the reviewer for his valuable time and comments on our article; this will be very helpful for us in future research. We added the some details of other non invasive methods in discussion as advised by reviewer"
}
]
},
{
"id": "90353",
"date": "20 Aug 2021",
"name": "Alexandru Constantin Moldoveanu",
"expertise": [
"Reviewer Expertise Gastroenterology",
"Gastrointestinal Endoscopy",
"Hepatology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nEsophageal varices are a frequent complication of cirrhosis and can be a life-threatening complication if ruptured. The risk of variceal bleeding is, however, not equal between patients, and the current gold standard method for assessing bleeding risk is upper gastrointestinal endoscopy - an invasive procedure, that is not easily tolerated by the patient. There are multiple non-invasive methods that were proposed over the years as either an alternative to endoscopy or as a method of reducing the number of endoscopies by performing them selectively only in patients with a high probability of also requiring endoscopic treatment.\nThe authors’ study presents a very simple parameter, thrombocyte count, as a non-invasive and very cost-effective alternative method of identifying patients with different grades of esophageal varices. Considering that both hypersplenism (and thrombocytopenia) and esophageal varices are results of portal hypertension, it appears to be a reasonable presumption that the two would be correlated.\nThe results indeed show as a very good correlation between the size of varices and platelet count, in both group analysis as well as continuous variable analysis. What is most interesting to me is that the platelet count has a very good sensitivity (approximatively 93% based on the results) for predicting patients with large varices (grades III and IV) requiring prophylactic endoscopic treatment. No patient with normal thrombocytes has had large varices in this study, which suggests that these patients might not require diagnostic endoscopy.\nRegarding the statistical analysis methodology, I believe that the methods could be expanded upon. An analysis of variance type test between groups would probably reveal statistically significant results given the values presented. Another possible analysis method is classifying patients into two groups: 1. needing endoscopic treatment and 2. not needing endoscopic treatment, and plotting an ROC curve, which could be used to determine sensitivity and specificity for an optimal cut-off.\nOne criticism that I could make is that imminent bleeding signs, such as red wale signs, were not assessed. While these signs appear more frequently in large varices, they have frequently been reported in grade 2 varices as well, making it more difficult to assess which patients do not require endoscopy using the grade of the varices alone.\nAnother criticism of the article is that, while the conclusions are very interesting, the information is not entirely new. The Baveno VI consensus has already proposed thrombocyte count as one of the most important factors to determine which patients can be ruled out from screening endoscopy. The authors’ study still has practical value for medical centres where measurement of the other main parameter in the Baveno VI consensus, liver stiffness, is either unavailable or not sufficiently cost-effective.\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? Partly",
"responses": [
{
"c_id": "7423",
"date": "24 Nov 2021",
"name": "Muhammad Nadeem",
"role": "Author Response",
"response": "We would like to thank the reviewer for his valuable time and comments on our article; this will be very helpful for us in future research. We had made few changes as suggested by reviewer. 1. We applied one way ANOVA (Analysis of Variance) test and added in results. 2. Reviewer raised an important point regarding the imminent bleeding signs, which we missed during data collection. As it is not possible to include it in article (we do not have data), we had mentioned it in limitations of our study in revised version so researchers in future can include this point. Another concern of reviewer was “information is entirely not new”. We agree with this statement but most of the studies used other parameters as well along with platelet count like spleen diameter, liver stiffness as mentioned by reviewer also. We used only platelet count to predict the varices size which is valuable for centres in developing world where other facilities are not available or cost is a problem, this was the main purpose of the study and also appreciated by reviewer."
}
]
}
] | 1
|
https://f1000research.com/articles/10-101
|
https://f1000research.com/articles/10-1195/v1
|
24 Nov 21
|
{
"type": "Research Article",
"title": "Acedia, loneliness, and the mandatory celibacy of Catholic parish clergy: a theological-sociological exploratory analysis",
"authors": [
"Vivencio Ballano"
],
"abstract": "This article utilizes the analytical concept of acedia as the fundamental theoretical framework and applies a systematic literature review of peer-reviewed materials and documents on spiritual sloth, spiritual dryness, Catholic clerical celibacy, social bonding and communal spirituality. This article explores how the Catholic parish clergy’s mandatory celibacy intensifies loneliness and facilitates the spiritual sloth of parish clergy or what is theologically known as acedia. Unlike religious priests who live in religious communities, parish clerics fundamentally live, work, and pray alone in the parish, without strong communal support from fellow priests, bishops, and lay parishioners; thus, making them prone to loneliness, a main component of acedia. This article argues that mandatory celibacy further deprives parish clerics of the social and spiritual support necessary to enhance diocesan clerical spirituality and strengthen spiritual resistance against acedia. It recommends a structural adjustment in the social and spiritual life of parish priests, creating small communities of priests situated in similar territory or districts to allow them to live and work as a team with strong social and spiritual support in the spirit of “living baptismally” to overcome priestly acedia.",
"keywords": [
"Celibacy",
"Acedia",
"Clerical Spirituality",
"Loneliness",
"Catholic Parish Clergy",
"Social Bonding",
"Diocesan Priesthood"
],
"content": "Introduction\n\nThe concept of acedia has recently garnered attention from some practical theologians and Catholic scholars in relation to the priesthood (e.g., McAlinden, 2014, 2015; Collingridge, 2019; Büssing, Starck, and van Treeck, 2021). Acedia is a Medieval theological concept that originated from the Greek accidie, which literally means “no caring” (a-, not; kedos, care). Although unable to capture its true meaning, it is popularly translated in English as sloth (Miles, 1985). Cardinal Quellet sees acedia as spiritual sloth, sadness, and a disgust with the things of God, driving monks to leave their monastic cells and abandon their intimacy with God (Nault, 2013).\n\nAcedia is one of the several Christian notions of spiritual dryness in theological literature. Ignatius of Loyola (1914), for instance, used the term “spiritual desolation” for dryness in prayer. St. John of the Cross called spiritual dryness the “dark night of the soul”, a form of spiritual purification for Christians (Büssing, Starck, and van Treeck, 2021). But the ascetic monk Evagrius Pontifikus (345–399), who popularized this concept in Catholic theological literature, views acedia as spiritual sloth, emotional fatigue, tired or even bored negligence that reduces prayer resulting in abandonment of spiritual life (Büssing, Starck, and van Treeck, 2021). Acedia is also associated with the group of feelings and behaviors that were considered unusual, undesirable, and indicative of a need for remedial attention. In the words of John Cassian (ca. A.D. 360-435), acedia is a weariness or distress of heart, akin to dejection (Jackson, 1986).\n\nIn Catholic priesthood, acedia has been connected to “a loss of taste or lack of care for the spiritual life leading eventually to questioning both the meaning of the spiritual life and priesthood” (Tomlinson, 2019: 177). It is a serious spiritual crisis, a “sense of carelessness, indifference, apathy, weariness, and discouragement that encourages priests to leave the priesthood or degrade their sacred vocation” (McAlinden, 2015: 269). There have been significant attempts to connect acedia to the current problems of Catholic priesthood (e.g., McAlinden, 2014, 2015; Morris, 2019; Tomlinson, 2019), but no research has considered mandatory celibacy as a primary contributory factor behind it. Thus, Morris (2019: 20) is correct when he claimed that no qualitative research has been done to focus on the clergy experiences of acedia. Specifically, there is a dearth of literature that analyzes the connection between clerical acedia and mandatory celibacy of parish clergy using both theological and sociological approaches. Owing to lack of integration of the social sciences in Catholic theology, most studies and literature on Catholic clerical celibacy (e.g., Sacerdotalis Caelibatus [Priestly Celibacy], 1967; Daly, 2009; Selin, 2016) and acedia focus more on its spiritual aspects (e.g., Nault, 2013; McAlinden, 2014, 2015; Tomlinson, 2019), thus tending to disregard their sociological and structural dimensions. Spiritual realities have structural and communal components, and thus require sociological analysis. As Dawson (2013) argues, material and spiritual factors interpenetrate one another so completely in a culture that they form an inseparable unity, so that religion and life become one. Starkcloff (1994) warned that there are “webs of meaning” that constitute cultural systems and cautioned theologians against isolating individuals from their own authentic environment. Thus, applying both the theological and sociological approaches can provide a holistic understanding of the dynamics of clerical acedia or spiritual sloth in actual social practice. This article aims to explore the spiritual and sociological factors behind the loneliness and laziness in clerical spiritual life: Does mandatory celibacy facilitate the current problem of loneliness and acedia or spiritual sloth among Catholic parish clerics? Specifically, it aims to explore how celibacy intensifies loneliness of Catholic priests in the parish and diminishes the communal aspect of clerical spirituality. It also intends to provide some recommendations on how Catholic parish clergy can overcome acedia and spiritual sloth if the Catholic Church does not allow married priesthood in the future.\n\nBoth acedia and celibacy denote loneliness and isolation for the parish clergy. The detachment diocesan priests experience from communal activity and support in the parish can provide a fertile ground for symptoms of priestly acedia. Absolute chastity for diocesan priests implies social isolation without a family or intimate support group which normally provide social bonding and spiritual support to inhibit sin and deviance. It also results in an unregulated life without intimate social bonding and common spiritual activities with fellow priests in the presbytery or religious community, which is normally experienced by religious clerics in the Roman Catholic Church (RCC) (Aschenbrenner, 2002). Sociological studies have shown that social bonding is one of the crucial factors for the inhibition of deviance (e.g., Akers and Cochran, 1985; Hirschi, 2009; Liljeberg et al., 2011). When members of the community form local social ties, their capacity to resist rule-breaking behavior increases because they can recognize strangers and are more apt to engage in guardianship behavior against victimization (Skogan, 1986: 216).\n\nAside from lack of social bonding, clericalism in the Roman Catholic Church (RCC) is also blamed for clerical abuses such as clerical sexual abuse (CSA) (e.g., Papesh, 2004; Wilson, 2008; Neuhaus, 2008; Plante, 2020) that can result in degradation of clerical spirituality and acedia. Shaw (2008) defines clericalism as “an elitist mindset, together with structures and patterns of behavior corresponding to it, which takes it for granted that clerics—in the Catholic context, mainly bishops and priests—are intrinsically superior to the other members of the Church and deserve automatic deference.” It sees the clergy as a privileged class in the Church and gives an impression to the laity that bishops and priests know best, resulting in the reluctance to acknowledge or report the clerical misconduct. Other studies also consider psychological factors such as the psychological past and formation of the priest as a factor in CSA. The 2011 national research commissioned by the United States Conference of Catholic Bishops (USCCB) on CSA, the John Jay College of Criminology study, for instance, largely blames the problematic past and psychological formation of priests and seminarians as encouraging CSA (John Jay College, 2004).\n\nDespite these external and internal factors that cause CSA and degrading of clerical spirituality, the RCC considers the abusive priest himself as ultimately responsible for committing CSA. Bishops and Church officials continue to view CSA in terms of personal sin and the moral fault of the priest (Doyle, 2006). CSA is sometimes preceded by the neglect of clerical prayer and spiritual life by the priest which can lead to acedia and weakening of his spiritual resistance against CSA (Cross and Toma, 2006). Acedia can encourage priests to degrade their vocation by committing clerical abuses such as CSA or by leaving the priesthood. The acedic condition manifests itself “in carelessness about the disciplines that nurture the spiritual life, presenting as a variety of psychosomatic symptoms: lack of self-care, emotional exhaustion, depersonalization and a diminished sense of accomplishment” (Tomlinson, 2019, 177). Cases of CSA are usually precluded by a collapse of clerical prayer life (Cross and Thoma, 2006). Thus, the priest can be seen to be responsible for any CSA which can be attributed in part to neglect of prayer life that leads to acedia and erosion of spiritual strength against the temptation of CSA. Mandatory celibacy for parish clergy also takes away the mutual support and communal spirituality that can strengthen the priest’s prayer life against acedia and clerical abuse.\n\nAbsolute privacy, which is a result of clerical celibacy, can potentially influence crimes in the parish such as CSA because of the absence of behavioral monitoring by brother priests (John Jay College, 2004). And when clerical ascetical discipline of the priest is weak due to neglect and lack of social bonding and communal spirituality, priests can become vulnerable to acedia resulting in the weakening of spiritual resistance against CSA and other serious sins. The power from not being under the surveillance of others is a social factor why religious leaders such as priests have the potential to engage in serious crimes such as sexual abuse (Capps, 1993). The autonomous lifestyle of celibate diocesan priests can be argued to be conducive to acedia and CSA. Wortley and Smallbone’s research (2006), for instance, revealed that CSA is usually committed in a private setting. Detachment from community surveillance in this sense can be seen to facilitate clerical misconduct with the absence of effective guardians.\n\nThis article explores how the mandatory celibacy for parish clergy greatly facilitates loneliness and clerical acedia among parish clerics in the RCC and proposes some structural reform to overcome it. It is divided into three major sections. The first section briefly discusses how celibacy deprives parish priests of the basic human need for social bonding and mutual support needed to lead a normal human and spiritual life to resist acedia. The second section explains the negative effect of mandatory celibacy on the clerical spirituality of Catholic parish clergy, which already lacks communal dimension, arguing that spirituality has both personal and social dimensions. The final section recommends some structural adjustments on how the parish clergy can overcome acedia despite mandatory celibacy in the RCC. Overall, it argues that mandatory celibacy, which deprives parish priests of mutual support, intimacy, and direct social control of their clerical behavior, can greatly facilitate acedia in Catholic diocesan priesthood. Compared to religious priests, diocesan clerics generally live alone in the parish without any intimate social bonding with their fellow priests and parishioners in the parish, thus making them prone to loneliness and acedia.\n\n\nMethods\n\nThis article used the qualitative research approach and fully utilized documentary data from published theological, sociological, and social science literature on acedia, clerical spirituality, loneliness, and mandatory celibacy for Catholic priests. It also cited some of the RCC’s official teachings and the Code of Canon law to briefly clarify the ecclesial understanding of celibacy, clerical spirituality, and Catholic priesthood. The textual data are largely collected from church documents, as well as from peer-reviewed journal articles and books. They were then organized according to the main themes and keywords of the study such as celibacy, acedia, clerical spirituality, loneliness, Catholic parish clergy, social bonding, and diocesan priesthood. These were then systematically classified and composed using the inductive, deductive, and comparative methods to achieve the study’s research objectives.\n\nThe practical theologian Martin McAlinden (2014) sees loneliness and isolation as two of the major contributors of acedia in the Catholic parish priesthood. He blames the doctrine and practice of celibacy for Catholic clergy as a major facilitator of clerical isolation that can lead to the experience and development of acedia (Collingridge, 2019). Although described by the RCC as “a precious gift from God” (Code of Canon Law 1983, para. 277) and as a “brilliant jewel in the crown of the priesthood” (Sacerdotalis Caelibatus [Celibacy of the Priest], 1967, para. 1) that facilitates priests’ full devotion to their Church ministry (Isacco, Sahker, and Krinock, 2016), mandatory celibacy can also heighten the loneliness of parish clergy who normally live alone in the parish without intimate support groups.\n\nSome scientific studies have already revealed several negative effects of celibacy in Catholic priesthood in contemporary times (e.g., Wills, 2000; Scheper-Hughes and Devine, 2003; Doyle, 2006; Mayblin, 2018), and it is mostly associated with the alarming problem of loneliness, a key component of acedia (Rausch, 1992; Hoge, 2002; John Jay College, 2004). Hoge’s (2002) study involving newly ordained priests, for instance, confirmed the difficult and demoralizing clerical life and ministry because of loneliness, which can have a direct effect on their decision to stay within or leave the priesthood. Declan Moriarte, a former parish priest in Ireland for 40 years, for example, published an article explaining why celibacy and loneliness constituted a major reason of why he left the priesthood. His personal testimony below also shows serious symptoms of acedia as celibacy and loneliness drove him to question God’s presence and leave the priesthood:\n\nIt took many years finally to make the decision to leave the priesthood. It was at times an intense feeling of loneliness and constant self-questioning along with self-doubt. I sought advice, I entered therapy, I hated myself, I hated my indecision, I felt depressed, I felt angry with myself, and I felt God had vanished when my need was greatest … Celibacy/sexuality is often seen as the only factor in the decision to leave the ministry. For myself celibacy meant loneliness, lack of intimacy, lack of emotional growth and lack of maturity. Yes, it was a major factor in my decision to leave. I had become convinced that my call to the priesthood was valid, but the imposition of celibacy was not (Moriarte, 2016: 34-35).\n\nAnother former priest, Jonathan Morris, who joined the Fox News in the US, also cited celibacy as a major reason why he left the ministry:\n\nTaking that step was something I had considered often and at length in years past and discussed with my spiritual guides. While I loved and thrived in so many aspects of my ministry, deep in my interior I struggled for years with my vocation and with the commitments the Catholic priesthood demands, especially not being able to marry and have a family (Morris, 2019, para. 2) .\n\nIn another study by Hoge, Shield, and Griffin (1995), loneliness is also found to be one of the main sources of stress for priests, together with other factors such as lack of support, encouragement from fellow priests, and lack of leadership (Raj and Dean, 2005). Unlike religious priests who live with their religious communities, diocesan clerics live autonomous lives with limited social bonding and communal prayer activities with their bishops and fellow priests in the presbytery.\n\nCelibacy creates a solitary life for parish clerics that can lead to spiritual dryness and acedia. It hinders the human and spiritual growth of secular priests in the deregulated environment of the parish. The early data of the National Opinion Research Center (NORC) survey at the University of Chicago showed that belief in the personal value of celibacy was waning among Catholic priests who believed that the restriction on marriage can be so costly to human growth that they leave the ministry to restore consonance between sexuality and spirituality (NORC, 1972). A study by Bauman et al. (2019) that analyzed data sets of 2,531 priests in Germany confirmed that low commitment to celibacy is also connected to spiritual dryness and loneliness. Its regression analyses also revealed that loneliness as an inability to be alone is connected to spiritual dryness (Bauman et al., 2019).\n\nPhilip Sheldrake (1994) argues that the celibacy is only a reflection of the superstructure of celibate culture that sees human intimacy as a distraction of one’s attention from God. Following Karl Marx’s theory, reality has been divided into two main strata: The base or the material infrastructure or economic system and the superstructure or the dominant idea systems in society such as culture that reflect the base. For Marx, dominant beliefs are only a reflection of the material reality in society (Williams, 1973). Thus, in the RCC, the dominant belief on the centrality of celibacy in the priesthood is only a reflection of the clericalist culture that primarily sees human sexuality as lust and distraction, dividing the priest’s attention in the ministry if he is married or having a sexual relation. But this view is opposed by Sheldrake who contends that the newer understandings of sexuality are focused on human connection rather than lust (Sheldrake, 1994). To him, the problem of celibacy is not only about a deprivation of sexual intercourse but also a denial of the positive values of relatedness and collaboration which are at the heart of sexuality. Clerical celibacy, therefore, alienates priests from human positive values of intimacy, relatedness, and mutual support which are crucial in the development of a healthy human sexuality (Sheldrake, 1994).\n\nIn the absence of a family and intimate group support in the parish, a celibate life is suited for religious priests who live in religious or monastic communities, but not for diocesan priests who usually live alone in their parishes. In fact, during the early years of the RCC, celibacy was practiced by monastic priests with strong asceticism and involved in religious communal life (Scheper-Hughes and Devine, 2003). But practicing celibacy in contemporary environments with a high level of social alienation can intensify the loneliness of the parish clergy. In the contemporary world, celibacy seems little more than cultural survival of the priesthood than an aid to spiritual growth for priests (Scheper-Hughes and Devine, 2003). Currently, Catholic diocesan priests, especially in the US, serve complex communities in highly urbanized settings. These communities are “increasingly multicultural and multiethnic because of changing immigration patterns set off by the globalization process and the availability of accessible travel. The pre-modern, modern, and postmodern worlds exist side by side, each demanding attention” (Hoge, 2002: ix), making clerical life and pastoral work in the parish more complex and stressful for priests. At present, many priests are assigned as pastors in multiple parishes. This implies that parish structures change as society becomes more complex (Froehle, 2007). Mandatory celibacy complicates Catholic priestly life. It restricts the pool of eligible candidates for priesthood and diminishes its quality. Daly (2029), for instance, argues that currently the population of priests is fast decreasing and is headed for extinction in Europe and in the Americas. “Worldwide, the number of Catholic priests has ‘flatlined’ at about 400,000 for the last 50 years … In the U.S., priestly vocations declined drastically by 40 percent because of celibacy” (Daly, 2019, para. 12).\n\nSpirituality is recognized as a resource to cope with burdening life events and chronic illness. It has both personal and communal dimensions. Monks of the early Christian era who experienced acedia live isolated lives and become neglectful of their communal rules on prayer. Nurturing personal spirituality needs some form of communal activities to strengthen it. Stark et al. (1980, 1982), concluded that communities displaying high levels of religious integration (“moral communities”) are the most effective in promoting conformity to the moral order. Enhancing the priest’s private spirituality also requires role modelling, communal prayer, and imitating the strong religiosity of fellow priests. Social support theory suggests that religious groups can promote positive behaviors through peer and adult modeling (Smith, 2003; Wallace and Forman, 1999). Social support can be a treatment for strain and can directly reduce anxiety (Beehr and McGrath, 1992). Thus, if diocesan priests of nearby parishes can live together as a small intimate community, social support can treat a lot of clerical problems such as loneliness, neglect of prayer, and even sexual abuse. Currently, the diocesan community of priests called a presbytery is a loose religious community which cannot provide strong peer support and modeling to support the spiritual formation of priests.\n\nMandatory clerical celibacy does not only facilitate loneliness but also diminishes the communal aspect of spirituality and encourages solitary spiritual life that can lead to spiritual negligence and acedia for parish clerics with the absence of communal monitoring and support for individual spirituality. A priest’s intimacy with God is crucial for their psychological health which can inhibit loneliness and acedia. Isacco et al. (2016), for instance, discovered that priests’ relationship with God has a positive effect on their psychological well-being. Catholic priests are less likely to be burned out, for instance, compared to people in other professions because of their strong relationship with God (Rossetti and Rhoades, 2013). Rossetti and Rhoades (2013) also discovered that a relationship with God is among the highest factors related to priests’ happiness in a sample of 2,482 priests.\n\nBut achieving a strong relationship with God is not only a personal effort but also a communal one. With celibacy and the absence of an intimate group such as the family, which the RCC’s calls the domestic church, a healthy spirituality requires a mutual support, role modelling, social bonding, and communal spiritual activities to deepen priests’ relationship with God. Absolute privacy, created by celibacy, isolation, and increased workload in the parish, can lead to spiritual sloth, negligence, spiritual dryness, and eventually acedia. Acedia is a state that lacks mutual care between parish clerics, bishops, and the lay community in the parish and diocese with the current celibate parish priesthood. It is “an unhealthy clerical discipleship where there is a lack of care or support for the priest by the community, or a lack of encouragement of the laity or unwillingness on their part to get involved in the pastoral life of the parish” (McAlinden, 2015: 273). In an acedic parish community, diocesan clerics can become lukewarm or neglectful of their spiritual duties without guardianship and companionship of fellow celibate priests. The local lay community is also apathetic towards the personal and spiritual needs of their parish priests, thus contributing to the serious vocational crisis that can encourage priests to leave the priesthood or commit clerical sexual abuse (CSA) as celibate priests and spiritual leaders (McAlinden, 2015).\n\nCSA threatens the existence of the Church, destroying the credibility of the entire institution and some of its leaders (Orobator, 2011, 7). The CSA in the RCC started to emerge publicly in the United States (US) in 1984 with the publicized case of Fr. Gilbert Gauthe, a diocesan priest of Lafayette who committed a series of child sexual abuse crimes between the 1970s to 1980s (Ballano, 2020). This was followed by a series of reports on CSA by Boston Globe and other media outlets on more than 3,700 clerics, mostly diocesan, who abused more than 16,000 victims (Bishop Accountability, 2011). Later, a Pennsylvania investigation by a grand jury also showed more than 300 diocesan priests abused 1,000 children over a period of 70 years (Goodstein and Otherman, 2018). Some studies indicated that CSA is facilitated by the absolute privacy of priests where victims were alone with predator clerics in the parish or rectory (e.g., Garland and Argueta, 2010; Wortley and Smallbone’s research (2006). Absolute privacy, primarily caused by clerical celibacy in the parish, can facilitate CSA because of the absence of behavioral monitoring by brother priests (John Jay College, 2004). And when clerical ascetical discipline is weak owing to the lack of social bonding and communal spirituality, priests can become vulnerable to various sins such as CSA (Cross and Thoma, 2006). Susan Collingridge (2019) aptly describes the solitary life of typical contemporary lone-working priests in the parish without a strong support of the laity and fellow priests:\n\nThey will work alone and eat alone. They will pray alone and sleep in an otherwise empty house. Not only that, but with fewer priests being ordained, today’s priests are both isolated as lone clergy in the presbytery, and also managing an increased workload (Collingridge, 2019: 122).\n\nMcAlinden (2015, 269) argues, “[i] f the church as institution or the parish community is acedic then its ability to care for clergy is diminished. If clergy perceive the church not to care, then a logical parallel process is priestly acedia”, which can encourage priests to degrade their vocation, resulting in various forms of abuse such as CSA. And this is usually precluded by a collapse of clerical ascetical discipline (Cross and Thoma, 2006).\n\nAllowing optional celibacy or married priesthood can provide the parish clergy with an intimate support group such as the family, which can be considered as the priest’s domus ecclesia or domestic church, to minimize loneliness, isolation, vocation crisis, and prevent serious symptoms of acedia. Despite calls to amend the rules on celibacy, the RCC currently remains adamant to allow it. Thus, to resist acedia, some structural adjustments must be made to minimize the loneliness of diocesan priests in their parishes. As Collingridge (2019: 118) argues, “the priests’ need for intimacy is not a naïve return to their families of origin to gain greater support. Rather, it is through a maturing personal awareness that they are able to be part of that family network in a healthy way”. Thus, Friedman (1985) recommends that parish clerics must live together in the presbytery as family-like groups with professional and spiritual support, companionship with peers and social interaction, to fight the sin of acedia. Living alone in the parish can lead to loneliness, a major component of acedia or spiritual sloth. Without a communal life, clerical diocesan spirituality can become individualist, lacking in public spirituality and role modeling of fellow priests. As shown in the study, isolation can lead to neglect of prayer life, spiritual dryness and eventually acedia. Thus, an alternative structure must be built in the parish where lay leaders and priests in nearby parishes meet regularly for communal prayer and social support.\n\nThe parish clergy in the contemporary world is largely living and ministering alone in the parish or community with mandatory celibacy, thus making them prone to isolation and acedia. In this regard, greater social bonding is necessary for parish clergy to cope with the stress and pressure of priestly ministry. The parish clergy’s “commitment to a single life must be met with an equally strong facilitation of opportunities for meaningful close interaction and partnership for them, not just as professional clergy, but as human beings” (Collingridge, 2019: 118). The RCC needs to create alternative structures such as small communities of priests living in the same territory or district, with priests working as team in the ministry, imitating the communal life of religious priests.\n\nFurthermore, addressing the solitary and acedic diocesan spirituality requires what McAlinden (2015) calls “living baptismally”. This implies establishing a flourishing priestly and lay discipleship in the parish with a commitment to collaborative ministry that provides mutual care. This entails a holistic conversion, “[f] aithfulness to prayer, celebrating the sacraments with meaning, commitment to nurturing spiritual practices which foster one’s relationship with God and oneself” (McAlainden, 2015: 274). Being baptized into a community demands the development of ways to pray with others and to grow spiritually. Thus, to become part of a flourishing parish community that is resistant to acedia implies establishing more parish spiritual communal activities such as a joint parish recollection or retreat between priests and lay leaders. A regular sharing of faith experiences in the parish between priests and lay leaders can also be a meaningful way to foster a strong spiritual community to counteract acedia.\n\nFinally, “living baptismally” demands a resilient spirituality that overcomes the limitations of spiritual formation and the anomic spirituality structure in the diocesan ministry. It requires creative ways to fill the gap between the monastic spiritual training in the seminary and the unregulated and individualist structure of clerical parish spirituality to “remain in one’s cell” and overcome the snares of acedia. “The sacrament of baptism offers a model for priestly living in the contemporary world which considers crises and acedia as invitations to renewed discipleship rather than despair” (McAlinden, 2015: 273), bearing in mind Christ’s promise in the Gospel to His faithful disciples that He will prepare a place for them in His Father’s house (John 14:4).\n\n\nConclusion\n\nThis article has illustrated that mandatory celibacy among Catholic priests, especially for parish clergy, intensifies loneliness and isolation of parish priests who generally live autonomous life in the parish. Mandatory celibacy also magnifies the solitude and seclusion of diocesan clerics who normally live and work alone in their parishes. Celibacy creates a solitary life for diocesan priests which can lead to lack of spiritual role modelling of fellow priests, spiritual dryness, and eventually acedia. It hinders the human and spiritual growth of the parish clergy in the deregulated environment of the parish. Celibacy can also diminish the communal aspects of spirituality and encourage an individualist spiritual life which can result in spiritual negligence, sloth, and acedia for parish clerics with the absence of communal monitoring and support. In this case, the RCC must reevaluate the relevance of mandatory celibacy of the parish clergy in contemporary times as several empirical and scientific studies have shown its negative effect on the priest’s spiritual, social, and psychological life. Christ only recommends optional celibacy to his disciples. Celibacy is not a dogma but only a disciplinary measure which can be abolished. In the light of the growing clerical problems such as sexual abuse, which is precluded by a weakening of clerical ascetism, acedia, and loneliness, it is time for the RCC to consider allowing married priests or optional celibacy for parish clergy.\n\nIf optional celibacy or married priesthood is not allowed by the RCC soon, the Catholic hierarchy of bishops needs to create alternative structures to allow greater social and spiritual intimacy for parish priests in order to avoid loneliness and acedia. This article recommends the creation of small clerical communities of diocesan priests situated in similar districts or territories to enhance social bonding, mutual support, and communal spirituality to strengthen the spirituality of the parish clergy against acedia. Lastly, by applying both theological and sociological perspectives to understand how celibacy greatly contributes to the loneliness and acedic life of priests in the parish, such as the lack social support and mandatory celibacy that facilitate it, this study departs from other studies on acedia. Unlike previous studies, this research provides an empirical assessment using sociological and social science theories and methods on the spiritual phenomenon called acedia or spiritual sloth in relation to mandatory celibacy in the Catholic diocesan priesthood.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
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}
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[
{
"id": "125422",
"date": "07 Mar 2022",
"name": "Edward Vacek",
"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 Catholic Church is going through crisis times. One area is a challenge to the idea and practice of priestly celibacy. The New Testament indicates that even St. Peter, the putative first pope, was married. In his letter to Timothy (4:1-16), St. Paul rejects those “who forbid marriage....For everything created by God is good, and nothing is to be rejected if it is received with thanksgiving, for it is made holy by the word of God and prayer.” Through the first 1000 years of the Church’s history, priest were able to marry. Martin Luther and other Reformers held that celibacy was a mistake and they encouraged marriage for priests. Eastern Orthodox priests, who are currently in communion with the Roman Catholic Church, can and do marry. Even now, Protestant married priests who convert to Catholicism are able to remain in their marriage. So there is no intrinsic contradiction with Catholic priests being married. Non-marriage for Catholic priests is a discipline, not a dogma.\nHowever, Jesus, by his own example and teaching, did offer an invitation to celibacy. He praised those who “became eunuchs” for the sake of the Kingdom (Matt 19:12). St Paul (1 Cor. 7:27) similarly urged the advantages of remaining celibate, in order to dedicate oneself to God's work.\nThe present article by Vivencio Ballono argues for an intermediate arrangement for priestly living. While it seems that the author would prefer making priestly celibacy optional in the Catholic Church, he offers a provisional alternative. Reflecting the insight of Genesis 2:18 (it is not good to be alone), his essay reflects mainly on the down sides of the single life. Jesus gathered around him 12 and more disciples who traveled with him. He sent his disciples out in pairs (Lk 10:1). So the wisdom of companionship is very important for many priests. But not all.\nMany diocesan priests live solitary lives. The author calls attention to this and to the isolation that some diocesan priests feel. This is an important issue for the health of the priests and for the sense of community that is so much a part of Christian living. He proposes an alternative.\nHe recognizes that companionship is also important for priests. But questions are often raised when a priest gets too close to a few parishioners, particularly female congregants. The author proposes one worthwhile alternative, namely, that several priests in a region live communally. Their commitment to one another would be occasioned not by shared vows, such as in religious orders, but rather by the unity of priestly brotherhood. Their commitment likely would not be permanent, but provisional, since the bishop could and likely would pick one or other priest to serve in a different area of the dioceses. Their commitment to their own parish likely would be somewhat diminished.\nInstead the author emphasizes the negative aspects of living alone. He neglects for the most part the positive aspects of priestly life, such as deep involvement in remedying or improving the lives of parishioners. He also overlooks the advantages of, e.g., a quiet evening after a full day of service. Many priests are happy introverts. He does not take into consideration the difficulties of living together. As one Jesuit saint remarked, “My greatest mortification is communal life.”\nThe living arrangements of Catholic priests changed greatly in New Testament times and down the ages. In the middle of the last century, many priests served with two or more other priests in the same parish. The great decrease in the number of priests makes that no longer possible. The author proposes another alternative that is worth trying.\nSee the attached file for detailed comments on the article: Detailed comments from Edward Vacek.\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? Partly",
"responses": []
},
{
"id": "121467",
"date": "08 Mar 2022",
"name": "Mark Regnerus",
"expertise": [
"Reviewer Expertise Sexual relationship behavior",
"marriage",
"religion",
"and methodology."
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting article, but is basically a literature review aimed at supporting one thesis—that celibacy contributes to acedia, and with it additional problems that plague priests.\nI’m familiar with the argument, but I had supposed there would be an empirical assessment of sorts, but the “data” here are just previous studies purported to be the data for a “qualitative research approach.” Don’t call it research per se; call it a literature review, a “state of the science” of sorts. (That said, it’s a pretty strong and ranging literature review.)\nSome pressing questions, observations, and criticisms:\nIt’s redundant. The reader is told at least seven times that living alone in a parish predicts loneliness, and in turn leads to spiritual sloth (or acedia).\nThere is a tacit causal assumption that this process contributes to criminal sexual abuse (of either sex, though most of the recent troubles have concerned the molestation of pre- and adolescent boys) despite the fact that the various reports about such (John Jay, etc.) have taken pains to distance themselves from implying that celibacy contributes to such—so far as I can tell. The fact is—there is not ample research on this. It’s a difficult matter to study.\nAcedia, as I understand it, is considered a personal vice. The article implies this about priests—that they are prone to it, but then elevates it to a congregational-level trait, even a diocesan one.\nI agree that “behavioral monitoring by brother priests” (page 4) is a safeguard. It’s also not failsafe by any stretch. I’m aware of numerous incidences of priestly misconduct by men who were monitored by fellow priests.\nThere’s a causal order concern I have. The author blames celibacy, and claims it causes loneliness, which in turn prompts acedia. But others perceive a different etiology to it—that our habits (of thought, practice, etc.) can invite acedia, which in turn fosters despair (of God’s love and mercy) and sadness. Reinhard Hutter (2012, First Things) notes that such a sadness “that will always cause problems.” Hence, the causal order may not be as obvious as the author suggests.\nThe author poses an interesting answer—the end of priestly celibacy—that is arguably unnecessary if the Church enables the formation of the author’s back-up plan: the formation of communities for priests to live in. So is the problem a lack of access to marriage to a woman (and then a family)? Or is the problem lack of brotherhood? They are both forms of companionship, and both rich in satisfactions. But they are quite different. So then basically, is this about sex or is it about fellowship of a sort? I think the author points more frequently to the latter, but nevertheless considers the former the central problem.\nFewer of the globe’s men and women are marrying, and at later and later ages. Hence, it can hardly be said that the population of priests is rapidly declining because marriage has become more pivotally important in the society around them. No, celibacy has lost cultural respect among many, while the presumed pleasures of access to sex (variety? consistency?) seem too important to forego. Basically, the priestly shortage is a complex thing. Moreover, because of clergy sexual abuse (again, mostly of boys), the barrier to the priesthood has shifted in many locales—to include evidence of a stable heterosexual orientation (see the Dallas Charter).\nMoreover, some priests do live in fellowship with other priests. The author seems to presume (page 3 of the pdf) a “lack of social bonding” is the reality in the Church. It may be for plenty of priests; it is not for many others. They form friendships with fellow priests, even those who don’t live with another priest, and/or they form friendships with parishioners’ families. Will this solve the acedia challenge? For many, yes. But it doesn’t rid one of temptation. Celibacy is a challenge even for the sociable priest. While the author blames celibacy for fostering acedia, other observers (like Hutter) blame pornography for the same. Would a spouse render pornography less attractive? Not by much, according to real data on the subject.\nBottom line is: celibacy is difficult, but hardly impossible. Sociability and friendship are important. Acedia is corrosive. But this study, lacking an empirical test, can only lean on previous studies to impugn celibacy. We can’t actually know from this study what is to blame for acedia (which is not a simple thing to measure, either.)\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "8045",
"date": "20 Apr 2022",
"name": "Vivencio Vivencio",
"role": "Author Response",
"response": "Dear Dr. Mark Regnerus, Peace of Christ! Thank you so much for reviewing this article, primarily from a sociological point of view. It is a privilege to have you as a reviewer for this article. I am posting my response here with the hope that you consider changing your final verdict. First of all, this article is not a literature review but qualitative secondary research that aims to explore a new research question on the relationship between celibacy, loneliness, and acedia using both theological and sociological approaches. It also attempts to \"inculturate\" (Inculturation is a buzzword in the Catholic Church which refers to the process of adapting the Christian faith in society as well as the adoption of the social sciences for evangelization) or adapt some sociological perspectives on the current theological issue of spiritual sloth and celibacy. For the distinction between a literature review and secondary analysis research see https://sru.soc.surrey.ac.uk/SRU22.html Second, this article adopts an emic perspective on the diocesan clerical formation and lifestyle, and pastoral background on the central issue. I believe that Dr. Regnerus missed the big difference in communal life between religious and diocesan priests. As a former diocesan and Jesuit seminarian for 10 years, I am aware of how diocesan spirituality and imposed celibacy can make parish clergy very lonely, lacking communal support from fellow priests and their bishops which really lead to spiritual sloth, while religious clergy generally has strong spiritual and communal support, although the Jesuit communal life is more similar to diocesan clerical life. The issue of loneliness and acedia is not more about the lack of sexuality in marriage but largely as a consequence of the solitary life due to celibacy. In the sociology of deviance, social bonding in a primary group such as the family is crucial against deviance. Although not an assurance that acedia and clerical abuse can be abolished, married priesthood can contribute a lot to more guardianship against sexual abuse. I discussed this in my Springer book on clerical sexual abuse (https://link.springer.com/book/10.1007/978-981-13-8825-5). Since I am aware that the Catholic Church is still not open to the married priesthood after the Amazon Synod in Rome, I recommended in this article the social bonding of diocesan priests who live in a common district to form a communal life. In this article, I really attempt to incorporate sociological perspectives to explain a more theological issue on celibacy and acedia in the Catholic Church. Many of my publications are attempts to \"inculturate\" or provide the empirical foundation and sociological analysis on church issues which are predominantly dominated by spiritual and theological perspectives of theologians in Catholic research and literature. With the foregoing, I hope that Dr. Mark would consider changing his overall judgment on this article. I am willing to revise this version following his other comments for this article. Thank you and God bless! Sincerely, Dr. Vivencio Ballano"
}
]
},
{
"id": "126989",
"date": "19 Apr 2022",
"name": "Lluis Oviedo",
"expertise": [
"Reviewer Expertise Studies of religious life",
"secularization and religious revival"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 offers a good systematic review on the topic of acedia in Catholic celibacy clergy. From this point of view the article is exhaustive and there is few we can add.\nMy own empirical work on consecrated men in the Catholic Church tells me about some more circumstances to take into account. Indeed, the main thesis that the article advances is that loneliness in diocesan clergy would be a main cause of distress and even abuses. There is some evidence that points in that direction, especially for the cases of abuses, but there are surely more factors involved. Indeed, it is quite intriguing that many priests in the communitarian religious life choose in the last years to leave this condition to become diocesan lonely priests; as if this other option would be perceived as more convenient. Other factor the article does not considers is the growing \"homosexualization\" in several areas of Catholic clergy, which adds another level of complexity.\nIn my opinion we need much more empirical research, beyond reviewing the available studies, to better address this question, and to help people in that condition to cope with it.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1195
|
https://f1000research.com/articles/10-1194/v1
|
24 Nov 21
|
{
"type": "Brief Report",
"title": "An Atlas of Plant Transposable Elements",
"authors": [
"Daniel Longhi Fernandes Pedro",
"Tharcisio Soares Amorim",
"Alessandro Varani",
"Romain Guyot",
"Douglas Silva Domingues",
"Alexandre Rossi Paschoal",
"Daniel Longhi Fernandes Pedro",
"Tharcisio Soares Amorim",
"Alessandro Varani",
"Romain Guyot"
],
"abstract": "Advances in genomic sequencing have recently offered vast opportunities for biological exploration, unraveling the evolution and improving our understanding of Earth biodiversity. Due to distinct plant species characteristics in terms of genome size, ploidy and heterozygosity, transposable elements (TEs) are common characteristics of many genomes. TEs are ubiquitous and dispersed repetitive DNA sequences that frequently impact the evolution and composition of the genome, mainly due to their redundancy and rearrangements. For this study, we provided an atlas of TE data by employing an easy-to-use portal (APTE website). To our knowledge, this is the most extensive and standardized analysis of TEs in plant genomes. We evaluated 67 plant genomes assembled at chromosome scale, recovering a total of 49,802,023 TE records, representing a total of 47,992,091,043 (~47,62%) base pairs (bp) of the total genomic space. We observed that new types of TEs were identified and annotated compared to other data repositories. By establishing a standardized catalog of TE annotation on 67 genomes, new hypotheses, exploration of TE data and their influences on the genomes may allow a better understanding of their function and processes. All original code and an example of how we developed the TE annotation strategy is available on GitHub (Extended data).",
"keywords": [
"mobile elements",
"atlas",
"large-scale",
"genome-wide",
"standardized",
"plants"
],
"content": "Introduction\n\nThe growing number of sequenced plant genomes is providing unprecedented opportunities for biological studies, evolution, and growing of many algal and Viridiplantae species. We estimate more than 13k plant genomes have been released (NCBI), revealing that plant genomes are faintly explored. High diversity in terms of ploidy, heterozygosity, and genome size, probably due to a dynamic set of old and recent bursts of transposable elements (TEs), are common hallmarks of many plant genomes.1 TEs can comprise between 32% to 56% (Utricularia genomes),2,3 to up to 90% in many plant genomes,4–6 e.g., maize7 and wheat.5,8,9\n\nTEs can be organized into two main classes. Each class is hierarchically organized into orders, superfamilies, families, and subfamilies. This terminology is primarily associated with the type of their transposition mechanisms.3,10 They are classified into: (i) retrotransposons (Class I), which are propagated by a “copy-and-paste” mobility mechanism and are the most redundant TE class in plant genomes; and (ii) DNA transposons (Class II), which are known for the “cut-and-paste” mechanism that allows them to move to a completely different position. Moreover, both Classes may contain autonomous members10,11 for which the transposition mechanism depends on an autonomous and cognate type of TE.11,12\n\nHowever, despite their significance, in-depth identification and analysis of TEs content in the sequenced plant genomes remains barely explored.13,14 The lack of concise data available may prevent the enrichment of in silico, functional genomics research and compromises the appearance of new strategies to investigate TEs. Recently, many computational models and entire wet-lab efforts have increasingly been helping to understand these sequences.15–18 For example, Ensembl Plants19 provides high-quality, primary genomic information for 67 plant (in the broad sense, including green plants, green and red algae) genomes, assembled near or at chromosome scale; however, mobile sequences are poorly systematized and have a humble coverage.\n\nThese observations prompted us to standardize tools and methods aiming to improve TE detection, annotation and standardization. In this work, we developed a new method for systematic annotation of plant TEs, using the 67 genomes available at Ensembl Plants assembled at chromosome scale as a starting point. Our identification was standardized, applying the same methodologies to all genomes and delivering a concise Atlas of TEs annotation in plant genomes. We also provided an updated analysis of non-coding RNAs (ncRNAs) overlapping TEs. This annotation is accessible on the Atlas website for exploration and download, which might be relevant to any type of research involving mobile sequences.\n\n\nMethods\n\nAll genomes (Supplementary Material 1, Extended data) were downloaded from the Ensembl Plants19 database, version 41 (57 genomes) and 45 (plus 10 new genomes).\n\nWe used similarity-based methods and de novo techniques to build a collection of putative transposable elements, based on the SPTEdb pipeline.21 We refined, extended and increased steps in order to produce a novel annotation (Figure 1). Our reformulated steps (details in Supplementary Material 2, Extended data) guarantee a comprehensive knowledgebase of these TEs.\n\nDataset: Genome assemblies were downloaded from Ensembl Plants. Identification: 1A) RepeatScout was used to search for putative repetitive sequences and further classification by PASTEClassifier, resulting in a library. 1B) RepeatModeler was also used to find a consensus of TEs sequences. 2) RepeatMasker was run with Repbase library and libraries from RepeatModeler and RepeatScout. 3) For Class II - Subclass 2 TEs, we also used HelitronScanner and MITE-Hunter. 4) In order to find LTR and Non-LTR retrotransposons, we used LTR_retriever and MGEScan-non-LTR, respectively. Filter: A cut-off filter was applied to remove low complexities, simple repeats and other nomenclatures that were not classified into TEs. Annotation: In result of the pipeline, we have a Transposable Element annotation for each genome analyzed.\n\nRepeatScout was performed separately; the output was unified in a library to be labeled by PASTEClassifier32 and later combined into a final annotation. To automate the pipeline, an in-house framework in Perl language was developed for each software output to be uniformized, described in steps 1 to 4. A main script in Bash starts the process of automatization using Perl scripts. All steps were supervised by researchers, carefully checked, and the output was manually verified at each step for each genome. Records classified as low complexity, simple repeat and other nomenclature not related to Class I or Class II TEs were discarded.\n\nDue to the extensive genome sizes of Triticum aestivum (14,5 Gb), Triticum dicoccum (10,4 Gb) and Triticum turgidum (10,4 Gb), we adapted our pipeline for their analysis, based on the approach of Jamilloux et al.24 For these species, we applied our pipeline on chromosome 1 (which is the longest pseudomolecule), as the large genomes were eventually duplicated into new copies, increasing the number of these same repeats in the genome, and did not significantly impact discoveries related to new or different TEs families.24\n\nTE evidence score\n\nTo test the reliability of our TE annotation pipeline, we scored sequences that had duplicated annotation in the same loci (Figure 2). We developed a statistical metric (labeled as TE-Score, shown in each record as the ninth column for each genome annotation file) that identify and ponder sequences types that have been identified by the programs. The TE-Score is a metric (0 to 1) that is given by\n\nTo test for correlations between genome size and transposable elements percentage by genome in base pairs, we first normalized using log10, and then we applied the Pearson Correlation Coefficient in SPSS version 25.\n\nAPTE is hosted at the Universidade Tecnológica Federal do Paraná (Cornélio Procópio, PR, Brazil). It uses Debian 11 as operating system, Apache 2 as web server, PHP 5.6 as web programming language. We also used Zend Framework 2, which implements model, view, controller (MVC), a methodology for web development that can be expanded for any future additional functionality. On the front-end, we used HyperText Markup Language 5 (HTML5), Cascading Style Sheet 3 (CSS3) and JavaScript to perform dynamic functions that provide user-friendly navigation. A built-in genome browser (JBrowse, version 1.14.1) is available to visualize and download the data as well.\n\nTo run the pipeline described in Figure 1, we used three platforms: (i) to runRepeatModeler,25,26 RepeatScout,26,27 RepeatMasker,27 LTR_retriever,28 MITE-Hunter29 and HelitronScanner30; (ii) to perform MGEScan-non-LTR31 and PASTEClassifier32; and (iii) to unify and filter outputs to the main annotation. The hardware utilized were (i) Xeon E7540 2.00 GHz 256GB memory, Xeon E5-2620v3 2.40 GHz 64GB memory, 2x Intel i7-3820 3.60Ghz 32GB memory and Intel i7-3820 3.60Ghz 64GB memory, (ii) Intel i7-3820 3.60Ghz 64GB memory, and (iii) Intel Core 2 Duo 2.4 GHz 8GB memory, a total of 30 physical cores and 456 GB of memory. In order to present a scale of time elapsed to measure, filter and standardize the results, we estimate that for the A. thaliana genome, the time needed to get the final annotation was ~18 hours, using all resources mentioned, including post-processing scripts (detailed on our website).\n\n\nResults and discussion\n\nWe retrieved a total of 49,802,023 TE records from 67 plant genomes, representing a total of 47,992,091,043 (~47,62%) base pairs (bp) of the total genomic space. This information is distributed in ~57,36% (28,565,034) TEs organized into class, order and superfamily. In addition, ~42,64% (21,236,989) elements could not be assigned to any type of known TE and they were labelled as unknown. They likely represent chimeric and/or partial elements for which we were not able to perform the full classification. For known TEs, we identified that ~62,85% were retrotransposons, and ~37,15% were DNA transposons. All assigned classifications of TEs identified along the 67 genomes are shown in Figure 3. The distribution of TEs in the analyzed genomes are somewhat similar (Figure 4), especially in genomes that have a shorter phylogenetic distance (e.g., Oryza spp, Triticum spp). However, even close-related genomes exhibit uneven TEs distribution (e.g., Arabidopsis spp). Two main hypotheses might explain the variation of TE content: (a) different evolutionary stories, since the two major genome duplication events are shared by all seed plants (epsilon) and flowering plants (gamma), followed by the lineage-specific duplication events,20 and (b) specific pressures to maintain, expand and purge TEs in each lineage.\n\nWe have noted that our approach permitted better TE annotations in genomes assembled at chromosome scale, and we also observed that the amount of TEs is generally related to the genome size, since larger genomes have higher occurrences of TEs (Figure 5). However, for incompletely and draft-assembled genomes, it tends to decrease the number of TEs, once the assembly into small parts (scaffolds or contigs) may impact the genome assembly quality, collapsing repeated contigs (mostly TE- derived) and interfering with the proper identification of these TEs.\n\nOn the left, the bar chart in blue, the genome size (in Gb), and, in green, the transposable elements distribution in analyzed genomes (in percentage). On the right, we normalized, in base pair, genome size and TE using log(10) and then we correlated (Pearson) the genome size by transposable elements. r and p-value are shown in the top-left of each chart. A) Using all the 67 annotated genomes; B) For all genomes with recent WGD (Whole Genome Duplication) events, blue circles; C) Excluding genomes that experienced recent WGD, red circles.\n\nTo compare the results of the identification performed and to ensure the reliability (details in Supplementary Material 1, Extended data) of our approach, we used SPTEdb21 annotation data of the genome Populus trichocarpa (black cottonwood), which is explored in Table 1. The second comparison of TE annotations was performed for the Glycine max (soybean) genome, in which we used SoyTEdb22 to compare the amount vs. type of TEs, shown in Table 1. A third comparison used data from GrTEdb23 to explore the amount of TEs in Gossypium raimondii (cotton), available in Table 1.\n\n\nConclusion\n\nOur analysis brought an exhaustive, systematic and comprehensive genome identification in plant genomes, using seven programs to annotate TEs in plant genomes. In both TE classes, several orders and superfamilies were found ubiquitously in all genomes. Additionally, 21,236,989 out of 49,802,023 mapped TE sequences could not be classified into any of the nomenclatures known for TEs, and were labeled as “Unknown” in GFF3, a standard file format for gene annotation.\n\nFor plant species whose TE complement may be quite well-annotated, i.e., Arabidopsis thaliana, we yielded an increased number of identified TEs. In species with less curated annotation in Ensembl, we were able to deliver a more detailed identification of TEs. For example, in three particular genomes, i.e., Populus trichocarpa (black cottonwood), Glycine max (soybean) and Gossypium raimondii (cotton), we increased the TE identification levels by 2,295%, 900% and 2,643%, respectively. We observe that for several other genomes, new types of TEs were identified and annotated; this ensures that our pipeline delivers not only the same TE identification, but also new ones, making the annotation process possible to use for any species.\n\nIn this study, we contributed to expand the knowledge on TEs, by providing a large-scale, organized and standardized TE Atlas. We integrated all annotations to make it available to download in each genome separately from the Atlas of Plant Transposable Elements (APTE) website. An example how our pipeline works using the A. thaliana genome, software dependencies, and in-house scripts developed, which can be downloaded, used and changed freely, are available from https://github.com/daniellonghi/te_pipelinehttps://github.com/alerpaschoal/apte_pipeline/.\n\n\nData availability\n\nAll data underlying the Plant TE Atlas is available in the portal http://apte.cp.utfpr.edu.br/.\n\nZenodo: Datasets from An Atlas of Plant Transposable Elements, https://doi.org/10.5281/zenodo.5672122.33https://doi.org/10.5281/zenodo.5574528\n\nThis project contains the following extended data:\n\n- SuppMat_1.xlsx (the gen ome assembly reference access from Ensembl Plants species used)\n\n- SuppMat_2.docx (a brief transposable elements annotation steps used in this work)\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 at: https://github.com/alerpaschoal/apte_pipeline/\n\nArchived code at time of publication: https://doi.org/10.5281/zenodo.5672122\n\nLicense: CC0",
"appendix": "References\n\nMichael TP, VanBuren R: Building near-complete plant genomes. Curr. Opin. Plant Biol. 2020; 54: 26–33. PubMed Abstract | Publisher Full Text\n\nSilva SR, Moraes AP, Penha HA, et al.: The terrestrial carnivorous plant utricularia reniformis sheds light on environmental and life-form genome plasticity. Int. J. Mol. Sci. 2020; 21(1): 3. Publisher Full Text\n\nLan T, Renner T, Ibarra-Laclette E, et al.: Long-read sequencing uncovers the adaptive topography of a carnivorous plant genome. Proc. Natl. Acad. Sci. 2017; 114(22): E4435–E4441. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWicker T, Sabot F, Hua-Van A, et al.: A unified classification system for eukaryotic transposable elements. Nat. Rev. Genet. 2007; 8: 973–982. PubMed Abstract | Publisher Full Text\n\nCharles M, Belcram H, Just J, et al.: Dynamics and differential proliferation of transposable elements during the evolution of the B and A genomes of wheat. Genetics. 2008; 180: 1071–1086. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHawkins JS, Kim H, Nason JD, et al.: Differential lineage-specific amplification of transposable elements is responsible for genome size variation in Gossypium. Genome Res. 2006; 16: 1252–1261. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnderson SN, Stitzer MC, Brohammer AB, et al.: Transposable elements contribute to dynamic genome content in maize. Plant J. 2019; 100(5): 1052–1065. PubMed Abstract | Publisher Full Text\n\nGardiner LJ, Joynson R, Hall A: Next-Generation Sequencing Enabled Genetics in Hexaploid Wheat. Applications of Genetic and Genomic Research in Cereals. Woodhead Publishing; 2019; (pp. 49–63). Publisher Full Text\n\nMaccaferri M, Harris NS, Twardziok SO, et al.: Durum wheat genome highlights past domestication signatures and future improvement targets. Nat. Genet. 2019; 51(5): 885–895. PubMed Abstract | Publisher Full Text\n\nBourque G, Burns KH, Gehring M, et al.: Ten things you should know about transposable elements. Genome Biol. 2018; 19(1): 1–12. Publisher Full Text\n\nChuong EB, Elde NC, Feschotte C: Regulatory activities of transposable elements: from conflicts to benefits. Nat. Rev. Genet. 2017; 18(2): 71–86. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchrader L, Schmitz J: The impact of transposable elements in adaptive evolution. Mol. Ecol. 2019; 28(6): 1537–1549. PubMed Abstract | Publisher Full Text\n\nHirsch CD, Springer NM: Transposable element influences on gene expression in plants. Biochimica et Biophysica Acta (BBA)-Gene Regulatory Mechanisms. 2017; 1860(1): 157–165. PubMed Abstract | Publisher Full Text\n\nJangam D, Feschotte C, Betrán E: Transposable element domestication as an adaptation to evolutionary conflicts. Trends Genet. 2017; 33(11): 817–831. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOrozco-Arias S, Candamil-Cortés MS, Jaimes PA, et al.: K-mer-based machine learning method to classify LTR-retrotransposons in plant genomes. PeerJ. 2021; 9: e11456. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOliveira LS, et al.: Computational Analysis of Transposable Elements and CircRNAs in Plants. Vaschetto LM, editor. Plant Circular RNAs. Methods in Molecular Biology. New York, NY: Humana; 2021; vol 2362. . Publisher Full Text\n\nOrozco-Arias S, Jaimes PA, Candamil MS, et al.: InpactorDB: a classified lineage-level plant LTR retrotransposon reference library for free-alignment methods based on machine learning. Genes. 2021; 12(2): 190. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOliveira LS, de Amorim TS , Pedro DLF, et al.: A Practical Guide on Computational Tools and Databases for Transposable Elements in Plants. Cho J, editor. Plant Transposable Elements. Methods in Molecular Biology. New York, NY: Humana; 2021; vol 2250. . Publisher Full Text\n\nBolser D, Staines DM, Pritchard E, et al.: Ensembl plants: integrating tools for visualizing, mining, and analyzing plant genomics data. Plant bioinformatics. New York, NY: Humana Press; 2016; (pp. 115–140). Publisher Full Text\n\nJiao Y, Wickett NJ, Ayyampalayam S, et al.: Ancestral polyploidy in seed plants and angiosperms. Nature. 2011; 473: 97–100. PubMed Abstract | Publisher Full Text\n\nYi F, Jia Z, Xiao Y, et al.: SPTEdb: a database for transposable elements in salicaceous plants. Database. 2018; 2018. Publisher Full Text\n\nDu J, Grant D, Tian Z, et al.: SoyTEdb: a comprehensive database of transposable elements in the soybean genome. BMC Genomics. 2010; 11(1): 1–7. Publisher Full Text\n\nXu Z, Liu J, Ni W, et al.: GrTEdb: the first web-based database of transposable elements in cotton (Gossypium raimondii). Database. 2017; 2017.\n\nJamilloux V, Daron J, Choulet F, et al.: De novo annotation of transposable elements: tackling the fat genome issue. Proc. IEEE. 2016; 105(3): 1–8. Publisher Full Text\n\nSmit AFA, Hubley R, Green P: RepeatModeler Open-1.0.2008-2019. Reference Source\n\nRepeatMasker. http\n\nPrice AL, Jones NC, Pevzner PA: De novo identification of repeat families in large genomes. To appear in Proceedings of the 13 Annual International conference on Intelligent Systems for Molecular Biology (ISMB-05). Detroit, Michigan: 2005. Reference SourceReference Source\n\nOu S, Jiang N: LTR_retriever: A Highly Accurate and Sensitive Program for Identification of Long Terminal Repeat Retrotransposons. Plant Physiol. 2018; 176: 1410–1422. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHan Y, Wessler SR: MITE-Hunter: a program for discovering miniature inverted repeat transposable elements from genomic sequences. Nucleic Acids Res. 2010; 38: e199. PubMed Abstract | Publisher Full Text | Free Full Text\n\nXiong W, He L, Lai J, et al.: HelitronScanner uncovers a large overlooked cache of Helitron transposons in many plant genomes. Proc. Natl. Acad. Sci. 2014; 111: 10263–10268. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRho M, Tang H: MGEScan-non-LTR: computational identification and classification of autonomous non-LTR retrotransposons in eukaryotic genomes. Nucleic Acids Res. 2009 Nov; 37(21): e143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPASTEClassifier. Reference Source\n\nPedro DLF, Amorim TS, Varani AdM, et al.: Datasets and Pipeline V1.0 from An Atlas of Plant Transposable Elements (v1.0) [Data set]. Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "101071",
"date": "01 Dec 2021",
"name": "Gökhan Karakülah",
"expertise": [
"Reviewer Expertise Bioinformatics",
"Genomics",
"Mobile elements",
"Repetitive DNA",
"Non-coding RNAs"
],
"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 work, Pedro and colleagues present a novel transposable elements database for plants using publicly available genome sequences from the Ensembl Plant database. The methodology was clearly described and seems reproducible. The main output of the current work is a publicly available database named APTE and its interfaces are elegantly designed. All transposon annotations are available without any restriction and the database is easy-to-use.\nI believe this unique and valuable database has potential to help researchers in both computational and wet lab analyses of mobile elements.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "116755",
"date": "04 Jan 2022",
"name": "Adriana Ludwig",
"expertise": [
"Reviewer Expertise Transposable elements"
],
"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\nPedro et al., presented an atlas of transposable elements from 67 well-assembled plant genomes. The full TE annotation is provided in the APTE database that is informative and straightforward. It is a very good source of data for other researchers that might be interested in proceeding deepest analysis of a specific group of elements. The authors have identified a great number of repetitive sequences in each genome. My biggest concern is related to the sequences that fail to be classified. These “Unknown” sequences make up a huge proportion of all the repetitive sequences found. Even with the filtering of low complexity and simple repeat sequences, they could still be false positive. The authors could mention this possibility. Moreover, the difference in the amount of TE identification between the two databases shown in Table 1 is impressive. My doubt is whether there is a possibility that part of this difference is caused by the artificial \"breaks\" of TE copies into a greater number of fragments. Finally, it is not clear if the authors have filtered short sequences that could also be false positive.\nMinor suggestions/comments:\nPage 6: “evolutionary stories”. I believe “evolutionary histories” would be more appropriate.\n\nConcerning the TE classification. In Figure 3, I suggest some modifications to become more accurate regarding the TE classification (according to Wicker et al.;20071):\n\nDIRS and Ngaro are mentioned as orders. The correct is to include both as superfamilies of order DIRS.\n\nMITE is not an order. They are non-autonomous elements from order TIR. In the same way, LARD and TRIM are not superfamilies, but non-autonomous elements related to some LTR superfamily. I suggest a change to “Superfamily/Group” since some groups specified are not independent established superfamilies, but rather groups/clades of a superfamily. The same occurs in Table 1. Moreover, in Table 1, Crypton should be placed as an order.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1194
|
https://f1000research.com/articles/10-1191/v1
|
24 Nov 21
|
{
"type": "Brief Report",
"title": "Chronic exposure to ∆9-tetrahydrocannabinol in adolescence decreases social play behaviours",
"authors": [
"Robin J. Keeley",
"Stephanie M. Himmler",
"Sergio M. Pellis",
"Robert J. McDonald",
"Robin J. Keeley",
"Stephanie M. Himmler",
"Sergio M. Pellis"
],
"abstract": "Background: Cannabis use remains a major public health concern, and its use typically begins in adolescence. Chronic administration of ∆9-tetrahydrocannabinol (THC), the main psychoactive compound in cannabis, during adolescence can produce deficits in adult learning and memory, stress reactivity and anxiety. One possible mechanism behind the disruptions in adulthood from adolescent exposure to THC includes changes in social behaviours, such as social play, which has been shown to be critical to socio-cognitive development. Methods: Here, using an established animal model of adolescent THC exposure in male and female Long–Evans rats, we explored the effects of THC on play behaviour during the chronic administration period. Following puberty onset, as indicated by external changes to the genitalia, THC (5mg/kg) was administered for 14 days. Play behaviour was assessed seven days following the onset of the injection period at approximately 1 hour post treatment. The frequency of nape attacks, the likelihood and tactics of defensive behaviour, and pins were scored and analyzed. Results: THC exposure decreased playfulness in adolescent rats including the number of attacks, likelihood of defense and pins compared to control and vehicle treated rats. Conclusion: This suggests that THC suppresses both the attack and defense components of social play. This is an important finding because there is evidence that attack and defense may be mediated by different mechanisms. Furthermore, the effect of THC exposure decreasing playfulness occurred similarly in males and females.",
"keywords": [
"THC",
"adolescence",
"rat",
"play",
"social behaviour"
],
"content": "Introduction\n\nThe first instance of cannabis use typically begins in adolescence,1 although the long-term consequences of adolescent cannabis exposure are not clear. Δ9-tetrahydrocannabinol (THC) is the main psychoactive component in cannabis,2 and accounts for many of its psychoactive properties.3 Chronic THC administration in adolescent rats can produce genetic background- and sex-specific deficits in adult learning and memory, stress reactivity and anxiety,4 although the mechanism producing the behavioural changes observed in adults exposed to THC as adolescents is poorly understood.\n\nAdolescence is an evolutionarily conserved period of brain development,5 and pharmacological or behavioural perturbations of this critical developmental period can induce long-term changes in adult brain and behaviour, specific to the background and sex of the individual.6 However, the complex interplay between adolescent manipulations and resultant changes in social behaviours remains underexplored [for review, see Ref. 7]. Social play peaks during the juvenile period8 and is critical to the development of socio-cognitive skills and their underlying brain mechanisms.9\n\nAcute administration of cannabinoids decreases social play,10 and chronic treatment with cannabinoids in adolescence can decrease play behaviour in adulthood.11 Given that our earlier research identified some long-term changes to adult brain and behaviour following adolescent THC exposure, it is crucial to understand whether these changes were purely pharmacological or involved a complex interplay between pharmacology and behaviour. Furthermore, the way in which play, which involves competitive wrestling,12 has been measured by most studies [for example, Ref. 10] in ways that do not allow the detailed assessment of which aspects of play change with treatment. Where such measures have been expanded to include direct assessment of attack and defense, there is some indication that some aspects of defense may be especially susceptible.11 The present study also seeks to expand the current literature by identifying whether all aspects of play or only specific aspects of play are affected by chronic exposure to THC. Here, we used a previously established animal model of adolescent drug exposure4,13 in male and female Long–Evans rats to explore the effects of THC on play behaviour during the chronic administration period.\n\n\nMethods\n\nA total of 48 Long–Evans rats (24 females and 24 males; RRID: RGD_18337282) were bred in-house at the Canadian Centre for Behavioural Neuroscience (CCBN) at the University of Lethbridge. Sample size was determined using a combination of prior literature14 as well as a power analysis. No animals were excluded from this analysis. All rats were placed in standard home cages (46×25×20 cm; maintained at 21°C and 35% relative humidity) and were given ad libitum access to food and water. Rats were weaned at postnatal day 21 and pseudo-randomly placed in same-sex quadrads, with no more than two littermates per quadrad. Following weaning, male and female rats were randomly assigned and counterbalanced to their experimental groups: comparison control (CC; N = 6), control (CON; N = 6) vehicle (VEH; N = 6) or THC (N = 6) so that each quadrad included one same-sex partner subject from each experimental group. Blinding occurred during group allocation as the person assigning the rats to each quadrad did not know the eventual treatment group of each rat. The CC group received handling like the CON group, but they were the play partner with which all other group members interacted. For each play bout measured, the behaviour of CON, VEH and THC treated rats was quantified. All procedures were done in accordance with the Canadian Council on Animal Care and were approved by the University of Lethbridge Animal Welfare Committee. Additionally, all experimental procedures were carried out according to the Institutional Animal Care and Usage Committee (ARRIVE guidelines).\n\nTreatment began following puberty onset as previously described,13 using the external changes to the genitalia, which reliably signal the onset of puberty.4 THC (in 1:1:18 solution of ethanol: cremaphor:saline) was administered i.p. at a dose of 5 mg/kg once a day starting on the day of puberty onset for 14 days. This dose of THC was chosen given that it can produce both acute and chronic effects on brain and behavior. VEH groups were given a vehicle injection. All injections were performed during the last third of the dark cycle. On each injection day, rats were removed from their home-cages and placed in a light-blocking transport tub and brought to a procedural room that was lit with a red incandescent bulb. All rats were weighed before treatment. For VEH and THC rats, the injection site was varied daily to eliminate any damage and/or irritation due to multiple injections at the same site. Following injections, all rats were brought back to their home-cages. All treatment groups were handled for approximately 5 min.\n\nPlay behaviour was tested using previously described procedures.14 Testing consisted of placing two play partners in large, clear Plexiglas arena (5050 × 50 cm), filled to a depth of ~1–2 cm with Betacob bedding. Play was recorded for 10 min in the dark using a video camera with night-shot capacity. Following the trial, rats were returned to their home cage. No adverse events were reported. Upon completion of the experiment, the rats were humanely sacrificed with an i.p. injection of sodium pentobarbital (300 mg/kg).\n\nA timeline of drug treatment and play behaviour assessment can be found in Figure 1. Play behaviour was assessed at least seven days following the onset of the injection period ~1 hour after treatment. Since we were interested in the acute effects of THC behaviour during the chronic administration period, we chose a time-point wherein the rats would be habituated to the treatment while still acutely intoxicated. On day 5 and 6 of treatment, quadrads were habituated to the play apparatus for 30 min. 24 hours before play trials, partners were separated and housed individually. To reduce isolation distress during this time period, all of the rats had access to a black tube and shredded paper for enrichment. Within a quadrad, all treatment rats (CON, VEH and THC) were paired with the CC rat for play bouts. The order of play bouts with the CC was counterbalanced, the play apparatus was cleaned between recordings using Virkon, and fresh bedding was replaced for each session.\n\nRats began THC exposure at puberty onset. On days 5 and 6, rat quadrads were habituated (H) to the play apparatus. On day 7, pairs of rats were isolated (I), always including the comparison control group, to which all other rats were paired. Play behaviour (P) was assessed on subsequent days. For all quadrads, there were three isolation days and three play behavior assessments to assess all pairings of treatment groups with the comparison control (CC–CON, CC–VEH and CC–THC).\n\nVideos were analyzed using previously described techniques.14 The experimenter scoring the videos were blind to the experimental groups, however, the THC group’s behaviour may have been different compared to the other groups and therefore complete concealment may not have been obtained. During play, rats compete to contact and nuzzle the partner’s nape of the neck.12 The frequency of nape attacks (in which the snout of one partner moves towards the nape of the other), the likelihood of the partner receiving a nape attack defending itself to avoid contact and if it did defend itself, the tactics used to do so were scored.14 The total frequency of nape attacks per 10 min were scored and analyzed, but as defense is contingent on attack, the frequency of defense was expressed as a percentage of attacks received, and the types of defense were expressed as a percentage of defended attacks. Defense can involve either evasion (the head and neck are turned away from the attacker) or facing defense (the defender turns to face the attacker). The percentage of evasion provides a measure of attempts by rats to avoid playful contact. In facing defense, the rats can either remain standing or roll over to supine, with the percentage of the latter providing a measure of the rat’s motivation to gain and maintain close body contact. A common configuration resulting from attack and defense in the juvenile period is for one rat to lie on its back and the partner to stand over it (i.e., a pin).15 As the absolute number of pins per trial can provide insight into the pattern of interaction,16 this was also scored. Data from this study has been archived.32\n\nAll statistical analyses used R (version 3.4.1; RRID:SCR_001905). Main effects of group, sex and group by sex interactions were examined for their effect on the frequency of nape attacks and pins as well as the percentage of defensive behaviours, the percentage of evasions (as a percentage of defended attacks) and the percentage of complete rotations (as a percentage of facing defenses). Post hoc comparisons were conducted when main effects or interactions were observed using Bonferonni corrections.\n\n\nResults\n\nFor all analyses, there was no significant effect of sex or an interaction between treatment group and sex (p’s > 0.05). Mean and SEM for all treatment groups as well as statistical output for the main effect of treatment and post hoc comparisons can be found in Table 1. There was a significant effect of treatment group on the total number of nape attacks (F(2,30) = 6.55, p = 0.00434; Figure 2a) and pins (F(2,30) = 11.61, p = 0.000184; Figure 2b). Post hoc comparisons between groups revealed that CON rats attacked (p = 0.0027) and pinned (p = 0.00012) significantly more than THC-exposed rats. Further, CON rats pinned significantly more than VEH-exposed rats (p = 0.0090). There was a significant effect of treatment group on the likelihood of defense (F(2,30) = 8.24, p = 0.0014). CON (p = 0.00096) and VEH (p = 0.019) rats were significantly more likely to defend themselves than the THC-treatment group (Figure 2c). There was a significant group effect on the likelihood of complete rotations (F(2,30) = 6.08, p = 0.00608), with CON rats engaging in significantly more complete rotations as compared to THC-treated (p = 0.0046) rats (Figure 2d). There was no significant group effect on the likelihood of evasion (Table 1).\n\n* p < 0.05.\n\n** p < 0.01.\n\n*** p < 0.001.\n\n* p < 0.05. ** p < 0.01. ** p < 0.001.\n\nHere, we assessed the effects of adolescent exposure to THC on play behaviours. Adolescent exposure to THC decreased attacks, pins and overall defensive behaviour. There was a significant reduction in the VEH-treated groups in the total number of pins. There are two possible explanations for this effect. First, injection stress could decrease overall playfulness. This is unlikely as injections of other play suppressing drugs have had significantly greater effects than injections of saline.17 Second, our vehicle contained alcohol, which, when administered chronically, suppresses adolescent play.18 However, when administered acutely at low doses, alcohol can facilitate play.19 Therefore, it is unclear whether the small doses of alcohol used in the vehicle for the present study would by itself suppress play. Still, although the possibility of a synergistic effect by combining THC and alcohol cannot be discounted, it seems highly unlikely. Nonetheless, where both the VEH and THC had an effect, the effects of THC were greater (Table 1, Figure 2), suggesting that the drug had an effect beyond that produced by the stress of injection or the added effects of low levels alcohol in the vehicle.\n\n\nDiscussion/conclusions\n\nRelative to the control condition, both the THC and the VEH groups had a lower likelihood that they would defend themselves when attacked. Combined with the reduced likelihood of initiating attacks by the THC-treated animals, this suggests that THC suppresses both the attack and defense components of social play. This is an important finding because there is evidence that attack and defense may be mediated by different mechanisms.16 Also, the effect on how the THC rats defend themselves relative to controls is not uniform. The THC rats are just as likely to evade nape contact, but if they turn to face the attacker they are less likely to roll over to supine. The reduced likelihood of rolling to supine in combination with an overall reduced likelihood of defending themselves can account for the reduced frequency of pinning, as in this strain of rats the majority of pins arise from the defender turning to supine.20 These changes are important in assessing the effects of THC because one possible mechanism is to make the animals lethargic, and so less inclined to attack, defend or facilitate the continued wrestling that is often accompanied by rolling over to the supine position.14 However, THC did not change the likelihood to evade attacks, a maneuver that can involve rapid swerving, jumping and running,12 so it is unlikely that THC induced lethargy. This is further supported by findings that THC-induced hypolocomotion is typically only observed after acute,21 but not repeated and chronic exposure to THC.22–24 Moreover, as complete rotation is calculated as a percentage of facing defense, a reduction in the percentage of complete rotation signals a concomitant increase in standing defense,14 which require a significant amount of energy expenditure as the animals’ push, grapple and kick one another.12 Additionally, any changes in play behaviour are not likely due to this dose of THC causing aversion, as 5 mg/kg of THC does not consistently produce aversion in standard place preference tasks.25 Thus, while the endocannabinoid system constitutes an important part of the play–reward system,26 it appears to have a selective effect on different aspects of what animals find rewarding during play.\n\nDisrupting sociality in adolescence alters multiple neurobiobehavioural metrics associated with anxiety, depression and substance abuse,7 and reduced exposure to play, such as through housing with an older conspecific, disrupts development of emotional regulation, cognition and sociality [as reviewed in Ref. 27]. The effects of a pharmacological manipulation that changes play behaviour could, in theory, result in secondary effects on brain development and adult behaviour, outside of the primary mechanism of the pharmacological manipulation. Supporting this possibility are studies with the use of different drugs in adolescence showing long lasting effects on brain and behaviour outside of their effects on play.28,29\n\nPrevious studies have found differences in play behaviour as a function of acute cannabinoid manipulation [for example, Ref. 10]. Social play itself induces endocannabinoid release in the amygdala and nucleus accumbens,30 thought to be washed out with systemic administration of THC, and the psychoactive properties of THC may block performance of complex behaviours like play.31 Thus, THC administration acutely decreases playfulness; although to date, ours is the first study to demonstrate that this decrease in playfulness persists through a chronic administration period, which could mediate the effects of THC on adult brain volume and behaviour observed using this same administration paradigm.4 These results suggest that effects of THC on subsequent adult brain and behaviour could be partially explained by an interaction between changing playfulness and the pharmacological effects of THC.\n\nAlthough these results have important implications for understanding the effects of adolescent cannabis use, limitations remain. We measured in detail one aspect of sociality, social play. Inclusion of additional measures of social behaviours could have indicated global deficits or compensatory engagement in other social behaviours. Furthermore, our measures did not examine the temporal profile of the observed decreases in play, leaving open the possibility that THC-exposed adolescent rats could increase their playfulness once they are not acutely under the drug’s influence. Repeated assessment of play behaviour throughout the drug-administration period would have elucidated whether the observed effects were truly due to chronic exposure to THC or were merely affecting behaviours as a series of acute manipulations with no carryover from day-to-day. In addition, we did not measure any behavioural changes in adults that had been exposed to THC in adolescence, potentially demonstrating correlational relationships among play behaviour and sociality in adulthood. It remains unclear whether these changes in rat play behaviour during adolescence mediate causal influence on adult brain and behaviour. Finally, although we did not detect a sex difference of the effects of THC on play behaviour, it is possible that our study was underpowered to detect sex differences.\n\nHere, we observed marked decreases in playfulness following acute administration of THC during a chronic administration period. We believe that this decrease in sociality could partially mediate some of the effects of THC in adolescence on adult brain and behaviour function. This study is especially important given the large number of adolescent humans that consume cannabis recreationally. Disruptions in social behaviour during this period could have long-term ramifications on adult brain and behaviour, and future research should consider the intersection between these two factors.\n\n\nData availability\n\nDryad: Underlying data for ‘Chronic exposure to ∆9-tetrahydrocannabinol in adolescence decreases social play behaviours’. https://doi.org/10.5061/dryad.v9s4mw6x4.32\n\nThe project contains the following underlying data:\n\nTHC_and_play_data_set_2021.csv\n\nThis_DATSETNAMEreadme_THC_and_Play_Oct_29.docx\n\n\nReporting guidelines\n\nDryad: ARRIVE checklist for ‘Chronic exposure to ∆9-tetrahydrocannabinol in adolescence decreases social play behaviours’.\n\nDOI: https://doi.org/10.5061/dryad.v9s4mw6x4\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\n\nAcknowledgements\n\nWe thank Brett Himmler and Vivien Pellis for comments and suggestions on earlier drafts of the paper.",
"appendix": "References\n\nCurrie C: World Health Organization, Regional Office for Europe, Social determinants of health and well-being among young people: Health Behaviour in School-Aged Children (HBSC) Study: international report from the 2009/2010 survey. Copenhagen, Denmark: WHO Regional Office for Europe; 2012. (accessed March 7, 2019).Reference Source\n\nMechoulam R: Marihuana chemistry. Science. 1970; 168: 1159–1166. PubMed Abstract | Publisher Full Text\n\nMoore TH, Zammit S, Lingford-Hughes A, et al.: Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007; 370: 319–328. Publisher Full Text\n\nKeeley RJ, Trow J, Bye C, et al.: Part II: Strain- and sex-specific effects of adolescent exposure to THC on adult brain and behaviour: variants of learning, anxiety and volumetric estimates. Behav. Brain Res. 2015; 288: 132–152. PubMed Abstract | Publisher Full Text\n\nSpear LP: The developing brain and adolescent-typical behavior patterns: An evolutionary approach. Adolesc. Psychopathol. Dev. Brain Integrating Brain Prev. Sci. 2007; 9–30. Publisher Full Text\n\nArain M, Haque M, Johal L, et al.: Maturation of the adolescent brain. Neuropsychiatr. Dis. Treat. 2013; 9: 449–461. Publisher Full Text\n\nBurke AR, McCormick CM, Pellis SM, et al.: Impact of adolescent social experiences on behavior and neural circuits implicated in mental illnesses. Neurosci. Biobehav. Rev. 2017; 76: 280–300. PubMed Abstract | Publisher Full Text\n\nPellis SM, Pellis VC: Differential rates of attack, defense, and counterattack during the developmental decrease in play fighting by male and female rats. Dev. Psychobiol. 1990; 23: 215–231. PubMed Abstract | Publisher Full Text\n\nPellis SM, Pellis VC: What is play fighting and what is it good for?. Learn. Behav. 2017; 45: 355–366. PubMed Abstract | Publisher Full Text\n\nTrezza V, Vanderschuren LJMJ: Bidirectional cannabinoid modulation of social behavior in adolescent rats. Psychopharmacology (Berl.). 2008; 197: 217–227. PubMed Abstract | Publisher Full Text\n\nSchneider M, Koch M: Deficient Social and Play Behavior in Juvenile and Adult Rats after Neonatal Cortical Lesion: Effects of Chronic Pubertal Cannabinoid Treatment. Neuropsychopharmacology. 2005; 30: 944–957. PubMed Abstract | Publisher Full Text\n\nPellis SM, Pellis VC: Play-fighting differs from serious fighting in both target of attack and tactics of fighting in the laboratory rat Rattus norvegicus. Aggress. Behav. 1987; 13: 227–242. Publisher Full Text\n\nKeeley RJ, Trow J, McDonald RJ: Strain and sex differences in puberty onset and the effects of THC administration on weight gain and brain volumes. Neuroscience. 2015; 305: 328–342. PubMed Abstract | Publisher Full Text\n\nHimmler BT, Pellis VC, Pellis SM: Peering into the dynamics of social interactions: measuring play fighting in rats. J. Vis. Exp. JoVE. 2013; e4288. Publisher Full Text\n\nPanksepp J: The ontogeny of play in rats. Dev. Psychobiol. 1981; 14: 327–332. PubMed Abstract | Publisher Full Text\n\nPellis SM, Pellis VC: Attack and Defense During Play Fighting Appear to be Motivationally Independent Behaviors in Muroid Rodents. Psychol. Rec. 1991; 41: 175–184. Publisher Full Text\n\nField EF, Pellis SM: Differential effects of amphetamine on the attack and defense components of play fighting in rats. Physiol. Behav. 1994; 56: 325–330. PubMed Abstract | Publisher Full Text\n\nBroadwater M, Varlinskaya EI, Spear LP: Chronic intermittent ethanol exposure in early adolescent and adult male rats: effects on tolerance, social behavior, and ethanol intake. Alcohol. Clin. Exp. Res. 2011; 35: 1392–1403. Publisher Full Text\n\nVarlinskaya EI, Spear LP, Spear NE: Acute effects of ethanol on behavior of adolescent rats: role of social context. Alcohol. Clin. Exp. Res. 2001; 25: 377–385. Publisher Full Text\n\nHimmler SM, Himmler BT, Stryjek R, et al.: Pinning in the play fighting of rats: A comparative perspective with methodological recommendations. Int. J. Comp. Psychol. 2016; 29. (accessed July 11, 2019). Publisher Full Text Reference Source\n\nTaffe MA, Creehan KM, Vandewater SA: Cannabidiol fails to reverse hypothermia or locomotor suppression induced by Δ9-tetrahydrocannabinol in Sprague-Dawley rats. Br. J. Pharmacol. 2015; 172: 1783–1791. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJavadi-Paydar M, Kerr TM, Harvey EL, et al.: Effects of nicotine and THC vapor inhalation administered by an electronic nicotine delivery system (ENDS) in male rats. Drug Alcohol Depend. 2019; 198: 54–62. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNguyen JD, Creehan KM, Kerr TM, Taffe MA: Lasting effects of repeated ∆9-tetrahydrocannabinol vapour inhalation during adolescence in male and female rats. Br. J. Pharmacol. 2020; 177: 188–203. Publisher Full Text\n\nNguyen JD, Aarde SM, Vandewater SA, et al.: Inhaled delivery of Δ9-tetrahydrocannabinol (THC) to rats by e-cigarette vapor technology. Neuropharmacology. 2016; 109: 112–120. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTzschentke TM: Measuring reward with the conditioned place preference (CPP) paradigm: update of the last decade. Addict Biol. 2007; 12: 227–462. PubMed Abstract | Publisher Full Text\n\nVanderschuren LJMJ, Achterberg EJM, Trezza V: The neurobiology of social play and its rewarding value in rats. Neurosci. Biobehav. Rev. 2016; 70: 86–105. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPellis SM, Himmler BT, Himmler SM, Pellis VC: Chapter 12 - Rough-and-Tumble Play and the Development of the Social Brain: What Do We Know, How Do We Know It, and What Do We Need to Know? In: Gibb R, Kolb B, editors. Neurobiol. Brain Behav. Dev. Academic Press; 2018; pp. 315–337. Publisher Full Text\n\nPascual M, Blanco AM, Cauli O, et al.: Intermittent ethanol exposure induces inflammatory brain damage and causes long-term behavioural alterations in adolescent rats. Eur. J. Neurosci. 2007; 25: 541–550. Publisher Full Text\n\nSchwarz JM, Bilbo SD: Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction. J. Neurosci. 2013; 33: 961–971. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrezza V, Damsteegt R, Manduca A, et al.: Endocannabinoids in Amygdala and Nucleus Accumbens Mediate Social Play Reward in Adolescent Rats. J. Neurosci. 2012; 32: 14899–14908. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrezza V, Baarendse PJJ, Vanderschuren LJMJ: The pleasures of play: pharmacological insights into social reward mechanisms. Trends Pharmacol. Sci. 2010; 31: 463–469. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKeeley RJ, Himmler SM, Pellis SM, et al.: Underlying data for ‘Chronic exposure to ∆9-tetrahydrocannabinol in adolescence decreases social play behaviours’.2021. Publisher Full Text"
}
|
[
{
"id": "101085",
"date": "06 Dec 2021",
"name": "Ming Li",
"expertise": [
"Reviewer Expertise Behavioral pharmacology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript reported a study that investigated the effects of chronic THC (the main psychoactive ingredient in cannabis) exposure during the early adolescent period on social behavior in adolescent male and female rats. The authors used a previously established animal model of adolescent THC exposure in male and female Long–Evans rats and provided a detailed analysis of social play behaviors affected by THC treatment (5 mg/kg, ip). They found that THC exposure decreased several components of social behavior in adolescent rats including the number of attacks, and the likelihood of defense and pins compared to control and vehicle treated rats. This work is significant as it may reveal one possible mechanism by which adolescent THC exposure alters the brain development and function seen in adulthood, that is, by changing social behavior of affected animals and causing secondary effects on brain development and adult behavior.\nThe study was straightforward and the methods and results were clearly presented. The rationale and treatment regimen were justified. One main strength of this study, and an often overlooked issue was its detailed analysis of social behaviors. With their analysis, they were able to determine the impaired social behavior by THC was not due to drug-induced lethargic reaction, and both the attack and defense components of social play were suppressed by THC. This latter finding is important as there is evidence that attack and defense may be mediated by different mechanisms. I also appreciate the authors’ comments on the limitations of this study. Overall it is a concise study that provides an important insight with regards to the neurodevelopmental impacts of adolescent THC exposure on adult brain and behavioral functions.\nI only have a few minor comments.\nThe authors mentioned that “The order of play bouts with the CC was counterbalanced”. Does this mean that on each test day, 2 from each group were tested?\n\nHow was “the likelihood of the partner receiving a nape attack defending itself to avoid contact” calculated? Was it the same as the “probability of defensive behaviors”?\n\nCould the authors define more clearly what the defending “tactics” are?\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? 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": []
},
{
"id": "101485",
"date": "20 Dec 2021",
"name": "Francesco Leri",
"expertise": [
"Reviewer Expertise Behavioural Neuroscience",
"Neuropsychopharmacology."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors administered 5 mg/kg THC to adolescent males and females LE rats for 14 days. Aspects of play behaviour were assessed 1 hour following the injection, after 7 days from the beginning of the administration period.\nIt is reported that THC decreased number of nape attacks, pins, as well as probability of defensive behaviours and complete rotations.\nThis reviewer can offer a few minor comments to possibly improve the clarity of the manuscript.\nThe Introduction section could be expanded to clarify why play behaviour was selected for investigation and what evidence in people would lead to the current investigation in animals. It will be important to focus on adolescent behaviour because animals were not tested in adulthood.\n\nThe introduction indicates that it is crucial to understand whether changes in adult behaviour are purely pharmacological or involve a complex interplay between pharmacology and behaviour, but it is not clear how the current experiment addressed this question.\n\nThe introduction mentions background- and sex-specific deficits in adults, but does not elaborate on why Long-Evans were selected and does not expand of sex-differences. These two relevant issues are also not examined in the discussion section.\n\nThe introduction could describe play behaviours in rats.\n\nThe methods section does not seem to explain complete rotations. This could be revised not only because this behaviour is reported in the results, but also because it is discussed as a measure of general motor activity.\n\nThe authors could report the ANOVA models employed to analyze the data, and could specify that data from males and females were pooled for subsequent analysis.\n\nIn the version of the manuscript that I reviewed, there is a paragraph in the results section beginning with \"Here\" that seems much more fitting to the discussion section.\n\nThe authors do a good job in addressing the issue of possible THC-induced hypo-activity. This said, additional data collected in locomotion chambers, in rats singly tested, may be needed to fully rule out this possible confound.\n\nThe authors also do a good job in addressing some of the limitations of the study. This said, they may need to indicate that their current findings are limited to a single THC dose, and to one dosing regimen.\n\nFinally, as mentioned above, it may be value to discuss the lack of sex differences.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? Yes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "101087",
"date": "07 Jan 2022",
"name": "Robin Murphy",
"expertise": [
"Reviewer Expertise Behavioural Neuroscience"
],
"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 piece of research, carefully conducted, analysed and reported. I have a few comments:\nI thought some of the introductory and concluding comments emphasising the public health concern was probably not necessary, but perhaps more importantly the attempt to classify behavioural effects as disruptions or impairments was perhaps premature. This paper seems to take a stronger negative perspective than one of the papers cited to support the negative claims. Citation 4 reports both increases and decreases in performance on learning and memory tasks. It would perhaps be wise to take a slightly less decisive stance on this?\n\nI have a similar comment about the concept of Play. Obviously play sounds good, but less good then attack and defence. The intro refers to play and the methods describe attacks. So playing devils advocate the the article could explain how THC supports lower aggression. I don't think I really mind which way, however, a more neutral stance might be preferred.\n\nWhile it is true that attack and defence involve different neural pathways, and therefore if there is an effect in both then that might suggest a separate mechanism, given that they are output via the same behaviour, the impact of THC might be at the same motor level, I'm not saying it does but I think you need to moderate that claim.\n\nI think the point about % attacks and defence being related to the frequency of the opponents engagement does require some mention of the analysis of any differences in frequencies. Normally the reader should be reassured that there were no significant differences in the frequencies or if not what that direction was. I'm sorry if this is reported and I just missed it.\n\nThe conclusions highlight that strain and sex differences matter, it would be good to highlight this when explaining your choice of LER over say WR especially given the differences that the two strains may have with respect to learning and memory.\n\nFinally and least importantly, the number of significant figures in the table was an annoyance. Choose 2 or 3 significant figures or a decimal number but at the moment the numbers seem formatted oddly.\n\nOverall I think this is interesting research, I like the social play measure, and while I understand the narrative that reduced play leads to future impairments in learning and memory, I could also understand a narrative that suggested that THC resulted in more peaceful play, and call this disruption to normal behaviour rather than an impairment?\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": []
}
] | 1
|
https://f1000research.com/articles/10-1191
|
https://f1000research.com/articles/10-1185/v1
|
23 Nov 21
|
{
"type": "Research Article",
"title": "Sickle cell segmentation and classification for thalassemia aid diagnosis",
"authors": [
"Yen-Siang Leow",
"Kok-Why Ng",
"Yih-Jian Yoong",
"Seng-Beng Ng",
"Yen-Siang Leow",
"Yih-Jian Yoong",
"Seng-Beng Ng"
],
"abstract": "Background: Thalassemia is a hereditary blood disease in which abnormal red blood cells (RBCs) carry insufficient oxygen throughout the body. Conventional methods of thalassemia detection through a complete blood count (CBC) test and peripheral blood smear image still possess a lot of weaknesses. Methods: This paper proposes a hybrid segmentation method to segment the RBCs. It incorporates adaptive thresholding and canny edge method to segment the RBCs. Morphological operations are performed to clean the leftovers. Shape and texture features are extracted using the segmented masks and the gray level co-occurrence matrix. Data imbalance treatment is used for solving the imbalance cell type class in distribution. In the data resampling layer, the synthetic minority oversampling technique (SMOTE), adaptive synthetic sampling (ADASYN), and random over sampling (ROS) are performed and evaluated using the decision tree and logistic regression. In the classification layer, the decision tree, random forest classifier and support vector machine (SVM) are assessed and compared for the best performance in classification. Results:The proposed method outperforms the other methods in the image segmentation layer with the structural similarity index measure (SSIM) of 89.88%. In the data resampling layer, ADASYN is employed as it is more accurate than the SMOTE and ROS. The random forest classifier is chosen at the classification layer as it is more accurate than the decision tree and support vector machine (SVM). Conclusions:The proposed method is tested on the latest dataset of erythrocyteIDB3 and it solves the issues of imbalanced data due to the insufficient cell classes.",
"keywords": [
"Red Blood Cell",
"Thalassemia",
"Image processing",
"Image Segmentation",
"Morphological Operations",
"Feature Extraction",
"Data Resampling",
"Machine Learning"
],
"content": "Introduction\n\nSickle cell disease is a hereditary disease that disrupts the efficiency of RBCs to carry sufficient oxygen to the body. Traditional methods to detect this disease relied on hematologists manually counting RBCs and classifying them based on their topologies. This has motivated us to explore and develop an automated process to detect the presence of the disease. However, this field poses a lot of challenges such as insufficient medical data, poor extraction methods, and the tedious pipeline-related issues.\n\nThis paper aims to solve some of the aforementioned problems. Firstly, a hybrid segmentation method is presented to accurately segment the RBCs. Next, the data imbalance treatment is used to solve the imbalance cell type class in a distribution manner. The pipeline of the paper includes the comparison between the conventional methods in the image segmentation layer, data resampling layer and the classification layer. The proposed method involves the image acquisition, image pre-processing, image segmentation, morphological operations, image cropping and manual classification, feature extraction, data resampling, and classification. The aim is to create a workflow that is able to detect the presence of thalassemia by recognizing the types of RBCs.\n\n\nRelated work\n\nIn image pre-processing, Rashid et al.1 and Das et al.2 employed a mixture of global contrast techniques, median blurring and color space conversion to increase the contrast. Color channel conversion is used to filter the unwanted cells in the image.\n\nIn image segmentation layer, an inter-combination of the thresholding, edge-based, region-based, clustering-based and artificial neural network (ANN) is used to perform the segmentation. Sharma et al.3 compared different techniques of thresholding; their findings showed that Otsu’s thresholding performed the best among other thresholding methods. This concurred with the observation done by Das et al.2 Marked water controlled segmentation was used to solve the segmentation of cells in.2,4 Tyagi et al.5 indicated that the Canny Edge technique was better at filtering noise presented in the image. Achargee et al.6 used Hough transformation (HT) to detect cells with varying diameter, while Seth and Palodhi7 proposed a modified version of the HT to detect white blood cells (WBC).\n\nFeature extraction in cell morphology are classified into boundary and region descriptors. Some of the features may overlap, but generally, boundary descriptors deal with the morphology of the RBCs and region descriptors extract the geometric and texture properties. Lotfi et al.4 used Fourier descriptors to represent cell morphology. Tyagi et al.5 used shape features such as area, perimeter solidity, eccentricity to describe the cells. Other features involved extracting the moment invariant such as invariant to scaling, translation and rotation were proposed by Lofti et al.4 Since the introduction of deep learning, many skipped this layer due to the models can automatically extract the features. Fadhel et al.8 proposed extracting features from the last fully connected layers and subsequently fed the features into the support vector machine (SVM) classifier. Purwar et al.9 proposed a hybrid method of features extracted from the convolutional neural network (CNN) models15-17 and hand clinical features extracted from a CBC test.\n\nHortinela et al.10 and Safca et al.11 used SVM to classify cells based on features extracted from different layers. In multiclass classification, Lotfi et al.4 compared the K-nearest neighbors and SVM method using the one versus all approach and found that SVM performed better. In a seperate study, Dalvi et al.12 showed that an ANN with ten hidden nodes and five output nodes performed better than decision tree. Tyas et al.13 used ANN with momentum backpropagation and produced the best results among the classifiers.\n\n\nMethods\n\nEthical approval number: EA1542021\n\nEthical approval body: Research Ethic Committee 2021, Multimedia University\n\nThe dataset used in this project was obtained from the erythrocytesIDB by Pedro et al.14 It is selected because of the image clarity and optimal cell size. Each subdirectory contains the raw image, ground truth labels, and binary segmented masks. Figure 1 shows the raw blood smear images and its ground truth label for two images.\n\nAs many of the images are extracted using different extraction techniques, to increase the quality of the images while standardizing all of the images, firstly, the images are contrastly increased by using the contrast limited adaptive histogram equalization (CLAHE) method. The image is primarily converted to L.A.B. color space. The L, which refers to the luminance channel is operated by CLAHE and is then merged back with the other two channels.\n\nNext, median filtering is applied to remove noise in the image. An unsharped mask operation is applied to sharpen the edges of the cells which are previously lost during the median filtering process. Image subtraction is then constructed from the original image to obtain the details and the edges. Figure 2 depicts the result after the pre-processed layer of the two images.\n\nA hybrid technique is proposed by merging the adaptive thresholding and the canny edge detection method. Gaussian adaptive thresholding is employed to segment the color images with varying intensities. However, this method unable to capture the edges of the cells. An additional of the canny edge detection method with the parameter of μ to be set to a lower value is applied. This allows the cell edges to be captured precisely and subsequently to be added to the threshold binary image later.\n\nLastly, the leftover edges that are protruding out are removed to show a clean finish. Figure 3 shows the result of the segmentation layer compared to the ground truth given from the dataset. The evaluation of this layer is performed by calculating the SSIM index of the binary segmented image with the ground truth binary given in the dataset.\n\nMorphological operations are performed on binary images to clean up the leftover noises from the previous layers. A hole-filling operation is performed to close up the holes that are created using the canny edge detection method. Next, binary opening is used to remove the small particles that are presented in the image. Finally, cells that are located at the border are removed because they do not accurately provide the full feature description of the cell. Figure 4 depicts the result of the morphological operations.\n\nEach of the cells in the microscopic blood sample images are cropped using the masks that are segmented from the previous layers. Figure 5 shows the individual cells that are being cropped, while Figure 6 depicts the sub-category of one particular cell. Each of the cropped cells has their own directory which is named based on their origin and cell number as depicted in Figure 7. The cells are manually classified into their own class which is based on the classification given by Pedro et al.14\n\nTwo types of features are extracted: shape features and texture features.\n\nThe shape features are extracted from the individually cropped masks and then to be combined into a data frame. The features extracted include the area, perimeter, major axis length, minor axis length, eccentricity, and the seven moment invariants immune to the scaling, translation, and rotation. Additional shape features which are circulatory factor and elliptical factor are calculated.\n\nNext, texture features are extracted using the gray level co-occurrence matrix (GLCM). The features extracted from the textures are the contrast, dissimilarity, homogeneity, ASM, energy and correlation.\n\nFinally, the two features are merged into a data frame with its correct label of either one of the three classes: circular, elongated, or other cells.\n\nThe number of circulars, elongated and other types of cells total up to 316, 53 and 59 respectively. This dataset is imbalanced and may result the classifier to be overfit or bias to certain category of data.\n\nThe synthetic minority oversampling technique (SMOTE), adaptive synthetic sampling (ADASYN) and random over sampling (ROS) are evaluated by using two classifiers, which are logistic regression and decision tree. Figure 8 shows the number of classes prior and after the resampling process. The bottom graph of Figure 8 demonstrations the best result for solving the imbalanced problem using ADASYN resampling technique.\n\nIn classification, a total of three classifiers are trained and compared. The chosen classifiers are the decision tree, random forest and the support vector machine.\n\nThe models are evaluated using the classification report which contains the information of accuracy, precision, recall f1-score and support.\n\nFor each classifier, the receiver operating characteristic (ROC) curve is plotted to observe the results. The images that are excluded before the sampling process are tested individually for their accuracy and reliability of the model chosen.\n\n\nResults and discussion\n\nThe ground truth masks are provided in the dataset. The evaluation are calculated based on the structural similarity index (SSIM) between the ground truth masks and the segmentation of the proposed method.\n\nThe average of the computed SSIM index from each image is 89.88%. However, it is worth noting that the value only estimates how well the segmentation is. In Figure 9, observing the ground truth mask, some cells are not presented in the ground truth mask (middle image), while it is presented in the proposed segmented image (right most image).\n\nFigure 10 shows the comparison of the resampling techniques between the SMOTE, ADASYN and ROS. Based on the result, logistic regression handles the unbalanced data-sets well as compared with the decision tree. ADASYN outperforms the rest at 84.49% of its accuracy through the logistic regression classifier. Also worth noting is that, even with the unbalanced dataset, its accuracy sits highly at 82.17%, which indicates that the features extracted optimally best describe the types of cells (Figure 11).\n\nThe classification layer is evaluated based on the accuracy of the classification report and the ROC curve of each classifier. Figures 12 to 14 depict the model evaluation summary for each of the classifiers.\n\nFrom the results, the random forest classifier performs the best with the accuracy of 90% while the others are below 90%.\n\nThe ROC curve for the SVM dips below the threshold where the number of incorrectly classified classes are more than the correctly classified classes, which indicates a bad classifier.\n\nComparing the area under curve (AUC) of the ROC curve, the random forest classifier covers the most area for all the three cell classes of the circular, elongated and other types of cell, which demonstrates a superior classifier.\n\n\nConclusion\n\nWe performed several comparisons and the implementation between different techniques in the segmentation layer, data resampling layer and the classification layer. These provide a good working pipeline for a complete aiding diagnosis for the sickle cell disease detection. The whole pipeline provides a precise classification for each of the cells in microscopic blood smeared images with a 90–95% of accuracy on average.\n\nIn addition, we present a strong baseline in the segmentation layer, which is able to detect some of the missing cells that were not presented in the previous work. At the same time, the data resampling layers are added to observe the effect of an unbalanced medical dataset. The combination of different models exhibits the performance of the best classification model.\n\n\nAuthor contributions\n\nLeow YS, Ng KW, Yoong YJ and Ng SB conceived the presented idea. Leow YS carried out the experiment and wrote the manuscript. Ng KW, Yoong YJ and Ng SB supervised the project and provided feedback.\n\n\nData availability\n\nData were obtained by permission from http://erythrocytesidb.uib.es/.\n\nData samples were obtained from volunteer patients. This dataset was not generated nor is it owned by the authors of this article; the listed owners are Universidad de Oriente, Cuba, and Universitat de les Illes Balears, Spain. Therefore, neither the authors nor F1000Research are responsible for the content of this dataset and cannot provide information about data collection.",
"appendix": "Acknowledgements\n\nWe thank the anonymous reviewers for their careful reading of our manuscript and their insightful comments and suggestions.\n\n\nReferences\n\nRashid NZN, Mashor MY, Hassan R: Unsupervised color image segmentation of red blood cell for thalassemia disease. 2015 2nd International Conference on Biomedical Engineering (ICoBE). IEEE; 2015, March; (pp. 1–6).\n\nDas D, Ghosh M, Chakraborty C, et al.: Invariant moment based feature analysis for abnormal erythrocyte recognition. 2010 International Conference on Systems in Medicine and Biology. IEEE; 2010, December; (pp. 242–247).\n\nSharma V, Rathore A, Vyas G: Detection of sickle cell anaemia and thalassaemia causing abnormalities in thin smear of human blood sample using image processing. 2016 International Conference on Inventive Computation Technologies (ICICT). IEEE; 2016, August; (Vol. 3: pp. 1–5).\n\nLotfi M, Nazari B, Sadri S, et al.: The detection of dacrocyte, schistocyte and elliptocyte cells in iron deficiency anemia. 2015 2nd International Conference on Pattern Recognition and Image Analysis (IPRIA). IEEE; 2015, March; (pp. 1–5).\n\nTyagi M, Saini LM, Dahyia N: Detection of poikilocyte cells in iron deficiency anaemia using artificial neural network. 2016 International Conference on Computation of Power, Energy Information and Commuincation (ICCPEIC). IEEE; 2016, April; (pp. 108–112).\n\nAcharjee S, Chakrabartty S, Alam MI, et al.: A semiautomated approach using GUI for the detection of red blood cells. 2016 International Conference on Electrical, Electronics, and Optimization Techniques (ICEEOT). IEEE; 2016, March; (pp. 525–529).\n\nSeth S, Palodhi K: An efficient algorithm for segregation of white and red blood cells based on modified hough transform. 2017 IEEE Calcutta Conference (CALCON). IEEE; 2017, December; (pp. 465–468).\n\nAlzubaidi L, Fadhel MA, Al-Shamma O, et al.: Deep learning models for classification of red blood cells in microscopy images to aid in sickle cell anemia diagnosis. Electronics . 2020; 9(3): 427. Publisher Full Text\n\nPurwar S, Tripathi RK, Ranjan R, et al.: Detection of microcytic hypochromia using cbc and blood film features extracted from convolution neural network by different classifiers. Multimed. Tools Appl. 2020; 79(7): 4573–4595. Publisher Full Text\n\nHortinela CC, Balbin JR, Fausto JC, et al.: Identification of Abnormal Red Blood Cells and Diagnosing Specific Types of Anemia Using Image Processing and Support Vector Machine. 2019 IEEE 11th International Conference on Humanoid, Nanotechnology, Information Technology, Communication and Control, Environment, and Management (HNICEM). IEEE; (pp. 1–6).\n\nSafca N, Popescu D, Ichim L, et al.: Image processing techniques to identify red blood cells. 2018 22nd International Conference on System Theory, Control and Computing (ICSTCC). IEEE; 2018, October; (pp. 93–98).\n\nDalvi PT, Vernekar N: Computer aided detection of abnormal red blood cells. 2016 IEEE International Conference on Recent Trends in Electronics, Information & Communication Technology (RTEICT). IEEE; 2016, May; (pp. 1741–1746).\n\nTyas DA, Ratnaningsih T, Harjoko A, et al.: The classification of abnormal red blood cell on the minor thalassemia case using artificial neural network and convolutional neural network. Proceedings of the International Conference on Video and Image Processing 2017, December; (pp. 228–233).\n\nPedro MF, Grethel CS, Wilkie EDF, et al.: erythrocytesIDB (Version 2, October 2017).Reference Source\n\nAcharya V, Kumar P: Identification and red blood cell classification using computer aided system to diagnose blood disorders. 2017 International Conference on Advances in Computing, Communications and Informatics (ICACCI). IEEE; 2017, September; (pp. 2098–2104).\n\nOng K, Haw SC, Ng KW: Deep Learning Based-Recommendation System: An Overview on Models, Datasets, Evaluation Metrics, and Future Trends. Proceedings of the 2019 2nd International Conference on Computational Intelligence and Intelligent Systems 2019, November; (pp. 6–11).\n\nAng JS, Ng KW, Chua FF: Modeling Time Series Data with Deep Learning: A Review, Analysis, Evaluation and Future Trend. 2020 8th International Conference on Information Technology and Multimedia (ICIMU). IEEE; 2020, August; (pp. 32–37)."
}
|
[
{
"id": "100976",
"date": "09 Feb 2022",
"name": "Naresh Babu Muppalaneni",
"expertise": [
"Reviewer Expertise Machine Learning",
"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\nThe authors have done extensive and novel work to bring this scientific work.\n\nFor Sickle cell, the circulatory feature is important, which is considered by authors in the feature set. The authors have extracted features based on shape and texture. The authors have addressed the imbalance problem also.\nPlease include the following in the next version of the paper:\nComparative studies of authors proposed methods and with literature\n\nMissing dataset details like the size of the dataset, training set size, test dataset size, etc.,\n\nReasons for the vast difference in accuracy for SVM and Decision Tree/Random Forest.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/10-1185
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https://f1000research.com/articles/10-1183/v1
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23 Nov 21
|
{
"type": "Research Article",
"title": "Can the financial performance of the micro, small, and medium-sized enterprise production sector in Medan be a signal in the use of a leanness strategy?",
"authors": [
"Muhammad Andi Abdillah Triono",
"Selamat Triono Ahmad",
"Cut Ermiati",
"Humisar Sihombing",
"Selamat Triono Ahmad",
"Cut Ermiati",
"Humisar Sihombing"
],
"abstract": "Background: Business actors need to take strategic steps to maintain and improve business performance. Studying and deepening the strategies used by micro, small, and medium-sized enterprises (MSMEs) to maintain their performance conditions are needed as a barometer of crisis resistance in the macroeconomic sector, especially those used by MSMEs in Medan, Indonesia. Thus, this research provides a real picture in the field of variables and indicators that affect the business strategy of MSMEs through the perspective of a lean approach. Methods: The population in this region was 466 business actors of MSMEs in Medan. A random stratified sampling strategy is used, and 169 businesses in the MSMEs production sector were obtained as samples, which has exceeded the standard achievement of 80 percent in detecting an R2 value of at least 0.10 (with a 5 percent probability of error). The research variables used consisted of one endogenous variable (use of a lean strategy), two exogenous variables (external lean practice and internal lean practice), and one mediating variable (financial performance). Seven hypotheses (inner models) were tested using structural equation modelling–partial least squares, nonparametric statistical data analysis techniques with mediation effects, assisted by Smart PLS 3.0. Results: Based on the path coefficient, internal lean practice predominantly influences the financial performance of MSMEs in Medan compared to external lean practice. Internal lean practice is the primary signal for identifying the degree of lean strategy practice in the MSMEs production sector in Medan city. Conclusion: These findings can be a map for practitioners, academics, and the government to improve the financial performance of MSMEs and assist them in their business strategies through internal business practices. Moreover, this study's impact can lead to an understanding of business strategies in operations that directly or indirectly affect the environment toward global warming and various environmental problems.",
"keywords": [
"Leanness Strategy",
"Financial Performance",
"External and Internal Practice of Leanness"
],
"content": "Introduction\n\nGlobally, the growth of micro, small, and medium-sized enterprises (MSMEs) is higher than that of large companies, especially in Indonesia. Based on MSME data,1 the growth of MSMEs in Indonesia from 2017 to 2018 was approximately 8.98 percent compared to large enterprises, which only grew by approximately 1.64 percent. The discussion on microenterprises (MEs) is challenging compared to small and medium-sized enterprises (SMEs) in various studies. There is a lack of information and data on microenterprises in the field regarding the fluctuating and inconsistent actions of microbusinesses. Furthermore, based on data, the SME sector plays a crucial and significant role as a driving force for the economy in creating new jobs, increasing the number of new entrepreneurs, and creating innovations at relatively economical and efficient costs.2 Additionally, data and facts show that SMEs contribute, on average, to developing countries in the range of 20 to 50 percent of total GDP.3,4 Based on Usaha Mikro Kecil Menengah (UMKM) data,1 SMEs in Indonesia have contributed 23.21 percent of the total GDP. The city of Medan is the third-largest city in Indonesia.12 It is the gateway to western Indonesia as a multi-cultural centre of trade, industry, and business since the Dutch East Indies era.11,12 If grouped by production characteristics, it contains eleven groups in the production sector (see data file 12).10 Based on the Office of Medan City Cooperatives and SMEs Service database in 2020, the majority of the production sector of the MSMEs from the 466 identified in Medan City are in the handicrafts production group with 95 businesses, followed by the fabric production group with 79 businesses (see data file 12).10 Therefore, the studying and deepening of MSMEs' strategies in maintaining their performance conditions are needed to act as a barometer of crisis resistance in the macroeconomic sector, especially concerning MSMEs in Medan.\n\nThere are various business strategies for improving business performance that can lead to environmental friendliness, one of which is the ‘leanness production strategy’.5 The mechanism and standardization of lean production in seeing its effect on financial performance (company) are still in the early stages. Currently, the practice of lean production is considered the gold standard of modern operations and supply chain management.6 Lean refers to eliminating waste in operational practices regarding costs in obtaining resources.7 Additionally, Hofer et al.,6 revealed that the application of internal and external lean practises, such as a decrease in inventory, an increase in quality, and a shorter operating time, will increase operating income, which will improve financial performance. Nawanir et al.,8 defined lean as ‘lean manufacturing’, a manufacturing process without residue; however, there are not enough studies conducted in Indonesia that discuss lean manufacturing strategies.\n\nThe studies relating to MSMEs' strategic practices in Indonesia have not provided comprehensive information, as they lack a conceptual approach and do not consider the characteristics that exist in Indonesia in general. Additionally, the effect of the deepening of business strategy practices on MSMEs' financial performance in Medan city, the third-largest city in Indonesia, can be considered a novelty. This study empirically focuses on the leanness strategy used by MSMEs in Medan. External and internal leanness strategy practices are exogenous variables, and financial performance is a mediating variable. Thus, there are seven research hypotheses in this study:\n\nThe external leanness strategy practices carried out by MSMEs in Medan city affect a company's financial performance.\n\nThe internal leanness strategy practices carried out by MSMEs in Medan city affect a company's financial performance.\n\nThe external leanness strategy practices carried out by MSMEs in Medan city affect or signal the leanness strategy's implementation or use.\n\nThe internal leanness strategy practices carried out by MSMEs in Medan city affect or signal the leanness strategy's implementation or use.\n\nA company's financial performance, achieved by MSMEs in Medan city, affects or can signal the leanness strategy's implementation or use.\n\nA company's financial performance, internal leanness strategy practices, and external leanness strategy practices simultaneously influence or signal the implementation or use of a leanness strategy by MSMEs in Medan city.\n\nA company's financial performance is a mediating variable for the effect of internal and external leanness strategy practices on the implementation or use of a leanness strategy by MSMEs in Medan city.\n\n\nMethods\n\nThe research data was obtained based on permits and ethical approval from the Medan City Cooperative and SMEs Office with approval number 800/2538, and The Medan State University Research and Community Service Institute with approval number 574a/UN33.8/LL/2020. Furthermore, written informed consent was obtained from the response of business owners or managers on the questionnaire that they returned through mail or online via google form at https://forms.gle/KhWRGTYW6hSKBbbWA (see Data file 9).10 The anonymity and confidentiality of business owners' information are maintained.\n\nThis research is in the form of exploratory research with quantitative descriptive and inferential properties. Both primary and secondary data are used. Therefore, this research designed a questionnaire instrument that replicates the previous instrument designed by Hofer et al.,6 and Shashi et al.5 Primary data were collected through a questionnaire distributed to businesses of all sizes of the Medan City MSMEs production sector in 21 districts (see data file 1)10 with a total of 466 respondents via mail, WhatsApp, and SMS based on the Office of Medan City Cooperative and SMEs database. The hardcopy form (see data file 10)10 of the questionnaire was sent to the respondent's address via postal mail. In this case, respondents who wish to fill in the questionnaire online could use the link https://forms.gle/KhWRGTYW6hSKBbbWA which is available on the hard copy questionnaire. The phone number that is mentioned on the database (secondary data) is not open to the public because it is restricted from being published publicly by the private data act or “Permenkominfo 20/2016”.21 However, for the public who want to know the address and number of SMEs in Medan City, in general, they can access the website owned by the Ministry of Cooperatives and SMEs of the Republic of Indonesia.13 To access the Medan City MSMEs data through the database Ministry of Cooperatives and SMEs of the Republic of Indonesia, first, go to the website http://umkm.depkop.go.id/. Then on the provincial (Provinsi) selection menu, select “Sumatera Utara,” and on the Regency (Kabupaten) selection menu, select “Kota Medan”. At the time of this study, based on data from August 3rd, 2021, 259,812 business actors that operate in Medan City were available prior to participant screening for this study.\n\nThe questionnaire as an instrument of research is a novelty on MSMEs in the production sector of Medan City, so testing the validity and reliability of the questionnaire was carried out before being used in the research target. The questionnaire testing was conducted in 23 districts in Deli Serdang Regency targeted at 100 MSMEs business owners in the production sector. The 100 MSMEs criteria to be selected for the testing of the questionnaires was that their businesses activities and factories were located in Medan City but their offices were located in the Deli Serdang Regency area. However, these 100 MSMEs were excluded from the main study. The main study only focused on the MSMEs which have their activities, factories, and offices located in Medan City. The results of the questionnaires testing had only 49 respondents return the instrument with complete answers. Deli Serdang Regency10 was selected as the location of the instrument testing due to its position as the nearest location or neighbouring regency to Medan and at the same time, a buffer zone from the city of Medan to reduce potential bias in this study. So, it can be judged that the MSMEs in the production sector in Deli Serdang Regency have similarities with Medan. The instrument validation test was carried out with convergence validation, and the reliability testing is done with Cronbach Alpha reliability.\n\nFrom June 10th, 2020 to June 30th, 2020, testing the questionnaire instrument was carried out (see data file 7).10 Validation testing is based on convergence validation, and the result showed that all indicators in each latent variable obtain a loading factor value of ≥ 0.5.9,10 This validity value can be interpreted that the statements in each latent variable in this study can be understood by respondents in the same way as intended by the researcher. Moreover, the instrument's reliability showed that the value Cronbach Alpha for all latent variables is above 0.81.9,10 These reliability results meant that all items in the instrument can be used several times to measure the same symptoms and provide relatively consistent measurement results. There was no modification to the questionnaires after this testing because all items had met the criteria of validity and reliability.\n\nFor the study, respondents included a total of 466 business participants in the production sector from August 1st, 2020 to October 25th, 2020. Based on the Medan City Cooperatives and SMEs Service database, there are 466 businesses who are actively operating with a valid location within the bounds of Medan city (see data file 1) as of June 2020. Although the number of Medan City MSMEs recorded in the database of the Ministry of Cooperatives and SMEs of the Republic of Indonesia is 259,812 business actors as of August 3rd, 2021, this number is a combination of various sectors, not only the production sector. Furthermore, the validity of their active businesses is not guaranteed. In this case, the researcher follows the Law of the Republic of Indonesia Number 16 of 1997 concerning Statistics, the second part of article 12 paragraph 1 (see data file 14),10 which states that sectoral statistics are carried out by government agencies according to their scope of duties and functions, independently or together with the Agency. Thus, based on this law, this study uses data released by the Medan City Cooperatives and SMEs Office, namely 466 businesses in the production sector, as a targeting sampling. Businesses that were not in the production sector were excluded from this study and the inclusion criteria included that is the participant must be a MSME business, identified as active at the time of the data extraction, and were fostered by the Medan City Cooperatives and SMEs Office in 2020. A random stratified sampling strategy was used to ensure the size of the business (micro, small, and medium enterprises (MSMEs)) and districts are represented in this research. Reminders were sent through SMS and WhatsApp to all nonresponding businesses and a second reminder by phone. The minimum sample size technique was based on a statistical power analysis of 80 percent, according to Cohen's table,9 which is measured based on how many indicators that a latent variable has. External leans practice as a latent variable has four indicators, so the minimum observation (sample) is 41 respondents to get 80 percent in detecting R2 at least 0.25 (with 5 percent probability of error). Furthermore, the internal leans practice as a latent variable has six indicators, so the minimum observation (sample) is 48 respondents to get 80 percent in detecting R2 of at least 0.25 (with a 5 percent probability of error). As with the external leans practice, the financial performance as mediating and also as latent variable must have minimum observations (sample) of 41 respondents to obtain 80 percent in detecting R2 of at least 0.25 (with a 5 percent probability of error). Finally, the latent variable use of leans strategy must have a minimum of 45 respondents to obtain 80 percent in detecting R2 of at least 0.25 (with a 5 percent probability of error).\n\nFrom the 466 businesses who were the target population, 169 businesses were willing to participate in the study and returned a completed questionnaire (see data file 11).10 In this case, five respondents returned the questionnaire through field interviews, 34 respondents returned the questionnaire via postal mail with all fields completed, and 130 respondents filled out the questionnaire online or from the link provided on the hardcopy questionnaire sheet. 89 respondents returned the questionnaire via postal mail with incomplete fields and were not included in this study, and 207 respondents were not willing to participate in the study and refused to fill out the questionnaire – non-participation was confirmed by a telephone call. Overall, only 36 percent of respondents from the total target population are participated in this study. This condition is the same as in the study of SMEs in Australia,15 Scotland,16 and South Africa.17\n\nData were obtained through mail and online which is utilizing a Google form with MSME business actors in Medan from the August 1st, 2020 to October 24th,2020 by paying attention to the COVID-19 protocol,14 with a database formed using a Google form.10\n\nThe data analysis carried out in this study consisted of two sub-model tests, namely testing the measurement model or often referred to as the outer model and testing the structural model or often referred to as the inner model with 0.10 as its’ significant level. Before testing the outer model and inner model, it is necessary to test whether the arrow direction in each construct is formative or reflective. In this case, a test will be carried out on each exogenous and endogenous construct whether there is an intercorrelation on the indicators owned. If there is an indication of intercorrelation between indicators, it can be concluded that the construct is reflective vice versa.9 Then testing the measurement model or outer model is carried out to determine which indicators have a significant role in explaining latent variables with the partial least square algorithm mechanism with the provisions of whether the construction is formative or reflective. This was done more than twice to obtain significant indicators in explaining the latent variables in each construct. After obtaining strong and significant indicators for each construct, the next step is to test the inner model. This test is helpful to see the strength of the influence between latent variables through the path or R-square value between latent variables. Testing the inner model will be carried out using the bootstrapping mechanism. After testing the inner model and outer model, the last step is testing the model fit of the built model, with each construct having significant indicators. Before it is known empirically whether the construct will be formative or reflective, this study assumes that all constructs are in a reflective position. Simultaneous equation modelling - partial least squares regression analysis, assisted by Smart PLS 3.0 and SPSS 18, was used. In this case, the constructs of two exogenous variables, one endogenous variable and one mediation variable along with each latent variable's manifest variable, are presented in Figures 1–5.\n\nNotes: ξ1 = external lean practice, η1 = financial performance, γ21 = the power of ξ1 in influencing η2, γ11 = the power of ξ1 in influencing η1, ξ2 = internal lean practice, η2 = the use of lean strategy, γ11 = the power of ξ1 in influencing η1, γ12 = the power of ξ2 in influencing η1, and β21 = the power of η1 in influencing η2.\n\nNotes: X1 = supplier feedback, X2 = supplier just in time, X3 = supplier development, X4 = customer involvement λ4 = the strength reflective power of X4 in influencing ξ1, λ3 = the strength reflective power of X3 in influencing ξ1, λ2 = the strength reflective power of X2 in influencing ξ1, and λ1 = the strength reflective power of X1 in influencing ξ1.\n\nNotes: X5 = pull system, X6 = continue flow, X7 = setup time reduction, X8 = statistical process control, X9 = employee involvement, X10 = total productive maintenance, λ10 = the strength reflective power of X10 in influencing ξ2, λ9 = the strength reflective power of X9 in influencing ξ2, λ8 = the strength reflective power of X8 in influencing ξ2, λ7 = the strength reflective power of X7 in influencing ξ2, λ6 = the strength reflective power of X6 in influencing ξ2, and λ5 = the strength reflective power of X5 in influencing ξ2.\n\nNotes: Y18 = return on investment, Y19 = return on assets, Y20 = sell growth, Y21 = total operating cost, λ11 = the strength reflective power of Y18 in influencing η1, λ12 = the strength reflective power of Y19 in influencing η1, λ13 = the strength reflective power of Y20 in influencing η1, and λ14 = the strength reflective power of Y21 in influencing η1.\n\nNotes: LE1 = pull production system, LE2 = inventory delivery, LE3 = business location, LE4 = consumer needs, LE5 = production time, λ15 = the strength reflective power of LE1 in influencing η2, λ16 = the strength reflective power of LE2 in influencing η2, λ17 = the strength reflective power of LE3 in influencing η2, λ18 = the strength reflective power of LE4 in influencing η2, and λ19 = the strength reflective power of LE5 in influencing η2.\n\n\nResults\n\nThe intercorrelation results for all constructs do not show a strong relationship with each other.10 Therefore, empirically the indicators that build the four constructs are formative, starting from external leans practice, internal leans practice, financial leans practice, and use of leans strategy. This report shows that testing the outer and inner models must be in line with the standard formative construct testing. Furthermore, examining the outer and inner models with formative constructs can only be analysed based on the bootstrapping calculation mechanism.9\n\nIn this case, based on bootstrapping results (see data file 5),10 to see the value of the indicator in each construct with a significant or insignificant value based on P-Values is through the tabulation of outer loadings. Based on the tabulation of outer loadings, the indicators (manifest variables) LE2 (inventory delivery) and LE3 (business location) have no significant value in explaining the use of leans strategy, with their P-Values values being 0.808 and 0.493, respectively (see data file 5).10 Moreover, in the external leans practice construct, only X4 (customer involvement) has no significant value to explain the latent variable with a P-Value value of 0.588.10 Thus, only indicators LE2, LE3, and X4 should be eliminated from each construct. Bootstrapping calculations are performed again after eliminating LE2, LE3, and X4. Even though, the P-Value of LE4 (consumer needs) on the outer loadings shows above 0.05, it can still be maintained because this study is exploratory with a significance level of 0.10 (see data file 5).10\n\nThe next step is to measure the strength of the inner model is through the path coefficient tabulation derived from the results of the bootstrapping calculation. In this case, it is known that the path between the external leans practice latent variable, and the use of leans strategy latent variable should be eliminated because the significance value is above 0.05 (see data file 13).10 Similarly, the latent variable financial performance on the latent variable use of leans strategy should be removed from the inner structural model because it has a significant value above 0.05 (see data file 13).10\n\nAfter eliminating three indicators or manifest variables and two inner model paths that are not significant at the 0.0.05 level, the final bootstrapping result (see data file 5)10 is obtained with overall outer loadings (see data file 5)10 and path coefficients (see data file 5),10 which have a significance value below 0.05. Thus, from the path diagram figure29 of the bootstrapping process, equation models can be made for this study's outer model and inner model.\n\nBased on the results of the bootstrapping calculation, it is known that the P-Value values for hypotheses three (H3) and five (H5) are above 0.05, namely 0.529 and 0.932, respectively (see path coefficient data file 13),10 which means that they are not significant at 0.05 and should be excluded from the study. Because H3 and H5 do not meet the 0.05 significance requirement, then hypothesis six (H6) automatically cannot be continued for analysis because it is clearly proven that the practice of external leans strategy does not affect or cannot be a signal for the use of leans strategy by MSMEs. Furthermore, hypothesis seven (H7) cannot be accepted or continued for analysis because H5 is actually excluded from the study, so it can be interpreted that empirically financial performance cannot be a mediating variable between internal and external practice of leans on the use of leans strategy. So, the final modification result of the bootstrapping (see data file 5)10 concludes that the first, second, and fourth hypotheses are empirically acceptable. Therefore, financial performance cannot signal the practice of leanness strategy in MSMEs in Medan's production sector. However, it was found that internal lean practice predominantly influences the financial performance of MSMEs in Medan city compared to external lean practice. Furthermore, internal lean practice is the primary signal of the lean strategy in the MSME production sector in Medan city. The mechanism for obtaining these research results can be seen in Figure 6, which presents a flow diagram of outer model evaluation, and Figure 7, which presents a flow diagram of inner model evaluation. From 169 respondents who returned the questionnaire with complete entries, it is known that 51 respondents are small-sized businesses, five respondents are medium-sized businesses, and 113 respondents are micro-sized businesses. Then, most of the production sector of MSMEs in Medan city are handicraft producers, followed by fabric producers, convection producers, shoe manufacturers, and household furniture manufacturers (see data file 12).10\n\n\nDiscussion\n\nBased on the results of path coefficient analysis (see data file 13),10 it is proven that empirically the first hypothesis, second hypothesis, and fourth hypothesis are acceptable. Therefore, this study contributes to the theory of business strategy used by MSMEs in the production sector of Medan by highlighting and investigating the role of internal and external leans practice and financial performance. The study results obtained the importance of internal leans practice in influencing leans strategy and financial performance. In addition, external lean practice is known to affect the financial performance of MSMEs.\n\nThe first hypothesis has been proven to be acceptable that external leanness strategy practices carried out by MSMEs in Medan (production sector) affect the company's financial performance. In this case, the characteristics of external lean practice carried out by MSMEs in the production sector of the city of Medan validly consist of three indicators or characters, namely providing supplier feedback (X1), suppliers just in time (X2), and referred to as supplier development (X3). So, based on the external leans practices character owned by MSMEs in the production sector, they can streamline and grow business financial performance. In contrast to the findings of the study conducted by Hofer et al.,6 that external leanness strategy practice is not significant in influencing business financial performance. Hofer et al.,6 states that financial performance will be good if cost reduction is realized, and cost reduction can be made if it is influenced by inventory leanness. However, some study results state that the external leanness strategy has a real significance in influencing financial performance.5,20\n\nThe second and third hypotheses are empirically proven,10 where internal lean practice in MSMEs in the production sector has an influence value of 63.6 percent positively on financial performance and 77.6 percent on lean strategies.10 Furthermore, the six indicators of internal lean practice proved to be valid with P-Values < 0.10.10 Thus, the results of this study prove that the characteristics of MSMEs in the production sector of the city of Medan in running a business during 2020 are by the six indicators that build an internal lean practice, namely carrying out business in a pull system (X5), continue flow (X6), setup time reduction (X7), statistical process control (X8), employee involvement (X9), and total productive maintenance. Furthermore, studies conducted by Hofer et al.,6 and Fullerton and Wempe18 prove that there is a positive influence between internal leans practice on financial performance. However, if between internal leans practice and financial performance the inventory leans variable or non-financial performance measures, there will decrease direct influence by 25 percent. Furthermore, a study conducted by Hallgren, M. et al.,19 and Chanegrih, T.20 show that the effort to practice leans strategy will result in more efficient financial performance than companies with agile characteristics. Therefore, it is empirically and theoretically proven that internal lean practice will positively affect the effectiveness of financial performance efficiently, which consists of five indicators, namely, return on investment (Y18), return on assets (Y19), cell growth (Y20), and total operating cost (Y21). Furthermore, something that is a novelty from this research is the proven internal lean practice as a strong signal in showing whether a business has used a leans strategy or not. In this case, the use of the leans strategy by MSMEs is seen from five indicators. However, only three indicators have proven significant as a characteristic of MSMEs business strategy in the production sector of Medan, namely, the use of a pull production system (LE1), based on consumer needs (LE4), and the use of time production (LE5).\n\nThe empirical proof of this study showed that financial performance could not signal using a strategy that the MSMEs production sector of Medan used (see path coefficient data file 13).10 However, internal and external lean practice empirically could be a signal on the financial performance of MSMEs production sector in Medan, which internal leans practice has a strong influence compared to external leans practice. Thus, based on the path coefficient, the financial performance of MSMEs cannot be a mediating variable between external and internal leanness practices toward the use of leans strategy. Therefore, based on path diagram figure (see data file 2)10 the prediction equation model (inner model equation) for the use of a leanness strategy in MSMEs production sector Medan is only influenced by the practice of internal leanness: with the model equation isasfollowsη2=0.776ξ2. Furthermore, empirically the equation model (inner model) for financial performance in MSMEs production sector in Medan is η1=0.155ξ1+0.636ξ2. This study proves that the role of external and internal leans practice affects the financial condition and business strategy of MSMEs in the production sector of Medan.\n\nThis study can be categorized as a study of lean manufacturing practices because it combines the perspectives of just-in-time (JIT), total quality management (TQM), and total productive/preventive maintenance (TPM) to obtain productivity and quality levels through waste reduction.22 An emphasis on internal and external strategic leanness practices can improve financial performance and environmental protection because resources will be limited to what is needed and not to what is desired.5 These findings can act as a map for practitioners, academics, and the government to improve MSMEs' financial performance and assist MSMEs with their business strategies through internal business practices. Furthermore, this finding can be an entry point for investigating whether MSMEs in the production sector of Medan have characteristics of agile manufacturing. The characteristics of MSMEs with agile manufacturing are needed in the current situation; where the growth of transactions or trade globally is increasing, the environment is uncertain, the development of technology is rapidly getting faster, and the pressure of competition between manufacturers requires different practices and different tools to improve the process company operations. In this case, a study conducted by M. Khalfallah and L. Lakhal22 proves that lean manufacturing can explain whether a company has agile manufacturing practices where agile manufacturing is essential in viewing operational performance.\n\nThe findings illustrate the business strategy carried out by MSMEs in the production sector in the city of Medan, where the regional and national economies are experiencing a decrease. The data obtained from this field research indicate that the financial performance of MSMEs cannot project the strategies used. However, internal business practices are the leading indicators in signalling the strategy used and financial performance.\n\nOnly one percent of the targeting sample was conducted with intensive interviews with the targeted business participants prior to the COVID-19 lockdown. The remaining (99 percent sample) used questionnaire by postal mail and online access because the Medan city government forbids us in conducting interviews directly due to the increase of COVID-19 infection from August 2020 to October 2020 with the lockdown policy enforced in Medan. Furthermore, the 1 percent (five respondents) who were willing to be interviewed were in the Medan Tembung district on the outskirts of the city.\n\n\nConclusion\n\nThese findings can act as a map for practitioners, academics, and the government to improve MSMEs' financial performance and assist them with business strategies through internal business practices. Moreover, this study's impact can lead to an understanding of operations business strategies that directly or indirectly affect the environment. Finally, in-depth knowledge of business actors' operational systems will assist regional, state, and international policies to fight global warming and various environmental problems through waste reduction.\n\n\nData availability\n\nFigshare: Underlying data.\n\nhttps://doi.org/10.6084/m9.figshare.17004067.\n\nThis project contains the following underlying data:\n\n• Data file 1. (Map of city of Medan with its 21 Districts (Kecamatan))\n\n• Data file 2. (Figure of path diagram from the final bootstrapping)\n\n• Data file 3. (Final path coefficient)\n\n• Data file 4. (Final outer loadings)\n\n• Data file 5. (The third (final) bootstrapping result)\n\n• Data file 6. (Validation and reliability result)\n\n• Data file 7. (Dataset for questionnaire validation and reliability (49 respondents) in testing stage)\n\n• Data file 8. (Intercorrelation testing result)\n\n• Data file 11. (Anonymized dataset of leanness strategy of Medan MSMEs [169 respondents])\n\n• Data file 12. (Groups in the Production Sector with 466 businesses identified for study)\n\n• Data file 13. (Path Coefficient - explanation for exclusion of H3, H5, H6, and H7)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nFigshare: Underlying data. https://doi.org/10.6084/m9.figshare.17004067.\n\nThis project contains the following extended data:\n\n• Data file 9. (Research questionnaire on Google form)\n\n• Data file 10. (Research questionnaire – hard copy)\n\n• Data file 14. Law of the Republic of Indonesia Number 16 of 1997 concerning Statistics\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 want to thank the State University of Medan, the Institute for Research and Community Service, which made this research possible.\n\n\nReferences\n\nKementerian Koperasi dan Usaha Republik Indonesia. (UMKM KKD): Data development of Micro, Small, Medium (UMKM) and Large Business (UB) Businesses.2018. [Accessed 10 5 2020].Reference Source\n\nKaradag H: The impact of industry, firm age and education level on financial management performance in small and medium-sized enterprises (SMEs): Evidence from sTurkey. J. Entrep. Emerg. Econ. 2017; 9(3): 300–314. Publisher Full Text\n\nDoan AT, Le AT, Tran Q: Economic uncertainty, ownership structure and small and medium enterprises performance. Aust. Econ. Pap. 2020; 59(2): 102–137. Publisher Full Text\n\nSopha BM, Hestiani A: A case study of Indonesian SMEs: an empirical evidence of SCM practices and their impact on firm performance. The International Journal of Services Technology and Management. 2018; 24(5-6): 394–413. Publisher Full Text\n\nShashi CP, Cerchione R, et al.: The impact of leanness and innovativeness on environmental and financial performance: Insights from Indian SMEs. Int. J. Prod. Econ. 2019; 212: 111–124. Publisher Full Text\n\nHofer C, Eroglu C, Rossiter HA: The effect of lean production on financial performance: The mediating role of inventory leanness. Int. J. Prod. Econ. 2012; 138(2): 242–253. Publisher Full Text\n\nVidyadhar R, Kumar R, Vinodh S, et al.: Application of fuzzy logic for leanness assessment in SMEs: a case study. J. Eng. Des. Technol. 2016; 14: 78–103. Publisher Full Text\n\nNawanir G, Lim KT, Othman SN: Lean manufacturing practices in Indonesian manufacturing firms: Are there business performance effects?. Int. J. Lean Six Sigma. 2016; 7: 149–170. Publisher Full Text\n\nJoseph J, Hair F, Hult GTM, et al.: A Primer On Partial Least Squares Structural Equation Modelling (PLS-SEM). Singapore: SAGE Publications Ltd; 2014.\n\nTriono MAA, Ahmad ST, Ermiati C, et al.: Underlying Data. figshare. Dataset. 2021. Publisher Full Text\n\nPurwanto A: Kota Medan: Paris van Sumatera. 2021. [Accessed 13 7 2021].Reference Source\n\nWikipedia Ensiklopedia Bebas: Kota Medan. 2021. [Accessed 13 7 2021].Reference Source\n\nKementerian Koperasi dan UKM Republik Indonesia: 2021. [Accessed 26 7 2020].Reference Source\n\nKomite Penangan Covid 19 dan Pumilahan Ekonomi Nasional, “Protokol,” Government Republic of Indonesia, 2 8: 2020. [Accessed 4 8 2020].Reference Source\n\nVerreynne M-L, Williams AM, Ritchie BW, et al.: Innovation diversity and uncertainity in small and medium sized tourism firms. Tour. Manag. 2019; 72: 257–269. Publisher Full Text\n\nFreel MS: Perceived Environmental Uncertainty and Innovation in Small Firms. Small Bus. Econ. 2005; 25: 49–64. Publisher Full Text\n\nOerlemans L, Pretorius M, Buys A, et al.: South African Innovation Survey 2001 for manufacturing and services: Report on the South African Innovation Survey for the Period 1998-2000. The Netherlands Eindhoven University of Technology Eindhoven Centre for Innovation Studies; 2003.\n\nFullerton RR, Wempe WF: Lean manufacturing, non-financial performance measures, and financial performance. Int. J. Oper. Prod. Manag. 2009; 29(3): 214–240. Publisher Full Text\n\nHallgren M, Olhager J: Lean and agile manufacturing: external and internal drivers and performance outcomes. Int. J. Oper. Prod. Manag. 2009; 29(10): 976–999. Publisher Full Text\n\nChanegrih T, Creusier J: The Effect of Internal and External Lean Practices on Performance: A Firm-Centered Approach. Management International/International Management/Gestiòn Internacional. 2016; 21(1): 114–125. Publisher Full Text\n\nSekretariat Website JDIH BPK RI: Perlindungan Data Pribadi Dalam Sistem Elektronik. 2016. [Accessed 21 7 2020].Reference Source\n\nKhalfallah M, Lakhal L: The impact of lean manufacturing practices on operational and financial performance: the mediating role of agile manufacturing. Int. J. Qual. Reliab. Manag. 2020; 38: 147–168. Publisher Full Text"
}
|
[
{
"id": "137637",
"date": "16 May 2022",
"name": "Rizwan Raheem Ahmed",
"expertise": [
"Reviewer Expertise Marketing",
"advertising",
"general managmenet"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 topic is interesting and has wider theoretical and practical applications. The authors have put their best efforts to execute this paper. However, I have the following reservations and suggestions for the sake of improvement of the undertaken study:\nThe logical sequence of the abstract should be as 1) objectives, 2) methodology, 3) findings, 4) conclusion, and 5) implications. Thus, the authors should also rewrite the abstract in this sequence. The authors did not establish the motivation, significance, and novelty of the undertaken study. The authors are suggested to improve this important factor in the \"Introduction\" section. The review of literature should be presented in a separate section, and in audit forms, and it should be linked with the objective of this paper. The authors should present a separate sub-section of sampling strategy and sample size, research design, and estimation techniques in the methodology section. The discussions section should be separated from the conclusion or added after the results section, the discussions section provides the opportunity for the authors to sell their idea to the readers. The discussions section should be complemented with the previous literature. The conclusion should be presented in a separate section. The conclusion is always one step ahead of the findings. The practical, theoretical and societal implications should be discussed after the conclusion, and in the light of the conclusion and discussions. The limitations and potential areas of future studies should be discussed in the end. The spelling and grammatical mistakes should be corrected throughout the paper.\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": []
},
{
"id": "320409",
"date": "04 Nov 2024",
"name": "Muhammad Reza Aulia",
"expertise": [
"Reviewer Expertise Entepreneurhsip",
"Management",
"Human Development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 has several significant strengths. First, the use of bootstrapping methods enhances the validity of the results and provides an in-depth analysis of the relationship between internal and external lean practices and the financial performance of SMEs in the production sector. The findings indicate that internal lean practices positively influence financial performance, offering a new perspective in the literature on lean strategies in Medan.\nAdditionally, the article highlights the relevance between business strategies and environmental sustainability, demonstrating that the implementation of lean strategies can reduce waste. This makes it beneficial not only for improving business performance but also relevant in social and environmental contexts.\nHowever, there are several areas for improvement that could enhance the article's quality. For instance, more explicit articulation of research objectives and implications could provide a clearer framework for understanding the study's contributions. Additionally, further exploration of the methodology, including details on data collection and analysis processes, would strengthen the overall reliability of the findings.\n\nOverall, while this article makes a significant contribution to understanding lean practices and their impact on the financial performance of SMEs, addressing these points could elevate its quality and broaden its applicability in various sectors.\nHere are some comments that can serve as a basis for improving the quality of the article:\nAbstract\n\nThis abstract lacks a clear logical order. The research objectives are not explicitly stated at the beginning, and no practical, theoretical, or social implications are discussed. Furthermore, the motivation and novelty of the study are not explained, and the conclusion and results section could be more detailed. There is also no information about limitations or potential areas for future research.\nIntroduction\n\nThe background lacks an explicit explanation of the research objectives and novelty at the outset. Although data is presented, there is no strong emphasis on the research gap that the study aims to address. Additionally, there is no clear explanation of the specific issues faced by MSMEs in Medan regarding the \"lean\" strategy. The relationship between the lean strategy and MSME financial performance could also be further clarified to improve narrative flow. Lastly, references to more recent sources could enhance credibility.\nMethod\n\nThe methodology presented has several shortcomings. Although a stratified random sampling method has been used, the rationale for selecting the sample size and region is not clearly explained. Furthermore, while ethical approval and participant involvement are mentioned, the process of obtaining written consent from respondents and how their information confidentiality is maintained is not explained in detail. Regarding external validity, there is no discussion of generalizing results beyond the Medan region or the implications of geographical limitations on the findings. While non-participation is mentioned, there is no analysis of potential non-response bias that could affect the results. Additionally, there is no explanation regarding the limitations of data collection methods, such as the potential bias in surveys sent by mail or filled out online, which should be further explained to improve the reliability of the study's methodology.\nAnalysis\n\nThe data analysis has several shortcomings. First, there is no detailed explanation of the process for determining whether a construct is formative or reflective, as well as its impact on the research results. Second, while the use of Smart PLS 3.0 and SPSS 18 is mentioned, there is no discussion of the steps or parameters used in model testing. Finally, there is no explanation of how the bootstrapping results are interpreted or how model fit was tested.\nResults\n\nThe research results lack details on the interpretation of statistical results, such as R-square values or the effectiveness of paths between variables. Insignificant results are only mentioned without further analysis of their implications for the overall model. Additionally, there is no detailed explanation of the specific influence of significant variables on the accepted hypotheses. The explanation of the distribution of business types is also not connected to the main findings.\nDiscussion\n\nThis discussion lacks depth in explaining the practical implications of the findings for MSME business actors and researchers. The explanation of differences in results with previous studies is not fully elaborated, especially regarding why these findings differ from those of Hofer et al. Moreover, the discussion of theoretical contributions, such as the relationship between lean strategy and financial performance, needs to be further explained in the context of MSMEs. The emphasis on the significance of indicators also lacks an explanation of how they contribute to the practical application of the lean strategy. The analysis of the relevance of agile manufacturing is only briefly mentioned without detailing its implications.\nConclusion\n\nThe conclusion lacks focus on summarizing the main findings of the study and its specific contributions to theory and practice. The explanation of how these findings concretely help improve MSME financial performance and business strategy is still too general. Additionally, the relevance and connection to environmental policy and waste reduction need to be clarified, specifically how this research contributes to policy in the context of climate change. The conclusion could also be stronger by suggesting concrete steps for business actors or policymakers.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1183
|
https://f1000research.com/articles/10-1179/v1
|
23 Nov 21
|
{
"type": "Research Article",
"title": "Metabolic response against traffic congestion-induced stress",
"authors": [
"Mirasari Putri",
"Hilmi Sulaiman Rathomi",
"Fajar Awalia Yulianto",
"Raden Aliya T. M. Djajanagara",
"Dony Septriana Rosady",
"Sadiah Achmad",
"M. Ahmad Djojosugito",
"Hilmi Sulaiman Rathomi",
"Fajar Awalia Yulianto",
"Raden Aliya T. M. Djajanagara",
"Dony Septriana Rosady",
"Sadiah Achmad",
"M. Ahmad Djojosugito"
],
"abstract": "Background: Traffic congestion is a common problem in large cities, which can induce stress in participants in vehicles as well as pedestrians. In such conditions, several stress hormones, such as catecholamines and cortisol are secreted by the adrenal glands resulting in metabolic responses. Prolonged metabolic changes can lead to metabolic diseases, such as metabolic syndrome and cardiovascular disease. This study aimed to examine the metabolic responses induced by traffic congestion in young adults. Methods: We enrolled 71 undergraduate students aged 20-30 years from the Faculty of Medicine Universitas Islam Bandung, who regularly go to campus on foot, by public transportation, motorcycles, and cars. Medical history was screened by questionnaires before the testing day. Blood samples were drawn soon after participants arrived on campus. We used bioimpedance analysis to measure fasting blood glucose, lipid profiles, and nutrient body status. Results: Most participants rode motorcycles (46.48%), and the most common travel time was short (<15 min, 54.9%.). Total cholesterol and low-density lipoprotein (LDL) levels were significantly lower in participants using vehicles - either private or public transportation - compared with pedestrians (p<0.05 and p<0.02, respectively). Participants with a short travel duration had significantly higher total cholesterol and LDL levels than those with longer ones (p<0.02 and p<0.05, respectively). Conclusions: Based on the above results, metabolic responses to traffic congestion such as changes to total cholesterol and LDL levels depended the type of transportation and travel duration.",
"keywords": [
"Metabolic responses",
"Stress",
"Traffic congestion",
"Travel duration",
"Transportation type"
],
"content": "Introduction\n\nA problematic issue in big cities is traffic congestion, which can induce stress in traffic users.1 Bandung, Indonesia, is ranked 14th on the list of 278 Asian cities with traffic congestion. Until 2013, the number of private four-wheeled vehicles in Bandung was 318,598, and that of two-wheeled ones 1,030,279 (Badan Pusat Statistik Kota Bandung, 2015).2\n\nStressors can induce both positive and negative responses, determined by a balance between tolerance and sensitivity. Stressors can be helpful; for example, they can motivate the body to produce the energy to get through challenging situations such as exams or job tasks. However, stressors in extreme amounts and over long periods can cause chronic stress affecting the immune system, cardiovascular, neuroendocrine, and central nervous systems.3,4\n\nStress induces several metabolic responses in the body; for example, the hypothalamus transmits signals directly through the sympathetic nervous system to the adrenal glands, resulting in the production of catecholamines in the adrenal medulla, including epinephrine, which increases the heart rate and respiration.5 In addition, norepinephrine, stimulates liver cells to release glucose for cellular respiration.5 In contrast, hormones secreted by the adrenal cortex signal a chronic response to stress. In such a case, under stress stimulation, the hypothalamus causes the anterior pituitary to secrete the adrenocorticotrophic hormone (ACTH), which induces cells in the adrenal cortex to produce and secrete corticosteroids, such as glucocorticoids, to break down fat and stimulate glucose synthesis. Cortisol is an example of glucocorticoid involved in this stress response, and regulates or supports various cardiovascular, metabolic, immunological, and homeostatic processes.3\n\nTsigos (2019) suggested that chronic stress is associated with hypercortisolemia and sympathetic system activation, resulting in metabolic changes. For example, visceral fat accumulation contributes to visceral obesity, type 2 diabetes mellitus (DM-2), and associated cardiometabolic complications.6,7 Currently, the prevalence of DM-2 in adults is approximately 6.4% of the world population and will continue to increase to 7.7% of the population by 2030.8 The prevalence of DM in urban areas in Indonesia is approximately 5.7%, and the incidence of this disease at young age tends to increase.9 This increase deserves particular attention, considering their productive role in society.9 However, studies on the effect of chronic stress due to traffic congestion on the metabolism at young age are still limited.\n\nIn this study, we investigated whether stress whilst driving would affect metabolic responses by examining several metabolic parameters such as fasting blood glucose, lipid profiles, and nutrient body status in young adult traffic users, which were active students at UNISBA Faculty of Medicine.\n\n\nMethods\n\nThe ethics committee of the university approved this study with the number: 003/KEPK-FK/XI/2017. Interviews were in the UNISBA Faculty of Medicine area, after written consent was obtained from the subjects following an explanation about the study, without any coercion.\n\nThis was a cross-sectional study to determine the correlation between driving stress caused by different types of transportation and travel duration, and lipid profile and glucose. The study was conducted from September 2017 to February 2018 on data from second-year and third-year students at UNISBA Faculty of Medicine, Bandung-Indonesia. Participants were approached by visiting classroom and offering participation in this study. Then, interviews for recruitment were conducted in the UNISBA Faculty of Medicine area after participants provided informed consent. The study materials including participant information sheet and questionnaire can be found as Extended data.19,20 We collected blood serum samples in the 7th-floor laboratory of the UNISBA Faculty of Medicine.\n\nWe followed the STROBE cross-sectional reporting guidelines.10 Restriction methods (by applying inclusion and exclusion criteria) were applied to variables that biologically possible to compromise the outcome variable, such as metabolic diseases, cholesterol-affecting medications, pancreatic disorders, and smoking-alcohol drinking habits. Valid variable measurements explained later on this section.\n\nThe minimum sample size in this study was 55 people, and calculated using the following correlation test formula:\n\nWith Zα: 1.96 (with α: 0.05), Zβ: 0.842 (with β: 0.2), r: 0.37 (obtained from previous research), N: 55.\n\nTo anticipate sample dropouts, the number of samples in this study was 10% of the minimum sample size (60.5) rounded up to 62 people.\n\nWe used consecutive sampling to obtain the 71 participants among students in the UNISBA Faculty of Medicine. After conducted interview for recruitment, the selected subjects fulfilled the following inclusion criteria: being active students (active in academic activity during the study period) and having performed academic activities for >1 year (this was to prevent sampling bias due to student adaptation to the campus environment). The exclusion criteria were: taking drugs which can interfere with the results, such as steroids, diazoxide, diuretics, and phenytoin, being active smokers or consuming alcohol, a history of DM-2 or cardiovascular disease, dyslipidemia, obesity, or pancreas abnormalities, family history of DM-2, cardiovascular disease, and dyslipidemia.\n\nIn this study, the travel duration was the time participants needed to go from their residence to campus as measured by themselves using a stopwatch application in their own mobile phone. Subjects were requested to use their usual transportation method to campus. Travel duration data were collected twice on different days within a week before blood sampling collection. As evidence, we asked the participants to share the location twice, namely, when they left the residence and reached the campus lobby. They shared their location and the measurement of their travel duration immediately with the researchers via text messages.\n\nThe participants fasted for 8-10 hours (fasting started 10 PM, night before the blood collection), then blood collection was conducted at 6-8 AM). First, we obtained venous blood 3-5 cc (venipuncture) from the median cubital vein, venous cephalic, or basilica vein. Then, the blood serum was centrifuged (ZENTRIFUGE EBA 200 HETTICH, Tuttlingen, Germany) at 1500 × g for 15 min at 4°C to separate the serum, which was stored at 80°C until further use.\n\nWe measured body composition by bioimpedance analysis (BIA) using Omron HBF-375 (Omron Healthcare, Kyoto, Japan). The procedure and normal reference values followed the manufacturer's protocol. Body fat percentage measurement = (body fat mass [kg] /body weight [kg]) × 100, skeletal muscle ratio = (skeletal muscle mass [kg] /body weight [kg]) × 100. As hydration status is essential for accurate body composition assessment using BIA.11 The participants were asked to avoid alcohol the night before the test and not exercise on the day before the test.\n\nBlood glucose levels were measured using a glutes sensor (Sanwa Kagaku, Aichi, Japan). In addition, we measured serum triglyceride levels (Triglyceride E-test, Wako Chemical, Osaka), total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) (NEFA C-test Wako Chemical, Osaka) following manufacturer's protocols.\n\nWe conducted univariate, bivariate, and multivariate data analysis by STATA/MP 16. First, we used univariate analysis to describe the frequency, distribution, and percentage of each variable in the study and specific measures of average, median, standard deviation, and the maximum and minimum values. Next, we performed bivariate analysis using t-test and ANOVA test followed by Dunnett's post hoc multiple comparison tests to determine the relationship between variables, and Pearson's correlation test to determine the power of the correlation if the data obtained had a normal distribution,12,13 with p < 0.05 considered as statistically significant. Finally, a logistic regression test was used for the multivariate analysis of the relationship between the variables.\n\n\nResults\n\nTable 1 presents the characteristics of the participants. The total number of participants in the study was 71.18 Most participants were female, with a mean age of 21 years, and the average body mass index (BMI) was normal. In addition, the participants' average fasting glucose and lipid profiles were normal, but 63.4% of participants had pre-diabetic fasting glucose levels and 12.7% at a diabetic level (Table 2).\n\nBefore univariate analysis, the Shapiro–Wilk normality test was conducted. All data had a normal distribution, except for travel duration, HDL, and triglyceride levels. In the variable duration of travel, data transformation to obtain normal data distribution could not be performed, so we converted this variable into a categorical/ordinal variable with the following categories: 1. Short duration (<15 min); 2. Medium duration (15–30 min); 3. Long duration (> 30 min). We performed data transformation using the Log function to conduct a parametric analysis of HDL and triglyceride levels.\n\nTable 2 shows that most respondents had a short travel duration (54.9%), and that motorcycle was the most used type of transportation in this study (46.48%). At the beginning of the research design, we divided public transportation into 2-wheeled and 4-wheeled public vehicles. However, in the study, the participants who used 2-wheeled public vehicles were very few (1 participant), so the categories were combined into general public transportation users. Next, despite the broad range of travel duration in participants using the same means of transportation, the median travel duration was 11 minutes.\n\nTable 3 shows that most respondents had a normal body fat percentage, visceral fat, and skeletal muscle ratio. The mean body fat percentage was 24.4 ± 7.39%, while the mean values of visceral fat and skeletal muscle ratio were 3.5 (0.5-13) and 26.8. There were no significant differences between the types of transportation and duration of travel with the three parameters. Next, we measured the proportion of high and very high body fat percentages. The highest body fat percentage was observed in private car users (46.67%), although the difference was not significant (Table 4).\n\nNext, we conducted a comparative bivariate analysis and Bonferroni's post hoc test. The results showed a significant relationship between the type of transportation and travel duration with total cholesterol (p = 0.0492 and 0.0214) and LDL levels (p = 0.0197 and 0.0494, respectively). However, there was no significant relationship between the two variables and other risk parameters, such as fasting glucose, HDL, and triglycerides (Table 5). Respondents with a short travel duration had higher total cholesterol and LDL levels than those with a long travel duration (177.1 vs. 152.4 mg/dL p = 0.016, 99.6 vs. 75.5 mg/dL p = 0.049, respectively). In addition, we found a significant difference between respondents who walked and those who used vehicles; pedestrians had higher levels of total cholesterol and LDL than other transportation users (p = 0.049 and p = 0.021, respectively)\n\n* One way-ANOVA test.\n\nAbbreviations: HDL, High density lipoprotein; LDL, Low density lipoprotein.\n\nTable 6 shows the correlation between variables using the Spearman rank test. There was a statistically significant correlation between duration and type of transportation with total cholesterol and LDL levels. The correlation coefficients for both travel duration and transportation type were negative, which means that the longer the trip, the lower the total cholesterol and LDL levels. However, the strength of the correlation between these variables was low (0.20-0.39).\n\n* Statistically significant difference between groups, Spearman rank correlation test.\n\nAbbreviations: HDL, High density lipoprotein; LDL, Low density lipoprotein.\n\nThe adequacy of the sample size for each metabolic parameter between travel duration and type of transportation was analyzed based on their correlation coefficient properties. The number of samples in the fasting glucose and HDL groups was inadequate for both travel duration and type of transportation classification (Table 7), as was the triglyceride sample for the type of transportation.\n\n\nDiscussion\n\nAccording to Jovanović et al. (2008), the driver's serum glucose, total cholesterol, LDL cholesterol, and triacylglycerol concentrations increase according to the work stress index.14 However, research identifying the metabolic responses to driving stress, primarily due to traffic congestion, is limited. The current study showed a correlation between travel duration and type of transportation with total cholesterol and LDL levels. Pedestrians showed the highest total cholesterol and LDL compared with other groups. In travel duration, the shortest travel duration was associated with the highest total cholesterol and LDL cholesterol levels. In the group with the shortest travel duration, >50% were pedestrians. The reason for this finding might be that during physical activity, substrate reserves are released to accommodate energetic needs. The primary sources of energy substrates are glucose and fatty acids. When needed, fatty acids can be obtained from both nutrients and adipose tissue reserves (triglycerides) by lipolysis. Triglycerides, an LDL content, are distributed to body tissues, including the skeletal muscle.15 Although we found no difference in triglycerides, it may be because the triglycerides in serum were found in the LDL fraction (LDLs consist of cholesterol, cholesterol esters, triglycerides, and phospholipids).\n\nWe also found that >50% of participants were pre-diabetic with a fasting glucose level >10% in the classification of diabetes. In addition, many risk factors influence DM-2. One of these is a modifiable behavioral factor. Therefore, it is essential to find pre-diabetes at a young age, because at this age, the average insulin sensitivity is still good; therefore, behavioral factors can be modified as soon as possible, such as diet, physical activity, and stress, to reduce the risk of DM-2.16\n\nTraffic congestion can cause stress. We suspected that external stress stimuli cause increasing metabolic stress at the cellular level and activate the hypothalamic-pituitary-adrenocortical (HPA) axis, which subsequently causes insulin resistance.6 Several studies have suggested that cortisol, as a product of the HPA axis, plays a role in the processes associated with DM-2.3,17 Nevertheless, this study showed no significant differences in fasting glucose levels associated with vehicle type and travel duration.\n\nThe limitations of this study are that we only focused on the metabolic responses of lipids and glucose. Furthermore, traffic congestion is a physiological stressor with different effects among people; some people may feel stress when they face this condition, while others may not because they face traffic congestion every day for instance. In addition, subjects in this study were not randomly pooled from the general population hence the results of this study only applicable to this group only.\n\n\nConclusions\n\nMetabolic responses such as total cholesterol and LDL levels were affected by traffic congestion depending on the type of transportation and travel duration. Our study gives another perspective that traffic condition could affect metabolic dynamic changes. Further study in older respondents and or longer traffic jam condition can be potential to see the possibility of traffic jam affect metabolic changes. Moreover, exploration of chronic stress pathway and other metabolic markers associated with stress, such as cortisol and catecholamine, is necessary to see the correlation between chronic stress and metabolic profile.\n\n\nData availability\n\nFigshare: Data Measurement of The Metabolic Response Against Stress Induced Traffic Congestion. https://doi.org/10.6084/m9.figshare.16529886.18\n\nFigshare: Questionnaire Correlation of Driving Stress with Fasting Blood Sugar Level and Lipid Profile. https://doi.org/10.6084/m9.figshare.16959637.v1.19\n\nFigshare: Information sheet and consent form of Correlation of Driving Stress with Fasting Blood Sugar Level and Lipid Profile. https://doi.org/10.6084/m9.figshare.16959649.v1.20\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 thank the staff of laboratory of Bandung Medical Center for excellent technical assistance, and the students of the UNISBA Faculty of Medicine who were willing to participate in this study.\n\n\nReferences\n\nBitkina OV, Kim J, Park J, et al.: Identifying Traffic Context Using Driving Stress: A Longitudinal Preliminary Case Study. Sensors (Basel, Switzerland). 2019; 19. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBandung BPSK: Kota Bandung Dalam Angka. Bandung: 2015.\n\nDo Yup Lee EK, Choi MH: Technical and clinical aspects of cortisol as a biochemical marker of chronic stress. BMB Reports. 2015; 48: 209–216. Publisher Full Text\n\nChrousos GP: Stress and disorders of the stress system. Nature Reviews Endocrinology. 2009; 5: 374–381. PubMed Abstract | Publisher Full Text\n\nNicolaides NC, Charmandari E, Chrousos GP: The hypothalamic-pituitary-adrenal axis in human health and disease. Introduction to translational cardiovascular research. Springer; 2015; p. 91–107. Publisher Full Text\n\nDiz-Chaves Y, Gil-Lozano M, Toba L, et al.: Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis. Journal of Endocrinology. 2016; 230: R77–R94. Publisher Full Text\n\nTsigos C, Stress KI: Endocrine Physiology and Pathophysiology - Endotext - NCBI Bookshelf.2019.\n\nShaw JE, Sicree RA, Zimmet PZ: Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes research and clinical practice. 2010; 87: 4–14. PubMed Abstract | Publisher Full Text\n\nMihardja L, Soetrisno U, Soegondo S: Prevalence and clinical profile of diabetes mellitus in productive aged urban Indonesians. J. Diabe. Invest. 2014; 5: 507–512. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVon Elm E, Altman DG, Egger M, et al.: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Epidemiology (Cambridge, Mass). 2007; 18: 800–804. PubMed Abstract | Publisher Full Text\n\nHeyward VH, Wagner DR: Applied body composition assessment. Human Kinetics. 2004.\n\nSalkind NJ: Encyclopedia of research design. sage; 2010.\n\nKremelberg D; Pearson’sr, chi-square, t-test, and ANOVA: Practical statistics: A quick and easy guide to IBM® SPSS® statistics, STATA, and other statistical software. 2011; 119–204.\n\nJovanović J, Stefanović V, Stanković DN, et al.: Serum lipids and glucose disturbances at professional drivers exposed to occupational stressors. Central European Journal of Public Health. 2008; 16: 54–58. PubMed Abstract | Publisher Full Text\n\nRodwell VW, Bender DA, Botham KM, et al.: Harper's illustrated biochemistry. New York (NY): McGraw-Hill Education; 2018.\n\nMahan LK, Escott-Stump S, Krause MV, et al.: Krause's Food & Nutrition Therapy. Saunders/Elsevier; 2008.\n\nHackett RA, Kivimäki M, Kumari M, et al.: Diurnal cortisol patterns, future diabetes, and impaired glucose metabolism in the Whitehall II cohort study. The Journal of Clinical Endocrinology & Metabolism. 2016; 101: 619–625. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPutri M, Rathomi HS, Yulianto FA, et al.: Data Measurement of The Metabolic Response Against Stress Induced Traffic Congestion. figshare. Dataset. 2021. Publisher Full Text\n\nPutri M, Rathomi HS, Yulianto FA, et al.: Questionnaire Correlation of Driving Stress with Fasting Blood Sugar Level and Lipid Profile. figshare. Dataset. 2021. Publisher Full Text\n\nPutri M, Yulianto FA, Rathomi HS, et al.: Information Sheet and Consent Form of Correlation of Driving Stress with Fasting Blood Sugar Level and Lipid Profile. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "144653",
"date": "29 Nov 2023",
"name": "Ivana Šarac",
"expertise": [
"Reviewer Expertise Obesity",
"metabolic syndrome",
"metabolic response to stress."
],
"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:\nTraffic congestion was not assessed in this study, nor level of stress, only the mode of transportation to university campus among students. So, we do not know if there was at all traffic congestion or traffic jam, which is more related to vehicles than to pedestrians, or if there was a stress (no scale which measured the level of stress).\nTherefore, this study assessed only the mode of transportation to university campus and related it metabolic health parameters, without considering other important confounders.\nAdditionally, we cannot conclude that traffic jam influenced metabolic health according to data from this study, there was no causality examination. The study title should be: “Mode of transportation to university campus and its relation to metabolic health of medical students in Universitas Islam Bandung, Indonesia.”\nAbstract:\nSimilarly to said above, it is incorrect to tell that “This study aimed to examine the metabolic responses induced by traffic congestion in young adults.” It should be: “This study aimed to examine the mode of transportation to university campus and to relate it to metabolic health of students in Indonesia.”\nIt is also incorrect to say: “We used bioimpedance analysis to measure fasting blood glucose, lipid profiles, and nutrient body status.” Bioimpedance only assesses body composition, not biochemical profiles. Therefore, the sentence should be “We to measured fasting blood glucose, lipid profiles, and body composition by bioimpedance analysis.”\nIt is also incorrect to conclude: \"Based on the above results, metabolic responses to traffic congestion such as changes to total cholesterol and LDL levels depended the type of transportation and travel duration”, since there was no examination of traffic congestion (just mode and duration of travelling), and we cannot propose the causality (only association we estimated), so the conclusion should be “ Based on the above results, total cholesterol and LDL levels were associated with the type of transportation and travel duration.”\nHowever, there are also numerous methodological issues.\nAll statistical analyses should be adjusted for BMI index, as well as other confounders, e.g., age, gender. Gender strongly influence HDL levels, visceral fat, skeletal muscle ratio. Also smoking should be considered as confounding, but smokers were excluded here, weren't they?\nBMI is one of the most important determinants of glucose and lipid levels, as well the % of fat and visceral fat.\nThis is the most important weakness of this study, and needs to be corrected.\nThe authors should make linear regression models, with glucose and lipid levels as dependent variables, and BMI, fat%, visceral fat, age, gender, smoking (in case smokers were not excluded), duration of transportation (in minutes) and each specific mode of transportation (separate, not as a scale) as predictors. So, make the separate variables for each transportation mode (coded 0 and 1). Variance inflation factors (VIF) should be tested in regression models, and models should not have variables with VIF higher than 5 (in case you have for some anthropometric measures such BMI, Fat% and visceral fat, exclude one of them, until VIF is lower of 5 for each variable in the model, while keep the ones who are the most correlated with glucose and lipid levels). In case you are using the stepwise regression, the program will automatically choose the best predictors in the model.\nThere was also lack of information on % of students who are underweight, normal weight and overweight (and obese. Why obese were excluded? Were they really excluded?).\nThe authors treated the mode of transportation as a scale, which is not correct. You can treat duration of transportation as a scale, but not mode of transportation, since the mode of transportation does not have increasing categories. So, the duration of transportation can be used for Spearman’s correlation in table 6, but the type of transportation can be only used for Point-biserial correlation in table 6 (see below). In table 6, the authors should better give correlation coefficients between BMI, fat percentages, visceral fat, skeletal muscle ratio, glucose level and lipids levels with all modes of transportation (separately!) and duration of travelling (in minutes!). Point biserial correlation can be used for each mode of transportation. Pearson or Spearman correlation should be used for other variables.\nEven worse, in the table 4 they combined all the modes of transportation and all categories of duration into only one scale, and represented only one P value for Fisher exact test for high and very high body fat percentages, which is absurd and meaningless.\nTable 3 does not include any statistical analysis, and does not give any observable information. It is better to give the figures the levels of glucose and lipids (in mmol/l) for each separate category.\nOne way ANOVA in table 5 should have post hoc analyses between the groups (not only in the text). In table 5, ANOVA should be also given for BMI, fat%, visceral fat and skeletal muscle ratio.\nTable 2 contains duplication of the rows. Data should be merged (median / range should go to rows with N and %). Also, Table 2 contains some absurd information on “borderline”, “almost optimal” lipid levels. The authors should present in methods the references for standardized cut-off values for glucose and lipids in the studied population (please, pay attention for gender differences).\nTable 7 is completely unnecessary, the same for table 3.\nAlso, here are some points in separate sections:\nIntroduction:\nAgain, it is also incorrect to say: “In this study, we investigated whether stress whilst driving would affect metabolic responses by examining several metabolic parameters such as fasting blood glucose, lipid profiles, and nutrient body status in young adult traffic users, which were active students at UNISBA Faculty of Medicine.”, because the authors did not measure the level of stress, they only assessed the mode of transportation and duration. The authors also did not assess the “nutrient body status”, only body composition (which is different, from nutrients, e.g., level of minerals, vitamins, fatty acids, etc. in the body). What is: “UNISBA” abbreviation? Universitas Islam Bandung? Please define.\nMethods:\nWhy a personal history of obesity, dyslipidaemia and diabetes were used as exclusion criteria? Were they, really? I can see that some of the students had dyslipidaemia and diabetes, according to table 2.\nReferences for cut-off values for glucose, lipid levels, and anthropometric indices are missing.\nStatistics:\nLinear regression models should be performed and adequate correlation analyses (not ANOVA or Fisher tests), please see above.\n\nResults:\nI have already had given some my comments above, however the sentence “In addition, the participants' average fasting glucose and lipid profiles were normal, but 63.4% of participants had pre-diabetic fasting glucose levels and 12.7% at a diabetic level (Table 2).” is absurd. A fasting blood sugar level of 99 mg/dL or lower is normal, 100 to 125 mg/dL indicates you have prediabetes, and 126 mg/dL or higher indicates you have diabetes.\nIt was completely unclear what the authors meant by.” The adequacy of the sample size for each metabolic parameter between travel duration and type of transportation was analyzed based on their correlation coefficient properties. The number of samples in the fasting glucose and HDL groups was inadequate for both travel duration and type of transportation classification (Table 7), as was the triglyceride sample for the type of transportation.”\nDiscussion:\nIs absurd if statistical analyses were not performed correctly. Adjustments for confounders must have been performed. Again, authors discuss traffic congestion, while nowhere the level of traffic congestion was examined in the study.\nConclusions:\nNot related to the presented data and results. No stress scale is used. No traffic congestion levels were measured.\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? No",
"responses": []
},
{
"id": "261137",
"date": "23 Apr 2024",
"name": "Santhosh Kareepadath Rajan",
"expertise": [
"Reviewer Expertise Affective experiences",
"Behaviour decisions",
"Resilience",
"Solution-Focused approaches",
"and Research Analytics."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript presents an interesting investigation into the metabolic response and congestion-induced stress. Overall, the research question is relevant, and the chosen methodology seems appropriate. However, there are a few areas where further clarification and improvement could strengthen the overall quality of the work. By addressing the following points, the authors can ensure their findings have a more robust foundation and contribute significantly to the field.\nSome of the studies that have been used as evidence to defend the findings (in the discussion) have not been updated in the background. For instance, study number 14 by Jovanović J, Stefanović V, Stanković DN, et al. has not been updated in the background. This reduces the link between the background of the study and the discussion. The rationale has been well placed.\nMethod\nIn the method, study design and setting, last statement “valid variable measurements were explained” is right. In statistical analysis: “If the data observed had a normal distribution, with p < .05,” misguides as the probability is for the test of normality. I hope it is for the correlation.\nResults\nWhy were the authors unable to transform the “data of duration of travel” to normal? “…we converted the variable into categorical with the following categories: 1. <15, 2. 15 to 30, and 3. > 30.” What was the logic in transforming the data into three categories? Did the author/s follow a standardized process to categorize? One-way ANOVA is not a bivariate analysis. It is comparative. Why did the authors refrain from saying that they did one-way ANOVA? ANOVA tells about the between-group differences. Why did the authors interpret it in terms of “relationship” instead of differences? The p-value definitely tells about the significance. An asterisk can represent it. But F is the real coefficient that represents ANOVA. Why did the authors not show the coefficient (F) in the explanation or the table? Authors have indicated that they have done the Spearman rank test. The coefficient for the Spearman rank test is not ‘r.’ It is ‘ρ’. Authors have already tested the difference in HDL, LDL, and triglycerides concerning the type of transportation and travel duration using ANOVA. Looks like redundant testing the correlation between them again. “However, the strength of the correlation between these variables was low.” In my opinion, if the correlation is significant, even if it is low, it indicates the relationship. A low correlation is not a “bad” correlation! Is Table 7 and its interpretation given to indicate the limitation of the study? After reading Table 7 and its interpretation, I doubt whether the reports from the study are reliable.\nDiscussion\nIs it because of the lack of sufficient samples that the cholesterol levels are lower in non-pedestrians? Authors have discussed that >50% of participants were pre-diabetic with a fasting glucose level >10%. Did the authors inform the participants (ethical concerns)? I feel that the discussion is half-baked. Request the authors to enhance the rigor of the discussion. Limitations are incomplete. There is scope to improve the clarity of the conclusion.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1179
|
https://f1000research.com/articles/9-624/v1
|
17 Jun 20
|
{
"type": "Research Article",
"title": "Convergent validity and reliability of a novel repeated agility protocol in junior rugby league players",
"authors": [
"Anthony Nicholls",
"Anthony Leicht",
"Jonathan Connor",
"Aaron Halliday",
"Kenji Doma",
"Anthony Nicholls",
"Anthony Leicht",
"Jonathan Connor",
"Aaron Halliday"
],
"abstract": "Background: Rugby league involves repeated, complex, change-of-direction movements, although there are no test protocols that specifically assesses these physical fitness profiles. Thus, the current study examined the convergent validity and reliability of a repeated Illinois Agility (RIA) protocol in adolescent Rugby League players. Methods: Twenty-two junior Rugby League players completed 4 sessions with each separated by 7 days. Initially, physical fitness characteristics at baseline (i.e., multi-stage fitness, countermovement jump, 30-m sprint, single-effort agility and repeated sprint ability [RSA]) were assessed. The second session involved a familiarisation of RIA and repeated T-agility test (RTT) protocols. During the third and fourth sessions, participants completed the RIA and RTT protocols in a randomised, counterbalanced design to examine the validity and test-retest reliability of these protocols. Results: For convergent validity, significant correlations were identified between RIA and RTT performances (r= >0.80; p<0.05). For contributors to RIA performance, significant correlations were identified between all baseline fitness characteristics and RIA (r = >0.71; p < 0.05). Reliability of the RIA protocol was near perfect with excellent intra-class correlation coefficient (0.87-0.97), good ratio limits of agreement (×/÷ 1.05-1.06) and low coefficient of variations (1.77-1.97%). Conclusions: The current study has demonstrated the RIA to be a simple, valid and reliable field test that can provide coaches with information about their athlete’s ability to sustain high intensity, multi-directional running efforts.",
"keywords": [
"Change of direction",
"anaerobic power",
"sprint",
"speed",
"recovery rate"
],
"content": "Introduction\n\nRugby League (RL) is an intermittent, invasion type game that requires players to complete repetitive bursts of sprinting and multi-directional movements in response to the dynamic constraints of the game1, typically referred to as ‘agility’ movements2. Traditionally, the physical component of agility has been assessed using change-of-direction routes with shorter time of completion considered a strong determinant of agility performance3. Some commonly used agility tests have included the Agility T-Test and the Illinois Agility test with both employed in many intermittent sports4. However, these two assessment protocols employ a single bout approach for the agility performance measure4,5. Athletes in RL encounter repeated bursts of change-of-direction movements to defend or evade defenders during a game6. Consequently, performance of repeated agility activities with brief periods of rest may be an important performance component necessary for RL athletes.\n\nAs a monitoring tool, the reliability of repeated agility protocols have been explored in a variety of sports7–9. Results from a study examining a Repeated T-Test (RTT) agility protocol in soccer players significantly correlated with anaerobic measures of power, speed and repeat-sprint ability (RSA), with excellent test-retest reliability9. While a good indicator of agility, the Agility T-Test consists of a linear sprint, lateral shuffles and a backwards run, which are movements that are sporadic in RL9. In fact, RL players change direction frequently and utilise evading movements5 that are not replicated by the Agility T-Test. Therefore, the Illinois Agility test may be more reflective of the evading activities undertaken in RL, as the protocol includes vigorous changes in direction by weaving in and out of cones4. As the validity and reliability of the Repeated Illinois Agility (RIA) test have yet to be determined, reporting these properties would be essential for widespread usability3.\n\nThe aims of this study were three-fold: 1) to examine the convergent validity of a novel RIA test with the repeated Agility T-test protocol (i.e. RTT); 2) to identify contributors of RIA performance by comparing its measures to speed, anaerobic capacity and recovery dynamics (i.e. RSA); and 3) to determine the test-retest reliability of the RIA protocol. It was hypothesised that the RIA would demonstrate acceptable convergent validity and reliability as a repeated agility test, with relationships identified between results of the RIA and the RTT, speed, and anaerobic capacity protocols. Identification of the convergent validity and reliability of the RIA will provide coaches with a tool to assist in monitoring and training RL athletes as well as in talent development and identification.\n\n\nMethods\n\nThe current study was a randomised, counter-balanced study conducted across five sessions from June, 2018 to August, 2018 (Figure 1). During the first session, the participants completed a Multistage Shuttle test to determine predicted maximal aerobic capacity (VO2max)10. The second session was utilised to obtain baseline assessments of speed (30-metre sprint), agility (Illinois Agility test, Agility T-Test) and repeat-sprint ability (RSA). The third session familiarised participants with the RTT and RIA tests. During the fourth and fifth sessions, participants undertook both the RIA and RTT, in randomised order, with at least 15-minutes of recovery between each protocol.\n\nAt the start of each session, muscle soreness rating was collected prior to performing a standardised warm up, using a 1-10 visual analogue scale, with 1 and 10 indicating ‘no soreness’ and ‘very, very sore’11. Participants then performed a progressive warm-up consisting of jogging for 3–5 minutes and 15-metre sprints at 50%, 70% and 100% of maximal effort. A countermovement jump (CMJ) test (Yard Stick, Swift Performance, Queensland, Australia) was then conducted to assess leg power12, which was also repeated before the second agility test to confirm recovery between the repeated agility tests.\n\nIn total, 22 adolescent, male, RL players (age 16.2 ± 0.8 yrs; body mass 80.7 ± 16.3 kg; height 1.77 ± 0.7 m) who engaged in the School of Athletic Excellence program were recruited via word of mouth, flyers and liaison with sporting teams. The participants were injury-free with at least 2 years of RL experience. According to an a priori calculation13, a sample size of 22 was sufficient to identify significant differences in repeated-agility performance (power of 80%, alpha level of 0.05). Participants were instructed to avoid strenuous physical activity and caffeine for up to 12 hours before each testing session. All protocols were approved by the Institutional Human Research Ethics Committee and written informed consent was received from the participants and their parents/guardians prior to partaking this study (Approval number H7248).\n\nFor the multistage shuttle test, participants ran back and forth in time with a series of audio signals on a 20m indoor court10. The time between audio signals progressively decreased during the test resulting in an increased effort and running speed for athletes each minute. Predicted VO2max was estimated using a previously developed regression equation10.\n\nThe countermovement jump protocol was measured with a vertical jump apparatus, based on 1 cm increments (Yard Stick, Swift Performance, Queensland, Australia). To ensure standardisation of the countermovement jump test, participants were instructed to draw their arms backwards upon the eccentric phase, then swing the arms forward during the concentric phase to gain momentum and maximise the stretch-shortening cycle mechanics14. The participants attempted three countermovement jumps, with approximately 30–60 seconds of rest in-between, and the highest jump reported.\n\nAssessment of speed was achieved by completing 30-m maximal sprints, the Agility T-test protocol was set up within a 10-m × 10-m figure-T course (Figure 2A), and the Illinois Agility protocol consisted of a 10m × 5m course (Figure 2B)3. To ensure protocol familiarity, the participants completed three trials at sub-maximal effort followed by one final maximal trial, with each trial interspersed by two minutes of recovery. Trial completion times were recorded using an electronic timing gate system (Speedlight Timing Gates, Swift Performance, Australia) positioned at the start/finishing line. The fastest time was used for later analysis.\n\nSchematic of A) T-Test Agility and B) Illinois Agility protocols.\n\nThe RSA, RTT and RIA protocols were completed by repeating the previously described protocols (i.e. 30-m sprint, T-test and Illinois Agility, respectively) across 6 cycles with varying recovery periods in-between each cycle. Specifically, each cycle within the RSA, RTT and RIA was separated by 20-, 35- and 60-second recovery, respectively, with work-to-rest ratios of approximately 1:38,9. Immediately after each repeated agility cycle, participant’s heart rate (HR, Polar Heart Rate Monitor, Polar H10, Finland) and maximum rating of perceived-exertion (RPE, Borg category scale 1–10) were then averaged across the 6 cycles for analysis15. The following parameters were also calculated for each repeated agility protocol: total time (TT) of 6 cycles, best cycle time (BT), the average cycle time (AT) and fatigue index (FI)8. FI was calculated as follows9:\n\n\n\nData was analysed using a statistical software (IBM SPSS version 25, Chicago, Illinois) and reported as mean ± standard deviation. Normality of the data was assessed using the Kolmogorov-Smirnov statistic. Convergent validity of the repeated agility protocols was identified via Pearson’s product moment correlation coefficients for RTT and RIA measures (i.e., TT, BT, AT and FI) and construct validity with aerobic capacity, leg power, speed and agility variables (i.e., VO2max, CMJ, 30-m sprint time, T-Test and Illinois Agility, respectively). The cut-off for acceptable convergent validity was established when the association was statistically significant with an r-value of ≥ 0.5016. Reliability of the repeated agility measures was determined via a paired T-test, intraclass correlation coefficients (ICC, SPSS 2-way mixed, 95% confidence intervals), coefficient of variation (CV, 95% confidence intervals) and systematic bias/ratio with 95% limits of agreement (LOA)17. Where significant relationships existed between the mean difference and average of test-retest values (i.e. heteroscedastic errors), variables were transformed (natural logarithm) prior to the calculation of measurement bias/ratio × / ÷ ratio LOA18. The level of significance for all analyses was set at 0.05. Finally, effect size (Cohen’s d) with 95% CI was used to calculate the magnitude of differences in muscle soreness and CMJ measures between RIA and RTT protocols to determine whether the recovery periods were appropriate. The ES classifications were set as small, moderate and large with values of 0.2, 0.5 and 0.8, respectively (Cohen, 1988).\n\n\nResults\n\nFor convergent validity, significant correlations were identified between RIA and most RTT variables (Table 119). For contributors to RIA performance, significant correlations were identified with RSA, 30-m sprint time, best effort agility measures, aerobic capacity and CMJ (Table 219).\n\nTT = total time; BT = best time; AT = average time; FI = fatigue index\n\n*P<0.05 **P<0.01 ***P<0.001\n\nCMJ = countermovement jump; TT= total time; BT = best time; AT = average time; FI = fatigue index ; Sprint 30m = 30 metre sprint; IA = Illinois Agility test; TTA = T-test agility; VO2max = maximal aerobic capacity , RPEAvg= Average Rate of Perceived Exertion, RPEMax = Maximum Rate of Perceived Exertion, HRAvg= Heart rate average, HRMax = Maximum heart rate *P<0.05 **P<0.01 ***P<0.001\n\nMuscle soreness ratings between the third (2.0 ± 1.5) and fourth (2.6 ± 1.7) were not significantly different (p = 0.10), with a small ES (0.37). Jump height prior to each repeated agility protocol remained unchanged between the first and second CMJ tests in the third (43.8cm ± 8.7cm and 45.4cm ± 8.4cm, respectively, p = 0.09) and fourth (44.1cm ± 9.3cm and 44.0cm ± 8.6cm, respectively, p=0.80) session, also with small ES (0.19 and 0.01, respectively).\n\nAll RIA measures were similar between sessions except for FI and maximum RPE (Table 319). Most RIA performance measures exhibited excellent test-retest reliability (ICC = 0.92–0.97), good levels of agreement (ratio LOA = 1.05–1.06) and low measurement error (CV = 2.17–2.68%, Table 319). However, FI and average RPE demonstrated moderate test-retest reliability (ICC = 0.87 and 0.76, respectively), poorer levels of agreement (ratio LOA = 2.57 and 2.23, respectively) and higher measurement error (CV = 25.3 and 15.8%, respectively, Table 319).\n\nTT= total time; BT = best time; AT = average time; FI = fatigue index, RPEAvg = Average Rate of Perceived Exertion, RPEMax = Maximum Rate of Perceived Exertion, HRAvg = Heart rate average, HRMax = Maximum heart rate P<0.05 **P<0.01 *** P<0.001\n\n† Significantly different (p<0.05)\n\nFor the RTT, excellent test-retest reliability (ICC = 0.91), good levels of agreement (ratio LOA = 1.08) and low measurement error (CV = 2.17–2.68%) were identified for a few variables (Table 319). However, high test-retest reliability (ICC = 0.93), lower levels of agreement (ratio LOA = 1.78) and higher levels of measurement error (CV = 12.3%) were observed for maximum RPE (Table 319). In addition, FI, average RPE and maximum HR displayed moderate to large reliability (ICC = 0.69 – 0.89), poorer agreement (ratio LOA = 1.10 – 2.59) and higher measurement error (CV = 2.38 – 27.6%) compared to the RIA protocol (Table 319).\n\n\nDiscussion\n\nThe current findings demonstrated strong correlations between the RIA and RTT protocols, specifically the BT, TT and AT measures. These results highlight that most time-derived measures (i.e., BT, TT and AT measures) of the RIA are replicable to a previously established repeated agility protocol, but with movement demands more representative of RL. In addition, the TT and BT of the RIA was strongly associated with the TT and BT of the RSA, indicating that the ability to maintain linear speed would result in superior performances in the RIA protocol, possibly due to similar metabolic demands7. Comparable findings were reported by Fessi, Makni9, with strong correlations identified between the BT and TT of their repeated agility protocol and RSA protocols in 45 team-sport athletes. Collectively, our results and others7,9, suggest that performance of repeated agility relies heavily upon the anaerobic system, a metabolic pathway predominant in RL20.\n\nThe current study also identified strong test-retest reliability for time-derived measures (i.e., BT, TT and AT) of the RIA, with minimal measurement error. However, the measurement error was substantially higher for FI, confirming previous studies that reported substantially stronger reliability measures for BT, TT and AT compared to that of FI from various repeated agility protocols7,8,21. It has been suggested that FI may exhibit weaker reproducibility as the measure is multifactorial and dependent on the stability of other variables (i.e., TT and BT)7,22. Subsequently, we, and others7,8,21,22, recommend that time-derived measures be primarily evaluated during repeated agility protocols.\n\nAnother novelty of the current study was the reliability of the psychophysiological responses during both RIA and RTT protocols. The test-retest reliability values for HR and RPE ranged between questionable-to-excellent classifications according to ICC scores for both RIA and RTT. However, distinctly greater measurement error and bias was observed for RPE when compared to HR measures for both RIA and RTT. These findings were similar to previous studies with poorer reliability for RPE than HR measures during various running protocols23–25. It has been postulated that HR has better stability across days given that it is an objective measure, compared to the highly subjective RPE26. It has also been reported that participant’s prior knowledge of the number of sprints during repeated sprint-type protocols may affect results due to pacing27. Accordingly, HR measures may be a better physiological indicator for monitoring exercise-induced stress during repeated agility protocols.\n\nAn additional, yet essential finding of this study was the relationship between baseline characteristics and performances measures from the repeated agility tests. Measures of CMJ, best-effort speed and best-effort agility correlated significantly with the time-derived variables of the RIA. These relationships indicated that lower limb power, linear speed and change-of-direction capabilities were contributing factors to successful repeated agility performances and key attributes needed for RL athletes28. Our findings aligned with those of Haj-Sassi, Dardouri8, who reported strong correlations between measures of jump performance and repeated agility performance with an Agility T-test protocol. These authors suggested that larger jumping performances reflected athlete’s superior ability to generate force into the ground and therefore a significantly greater change-of-direction ability8. The significance of this finding attests to lower limb power production being a critical component of repeated agility performance, especially within the RIA.\n\nFinally, the current study identified significant correlations between VO2max and RIA performance measures. These findings are similar to previous studies using various repeated agility protocols21,22 as well as RSA protocols29–31. Measures of VO2max has been considered essential for repeated-sprint type protocols, due to muscular reoxygenation rate8,32, optimal capacity to remove and buffer hydrogen ions within working muscles33 and efficiently replenish phosphagen stores34. The findings of the present study suggest that aerobic capacity is a strong contributor to superior repeated agility efforts, further highlighting the need to optimise recovery capacities between high-intensity bouts for RL athletes.\n\nIn conclusion, the RIA protocol exhibited moderate-to-excellent test-retest reliability and low measurement error for the majority of time-derived measures and psychophysiological measures, and questionable reliability for FI. Further, this study has clearly demonstrated that repeated agility performances rely upon contributions from both anaerobic and aerobic systems with the RIA, demonstrating that the qualities required for optimal RIA performance may be representative of the physical demands in RL. The RIA protocol may provide practitioners with a simple, yet effective monitoring tool to quantify athlete’s ability to generate and sustain multi-directional efforts, and their ability to recover during intermittent activities.\n\n\nData availability\n\nJames Cook University Research Data: Convergent validity and reliability of a novel repeated agility protocol in junior rugby league players. https://doi.org/10.25903/5eb0f568fad2019\n\nThis project contains the following underlying data:\n\n- Raw_data_De-identified.xlsx (Agility protocol data in excel format)\n\n- Raw_data_De-identified.ods (Agility protocol data in ods format)\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nAustin DJ, Gabbett T, Jenkins DJ: Repeated high-intensity exercise in a professional rugby league. J Strength Cond Res. 2011; 25(7): 1898–1904. PubMed Abstract | Publisher Full Text\n\nNimphius S, Callaghan SJ, Bezodis NE, et al.: Change of direction and agility tests: Challenging our current measures of performance. Strength Cond J. 2018; 40(1): 26–38. Publisher Full Text\n\nRaya MA, Gailey RS, Gaunaurd IA, et al.: Comparison of three agility tests with male servicemembers: Edgren Side Step Test, T-Test, and Illinois Agility Test. J Rehabil Res Dev. 2013; 50(7): 951–960. PubMed Abstract | Publisher Full Text\n\nDurandt J, du Toit S, Borresen J, et al.: Fitness and body composition profiling of elite junior South African rugby players. South Afr J Sports Med. 2006; 18(2): 38–45. Publisher Full Text\n\nWheeler K: Agility skill execution in rugby union. In: Faculty of Science, Health and Education. University of Sunshine Coast. 2010. Reference Source\n\nKing T, Jenkins D, Gabbett T: A time-motion analysis of professional rugby league match-play. J Sports Sci. 2009; 27(3): 213–219. PubMed Abstract | Publisher Full Text\n\nWong DP, Chan GS, Smith AW: Repeated-sprint and change-of-direction abilities in physically active individuals and soccer players: Training and testing implications. J Strength Cond Res. 2012; 26(9): 2324–2330. PubMed Abstract | Publisher Full Text\n\nHaj-Sassi R, Dardouri W, Gharbi Z, et al.: Reliability and validity of a new repeated agility test as a measure of anaerobic and explosive power. J Strength Cond Res. 2011; 25(2): 472–480. PubMed Abstract | Publisher Full Text\n\nFessi MS, Makni E, Elloumi M, et al.: Reliability and criterion-related validity of a new repeated agility test. Biol Sport. 2016; 33(2): 159–164. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRamsbottom R, Brewer J, Williams C: A progressive shuttle run test to estimate maximal oxygen uptake. Br J Sports Med. 1988; 22(4): 141–144. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoma K, Nicholls A, Gahreman D, et al.: The effect of a resistance training session on physiological and thermoregulatory measures of sub-maximal running performance in the heat in heat-acclimatized men. Sports Med Open. 2019; 5(1): 21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoma K, Schumann M, Leicht AS, et al.: The repeated bout effect of traditional resistance exercises on running performance across 3 bouts. Appl Physiol Nutr Metab. 2017; 42(9): 978–985. PubMed Abstract | Publisher Full Text\n\nRamírez-Campillo R, Meylan C, Alvarez C, et al.: Effects of in-season low-volume high-intensity plyometric training on explosive actions and endurance of young soccer players. J Strength Cond Res. 2014; 28(5): 1335–42. PubMed Abstract | Publisher Full Text\n\nDoma K, Schumann M, Sinclair WH, et al.: The repeated bout effect of typical lower body strength training sessions on sub-maximal running performance and hormonal response. Eur J Appl Physiol. 2015; 115(8): 1789–99. PubMed Abstract | Publisher Full Text\n\nZamunér AR, Moreno MA, Camargo TM, et al.: Assessment of subjective perceived exertion at the anaerobic threshold with the borg CR-10 scale. J Sports Sci Med. 2011; 10(1): 130–6. PubMed Abstract | Free Full Text\n\nCordier R, Chen YW, Speyer R, et al.: Child-report measures of occupational performance: a systematic review. PLoS One. 2016; 11(1): e0147751. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLeicht AS, Sealey RM, Sinclair WH: The reliability of VO2(peak) determination in healthy females during an incremental arm ergometry test. Int J Sports Med. 2009; 30(7): 509–15. PubMed Abstract | Publisher Full Text\n\nNevill AM, Atkinson G: Assessing agreement between measurements recorded on a ratio scale in sports medicine and sports science. Br J Sports Med. 1997; 31(4): 314–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoma K: Convergent validity and reliability of a novel repeated agility protocol in junior rugby league players. James Cook University. (dataset). 2020; 89b303814f7501cfee8dd987fb606ad5.\n\nGabbett TJ: Physiological and anthropometric characteristics of junior rugby league players over a competitive season. J Strength Cond Res. 2005; 19(4): 764–771. PubMed Abstract | Publisher Full Text\n\nZagatto AM, Ardigò LP, Barbieri FA, et al.: Performance and metabolic demand of a new repeated-sprint ability test in basketball players: does the number of changes of direction matter? J Strength Cond Res. 2017; 31(9): 2438–2446. PubMed Abstract | Publisher Full Text\n\nDaneshfar A, Gahreman DE, Koozehchian MS, et al.: Multi directional repeated sprint is a valid and reliable test for assessment of junior handball players. Front Physiol. 2018; 9(1): 317. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoma K, Deakin GB, Leicht AS, et al.: The reliability of running economy among trained distance runners and field-based players. J Exerc Sci Phys Fit. 2012; 10(2): 90–96. Publisher Full Text\n\nLamb KL, Eston RG, Corns D: Reliability of ratings of perceived exertion during progressive treadmill exercise. Br J Sports Med. 1999; 33(5): 336–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nScott TJ, Black CR, Quinn J, et al.: Validity and reliability of the session-RPE method for quantifying training in Australian football: a comparison of the CR10 and CR100 scales. J Strength Cond Res. 2013; 27(1): 270–6. PubMed Abstract | Publisher Full Text\n\nVera J, Perales JC, Jiménez R, et al.: A test-retest assessment of the effects of mental load on ratings of affect, arousal and perceived exertion during submaximal cycling. J Sports Sci. 2018; 36(22): 2521–2530. PubMed Abstract | Publisher Full Text\n\nBillaut F, Bishop DJ, Schaerz S, et al.: Influence of knowledge of sprint number on pacing during repeated-sprint exercise. Med Sci Sport Exerc. 2011; 43(4): 665–672. PubMed Abstract | Publisher Full Text\n\nHoffman JR, Epstein S, Einbinder M, et al.: A comparison between the wingate anaerobic power test to both vertical jump and line drill tests in basketball players. J Strength Cond Res. 2000; 14(3): 261–264. Publisher Full Text\n\nBishop D, Edge J: Determinants of repeated-sprint ability in females matched for single-sprint performance. Eur J Appl Physiol. 2006; 97(4): 373–9. PubMed Abstract | Publisher Full Text\n\nGharbi Z, Dardouri W, Haj-Sassi R, et al.: Aerobic and anaerobic determinants of repeated sprint ability in team sports athletes. Biol Sport. 2015; 32(3): 207–12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGlaister M: Multiple sprint work: physiological responses, mechanisms of fatigue and the influence of aerobic fitness. Sports Med. 2005; 35(9): 757–77. PubMed Abstract | Publisher Full Text\n\nBuchheit M, Ufland P: Effect of endurance training on performance and muscle reoxygenation rate during repeated-sprint running. Eur J Appl Physiol. 2011; 111(2): 293–301. PubMed Abstract | Publisher Full Text\n\nSahlin K, Henriksson J: Buffer capacity and lactate accumulation in skeletal muscle of trained and untrained men. Acta Physiol Scand. 1984; 122(3): 331–9. PubMed Abstract | Publisher Full Text\n\nBogdanis GC, Nevill ME, Boobis LH, et al.: Contribution of phosphocreatine and aerobic metabolism to energy supply during repeated sprint exercise. J Appl Physiol (1985). 1996; 80(3): 876–84. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "74005",
"date": "09 Nov 2020",
"name": "James Dugdale",
"expertise": [
"Reviewer Expertise Fitness testing",
"youth athletes",
"talent identification",
"talent development",
"physical performance",
"strength and conditioning"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe present study aimed to explore the validity and reliability of repeated “agility” tests in a sample of youth rugby players. The study provides interesting data for an applied audience and is methodologically sound and accurate in the presentation of findings. This being said, I have identified a range of areas that should be improved prior to potential resubmissions of this manuscript. For example, the introduction (and study in its entirety) is inaccurate in its use of the term “agility” (opposed to COD which the authors actually assess). Furthermore, the introduction needs to be further developed to support the scope of the study. The authors need to create more of a rationale for running such a large number of correlations – exploring correlational analyses needs to be warranted based upon an assumption of a relationship (or lack thereof) between variables. In its current form, I am unsure whether this manuscript provides such rationale. The methods and results are accurate, but with a large number of small errors. Finally, the discussion addresses key discussion points formulated from the findings of the study, but similar to the introduction, lacks some critical depth.\nI do think that the authors have a publishable study here, however, a number of revisions will be required before I would be happy to approve this manuscript for indexing. I hope that my comments are received as I intend them and are useful in further strengthening this manuscript. I hope to receive the opportunity to review this manuscript again in its revised form.\nAbstract The abstract is concise and accurate to the details of the study. I have just a couple of minor comments (below): The initial sentence is accurate and outlines the requirement of the study. However, I would encourage the authors to insert a word such as ‘simultaneously’ or ‘congruently’, or attempt to capture the lack of a suitable test to capture the performance of these abilities in combination. Abstract Methods – the inclusion of the repeated T-agility test appears suddenly with no prior reference. If this is a key concentration of your study, I would encourage to insert earlier in the abstract along with the RIA. Abstract Results – please specify exact p values rather than just <0.05. CV% can be presented to 1dp for brevity.\nIntroduction The introduction is short and concise. However, I feel some key information that would further support the rationale for your study has been omitted. I would encourage the authors to further develop this section. A suggestion would be to expand the second paragraph into two: the first discussing the validity aspects, the second the reliability aspects. I do not expect these changes to be too onerous, but believe it would strengthen this section of your manuscript if you were to implement these changes. I have some further specific comments below. The opening sentence would read better if it were split into two separate sentences. The authors should attempt to clarify during opening paragraph that they are discussing change of direction (COD) performance, rather than agility. Although COD performance is a key component of agility performance, the lack of an external stimuli prevents classification of agility. Although the tests identified by the authors in this opening paragraph have titled themselves ‘agility’ tests, by definition they are not. The authors should be careful in their stance here as the literature has evolved substantially since the inception of tests such as these, and appropriate classification and terminology is essential for the present study. Young, W.;\n\nDawson, B.;\n\nHenry, G. Agility and Change-of-Direction Speed are Independent Skills: Implications for Agility in Invasion Sports. Int. J. Sports Sci. Coach. 2015, 10, 159–169.1 Nimphius, S.;\n\nCallaghan, S.J.;\n\nBezodis, N.E.;\n\nLockie, R.G. Change of Direction and Agility Tests: Challenging Our Current Measures of Performance. Strength Cond. J. 2018, 40, 26–38. 2 Sheppard, J.M.; Young, W.B. Agility literature review: Classifications, training and testing. J. Sports Sci. 2006, 24, 919–932.3 Regarding the reliability aspect of the study, two recent papers have suggested that reliability of COD and agility may be lower in adolescent and youth athletes (as per your sample). Although these authors observed this during maximal COD/agility performance, opposed to repeated as in the present study, I believe this would be worth including and would further warrant the exploration of your research question and study. Taylor, J.M.; Cunningham, L.; Hood, P.; Thorne, B.; Irvin, G.; Weston, M. The reliability of a modified 505 test and change-of-direction deficit time in elite youth football players. Sci. Med. Footb. 2019, 3, 157–162.4 Dugdale JH, Sanders D, Hunter AM. Reliability of Change of Direction and Agility Assessments in Youth Soccer Players. Sports (Basel). 2020 Apr 18; 8 (4): 51. doi: 10.3390/sports8040051.5 James H. Dugdale, Calum A. Arthur, Dajo Sanders & Angus M. Hunter (2019) Reliability and validity of field-based fitness tests in youth soccer players, European Journal of Sport Science, 19:6, 745-756, DOI: 10.1080/17461391.2018.15567396\nMethods The methods report the appropriate details relating to the study design, protocols, participants, and analyses performed. However, further clarity is required in a few places throughout this section (specific comments below). Further, there are a number of oversights throughout this section that require careful attention. None of these are major points, and should take little time to amend. Yet, need to be addressed prior to potential resubmissions of this manuscript. Figure 1: I am unsure how much this figure aids the interpretation of the study design. I personally do not feel the visual nature of this schematic clarifies the description of the trials from the text, as the study is relatively simplistic. I do not insist that the authors remove this figure, however, please consider my suggestion that it may not add value to the manuscript and may just be a “figure for the sake of a figure”. Secondly, between the trials, the authors have stated that washout periods of > 7 days were implemented. The authors should consider including the range of days (e.g. 7-14 days), as this would provide further information to the reader and allow for more accurate interpretation of the results. Can a citation or elaboration be provided to rationalise the >15 min rest interval between attempts? The term ‘respectively’ needs to be included after the explanation of the 1-10 muscle rating scale. Also, a brief sentence as to why this was collected should accompany this methodological point. The authors state that the warm up was the same prior to each session. I would encourage using the term ‘standardised’ when describing this in their methods to add certainty around their controls. Also, a citation needs to accompany the statement that the CMJ test was implemented to assess recovery. If this is what was intended by the insertion of citation 12, I would encourage moving this citation to the end of the sentence. Participant details – participant height needs to be reported to 2dp. Can the authors further elaborate on what the “School of Athletic Excellence” is? For example, what standard is this, is it affiliated to a specific school, or region performance programme? This may not be clear to readers. Multistage shuttle test – a brief sentence stating how performance or a score was derived is necessary (i.e. maximum number of shuttles completed, level, etc.). This information is currently not evident. CMJ – please state the unit of measurement for this test, and to what degree (e.g. recorded in cm to the nearest 0.1cm). 30-m sprint and agility protocols – please separate each test into a separate sentence. At present, they appear too cramped together and it is difficult to read (particularly with reference to figures and citations within). Also, please provide citations for the original studies for the T-drill and Illinois agility tests. These need to be credited within the manuscript. Repeated sprint and agility protocols – were these tests performed one after the other (what I interpret from the term ‘cycles’) or were they performed independently? Clarity is required to ensure the reader understands which of these interpretations is correct. The sentence starting “Immediately after each repeated agility cycle…” does not make sense. Please rephrase this. Statistical analysis – Reference 16 seems a weak reference for this point. I encourage the authors to consider a more suitable citation for selecting this acceptable correlation cut off point.\nResults The section of the results dedicated to the muscle soreness and CMJ differences (or lack thereof) should be condensed to a singular sentence and placed at the foot of the results section. This is a methodological control and not a key finding from your study, therefore, it should not feature so early and heavily within your results section. Stating that there were no differences, providing ES, and significance values would suffice. Table 3 – I am interested in your rationale for not providing ES to demonstrate differences (or lack thereof) for your test-retest data? This would add value in my opinion. I would also encourage the authors to present CV% data to 1dp both within this table and throughout the manuscript. I notice that the authors use terminology such as “excellent” or “moderate” test-retest reliability, yet they have not included these threshold within the statistical analysis section of the methods. Please include this detail so that the reader understands your criteria. I also note that the authors say “most RIA performance measures exhibited excellent test-retest reliability…”. Could the authors rephrase this to say “all RIA performance measures except… measures exhibited excellent test-retest reliability”? This would be more accurate and less ambiguous for the reader. This comment also applies later in this section where the authors refer to “a few variables…”.\nDiscussion I found the discussion well-written and thought the authors accurately interpreted and attempted to explain their findings. However, similar to the introduction, I felt this section lacked depth when discussing the main findings of the study. I encourage the authors to discuss their findings in greater depth, utilising some of the reading attached to this review. I encourage the authors to utilise the first paragraph of the discussion to summarise all of their main findings, and then progress to discussing each point in turn. The third paragraph begins “another novelty of this study”, yet this appears to be the first time novelty is addressed in the discussion? The fourth paragraph can draw upon a wealth of correlational studies to further support the findings observed here. Young WB, Dawson B, Henry GJ. Agility and Change-of-Direction Speed are Independent Skills: Implications for Training for Agility in Invasion Sports. International Journal of Sports Science & Coaching. 2015;10(1):159-169. doi:10.1260/1747-9541.10.1.1591 Spiteri T, Nimphius S, Hart NH, Specos C, Sheppard JM, Newton RU. Contribution of strength characteristics to change of direction and agility performance in female basketball athletes. J Strength Cond Res. 2014 Sep;28(9):2415-23. doi: 10.1519/JSC.0000000000000547. PMID: 24875426.7 Gabbett, T. J., Kelly, J. N., & Sheppard, J. M. (2008). Speed, Change of Direction Speed, and Reactive Agility of Rugby League Players. The Journal of Strength & Conditioning Research, 22, 174-181. http://dx.doi.org/10.1519/JSC.0b013e31815ef7008 Sheppard, J.M.; Young, W.B.; Doyle, T.L.A.; Sheppard, T.A.; Newton, R.U. An evaluation of a new test of reactive agility and its relationship to sprint speed and change of direction speed. J. Sci Med. Sport 2006, 9, 342–349.9 The conclusion should be reframed around the key objectives of the study (i.e. that it is reliable and valid). The mention of aerobic and anaerobic energy systems seems misplaced here.\nReferences While a variety of key texts are identified and listed within the bibliography and cited throughout the manuscript, a number of key texts are omitted. I encourage the authors to further familiarise themselves with relevant studies assessing reliability and validity of COD and agility in team sport athletes, as well as the texts identified earlier within this review. Dos’Santos, T.; Thomas, C.; Jones, P.A.; Comfort, P. Mechanical Determinants of Faster Change of Direction Speed Performance in Male Athletes. J. Strength Cond. Res. 2017, 31, 696–705.10 Gabbett, T.J.; Kelly, J.N.; Sheppard, J.M. Speed, change of direction speed, and reactive agility of rugby league players. J. Strength Cond. Res. 2008, 22, 174–181.8 Oliver, J.L.; Meyers, R.W. Reliability and generality of measures of acceleration, planned agility, and reactive agility. Int. J. Sports Physiol. Perform. 2009, 4, 345–354.11\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": "7210",
"date": "08 Oct 2021",
"name": "Kenji Doma",
"role": "Author Response",
"response": "Reviewer’s comment: The present study aimed to explore the validity and reliability of repeated “agility” tests in a sample of youth rugby players. The study provides interesting data for an applied audience and is methodologically sound and accurate in the presentation of findings. This being said, I have identified a range of areas that should be improved prior to potential resubmissions of this manuscript. For example, the introduction (and study in its entirety) is inaccurate in its use of the term “agility” (opposed to COD which the authors actually assess). Furthermore, the introduction needs to be further developed to support the scope of the study. The authors need to create more of a rationale for running such a large number of correlations – exploring correlational analyses needs to be warranted based upon an assumption of a relationship (or lack thereof) between variables. In its current form, I am unsure whether this manuscript provides such rationale. The methods and results are accurate, but with a large number of small errors. Finally, the discussion addresses key discussion points formulated from the findings of the study, but similar to the introduction, lacks some critical depth. I do think that the authors have a publishable study here, however, a number of revisions will be required before I would be happy to approve this manuscript for indexing. I hope that my comments are received as I intend them and are useful in further strengthening this manuscript. I hope to receive the opportunity to review this manuscript again in its revised form. Author’s response: Dear reviewer, thank you for your comments on the paper. We agree that your comments have improved the quality of our work. Abstract Reviewer’s comment: The abstract is concise and accurate to the details of the study. I have just a couple of minor comments (below): The initial sentence is accurate and outlines the requirement of the study. However, I would encourage the authors to insert a word such as ‘simultaneously’ or ‘congruently’, or attempt to capture the lack of a suitable test to capture the performance of these abilities in combination. Author’s response: The word ‘simultaneously’ has been included. Reviewer’s comment: Abstract Methods – the inclusion of the repeated T-agility test appears suddenly with no prior reference. If this is a key concentration of your study, I would encourage to insert earlier in the abstract along with the RIA. Author’s response: Repeated T-agility protocol now mentioned in the Background. Reviewer’s comment: Abstract Results – please specify exact p values rather than just <0.05. CV% can be presented to 1dp for brevity. Author’s response: We were unable to provide exact p-values, as several outcome measures from the repeated COD protocols, such as average time, best time, total time etc were presented as “performances”. This same approach was used for the r-values as well to ensure the word limit did not exceed journal guidelines. However, we did present the CV% to 1dp as requested. Introduction Reviewer’s comment: The introduction is short and concise. However, I feel some key information that would further support the rationale for your study has been omitted. I would encourage the authors to further develop this section. A suggestion would be to expand the second paragraph into two: the first discussing the validity aspects, the second the reliability aspects. I do not expect these changes to be too onerous, but believe it would strengthen this section of your manuscript if you were to implement these changes. I have some further specific comments below. Author’s response: The second paragraph has been further developed into two as requested, with the first focusing on reliability and the second on validity. Reviewer’s comment: The opening sentence would read better if it were split into two separate sentences. Author’s response: We have simplified the first sentence by removing the context of ‘agility’, as we have converted all ‘agility’ terms to ‘change-of-direction’. Reviewer’s comment: The authors should attempt to clarify during opening paragraph that they are discussing change of direction (COD) performance, rather than agility. Although COD performance is a key component of agility performance, the lack of an external stimuli prevents classification of agility. Although the tests identified by the authors in this opening paragraph have titled themselves ‘agility’ tests, by definition they are not. The authors should be careful in their stance here as the literature has evolved substantially since the inception of tests such as these, and appropriate classification and terminology is essential for the present study. Young, W.; Dawson, B.; Henry, G. Agility and Change-of-Direction Speed are Independent Skills: Implications for Agility in Invasion Sports. Int. J. Sports Sci. Coach. 2015, 10, 159–169.1 Nimphius, S.; Callaghan, S.J.; Bezodis, N.E.; Lockie, R.G. Change of Direction and Agility Tests: Challenging Our Current Measures of Performance. Strength Cond. J. 2018, 40, 26–38. 2 Sheppard, J.M.; Young, W.B. Agility literature review: Classifications, training and testing. J. Sports Sci. 2006, 24, 919–932.3 Author’s response: Thank you for your suggestion. As mentioned earlier, we have changed all ‘agility’ terms into ‘change-of-direction’. Reviewer’s comment: Regarding the reliability aspect of the study, two recent papers have suggested that reliability of COD and agility may be lower in adolescent and youth athletes (as per your sample). Although these authors observed this during maximal COD/agility performance, opposed to repeated as in the present study, I believe this would be worth including and would further warrant the exploration of your research question and study. Taylor, J.M.; Cunningham, L.; Hood, P.; Thorne, B.; Irvin, G.; Weston, M. The reliability of a modified 505 test and change-of-direction deficit time in elite youth football players. Sci. Med. Footb. 2019, 3, 157–162.4 Dugdale JH, Sanders D, Hunter AM. Reliability of Change of Direction and Agility Assessments in Youth Soccer Players. Sports (Basel). 2020 Apr 18; 8 (4): 51. doi: 10.3390/sports8040051.5 James H. Dugdale, Calum A. Arthur, Dajo Sanders & Angus M. Hunter (2019) Reliability and validity of field-based fitness tests in youth soccer players, European Journal of Sport Science, 19:6, 745-756, DOI: 10.1080/17461391.2018.15567396 Author’s response: Thank you for your suggestion, we have included the references above in the paragraph explaining studies on the reliability of COD protocols. Methods Reviewer’s comment: The methods report the appropriate details relating to the study design, protocols, participants, and analyses performed. However, further clarity is required in a few places throughout this section (specific comments below). Further, there are a number of oversights throughout this section that require careful attention. None of these are major points, and should take little time to amend. Yet, need to be addressed prior to potential resubmissions of this manuscript. Author’s response: Thank you for your comments, we have addressed these below. Reviewer’s comment: Figure 1: I am unsure how much this figure aids the interpretation of the study design. I personally do not feel the visual nature of this schematic clarifies the description of the trials from the text, as the study is relatively simplistic. I do not insist that the authors remove this figure, however, please consider my suggestion that it may not add value to the manuscript and may just be a “figure for the sake of a figure”. Secondly, between the trials, the authors have stated that washout periods of > 7 days were implemented. The authors should consider including the range of days (e.g. 7-14 days), as this would provide further information to the reader and allow for more accurate interpretation of the results. Author’s response: Thank you for your comment. We have decided to keep the figure to ensure clarity as we used a cross-over randomized design, which is unusual for a study examining the reliability and validity of protocols. We have included 7-14 days as a washout period as suggested in the figure. Reviewer’s comment: Can a citation or elaboration be provided to rationalise the >15 min rest interval between attempts? Author’s response: A citation has been included with a study that used a 15-minute recovery period in-between repeated sprint and COD protocols in the one testing session. Reviewer’s comment: The term ‘respectively’ needs to be included after the explanation of the 1-10 muscle rating scale. Also, a brief sentence as to why this was collected should accompany this methodological point. Author’s response: Included as requested. Reviewer’s comment: The authors state that the warm up was the same prior to each session. I would encourage using the term ‘standardised’ when describing this in their methods to add certainty around their controls. Also, a citation needs to accompany the statement that the CMJ test was implemented to assess recovery. If this is what was intended by the insertion of citation 12, I would encourage moving this citation to the end of the sentence. Author’s response: The term ‘standardised’ has been included when describing the warm-up as requested in the Methods section. The citation explaining the use of CMJ to determine recovery dynamics was moved to the end of the sentence as requested. Reviewer’s comment: Participant details – participant height needs to be reported to 2dp. Can the authors further elaborate on what the “School of Athletic Excellence” is? For example, what standard is this, is it affiliated to a specific school, or region performance programme? This may not be clear to readers. Author’s response: The participant height is reported to 2dp (1.77m). Further information on the excellence program has been included. Reviewer’s comment: Multistage shuttle test – a brief sentence stating how performance or a score was derived is necessary (i.e. maximum number of shuttles completed, level, etc.). This information is currently not evident. Author’s response: The VO2max was estimated based on the level completed, which has now been included in the Methods section. Reviewer’s comment: CMJ – please state the unit of measurement for this test, and to what degree (e.g. recorded in cm to the nearest 0.1cm). Author’s response: The CMJ was recorded to the full cm, not to the nearest 0.1cm. This has now been clarified. Reviewer’s comment: 30-m sprint and agility protocols – please separate each test into a separate sentence. At present, they appear too cramped together and it is difficult to read (particularly with reference to figures and citations within). Also, please provide citations for the original studies for the T-drill and Illinois agility tests. These need to be credited within the manuscript. Author’s response: The sentences for the description of the protocols have been separated as requested. The original studies have also been included as requested. Reviewer’s comment: Repeated sprint and agility protocols – were these tests performed one after the other (what I interpret from the term ‘cycles’) or were they performed independently? Clarity is required to ensure the reader understands which of these interpretations is correct. Author’s response: We have reworded the term ‘cycles’ to ‘repetitions’ to improve clarity. As mentioned in Research Design and in Figure 1, RSA was conducted in Session 2, whilst RTT and RIA were conducted in the same session with 15-min rest in-between each protocol. The Figure reinforces this design, and rewording ‘cycles’ to ‘repetitions’ improves the clarity of the protocols. Reviewer’s comment: The sentence starting “Immediately after each repeated agility cycle…” does not make sense. Please rephrase this. Author’s response: This has been reworded to, “The participant’s heart rate (HR, Polar Heart Rate Monitor, Polar H10, Finland) and rating of perceived-exertion (RPE, Borg category scale 1-10) were collected at the completion of each repetition of the RSA, RTT and RIA protocols. The maximum and average HR and RPE values were then reported from the 6 repetitions” Reviewer’s comment: Statistical analysis – Reference 16 seems a weak reference for this point. I encourage the authors to consider a more suitable citation for selecting this acceptable correlation cut off point. Author’s response: Additional reference included as requested. Results Reviewer’s comment: The section of the results dedicated to the muscle soreness and CMJ differences (or lack thereof) should be condensed to a singular sentence and placed at the foot of the results section. This is a methodological control and not a key finding from your study, therefore, it should not feature so early and heavily within your results section. Stating that there were no differences, providing ES, and significance values would suffice. Author’s response: Simplified and included at the end of the Results section as requested. Reviewer’s comment: Table 3 – I am interested in your rationale for not providing ES to demonstrate differences (or lack thereof) for your test-retest data? This would add value in my opinion. I would also encourage the authors to present CV% data to 1dp both within this table and throughout the manuscript. Author’s response: Thank you for your comment. The ES was not reported as we based the measurement error on CV, with larger CV% values exhibiting greater measurement error and poorer test-retest reliability. In our opinion, inclusion of ES would not provide any further clarity about the reliability of the tests, beyond that of CV. Reviewer’s comment: I notice that the authors use terminology such as “excellent” or “moderate” test-retest reliability, yet they have not included these threshold within the statistical analysis section of the methods. Please include this detail so that the reader understands your criteria. Author’s response: Included as requested. Reviewer’s comment: I also note that the authors say “most RIA performance measures exhibited excellent test-retest reliability…”. Could the authors rephrase this to say “all RIA performance measures except… measures exhibited excellent test-retest reliability”? This would be more accurate and less ambiguous for the reader. This comment also applies later in this section where the authors refer to “a few variables…”. Author’s response: Thank you for your suggestion. We have reworded this to, “Most RIA measures exhibited excellent test-retest reliability (ICC = 0.92-0.97), good levels of agreement (ratio LOA = 1.05-1.06) and low measurement error (CV = 2.17 - 2.68%) (Table 3). However, FI and average RPE demonstrated moderate test-retest reliability (ICC = 0.87 and 0.76, respectively), poorer levels of agreement (ratio LOA = 2.57 and 2.23, respectively) and higher measurement error (CV = 25.3 and 15.8%, respectively, Table 3).” The next paragraph has been rewritten to, “For the RTT, excellent test-retest reliability (ICC = 0.91), good levels of agreement (ratio LOA = 1.08) and low measurement error (CV = 2.17-2.68%) were identified for TT, BT and AT (Table 3), although maximum RPE demonstrated higher levels of measurement error (CV = 12.3%) between Sessions 4 and 5 (Table 3).” Discussion Reviewer’s comment: I found the discussion well-written and thought the authors accurately interpreted and attempted to explain their findings. However, similar to the introduction, I felt this section lacked depth when discussing the main findings of the study. I encourage the authors to discuss their findings in greater depth, utilising some of the reading attached to this review. Author’s response: Thank you for your comments. The Discussion has been adjusted to address the comments below. Reviewer’s comment: I encourage the authors to utilise the first paragraph of the discussion to summarise all of their main findings, and then progress to discussing each point in turn. Author’s response: Summary of findings included as requested in the first paragraph. Reviewer’s comment: The third paragraph begins “another novelty of this study”, yet this appears to be the first time novelty is addressed in the discussion? Author’s response: This specific text has been deleted to improve clarity. Reviewer’s comment: The fourth paragraph can draw upon a wealth of correlational studies to further support the findings observed here. Young WB, Dawson B, Henry GJ. Agility and Change-of-Direction Speed are Independent Skills: Implications for Training for Agility in Invasion Sports. International Journal of Sports Science & Coaching. 2015;10(1):159-169. doi:10.1260/1747-9541.10.1.1591 Spiteri T, Nimphius S, Hart NH, Specos C, Sheppard JM, Newton RU. Contribution of strength characteristics to change of direction and agility performance in female basketball athletes. J Strength Cond Res. 2014 Sep;28(9):2415-23. doi: 10.1519/JSC.0000000000000547. PMID: 24875426.7 Gabbett, T. J., Kelly, J. N., & Sheppard, J. M. (2008). Speed, Change of Direction Speed, and Reactive Agility of Rugby League Players. The Journal of Strength & Conditioning Research, 22, 174-181. http://dx.doi.org/10.1519/JSC.0b013e31815ef7008 Sheppard, J.M.; Young, W.B.; Doyle, T.L.A.; Sheppard, T.A.; Newton, R.U. An evaluation of a new test of reactive agility and its relationship to sprint speed and change of direction speed. J. Sci Med. Sport 2006, 9, 342–349.9 Author’s response: A sentence with relevant references listed above were included as requested. Reviewer’s comment: The conclusion should be reframed around the key objectives of the study (i.e. that it is reliable and valid). The mention of aerobic and anaerobic energy systems seems misplaced here. Author’s response: A sentence on the validity of the RIA protocols has been included. References Reviewer’s comment: While a variety of key texts are identified and listed within the bibliography and cited throughout the manuscript, a number of key texts are omitted. I encourage the authors to further familiarise themselves with relevant studies assessing reliability and validity of COD and agility in team sport athletes, as well as the texts identified earlier within this review. Dos’Santos, T.; Thomas, C.; Jones, P.A.; Comfort, P. Mechanical Determinants of Faster Change of Direction Speed Performance in Male Athletes. J. Strength Cond. Res. 2017, 31, 696–705.10 Gabbett, T.J.; Kelly, J.N.; Sheppard, J.M. Speed, change of direction speed, and reactive agility of rugby league players. J. Strength Cond. Res. 2008, 22, 174–181.8 Oliver, J.L.; Meyers, R.W. Reliability and generality of measures of acceleration, planned agility, and reactive agility. Int. J. Sports Physiol. Perform. 2009, 4, 345–354.11 Author’s response: Thank you for kindly providing the references. A number of these have been included in the paper as requested."
}
]
},
{
"id": "90678",
"date": "03 Aug 2021",
"name": "Aaron T. Scanlan",
"expertise": [
"Reviewer Expertise Exercise and sport science"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for the opportunity to review this manuscript. A logical study with potential practical impact was presented exploring the validity and reliability of a repeated change-of-direction speed test suited to rugby league. This aspect of fitness testing is lacking in the literature and of use for end-users, so this manuscript has merit for publication. I do however have some suggestions and queries listed below that will help strengthen some aspects of the work that should be addressed by the authors:\nAbstract, Methods – indicate whether you are referring to the multi-stage fitness test (i.e., Beep test) here or if just an assessment of multi-stage fitness was performed.\n\nAbstract – some justification of using the repeated T-agility test as the other standard repeated change-of-direction performance to assess convergent agility of the repeated Illinois Agility test is needed in the Abstract.\n\nAbstract – the focus of exploring the contribution of different fitness attributes to repeated Illinois Agility test performance is not made in the Abstract. Consider including this as a secondary objective and/or making it clear why this analysis is needed.\n\nAbstract, Conclusions – make it clear that this test is useful for Rugby League coaches specifically, and change “athlete” to plural form or indicate “team” here instead.\n\nIntroduction, opening paragraph – in this paragraph you identify “agility” and hint that it involves physical and cognitive components. So in essence, you are examining change-of-direction speed (the physical component) rather than “agility” per se. Consider making this clear and using the term “change-of-direction speed” or “change-of-direction performance” thereafter when referring to tests and attributes that are purely physical without the cognitive component.\n\nIntroduction, opening paragraph – stronger rationale is needed justifying the inclusion of the Agility T-test and Illinois Agility test in rugby league. Can you add a sentence or two outlining why these tests are suited to the sport and therefore the focus of your study?\n\nIntroduction, end of second paragraph – here indicate whether the validity and reliability of this test has not been investigated at all or just specifically in Rugby League athletes. Also, at the end of this sentence make it clear that you are referring to the usability of this test.\n\nIntroduction, aims – for the second aim, you are not comparing the RIA measures to other measures, but instead correlating them, so please change this aim accordingly. Also, consider including a little rationale around this aim in the previous paragraph as it is unclear as to why this is important.\n\nIntroduction, aims – it might pay to include a sentence stating why examining convergent validity (e.g. to show that you are assessing similar attributes with a new test that is more practical and specific to Rugby League when compared to a standard, generic test routinely used) and retest reliability (e.g. to detect the inherent error in the test and ascertain whether it can be reliably adopted in practice to assess repeated measurements in athletes) are needed for practical uptake of the test, which would strengthen the rationale of the first and third aims as well in the Introduction section.\n\nIntroduction, hypotheses – you only mention speed and anaerobic capacity as your fitness attributes here, but you also included aerobic fitness (Multistage Fitness test)?\n\nMethods, Research design – why was the order flipped between session 4 and session 5? It seems like you would want to the athletes to complete the same exact session across both when assessing retest reliability as it is introducing a confounding factor? Also, no hyphen needed between “15” and “minutes” here.\n\nMethods, Participants – can you provide some further indication as to the specific playing level of the athletes? The name of the program is great, but this is not exactly clear for all readers.\n\nFigure 1 – consider changing the session numbers, as in text you identify the Multistage Fitness test as session 1, but here you indicate the other fitness testing as session 1. Consistency needed.\n\nMethods, Participants – add “in” after “partaking” and make parents/guardians singular rather than plural.\n\nMethods, Multistage Shuttle test – stay consistent with capitalising the test names like this one as it is done inconsistently throughout. Also, hyphenate “20m” here.\n\nMethods, Countermovement jump test – hyphenate “1 cm” here. Also, try to indicate what units the key outcomes from each test were reported in (e.g. mL/kg/min, cm, s).\n\nMethods, 30-m Sprint and Agility protocols – separate statements on linear and change-of-direction speed here. Also, hyphenate “10m” and “5m” for the Illinois Agility test.\n\nMethods, repeat protocols – to calculate average HR and RPE, was HR measured from when the test started to when the test finished in 1-second intervals? And was RPE taken after each effort or just after all efforts for each specific test? These are not quite clear.\n\nMethods, Statistical analysis – you mention “construct” validity for the first time here. If this is a key aim and aspect of the study (i.e., correlating performance during the test with fitness attributes), then this needs to be established earlier (i.e., introduction and aims).\n\nMethods, Statistical analysis – an r value of 0.5 seems quite low to establish convergent validity (only 25% shared variance)? In this regard, what was the cut-off for construct validity?\n\nResults, first paragraph – clarify whether this is CMJ height specifically.\n\nResults, second paragraph – make it clear that you are referring to the third and fourth sessions here (and make sure this is consistent as you identify these as the fourth and fifth sessions earlier).\n\nResults, third paragraph – you do not indicate the maximum RPE was taken as an outcome in the methods anywhere (only average), yet it is listed here? Same for maximum HR, which appears later in this section also.\n\nTable 1 – shouldn’t RIA and RTT be the two key tests going from left to right rather than RIA and RSA? In fact, it is not clear why RSA is included here given you identify RIA vs. RTT for convergent validity assessment throughout the manuscript. Please adjust or rework earlier sections.\n\nDiscussion, first paragraph – some minor errors, but change “was” to “were” in the 7th line.\n\nDiscussion, first paragraph – at the end of this paragraph, some explanation as to how yours (and the previous studies) support that anaerobic fitness is predominantly stressed in the repeated COD tests. I am assuming the strong correlations with mostly anaerobic fitness attributes, but this is an assumption and should be explained further to clarify this statement.\n\nDiscussion, fourth paragraph – be careful with your statement suggesting they are “key attributes for RL athletes”. You did not show this but state it, so rework or remove this part to focus specifically on what your data show.\n\nDiscussion, concluding paragraph – here you highlight how anaerobic and aerobic fitness underpin test performance, but previously you focus on anaerobic fitness in other sections and in this section. Please make sure the message is consistent throughout.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7211",
"date": "08 Oct 2021",
"name": "Kenji Doma",
"role": "Author Response",
"response": "Reviewer’s comment: Thank you for the opportunity to review this manuscript. A logical study with potential practical impact was presented exploring the validity and reliability of a repeated change-of-direction speed test suited to rugby league. This aspect of fitness testing is lacking in the literature and of use for end-users, so this manuscript has merit for publication. I do however have some suggestions and queries listed below that will help strengthen some aspects of the work that should be addressed by the authors: Author’s response: Dear Reviewer, thank you very much for your comments. We believe your feedback has improved the quality of our work. Reviewer’s comment: Abstract, Methods – indicate whether you are referring to the multi-stage fitness test (i.e., Beep test) here or if just an assessment of multi-stage fitness was performed. Author’s response: A Beep test was performed, which is now included in the Abstract. Reviewer’s comment: Abstract – some justification of using the repeated T-agility test as the other standard repeated change-of-direction performance to assess convergent agility of the repeated Illinois Agility test is needed in the Abstract. Author’s response: This is a valid point. The Background now includes, “Thus, the current study examined the convergent validity of a repeated Illinois Agility (RIA) protocol with the repeated T-agility protocol, and the repeatability of the RIA protocol in adolescent Rugby League players.” Reviewer’s comment: Abstract – the focus of exploring the contribution of different fitness attributes to repeated Illinois Agility test performance is not made in the Abstract. Consider including this as a secondary objective and/or making it clear why this analysis is needed. Author’s response: Thank you for the suggestion. We have now included, “Furthermore, aerobic capacity and anaerobic and COD performance were assessed to determine whether these physical qualities were important contributors to the RIA protocol.” Reviewer’s comment: Abstract, Conclusions – make it clear that this test is useful for Rugby League coaches specifically, and change “athlete” to plural form or indicate “team” here instead. Author’s response: The conclusion has been rewritten to, “The current study has demonstrated the RIA to be a simple, valid and reliable field test for RL athletes that can provide coaches with information about their team’s ability to sustain high intensity, multi-directional running efforts.” Reviewer’s comment: Introduction, opening paragraph – in this paragraph you identify “agility” and hint that it involves physical and cognitive components. So in essence, you are examining change-of-direction speed (the physical component) rather than “agility” per se. Consider making this clear and using the term “change-of-direction speed” or “change-of-direction performance” thereafter when referring to tests and attributes that are purely physical without the cognitive component. Author’s response: All the terms with ‘agility’ has been replaced with ‘change-of-direction’ performance or protocols throughout the text. Reviewer’s comment: Introduction, opening paragraph – stronger rationale is needed justifying the inclusion of the Agility T-test and Illinois Agility test in rugby league. Can you add a sentence or two outlining why these tests are suited to the sport and therefore the focus of your study? Author’s response: We have removed Agility T-test and Illinois Agility test from the first paragraph, and focused the justification of the Illinois Agility test for RL in the second paragraph (see lines 41-47). Reviewer’s comment: Introduction, end of second paragraph – here indicate whether the validity and reliability of this test has not been investigated at all or just specifically in Rugby League athletes. Also, at the end of this sentence make it clear that you are referring to the usability of this test. Author’s response: We separated the second paragraph into two paragraphs. Thus, we highlighted that no studies have examined the validity and reliability of the RIA protocol at the end of the fourth paragraph. Reviewer’s comment: Introduction, aims – for the second aim, you are not comparing the RIA measures to other measures, but instead correlating them, so please change this aim accordingly. Also, consider including a little rationale around this aim in the previous paragraph as it is unclear as to why this is important. Author’s response: Changed to ‘correlating’ as requested. The previous paragraph expanded on the need to examine the validity of the RIA protocol, which we now hope provides further justification of our aims. Reviewer’s comment: Introduction, aims – it might pay to include a sentence stating why examining convergent validity (e.g. to show that you are assessing similar attributes with a new test that is more practical and specific to Rugby League when compared to a standard, generic test routinely used) and retest reliability (e.g. to detect the inherent error in the test and ascertain whether it can be reliably adopted in practice to assess repeated measurements in athletes) are needed for practical uptake of the test, which would strengthen the rationale of the first and third aims as well in the Introduction section. Author’s response: This is a great suggestion. We have now worded the end of the Introduction to, “Examining the convergent validity of the RIA protocol will determine whether this novel assessment exhibits similar attributes to a standardised COD protocol (i.e., RTT). In addition, the reliability of the RIA will determine whether this test can be reliably adopted in practice by accounting for the inherent error of the test across repeated measurements. The quality of these psychometric properties will provide coaches with a tool to assist in monitoring and training RL athletes as well as in talent development and identification.” Reviewer’s comment: Introduction, hypotheses – you only mention speed and anaerobic capacity as your fitness attributes here, but you also included aerobic fitness (Multistage Fitness test)? Author’s response: Included aerobic capacity in the hypotheses. Reviewer’s comment: Methods, Research design – why was the order flipped between session 4 and session 5? It seems like you would want to the athletes to complete the same exact session across both when assessing retest reliability as it is introducing a confounding factor? Also, no hyphen needed between “15” and “minutes” here. Author’s response: This is a good question. We employed a cross-over design for sessions 4 and 5 to limit the confounder of any learning effects (i.e., were participants still able to exhibit reproducible measures when the protocols were swapped around, as opposed to the participants becoming accustomed to the order effects between sessions). We have also included the hyphen. Reviewer’s comment: Methods, Participants – can you provide some further indication as to the specific playing level of the athletes? The name of the program is great, but this is not exactly clear for all readers. Author’s response: Further description of the excellence program has been provided. Reviewer’s comment: Figure 1 – consider changing the session numbers, as in text you identify the Multistage Fitness test as session 1, but here you indicate the other fitness testing as session 1. Consistency needed. Author’s response: Session 1 included in the Multistage Fitness test as requested (see updated Figure 1). Reviewer’s comment: Methods, Participants – add “in” after “partaking” and make parents/guardians singular rather than plural. Author’s response: Amended as requested. Reviewer’s comment: Methods, Multistage Shuttle test – stay consistent with capitalising the test names like this one as it is done inconsistently throughout. Also, hyphenate “20m” here. Author’s response: Amended the test name to upper case as requested and hyphenated to 20-m. Reviewer’s comment: Methods, Countermovement jump test – hyphenate “1 cm” here. Also, try to indicate what units the key outcomes from each test were reported in (e.g. mL/kg/min, cm, s). Author’s response: Hyphenated to 1-cm and reported units of measure as requested for each test. Reviewer’s comment: Methods, 30-m Sprint and Agility protocols – separate statements on linear and change-of-direction speed here. Also, hyphenate “10m” and “5m” for the Illinois Agility test. Author’s response: Statements have been separated and hyphenated as requested. Reviewer’s comment: Methods, repeat protocols – to calculate average HR and RPE, was HR measured from when the test started to when the test finished in 1-second intervals? And was RPE taken after each effort or just after all efforts for each specific test? These are not quite clear. Author’s response: We have included “ “The participant’s instantaneous heart rate (HR, Polar Heart Rate Monitor, Polar H10, Finland) and rating of perceived-exertion (RPE, Borg category scale 1-10) were collected at the completion of each repetition of the RSA, RTT and RIA protocols. The maximum and average HR and RPE values were then reported from the 6 repetitions. – see lines 138-141. Reviewer’s comment: Methods, Statistical analysis – you mention “construct” validity for the first time here. If this is a key aim and aspect of the study (i.e., correlating performance during the test with fitness attributes), then this needs to be established earlier (i.e., introduction and aims). Author’s response: We have taken out “construct validity” and mentioned aerobic capacity, power and COD as “contributors to the RIA protocol”. Reviewer’s comment: Methods, Statistical analysis – an r value of 0.5 seems quite low to establish convergent validity (only 25% shared variance)? In this regard, what was the cut-off for construct validity? Author’s response: This has been re-established to a minimum r-value of 0.7 for both convergent validity and contributors to the RIA protocol. Reviewer’s comment: Results, first paragraph – clarify whether this is CMJ height specifically. Author’s response: Height included as requested. Reviewer’s comment: Results, second paragraph – make it clear that you are referring to the third and fourth sessions here (and make sure this is consistent as you identify these as the fourth and fifth sessions earlier). Author’s response: Sessions numbers included as requested, and we also applied this approach in the next paragraph for the RTT protocol to ensure clarity. Reviewer’s comment: Results, third paragraph – you do not indicate the maximum RPE was taken as an outcome in the methods anywhere (only average), yet it is listed here? Same for maximum HR, which appears later in this section also. Author’s response: This is a great pick up. In the methods section, we have now included, “The participant’s heart rate (HR, Polar Heart Rate Monitor, Polar H10, Finland) and rating of perceived-exertion (RPE, Borg category scale 1-10) were collected at the completion of each repetition of the RSA, RTT and RIA protocols. The maximum and average HR and RPE values were then reported from the 6 repetitions.” Reviewer’s comment: Table 1 – shouldn’t RIA and RTT be the two key tests going from left to right rather than RIA and RSA? In fact, it is not clear why RSA is included here given you identify RIA vs. RTT for convergent validity assessment throughout the manuscript. Please adjust or rework earlier sections. Author’s response: Table 1 has now been amended as requested. RSA was included more to determine the importance of the athlete’s ability to sustain speed and effort over repeated bouts, which has now been included in the second aim. Reviewer’s comment: Discussion, first paragraph – some minor errors, but change “was” to “were” in the 7th line. Author’s response: Amended as requested. Reviewer’s comment: Discussion, first paragraph – at the end of this paragraph, some explanation as to how yours (and the previous studies) support that anaerobic fitness is predominantly stressed in the repeated COD tests. I am assuming the strong correlations with mostly anaerobic fitness attributes, but this is an assumption and should be explained further to clarify this statement. Author’s response: Closer to the end of this paragraph, we have included a sentence that reads, “The comparable measures between RIA, RTT and RSA suggests that anaerobic fitness, in conjunction with efficient recovery dynamics during short periods of rest in-between explosive activities, are essential qualities for optimal performance in an RIA protocol.” Reviewer’s comment: Discussion, fourth paragraph – be careful with your statement suggesting they are “key attributes for RL athletes”. You did not show this but state it, so rework or remove this part to focus specifically on what your data show. Author’s response: Removed as requested. Reviewer’s comment: Discussion, concluding paragraph – here you highlight how anaerobic and aerobic fitness underpin test performance, but previously you focus on anaerobic fitness in other sections and in this section. Please make sure the message is consistent throughout. Author’s response: We have now included aerobic capacity as possible important contributors to the RIA protocol in the Abstract, Introduction (aim and hypothesis) and earlier sections in the Discussion."
}
]
}
] | 1
|
https://f1000research.com/articles/9-624
|
https://f1000research.com/articles/10-901/v1
|
08 Sep 21
|
{
"type": "Research Article",
"title": "Improving the data access control using blockchain for healthcare domain",
"authors": [
"Olaosebikan Tahir Yinka",
"Su-Cheng Haw",
"Timothy Tzen Vun Yap",
"Samini Subramaniam",
"Olaosebikan Tahir Yinka",
"Timothy Tzen Vun Yap",
"Samini Subramaniam"
],
"abstract": "Introduction Unauthorized access to data is one of the most significant privacy issues that hinder most industries from adopting big data technologies. Even though specific processes and structures have been put in place to deal with access authorization and identity management for large databases nonetheless, the scalability criteria are far beyond the capabilities of traditional databases. Hence, most researchers are looking into other solutions, such as big data management. Methods In this paper, we firstly study the strengths and weaknesses of implementing cryptography and blockchain for identity management and authorization control in big data, focusing on the healthcare domain. Subsequently, we propose a decentralized data access and sharing system that preserves privacy to ensure adequate data access management under the blockchain. In addition, we designed a blockchain framework to resolve the decentralized data access and sharing system privacy issues, by implementing a public key infrastructure model, which utilizes a signature cryptography algorithm (elliptic curve and signcryption). Lastly, we compared the proposed blockchain model to previous techniques to see how well it performed. Results We evaluated the blockchain on four performance metrics which include throughput, latency, scalability, and security. The proposed blockchain model was tested using a sample of 5000 patients and 500,000 observations. The performance evaluation results further showed that the proposed model achieves higher throughput and lower latency compared to existing approaches when the workload varies up to 10,000 transactions. Discussion This research reviews the importance of blockchains as they provide infinite possibilities to individuals, companies, and governments.",
"keywords": [
"Blockchain",
"Healthcare datasets",
"Chaincode",
"Directed Acyclic Graph",
"Access Control."
],
"content": "Introduction\n\nThe US social insurance system, such as healthcare, is gradually obtaining digital medical information, thanks to the fast-expanding availability of data which will considerably build up the number of medical information collected securely.1 Furthermore, a change in perspective in the medical services sector has seen the new trend of computerizing medical records. The medical services sector is therefore rapidly rising in data volume as far as randomness and simplicity are concerned. Although the public healthcare sector is struggling with the magnitude of big data, security and privacy concerns are converging as threats and vulnerabilities grow.2,3\n\nThe modern and revolutionary technology to build safer, more private, and interoperable health systems, blockchain technology has proven to be efficient. The aim of this paper is to propose a decentralized model for sharing and storing medical information utilizing blockchain technology to ensure security, preserving complete privacy, and allowing the owner to be completely in control of their data. In this research, additional efforts were made to harness and itemize all blockchain technology technical tools and the current influence of this developing technology on healthcare and industry.\n\nRecent studies in the healthcare sector dealing with is-sues of scalability have used blockchain. Nonetheless, the application of blockchain in these studies was limited to the healthcare dataset index and the storage of verified transaction by endorsing peers. In contrast to these approaches, the current blockchain model pro-poses the storage of all medical datasets in blockchain and also improving data throughput limitations. In light of these proposed improvements, Yang et al.4 proposed the use of blockchain as an index of a medical dataset and a list of user’s information. Similarly, Daraghmi et al.5 introduced a data-sharing and access authentication scheme based on a private blockchain. Likewise, Genestier et al.6 offered a novel proposal for reshaping healthcare permission monitoring using blockchain technology and allow users to access their entire health record data. In their implementation, there is no permission settings and no access restriction. MedRec7 is a software system developed using blockchain technology by the MIT media lab to handle electronic health records. They created a hospital management system that responds to four major issues: disjointed, delayed access to health care information; process compatibility; respect for autonomy; and enhanced data quantity and quality for clinical research.\n\nMedical Chain8 project began in 2016, with the launch of the first model in mid-2017. Later in 2017, a partnership with the Linux Foundation was created. In the early months of 2018, a beta version of the program was published. The primary objective is to develop a single, accurate version of the user's health data.\n\nMedBlock,9 which is architecture based on a hybrid blockchain to protect Electronic Medical Records (EMRs). Their design nodes identify them as endorsers, orderers, and committers. Yet, the access control strategy to allow third-party researchers access to medical data is not specified precisely.\n\nXia et al.10 introduced the Blockchain-Based Data Sharing (BBDS) system allowing owners and participants to access EMR from a shared repository theory based on positive identity and key verification.\n\nDiversely, other research projects related to adopting blockchain in the healthcare domain are summarized as follows.\n\nBlockchain Health,11 ASTRI12 and Bloq13 allow users to use the integrated platform to share health data with researchers, which creates a tamper-proof knowledge custody chain. Similarly, HIE of One14-16 is a blockchain software initiative that provides resources for patients to access their own records. Hyperledger17 and IBM Blockchain18 is hyperledger fabric's first regulated platform, allowing the development of company blockchain platforms that users can monitor and spread through various organizations.\n\nAll the principal functions of blockchain technology and some true blockchain applications in healthcare were discussed at this point. More concretely, issues addressed in this chapter include authentication management, identity management, and cryptography. In the next section we will clarify the model that helps to il-lustrate how the blockchain network communicates with the developed model.\n\nThe paper contributions are summarized as follows:\n\n1. A file storage and sharing system for a pure decentralized network utilizing blockchain technology is proposed.\n\n2. An extensive evaluation of the proposed system, which demonstrated that our proposed system achieves higher throughput and lower latency com-pared to some existing approaches at higher work-load varied up to 10,000 transactions.\n\n\nMethods\n\nThe overall data storage workflow is displayed in Figure 1 based on the following steps:\n\n(1) A user joins through the graphical user inter-face (GUI) and the request for permission to access information can be inserted into the network when successfully authenticated.\n\n(2) The user's request is sent to the cloud server by the GUI.\n\n(3) The blockchain component, the server query enabled, or revoked access.\n\n(4) The blockchain component handles content verification, signing, and encryption via Public Key Infrastructure (PKI).\n\n(5) Finally, data updated/stored with the authenticated token takes place.\n\nFrom Figure 1, steps (a) to (f) depict the procedures for accessing a data source:\n\n\n\n(a) A user authenticates using the GUI. Upon successful authentication, user input will be taken into the system.\n\n(b) Through the GUI, user input is forwarded to the cloud server.\n\n(c) The cloud server then run queries against the blockchain for the user's access token by running the proposed PKI algorithm.\n\n(d) The access token retrieved is been decrypted with the appropriate user keys.\n\n(e) Data access is granted and retrieved with the help of a database connector.\n\n(f) The server returns updates to display data in a format that is readable to the user.\n\nWe first analyzed a case study concerning the healthcare domain. We will then describe each of the key components in the case studies: (i) join function, (ii) content authentication function, and (iii) secure content access function.\n\nThe whole scheme works as follows. Consider a healthcare scenario of file storing and sharing. For each transaction, the ‘patient’ provides the contents to be stored and accessed. The ‘hospital administrator’ and ‘doctor’ request access to these contents. We assume that ‘hospital administrator’ and ‘doctor’ use our proposed model (see Figure 1), acting as the search mechanism to engage in the process of searching for content.\n\nThe join function: Let us consider a contrary of the scenario described above, if the doctor has no clearance of access, the doctor is, therefore, unable to access the desired content. In this case, by initiating the join function (Algorithm 1), the content provider can update the doctor's clearance or refuse the proposal.\n\nAs shown in Algorithm 1 below, the identity is made up of signature key-pairs marked as SK for Bob and Alice, with reference pointers to the keys represented by RPSK. A public key denoted as PK is used to encrypt (and decode) the data, ensuring that the data is secured from all other players in the system.\n\n\n\nThe content authentication function: In the same scenario described earlier in the join function, once the ‘user’ has access to the desired content, the ‘user’ must verify their authenticity with the content authentication function, this is done on the blockchain (Algorithm 2).\n\n\n\nParse(x), also known as xp, is an auxiliary function that de-serializes a transaction's message, which includes the parameters. As seen in Algorithm 2, POLICYCHECK (PKK, xp) checks that the originator has the proper permissions. Memory on the blockchain, indicated by the letter “M”: We'll call M the blockchain memory space, which can hold suitably big documents and is represented by the hashtable L: {0, 1}256 → {0, 1} N, where N >> 256.\n\nThe secure content access function: Consider a situation where a ‘user’ wishing to use our model to access the desired content. The built model includes access chaincodes that record on the blockchain database all ‘user’ activities, such as, record of shared data or records of information access history. Similarly as proposed by,19 Algorithm 3 is executed when read/write transaction access is requested.\n\n\n\nAs described earlier in this section, this architecture was designed for secure, scalable storage and data sharing in healthcare. The hyperledger network system is a permissioned blockchain implementation, providing unique properties suitable for implementing our proposed model. It runs chaincodes written in Java and Go programming language. The proposed model also supports data transaction validation applications and a plug-in consensus validation protocol. It is also important to note that hyperledger fabric collaboration network utilized consensus validation entities of a different kind, such as clients, ordering service nodes, and peer nodes, which belong to various participating entities or organizations.\n\n\nExperimental evaluations and results\n\nIn the evaluations, we observed the various experimental evaluations conducted for Hyperledger fabric. In the experiment, we considered scenarios where a client or user sends ‘N’ transactions of a certain type ‘f’ to the blockchain in an asynchronous manner. The number of requests is set from 1000 to 10,000 transactions, with increments of 1000 transactions in-between them, a sample digitized data collection, namely OpenMRS that consists of 5000 patients and 500,000 observations is used for our evaluation (see Table 1). Our proposed approach was benchmarked against approaches proposed by4,5 for fair comparison.\n\nFigure 2 depict the average latency across specific block sizes, analyzing various datasets or arrival rates of transactions. From Figure 2, we made several observations. This include the average latency in our approach is almost two-times less than that of average latency in both approaches by4,5 for all block sizes, except for when the transaction is at 1000 TX, we saw that latency of all approaches are lower. This is because the volume of pending transactions at validation stage grew on high count which affected commit latency.\n\nFigure 3 depict the average latency time of endorsement policy with the various number of transactions per second (TPS) (for the number of transactions ranging from 1000 to 10000). From Figure 3, it can be observed that the number of sub-policies and the number of signature validation has caused high latency for the join, content authentication and secure content access functions in4,5 approaches.\n\nWe study the throughput and latency over varying transaction arrival rates for database utilized in the three approaches with different transaction complexity.\n\nFrom Figures 4 and 5, shows that as transaction arrival increased for read/write only complexity, the throughput increased and latency decreased. This was observed while utilizing CouchDB as the state database.\n\nThe result shows that GoLevelDB performance was better than CouchDB with respect to ledger database. The reason behind the relatively good performance is the existence of key-value state database embedded in the peer mechanism.\n\n\nDiscussion\n\nThe performance evaluation results further showed that the proposed model achieves higher throughput and lower latency compared to existing approaches when the workload varies up to 10,000 transactions.\n\nIt's also worth noting that the proposed model preserves confidentiality and security by controlling transactions with timed-based chaincodes. The use of sophisticated encryption maintains security and access control.\n\nSecurity and access control are maintained by the adoption of advanced encryption (such as the proposed hybrid PKI) and authentication methods that defend against adversarial efforts to change unwanted entry when issuing encryption information to verify and validate transactions to network users.\n\n\nConclusions\n\nWe had presented a model, which describes the interaction between a blockchain network and the designed model. To ensure a safe and private environment to communicate and store health data, the designed model exploits the most significant elements of blockchain technology while suppressing features that are not significant. In future work, we expect to perform refined simulations so that our model is tested more rigorously. We could do this by downloading and testing a wider range of various blockchain frameworks in a verified setting, for instance, using the blockchain instance of Amazon Web Services' blockchain.\n\n\nAuthor contributions\n\nOlaosebikan Tahir Yinka constructed the protytpe and conducted the experimental evaluations under the guidance of his supervisors, Su-Cheng Haw and Timothy Tzen Vun Yap. Samini Subramaniam is the external collaborator while Su-Cheng Haw is the corresponding author for this paper.\n\n\nData availability\n\nNo data are associated with this article.\n\n\nSoftware availability\n\n• Source code available from: https://github.com/captaintaheer/Solution_Code\n\n• Archived source code at time of publication: https://doi.org/10.5281/zenodo.5226652\n\n• License: Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).\n\n\nEthics approval\n\nEthical approval was given by the ethical approval board of Multimedia University, with number: EA1762021.",
"appendix": "References\n\nZyskind G, Nathan O, Pentland A: Decentralizing Privacy: Using Blockchain to Protect Personal Data. IEEE Security and Privacy Workshops; 2015.\n\nAljawarneh S, Yassein MB, Talafha WA: A resource-efficient encryption algorithm for multimedia big data. Multimedia Tools and Applications . 2015; 76(21): 22703–22724. Publisher Full Text\n\nHilbert M: Big Data for Development: A Review of Promises and Challenges Development Policy Review.2015; 34(1), pp. 135–174. Publisher Full Text\n\nYang J, Onik M, Lee N, et al.: Proof-of-Familiarity: A Privacy-Preserved Blockchain Scheme for Collaborative Medical Decision-Making. Appl. Sci. 2019; 1370. Publisher Full Text\n\nDaraghmi E-Y, Daraghmi Y-A, Yuan SM: MedChain: A Design of Blockchain-based System for Medical Records Access and Permissions Management. IEEE Access. 2019; 1–1. Publisher Full Text\n\nGenestier P: Blockchain for consent management in the eHealth environment: A nugget for privacy and security challenges. J. Int. Soc. Telemedicine eHealth . 2017, April; 5: 1–4.\n\nAzaria A, Ekblaw A, Vieira T, et al.: MedRec: Using blockchain for medical data access and permission management. 2nd Int. Conf. Open Big Data. Aug. 2016; (p. 2530).\n\nAlbeyatti A, Tayeb M, Yin A, et al.: Medicalchain (Whitepaper).2018; pp. 1–42.\n\nChen M, Qian Y, Chen J, et al.: Privacy Protection and Intrusion Avoidance for Cloudlet based Medical Data Sharing. IEEE Transactions on Cloud Computing . 2016; 1(1). Publisher Full Text\n\nAmofa S, Sifah EB, Agyekum KO-B, et al.: A blockchain-based architecture framework for secure sharing of personal health data. IEEE 20th Int. Conf. e-Health Netw., Appl. Services (Healthcom). 2018; 16. Publisher Full Text\n\nASTRI: Whitepaper on Distributed Ledger Technology.2016. Reference Source\n\nCulver K: Blockchain technologies: A whitepaper discussing how the claims process can be improved . Workshop: ONC/NIST Use Blockchain Healthcare Res; 2016.\n\nGenestier P: Blockchain for consent management in the eHealth environment: A nugget for privacy and security challenges. J. Int. Soc. Telemedicine eHealth; 2017, April; 5: 1–4.\n\nGropper A, MD: Powering the PhysicianPatient Relationship with HIE of One Blockchain Health IT.H N, S K, H G2017.\n\nDistributed ledger technology and blockchain. yesWorld Bank. . http\n\nT L: Foundation Hyperledger Overview.2018.\n\nDagher GG, Mohler J, Milojkovic M, et al.: Ancile: Privacy-preserving framework for access control and interoperability of electronic health records using blockchain technology. Sustain. Cities Soc . 2018, May; 39: 283297. Publisher Full Text\n\nGuo R, Shi H, Zhao Q, et al.: Secure attribute-based signature scheme with multiple authorities for blockchain in electronic healthrecords systems. IEEE Access . 2018; 6: 1167611686. Publisher Full Text\n\nAazam M, Zeadally S, Harras KA: Health fog for smart healthcare. IEEE Consum Electron Maga . 2020; 9(2): 96–102. Publisher Full Text\n\nShadab A, F AR, S MZHKKR, et al.: Towards Trustworthiness of Electronic Health Record system using Blockchain. Annals of the Romanian Society for Cell Biology . 2021; 25(6): 2425–2434. Reference Source"
}
|
[
{
"id": "94763",
"date": "08 Oct 2021",
"name": "Huo Chong Ling",
"expertise": [
"Reviewer Expertise Security"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 decentralized network using blockchain technology to store and share health data securely by adopting a PKI model in their blockchain framework. The PKI model consists of content verification and authentication and secure access. Experiments were conducted to evaluate the performance of the proposed blockchain framework in terms of throughput, latency, scalability, and security, and compared to existing approaches in the literature. The experiments showed promising results, which indicate the feasibility of the framework to be used in the healthcare domain.\nHowever, there are a few doubts regarding the statistical analysis of the experimental results as follows:\nDo the results obtained consist of the average of several runs or just one run?\n\nAre the algorithms used in [4] and [5] implemented as well on the same PC that is used for the proposed approach? This is to ensure fair performance evaluation.\n\nThe latency results showed the average for the block size of 200-400. How about the latency results for the block size of 400 and above?\nOther comments on the article are as follows:\nThe year of publication for Yang et al. is 2019, but in your figures, it is shown as 2018.\n\nIt's better to write \"Proposed approach\" instead of \"My approach\" in the figures.\n\nReference 20 is not cited in the text.\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": "7337",
"date": "27 Oct 2021",
"name": "Haw Su Cheng .",
"role": "Author Response",
"response": "Do the results obtained consist of the average of several runs or just one run? Author response: Yes, between 1000 to 10,000 transactions were asynchronously sent to the blockchain server. The number of requests is set from 1000 to 10,000 transactions, with increments of 1000 transactions for every run. Are the algorithms used in [4] and [5] implemented as well on the same PC that is used for the proposed approach? This is to ensure fair performance evaluation. Author response: Yes, this was included in the proposed model access chaincodes, which record all ‘user’ activities, such as the record of shared data or information access history on the blockchain. Algorithm 3 is executed when transaction access is requested, and similarly, Algorithm 4 is executed for read/write transactions. The latency results showed the average for the block size of 200-400. How about the latency results for the block size of 400 and above? Author response We have studied latency and throughput up to 600 blocks in the thesis presented for the work. Also, as stated in observations for all block sizes as for all block sizes, except for when the transaction is at 1000, we saw that latency of all approaches are lower. Other comments on the article are as follows: The year of publication for Yang et al. is 2019, but in your figures, it is shown as 2018. Author response: This has been adjusted in figures It's better to write \"Proposed approach\" instead of \"My approach\" in the figures. Author response: This has been adjusted in figures as advised Reference 20 is not cited in the text. Author response: Citation added."
}
]
}
] | 1
|
https://f1000research.com/articles/10-901
|
https://f1000research.com/articles/10-1056/v1
|
18 Oct 21
|
{
"type": "Systematic Review",
"title": "Synchronous online learning during movement control order in higher education institutions: a systematic review",
"authors": [
"Yee Wan Lee",
"Magiswary Dorasamy",
"Abdul Aziz Bin Ahmad",
"Manimekalai Jambulingam",
"Peik Foong Yeap",
"Sharbani Harun",
"Abdul Aziz Bin Ahmad",
"Manimekalai Jambulingam",
"Peik Foong Yeap",
"Sharbani Harun"
],
"abstract": "Background: Higher education institutions (HEI) are not spared from the coronavirus disease 2019 (COVID-19) pandemic. The closure of campuses because of the movement control order (MCO) to mitigate the spread of the COVID-19 has forced HEIs to adopt online learning, especially synchronous online learning (SOL). Although teaching and learning can be continued via SOL, retaining students’ interest and sustaining their engagement have not been sufficiently explored. This study presents a systematic review of the research pertaining to SOL associated with students’ interest and engagement in HEIs during the MCO environment. Methods: Five major online databases, i.e., EBSCOhost, Science Direct, Emerald, Scopus and Springer were searched to collect relevant papers published between 1st January 2010 to 15th June 2021 including conference proceedings, peer-reviewed papers and dissertations. Papers written in the English language, based in full-fledged universities, and with these five keywords: (i) synchronous online learning, (ii) engagement, (iii) interest, (iv) MCO/Covid-19 and (v) HEI, were included. Papers focussing on synchronous and asynchronous online learning in schools and colleges were excluded. Each paper was reviewed by two reviewers in order to confirm the eligibility based on the inclusion and exclusion criteria. Results: We found 31 papers of which six papers were related to SOL, engagement and interest in HEIs in the MCO environment. Our review presents three major findings: (i) limited research has been conducted on SOL associated with students’ engagement and interest, (ii) studies related to the context of HEIs in the MCO environment are limited, and (iii) the understanding of the new phenomena through qualitative research is insufficient. We highlight the SOL alignment with students’ engagement, interest, style preference, learner interaction effectiveness, behavior and academic performance. Conclusions: We believe that the findings of this study are timely and require attention from the research community.",
"keywords": [
"Interest",
"Engagement",
"Synchronous Online Learning",
"Higher Education Institution",
"Movement Control Order",
"Pandemic",
"Covid-19",
"Malaysia"
],
"content": "Introduction\n\nThe Malaysian online learning movement started in the 1990s with the objective of providing learners access to quality education and lifelong learning opportunity.1 Despite the growing online learning trend, physical learning remains the mainstream learning mode for full-time undergraduate students because most of the Malaysian universities’ infrastructures, facilities and program structures are built for physical teaching and learning.2 However, the eruption of the coronavirus disease 2019 (COVID-19) pandemic in 2019 changed this norm. The enforcement of movement control order (MCO) in Malaysia has pushed universities towards online learning. Therefore, synchronous online learning (SOL) has been adopted as a temporary solution in the time of the pandemic to ensure the continuity of academic activities. Even though literature abounds regarding online learning for adult learners in the normal environment, synchronous online learning (SOL) for undergraduate students during the COVID-19 pandemic is a new phenomenon that warrants the attention of research community. Therefore, a systematic literature reviews will help the researchers to identify the research gaps in this new environment.\n\nSOL is a form of online learning where teaching and learning occur simultaneously and at the same place.3 In SOL, students and instructors can login remotely from any location in the world and concurrently participate in the learning process.4,5 The advancement of online learning technologies, such as audio, video, and text, has allowed instant feedback and real-time interaction between students, instructors and fellow students.6-11 These features of SOL that resemble physical learning are well accepted by students.12,13 Despite the benefits of live session, immediacy and real-time guidance and feedback, SOL has its limitations.6,14,15 For instance, technical difficulties, availability of electronic devices, internet connection, interface and bandwidth and students’ interest and engagement are issues related to SOL in higher education institutions (HEIs) in the MCO environment.16\n\nEngagement is referred to as the interaction between the time, effort and relevant resources invested to optimize student’s experience, learning outcomes and performance.17 Engagement is also related to student’s attitudes towards the learning process and psychological involvement in the learning activities to attain positive learning outcomes, such as satisfaction, achievement and performance.18,19 Behavioral, cognitive and emotional engagement are the three main engagement components.20 Behavioral engagement requires students to comply with the behavioral norms, where students do not demonstrate disruptive or negative behavior. Students with positive behavioral engagement will attend classes and participate enthusiastically in the learning process. Next, students with emotional engagement demonstrate interest and enjoyment in the learning process. Lastly, students with cognitive engagement will go the extra mile in the learning process to perform beyond expectation.\n\nInterest is the underlying psychological factor of being engaged or engrossed in an activity and a guiding factor in energising learning and academic performance.21,22 Next, continuing interest requires students to endure and reengage in the learning activities over time.23 Therefore, educational activities that meet individual students’ needs can catch students’ attention, such as by varying the novelty, complexity and incongruity of visual stimuli.21,22,24 Nevertheless, the heterogeneity of individual interest and the large class size have made these tasks challenging.25 Hence, creating situational interest in the learning process is the first step in developing students’ individual interest26,27 because students with a positive individual interest are highly engaged and attentive to achieve good academic performance as individual interest is a psychological behavior of positive affect and persistency in the learning process.28,29 When students’ individual interest matches the specific contextual affordances, students will be focused and enjoy learning. A study suggests that interest will develop into a self-sustained and well-developed interest with the passage of time.21\n\nGiven this backdrop, the three research questions for this study are as follows:\n\n1. Do research gaps in SOL pertaining to students’ engagement and interest in HEIs in the MCO environment exist?\n\n2. What are the limitations in the current research within SOL in HEIs in the MCO environment?\n\n3. What is the conceptual framework for SOL pertaining to students’ engagement and interest in HEIs in the MCO environment?\n\nThe objectives of this proposal are as follows:\n\n1. To identify research gaps in SOL pertaining to students’ engagement and interest in HEIs in the MCO environment.\n\n2. To understand the limitations of the current research within SOL in HEIs in the MCO environment.\n\n3. To develop a conceptual framework for SOL pertaining to students’ engagement and interest in HEIs in the MCO environment.\n\n\nMethods\n\nThis study was approved by the Research Ethical Committee (REC) of Multimedia University (EA2742021).\n\nThis paper was designed to present a literature review, a research gap analysis and insights into SOL pertaining to undergraduate students’ engagement and interest in HEIs in the MCO environment. The five stages of literature review proposed by30 were used in this process:\n\nStage 1: Planning the review\n\nStage 2: Identifying and evaluating studies\n\nStage 3: Extracting and synthesising data\n\nStage 4: Reporting descriptive findings\n\nStage 5: Utilising the findings to inform research and practice\n\nThis review is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines.62\n\nThe main purpose of this review is to identify research gaps in terms of theories, factors, methods and processes pertaining to SOL and the engagement and interest elements in HEIs in the MCO environment.\n\nThe main focus of this study is SOL. Therefore, papers on asynchronous learning were excluded in the selection and evaluation process. Nevertheless, the identification and evaluation were hampered because not all the papers used the term synchronous and asynchronous explicitly.\n\nSelection process\n\nFive major online databases, namely EBSCOhost, Science Direct, Emerald, Scopus and Springer were searched to collect relevant papers published between 1st January 2010 to 15th June 2021 including conference proceedings, peer-reviewed papers and dissertations. Papers written in the English language and based in full-fledged universities with these five keywords: (i) synchronous online learning, (ii) engagement, (iii) interest, (iv) MCO/COVID-19 and (v) HEI, were included in the selection process. Papers that focused on synchronous and asynchronous online learning in schools and colleges were excluded. Figure 1 presents the paper selection process. Next, each paper was reviewed by two reviewers collectively in order to confirm the eligibility based on the inclusion and exclusion criteria.\n\nSearch strategy\n\nThe search strategy was to sift through papers that discuss SOL pertaining to students’ engagement and interest in the time of MCO using the combination of keywords (Table 1). However, the search strategy that based on the five identified keywords in the selection process may lead to publication bias risk. Therefore, future researchers may expand the selection of keywords in order to reduce the risk of missing some relevant articles.\n\nIn this extraction process, only conceptual and empirical papers associated with SOL, engagement and interest in HEIs under MCO were selected for synthesis. Further, data on theories, methods, factors and limitations of the selected papers were reviewed and evaluated. Table 2 presents the focus areas in extracting and synthesising data from the selected papers.\n\nFigure 2 presents the papers extraction process.\n\nThe Transfield stages 4 and 5 are presented in the following sections.\n\n\nResults\n\nTable 3 presents the online databases search result. A total of 21,431 papers are listed as “synchronous online learning”. The number dropped to 4,970 (23%) after adding the word “engagement” and dropped further to 2,020 (9.4%) after adding the word “interest”.\n\nWe examined 31 papers. However, as shown in Table 4, only six out of the 31 papers are associated with SOL in HEI in the MCO environment. Further, only two out of these six papers are related to engagement, and no paper is related to the interest element.\n\nTable 5 summarizes the theories, methods and factors used in these 31 papers. Only 8 papers (26%) used qualitative methods, 8 papers (26%) are associated with SOL, 5 papers (16%) are related to engagement, no paper (0%) is related to interest, 11 papers (35%) are related to HEI and 19 papers (61%) are related to MCO. However, only 2 papers (6%) were associated to SOL, engagement, HEI and MCO. Therefore, the research in the area of student’s engagement and interest, particularly that associated with SOL in HEI in the MCO environment.\n\nSOL = synchronous online learning; MCO = movement control order; HEI = higher education institution.\n\nTable 6 presents the plotting of 31 papers to engagement, interest, synchronous online learning (SOL), movement control order (MCO) and higher education institutions (HEIs).\n\nTable 5 and Table 6 show that, student’s engagement and interest associated with SOL in HEIs in the MCO environment is insufficiently researched. The online databases search results in Figure 3 also shows that only two papers are relevant to our research.\n\n\nDiscussion\n\nTable 7 presents the summary of the six papers related to synchronous online learning (SOL) in higher education institutions (HEIs) in the movement control order (MCO) environment.\n\nCOVID-19 = coronavirus disease 2019.\n\nThree major research gaps were identified:\n\nResearch gap 1: SOL in HEI during MCO context\n\nOnly six papers31–36 are related to HEI in the MCO environment. Therefore, this new phenomenon warrants further investigation by the research community.\n\nResearch gap 2: Engagement and interest elements\n\nOnly two papers31,32 related to engagement are associated with SOL in the MCO environment. The study on SOL associated with engagement and interest is clearly insufficient. Moreover, Paper 131 focused only on students’ cognitive engagement, such as attitude, affect, and motivation, whereas Paper 232 focused on accounting lecturers’ reflection regarding students’ engagement during synchronous and asynchronous online classes. Engagement can be categorized into cognitive, behavioral and emotional engagement.20 A holistic view on students’ engagement should include these three dimensions. Next, students’ interest in learning via SOL will affect the quality of engagement. Nevertheless, interest as a factor associated with SOL in HEI in the MCO environment has not been researched intensively. Therefore, the inclusion of interest warrants the attention of the research community.\n\nResearch gap 3: Method\n\nIn total, seven qualitative research methods were identified from the 31 papers. Only one paper used case study method. SOL in HEIs in the MCO environment is a new phenomenon that may require a more in-depth investigation method, such as a case study method to gain better insights.\n\nTable 8 presents the following limitations of the six papers pertaining to SOL associated with engagement and interest in HEI in the MCO environment.\n\nThree limitations were identified from the 31 selected papers:\n\ni. These papers mainly focused on the cognitive dimension of engagement. Therefore, the inclusion of behavioral and emotional dimensions may be important for a holistic understanding of students’ engagement. Next, engagement is a personal factor. Therefore, investigating students directly to gauge their engagement level is important.\n\nii. Few papers related to the interest element pertaining to SOL in the MCO environment exist. Interest is closely associated with engagement in the learning process. Therefore, interest must be included in the study of SOL in HEI in the MCO environment.\n\niii. An in-depth understanding of how students are engaged, and their interest sustained through case study research will help complement the findings derived from quantitative studies pertaining to SOL associated with engagement and interest in HEI in the MCO environment.\n\nTherefore, Figure 4 is the conceptual framework for students’ engagement and interest pertaining to SOL in HEI in the MCO environment.\n\nCOVID-19 = coronavirus disease 2019.\n\n\nFuture recommendations\n\nGiven the findings and discussions for this systematic literature review, Table 9 presents recommendations for future research in association with SOL in HEI under MCO.\n\n\nConclusions\n\nThis systematic literature review highlighted three research gaps associated with SOL in HEI in the MCO environment. A conceptual framework is proposed for future research.\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 flow diagram and checklist for ‘Synchronous online learning during movement control order in higher education institutions: a systematic review. https://doi.org/10.6084/m9.figshare.16752031.v1.62\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgements\n\nWe thank the Multimedia University, Malaysia for supporting this research.\n\n\nReferences\n\nStudyMalaysia.com: The Malaysian Higher Education System – An Overview.2015, March 14.\n\nNoordin N: Higher Education in the time of the coronavirus. The Star Online. 2020, April 14.\n\nBhowmick A, Khasawneh MT, Bowling SR, et al.: Evaluation of alternate multimedia for web-based asynchronous learning. Int. J. Ind. Ergon. 2007; 37(7): 615–629. Publisher Full Text\n\nDlab MH, Boticki I, Hoic-Bozic N, et al.: Exploring group interactions in synchronous mobile computer-supported learning activities. Comput. Educ. 2020; 146: 103735. Publisher Full Text\n\nMartin F, Oyarzun B:Distance Learning.West RE, editors. Foundations of Learning and Instructional Design Technology. EdTech Books;2018.Reference Source.\n\nWatts L: Synchronous and asynchronous communication in distance learning: A review of the literature. Quarterly Rev. 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Publisher Full Text\n\nCaligiuri P, De Cieri H, Minbaeva D, et al.: International HRM insights for navigating the COVID-19 pandemic: Implications for future research and practice.2020.\n\nPacheco JA: The “new normal” in education. Prospects. 2020; 0123456789. Publisher Full Text\n\nMoura GG, Nascimento CRR, Ferreira JM: COVID-19: Reflections on the Crisis, Transformation, and Interactive Processes Under Development. Trends in Psychology. 2021; 29(2): 375–394. Publisher Full Text\n\nChang S, Kuo AC: Indulging interactivity: a learning management system as a facilitative boundary object. SN Soc. Sci. 2021; 1(2): 1–15. Publisher Full Text\n\nLeal Filho W, Price E, Wall T, et al.: COVID-19: the impact of a global crisis on sustainable development teaching. Environ. Dev. Sustain. 2021; 23: 11257–11278. Publisher Full Text\n\nDorasamy M, Lee YW: Prisma Flow Diagram and Checklist. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "97295",
"date": "02 Nov 2021",
"name": "Manjula Nagarajan",
"expertise": [
"Reviewer Expertise Synchronous Online learning (SOL)",
"Impact of the learning process during the pandemic",
"impact of SOL on the Case teaching method a pedagogy in Management 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 authors have done a very good work. During Pandemic ( the MCO Environment) the learning process was the most hit and children were really suffering across globe. This systematic review would help authors to get into an in-depth research of SOL. Hence the area and the topic of the research is well connected with the need of the hour.\nIn this paper the analysis is done well and it is suggested that the authors can add on a country-wise analysis of the research papers. This could give us an idea as to which continent had contributed to this area of research more and would have paved way for increasing the scope of the research.\n\nAre the rationale for, and objectives of, the Systematic Review clearly stated? Yes\n\nAre sufficient details of the methods and analysis provided to allow replication by others? Yes\n\nIs the statistical analysis and its interpretation appropriate? Not applicable\n\nAre the conclusions drawn adequately supported by the results presented in the review? Yes",
"responses": [
{
"c_id": "7443",
"date": "08 Dec 2021",
"name": "Magiswary Dorasamy",
"role": "Author Response",
"response": "Thank you so much. We have addressed the comment: In this paper the analysis is done well and it is suggested that the authors can add on a country- wise analysis of the research papers. This could give us an idea as to which continent had contributed to this area of research more and would have paved way for increasing the scope of the research. Author's comment: Included a column of country-wise analysis for all the 31 identified papers in Table 5."
}
]
},
{
"id": "97281",
"date": "09 Nov 2021",
"name": "Jessica Sze Yin",
"expertise": [
"Reviewer Expertise Digital Marketing",
"higher education",
"sustainability"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis study is an interesting study in view of the lockdown situation. The paper is also written in a very straight-forward manner that makes it easy to follow.\nSome additional comments on the paper:\nSOL is also sometimes used in different terminologies for example hybrid-classroom. Has this been incorporated as a search term? If not, including this in the limitation of this research will be helpful for future research.\n\nSimilarly, MCO is a local term. It is good to see that COViD-19 has been used as a keyword. To appeal to a larger audience, other terms such as lockdown or circuit-breaker may have been studied globally. Adding more papers incorporating these search terms can help to attract a larger international audience. Justifying this will be essential for this study.\n\nGenerally, the findings of this paper is rather limited. The ultimate findings were based on 6 papers. Are there any other literature gaps that can be identified in this systematic literature review based in the 31 papers identified?\n\nMore critical discussion on the findings is expected - implication to theory and practice.\n\nConclusion - needs enhancement.\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? No",
"responses": [
{
"c_id": "7432",
"date": "08 Dec 2021",
"name": "Lee Yee Wan",
"role": "Author Response",
"response": "Thank you very much for the feedback. The authors feedback - 1. Will include hybrid-classroom as limitation in this study. 2. Agreed that search strategy should include other terminologies as suggested. 3. The rest of the papers in the systematic literature review are irrelevant to our research's focus areas. 4. Implication to theory: new conceptual framework related to synchronous online learning during movement control order. Implication to practice: suggestions and recommendations for future synchronous online learning during movement control order. 5. Will enhance the conclusion as suggested. Thank you very much."
},
{
"c_id": "7442",
"date": "08 Dec 2021",
"name": "Magiswary Dorasamy",
"role": "Author Response",
"response": "1. SOL is also sometimes used in different terminologies for example hybrid-classroom. Has this been incorporated as a search term? If not, including this in the limitation of this research will be helpful for future research. Author's comment: This suggestion had been addressed in the “selection process” first paragraph in the last second and third lines of this paragraph. This suggestion had been addressed in the “selection process” first paragraph in the last second and third lines of this paragraph. 2. Similarly, MCO is a local term. It is good to see that COViD-19 has been used as a keyword. To appeal to a larger audience, other terms such as lockdown or circuit-breaker may have been studied globally. Adding more papers incorporating these search terms can help to attract a larger international audience. Justifying this will be essential for this study. Author's Comment: This suggestion had been addressed in the “selection process” first paragraph in the last line of this paragraph. 3. Generally, the findings of this paper is rather limited. The ultimate findings were based on 6 papers. Are there any other literature gaps that can be identified in this systematic literature review based in the 31 papers identified? Author's Comment: Added one more limitation related to the rest of identified papers (25 papers) in the section of the “Four limitations were identified from the 31 identified papers”. 4. More critical discussion on the findings is expected - implication to theory and practice. Author's comment: Added more discussions in the discussion section. 5. Conclusion - needs enhancement. Author's comment\" Enhanced the conclusion."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1056
|
https://f1000research.com/articles/10-1170/v1
|
18 Nov 21
|
{
"type": "Research Article",
"title": "Mobile banking adoption and usage among Generation Y Malaysians",
"authors": [
"Momen Tarawneh",
"Lan Thi Phuong Nguyen",
"Yong Fie",
"Lan Thi Phuong Nguyen",
"Yong Fie"
],
"abstract": "Background: By 2018, Malaysian mobile banking services made the third-largest amount of banking transactions, following credit card and Internet banking. In addition, it significantly contributes to the banking industry by providing easier transactions to banking consumers. This study examined factors affecting the intention to use, and the actual use of mobile banking services in Malaysia. Methods: Two main theories of the unified theory of acceptance and use of technology (extended version, UTAUT2), and the model of perceived risk, were used to propose a modified framework. Based on the non-probability sampling method, the data were collected from 504 respondents. The data vas analyzed using SPSS and PLS-SEM to derive the findings. Results: The study's findings revealed that the independent variables could explain 55.3% of the variance in mobile banking use and 60.3% of variance in intention to use variables. Moreover, it demonstrated that common factors that have significantly affected the actual use and intention to use mobile banking were habit, facilitating condition, and interface design quality. In contrast, perceived risk and intention to use were found to only have significant impacts on the use of mobile banking, while effort expectancy was found to only have a significant impact on the intention to use. Conclusions: The findings of this study provide significant new knowledge on mobile banking, from which mobile banking providers and interface designers can develop potential solutions to increase the usage of mobile banking services in Malaysia. However, using a qualitative method, the proposed model could only explain 55% of actual use and 60% of intentional use. Thus, additional variables and qualitative techniques may help increase the understanding on the actual use and intention to use.",
"keywords": [
"Mobile banking",
"Information system quality",
"UTAUT2",
"Interface design quality"
],
"content": "Introduction\n\nWith the development of technology, financial technology (fintech) innovations profoundly changed the customer experience and delivered financial products and services. The growth of fintech start-ups shows that in 2006 alone, their numbers had doubled by more than 2,000.\n\nThe continued growth was highly expected, as innovators tap into the preferences of millions of millennials, who are technology savvy and more interested in the new ways of using financial services (BNM, 2016).\n\nMobile banking is a subcategory of online banking. Online banking, Internet banking, or e-banking are based on the same concept of allowing the banking services such as monitoring, payment, and transfer to be available to the banks' customers via a secure website. Mobile banking is the other side of the coin of Internet banking, but instead of using desktop Internet applications, it uses intelligent device applications (Aithal and Kumar, 2016). Moreover, developers and practitioners have designed and added multiple new alternatives of banking solutions, which are more practical, flexible and easy to use than traditional banking services.\n\nContemporary banking services have become essential for all generations, especially customers from generation Y, who were born between 1981 and 1996 (Hui-Chun et al., 2003). As stated by the Asian Institute of Finance in 2015, “Generation Y in Malaysia's business domain are an enormous pie of the consumer's national cake. They will rapidly occupy the governance and high-level managerial positions in today's business. Therefore, the banking industry has an excellent opportunity to develop and offer creative solutions to satisfy these influential technology-guru consumers needs and behaviour” (Asian Institute of Finance, 2015).\n\nAccording to the 2018 report issued by the Bank Negara of Malaysia, among the amounts of money transferred through various payment channels such as Internet banking, mobile banking, ATM payment transaction, credit card, charge card and debit card between 2005 to 2018, the Internet banking channel had the highest-value transaction channel in 2018, i.e., RM607.5 billion (equivalent to USD146.24 million). In comparison, mobile banking had the third-ranking overpayment channel value, with RM 78.36 billion in the same year.\n\nNoticeably, the trend of Internet banking value started falling from 2017 to 2018, while the value of mobile banking showed a dramatic four-fold upsurge trend between 2015 and 2018. The number of transactions using the mobile banking channel is substantial. Statistics show that the number of transactions increased naturally, except for the volumes of the mobile banking channel. However, they revealed a swift increase starting from 2012 and continuous growth, reaching 1688.8 million transactions in 2018, and surpassing the volumes of both credit cards (366.4 million transactions) and Internet banking (557.2 million transactions).\n\nAlthough the mobile banking channel has been welcomed by most countries worldwide, including Malaysia, many challenges are faced in terms of privacy, security, bank customers' sophistication, banking infrastructure, and governmental regulation. In terms of the adoption of mobile banking services, limited studies were done in Malaysia (Amin et al., 2007; Cheah et al., 2011; Ewe and Yap, 2012; Krishanan et al., 2015; Shaikh and Karjaluoto, 2014).\n\nThe lack of trust in financial technology may lead to a low volume of payments made through mobile banking and electronic banking (Sun et al., 2017). David Carf (2012) studied the operational risks of mobile banking and put forward the existence of significant operational risks: mobile phone operation risk, information asymmetry risk, credit risk, and mobility risk. Afshan and Sharif (2016) analyzed the security structure of mobile banking, the quality of mobile communications technology, making a significant contribution to the use of mobile banking. Lin (2013) studied the relationship between trust in mobile banking and mobile banking payment process, using diffusion of innovation and trust theories. Their results showed that the relative advantage and perceived ease of use strongly influence mobile phone users' attitudes towards mobile banking.\n\nMobile devices that serve as channels for accessing banking services have presented a critical concern for many financial organizations. Using mobile devices, customers can access other third-party services from multiple agencies via the Internet (Kalkbrenner and McCampbell, 2011). The quality of the information provided through mobile banking technologies is seen as one of the most critical factors towards organizational achievement and success. Currently, there is a lack of research on the framework for evaluating the quality of interface design for mobile banking. The evaluation of information quality on mobile interface design for banking services is unclear (Zamzami et al., 2012). The interface design quality of mobile banking services is examined in this research.\n\nThis work investigated the phenomenon of the inefficient use of mobile banking service among Malaysian citizens; this study will emphasize the roles of perceived risk and interface design quality, among other technical and human factors. Hence, this study aims to bridge the gaps in previous literature and provide valuable guidelines to determine the factors that influence the intention to use mobile banking among banking users in Malaysia.\n\nThis study is structured as follows: the next section discusses the study's theoretical background; the third section presents the study's conceptual framework; the fourth section highlights the methodology used; the fifth section describes the interpretations and discussion of the analyses. Finally, the sixth section highlights the concluding remarks and future directions of the study.\n\nTwo main theories contribute to the construction of the proposed model, its variables and relations. Those two theories are the unified theory of acceptance and use of technology – extended version (UTAUT2) and model of perceived risk. In addition, the interface design quality variable was added for its importance in mobile applications.\n\nWhen the founder of the UTAUT model, Venkatesh et al. (2003), attempted to develop a new model, they examined eight known models that could explain up to 53% of the behavioural intention to use and actual use. While Venkatesh et al. (2003) proposed the UTAUT model by integrating the concepts of eight related models and frameworks, empirical results show that the model can explain 70% of the variance in the behavioural intention to use and actual use. The UTAUT model is comprised of four factors: performance expectancy, effort expectancy, social influence, and facilitating conditions, to predict behavioural intention of using and actual use of technology. Venkatesh, Thong, and Xu (2012) proposed an extension of their previous model by adding three new variables to comprehend the coverage of consumer context. These additional three variables were “hedonic motivation”, “price value”, and “habit”.\n\nFeatherman and Pavlou (2003) expanded the scope of the e-services adoption decision by including the potentially harmful use (potential risks), to determine the importance of risk perceptions to the e-services adoption and use. The potential risks were defined and integrated with the technology acceptance model (TAM). The newly proposed model was then empirically tested using the second-order confirmatory factor analysis, to measure the relative importance of each potential risk, using a structural equation modelling for overall fit to the model. Figure 2 shows an infographic of the concepts and relations. The model is built upon TAM model assumptions, as it has the three variables mentioned earlier: usefulness, ease of use, and behavioural intention. The new dimension is perceived risk with seven sub-dimensions. Within the model, adoption intention towards electronic systems is influenced by perceived usefulness and ease of use. Perceived ease of use relates to perceived usefulness and perceived risk, which is the predictor of perceived usefulness. The model assumption is that the more perceived risk the consumer encounters, the less they perceive a usefulness from the desired electronic system. The seven sub-dimensions of perceived risk are “performance risk, financial risk, privacy risk, time risk, psychology risk, and social risk” (Featherman and Pavlou, 2003).\n\nInterface design quality concept refers to techniques and methods to facilitate information display and presentation (Bharati and Chaudhury, 2004). The primary and first act in mobile banking is looking at a small screen, therefore making an excellent first impression is critical to appealing to consumers (Everard and Galletta, 2005). Likely, Everard and Galletta (2005) stated that decent interface design quality such as appearance, format, and processing quality increase mobile banking adoption. Several studies have measured similar factors such as display colours, display formats, graphical design and how these elements affect adoption and satisfaction (Everard and Galletta, 2005; Lohse and Spiller, 1998, among others).\n\nFeatherman and Pavlou (2003) expanded the scope of the e-services adoption decision by including the potentially harmful use (potential risks), to determine the importance of risk perceptions on e-services adoption and use. The potential risks were defined and integrated with the technology acceptance model (TAM). The newly proposed model was then empirically tested using the second-order confirmatory factor analysis, to measure the relative importance of each potential risk, using a structural equation modelling for overall fit to the model. Figure 2 shows an infographic of the concepts and relationships. The model was built upon TAM model assumptions, as it comprised the three following variables: usefulness, ease of use, and behavioural intention. The new dimension was perceived risk, with seven sub-dimensions. Within the model, adoption intention towards electronic systems was influenced by perceived usefulness and ease of use. Perceived ease of use relates to perceived usefulness and perceived risk, which is the predictor of perceived usefulness. The model assumption was that the more perceived risk the consumer encounters, the less perceived usefulness from the desired electronic system they will experience. The seven sub-dimensions of perceived risk are “performance risk”, “financial risk”, “privacy risk”, “time risk”, “psychology risk”, and “social risk” (Featherman and Pavlou, 2003).\n\nInterface design quality concept refers to techniques and methods employed to facilitate information display and presentation (Bharati and Chaudhury, 2004). The first action in mobile banking use is looking at a small screen, therefore making an excellent first impression is critical to appeal to consumers (Everard and Galletta, 2005). Likely, Everard and Galletta (2005) stated that decent interface design quality such as appearance, format, and processing quality increased mobile banking adoption. Several studies have measured similar factors such as display colours, display formats, graphical design, as well as how these elements affected adoption and satisfaction (Everard and Galletta, 2005; Lohse and Spiller, 1998).\n\nThis study proposes a modified framework with eleven variables: “actual use”, “behavioural intention”, “performance expectancy”, “effort expectancy”, “social influence”, “facilitating conditions”, “hedonic motivation”, “price value”, “habit”, “perceived risk”, and interface design quality”.\n\nPerformance expectancy and intention\n\nThe performance expectancy concept is defined as the extent to which individuals believe that the desired technology will offer a better reward and benefits (Venkatesh et al., 2003). Yang (2013) indicated that performance expectancy positively affects students' mobile learning adoption. Also, Raman and Don (2013) mentioned that performance expectancy significantly impacts consumer behavioural intention. Furthermore, Kit et al. (2014) found that performance expectancy influences behavioural intention in adopting mobile applications. Based on the above, it is hypothesized that:\n\nPerformance expectancy has a positive influence on behavioral intention.\n\nEffort expectancy and intention\n\nAccording to Kit et al. (2014), Effort Expectancy (EE) influences behavioural intention to adopt mobile applications. The effort expectancy concept is defined as the extent to which an individual believes that he will encounter a technology that is simple, easy and that fits within his skills (Venkatesh et al., 2003). Cheah et al. (2011) found that perceived ease of use was positively related to adopting mobile banking services. This result is supported by Tan and Leby Lau (2016), who mentioned that EE is considered a strong predictor of intention to adopt mobile banking. Based on the above, it is hypothesized that:\n\nEE has a positive influence on behavioral intention.\n\nSocial influence and intention\n\nThe social influence concept is defined as the extent of pressure an individual can encounter from society or surrounding people regarding the new technology use and adoption (Venkatesh et al., 2003). Phonthanikitithaworn, Sellitto, and Fong (2015) found that the subjective norm significantly affects consumer adoption of mobile payment services in Thailand. This result was consistent with Yang (2013), who indicated that social influence positively affects students' mobile learning adoption. Moreover, social influence had a significant impact on the behavioural intention to use Moodle, known as Learning Management System, designed to assist educators at University Utara Malaysia (Raman and Don, 2013). Similarly, AbuShanab and Pearson (2007) found that the social influence variable significantly predicted customers' intention to adopt Internet banking in Jordan.\n\nBased on the above, it is hypothesized that:\n\nSocial influence has a positive influence on behavioral intention.\n\nHedonic motivation and intention\n\nThe hedonic motivation concept is defined as the extent individuals believe that using the desired technology will provide fun, enjoyment, or pleasure (Venkatesh et al., 2003). A study by Raman and Don (2013) indicated that hedonic motivation is considered as a predictor of behavioural intention. In addition, Yang (2013) indicated that hedonic motivation positively affects students' mobile learning adoption. Kit et al. (2014) found that hedonic motivation influences behavioural intention in adopting mobile applications for mobile banking in Malaysia. Alalwan et al. (2017) found that the influence of Hedonic motivation positively predicts behavioral intention, which, in turn, positively influenced the adoption of mobile banking. Based on the above, it is hypothesized that:\n\nHedonic motivation has a positive influence on behavioral intention.\n\nPrice value and intention\n\nPrice value was one of the most significant factors that influenced behavioral intention to adopt mobile banking (Slade et al., 2013). The price value concept is defined as the extent consumers believe that any additional cost of using the technology is worthy, meaning the consumer will evaluate whether the perceived benefits deserve any additional cost (Venkatesh, Thong, and Xu, 2012). Individual intention to adopt mobile banking was significantly influenced by perceived financial cost (Yu, 2012). Similarly, Phonthanikitithaworn et al. (2015) indicated that consumer adoption of mobile payment and mobile banking services in Thailand were significantly influenced by perceived cost. Based on the above, it is hypothesized that:\n\nPrice value has a positive influence on Behavioral Intention.\n\nHabit and intention\n\nThe habit concept is defined as the routine and dependency of the consumer towards using the desired technology and is usually related to the consumer's prior use of the system (Venkatesh, Thong, and Xu, 2012). Based on empirical analysis of young users of 'smart devices', Kit et al. (2014) found that Habit influences behavioural intention to adopt mobile applications. On the contrary, Raman and Don (2013) found that habit does not influence behavioural intention to accept the Learning Management System designed for educators at University Utara Malaysia. This result is consistent with the findings of Yang (2013), who found that the habit of using a mobile device has an insignificant influence on the students' intention to use mobile learning. Based on the above, it is hypothesized that:\n\nHabit has a positive influence on behavioral intention.\n\nHabit has a positive influence on system use.\n\nFacilitating conditions and intention\n\nThe concept of facilitating conditions is defined as the extent to which individuals believe that the technical and organizational infrastructures are enough and ready for use and adoption of the new technology (Venkatesh et al., 2003). The study by Raman and Don (2013) indicated that facilitating conditions are considered a predictor of behavioural intention. However, according to Kit et al. (2014), facilitating conditions do not influence behavioural intention to adopt mobile applications. Likewise, Alalwan et al. (2015) found that the facilitating conditions can positively predict behavioral intention, which, in turn, positively influences the adoption of mobile banking. Moreover, Zhou et al. (2010) revealed consistent findings that facilitating conditions could significantly affect a user’s mobile banking adoption. Based on the above, it is hypothesized that:\n\nThe facilitating conditions concept has a positive influence on behavioral intention.\n\nThe facilitating conditions concept has a positive influence on System Use.\n\nPerceived risk and intention\n\nFeatherman and Pavlou (2003) defined “perceived risk” as “the potential for loss in the pursuit of the desired outcome of using an e-service”. They identified seven types of potential risks: performance risk, financial risk, time risk, psychological risk, social risk, privacy risk and overall risk. Wong et al. (2009) investigated whether the perceived risk would influence e-banking trust and the willingness to use e-banking. They found that perceived risk has a direct influence on a consumer's intention to use e-banking. Furthermore, consumers who have a low perceived risk when using the Internet for transactions generally show more intention to use e-banking. In a study of customer risk perceptions of Internet banking in Turkey, Demirdogen et al. (2010) showed that financial, psychological, and safety risks are more evident among customers not using Internet banking than in e-banking users. In another study by Khraim et al. (2011), perception was one of the most influential factors affecting consumers' adoption of mobile banking services. Based on the above, it is hypothesized that:\n\nPerceived risk has a positive influence on behavioral intention.\n\nPerceived risk has a positive influence on system use.\n\nInterface design quality\n\nEverard and Galletta (2005) examined features such as screen appearance, format, and processing quality. Several studies have measured similar factors such as display colours, display formats, graphical design and how these elements affect adoption and satisfaction (Everard and Galletta, 2005; Lohse and Spiller, 1998). Based on the above, it is hypothesized that:\n\nInterface design quality has a positive influence on behavioral intention.\n\nInterface design quality has a positive influence on system use.\n\nThe study is proposing a refined model that is partly based on the UTAUT 2 model. The seven determining factors of the UTAUT 2 model were “performance expectancy”, “effort expectancy”, “social influence”, “facilitating conditions”, “hedonic motivation”, “price value”, and “habit”; the proposed model includes two additional dependent variables: intention to use mobile banking and actual use of mobile banking. Two additional determinants, perceived risk and interface design quality were added to the model. The perceived risk dimension was added with the support of the perceived risk model proposed by Featherman and Pavlou (2003). The proposed model in this study is shown in Figure 1.\n\n\nMethods\n\nThe study's sampling design aimed to be representative of all Malaysian Generation Y citizens, to assess their use of mobile banking services from commercial, public banks in the Klang Valley, Malaysia. The banks were AmBank (M) Berhad, CIMB Bank Berhad, Malayan Banking Berhad, OCBC Bank (Malaysia) Berhad, Public Bank Berhad, RHB Bank Berhad, and Alliance Bank Malaysia Berhad.\n\nBased on the statistics from the World Population Review (2017), the Klang Valley population was estimated to be 7.3 million. According to the statistics from AseanUp (2016), 33.6% of Malaysian citizens belonged to Generation Y. Therefore, the estimated population for this study was 2.5 million. According to Morgan's formula (1970) the optimal sample size required to represent a 2.5 million population was 384. The study adopted a purposive sampling technique and employed a self-administered survey, to collect empirical data from a sample of 384 Malaysians born between 1981 and 1996.\n\nThe questionnaire was constructed based on well-designed ones used by Venkatesh et al. (2003); Featherman and Pavlou (2003); and Lee and Chong (2009). The questionnaire data were collected in August, September, and October 2018 directly, by distributing the questionnaire in a variety of Universities, banks and shopping malls within the Klang Valley area. The questionnaire consisted of two parts: (1) socio-demographic characteristics and consumers' perception towards the use of mobile banking; (2) questions on the studied variables regarding the participants’ perception of the mobile banking system.\n\nData obtained from the survey were transformed and coded in an Excel spreadsheet and analyzed by the researcher himself using Statistical Package for the Social Sciences (SPSS v.22) software and SmartPLS v.3.0. Partial least square (PLS) is a structural equation modelling (SEM) technique that can simultaneously test the measurement model and structure model (relationships between constructs).\n\nA total of 655 surveys were distributed, of which 583 were collected; the final cleaned data set comprised 536 responses. The survey collection rate was 89 %, and the valid surveys rate was 91.94%.\n\nInformation filtering was performed both manually and using analytical procedures. We manually filtered the 16 unfitted cases due to the participants of the study stating that their age was outside the Generation Y group (18-38 years), or that they were not Malaysian residents, as well as 31 unfinished cases where participants did not respond to all items (see Table 1). The analytical procedures filtered the unengaged cases, which corresponded to one case in which the participant's responses presented a repetitive norm, and the univariate outlier cases, which corresponded to 31 cases where the participant's explanation for a solitary variable was uncommon (see Table 1).\n\nFor the respondents' profile, 52.2% of the respondents were female, 53.6% of the respondents were male. All respondents were aged between 18-27 years, among which 57.1% were Malay, 50.8 % had a Bachelor's degree education, 39.3% were working in the private sector, 59.9% had an income lower than 3000 RM, and 64.1% were using mobile banking for at least one year. By asking the respondents about their experience of using mobile banking, more than 87.9% of respondents answered that they had good experience with mobile banking use.\n\nThis study was approved by the Ethical Review Board of the Multimedia University, Cyberjaya, Malaysia, with reference number TTO/REC/EA/124/2021.\n\nAll respondents were informed about the objectives of the survey and that participation was voluntary, and therefore consent was assumed from participation.\n\n\nResults\n\nThe selected sample satisfied standards of data validity and reliability, indicator reliability, internal consistency reliability, convergent validity, discriminant validity, and collinearity assessment. The model was fit for path coefficient estimations. The outer loading test carried out to ensure that the absolute contribution of each indicator to the construct was at least 0.708was passed successfully after excluding the overall risk (see Table 2). For discriminate validity, cross-loadings of each item in the construct were examined. The cross-loading test showed that all indicators had higher loadings with their respective construct than the cross-loadings with the other constructs in the model (see Table 3).\n\nAVE: average variance extracted.\n\nEE: effort expectancy; FC: Facilitating conditions; MBU: mobile banking use; IU: intention to use mobile banking; PE: performance expectancy; SI: social influence; HM: hedonic motivation; PV: price value; HA: habit; IDQ: interface design quality; FR: financial risk; PR: performance risk; TR: time risk; SR: social risk; PsR: psychological risk; PvR: privacy risk.\n\nThe primary endogenous latent variable is mobile banking use; the findings in Table 3 demonstrates that the associated predictive power (coefficient of determination) R-square was 0.553, and the associated predictive relevance Q-square was 0.473. For the proposed model, the exogenous variables habit, facilitating conditions, interface design quality, perceived risk and intention to use mobile banking had a sizeable predictive relevance and moderate predictive power. The second endogenous latent variable was intention to use; results show that the associated predictive power (coefficient of determination) R-square was 0.603, and the associated predictive relevance Q-square was 0.58.5. For the study model, the exogenous variables effort expectancy, facilitating conditions, performance expectancy, social influence, hedonic motivation, price value, habit, interface design quality and perceived risk had a sizeable predictive relevance and a moderate predictive power. The detailed results are given in Table 4.\n\nTable 5 shows the path coefficient assessment with t-statistic values and Beta values. For the main dependent variable, mobile banking use, all five variables were significantly correlated to mobile banking use. The precedence for the correlations based on the path coefficient value (Beta) were interface design quality (0.298), habit (0.187), facilitating conditions (0.272), intention to use mobile banking (0.161), and perceived risk (−0.076). Eight variables were significantly correlated to the second dependent variable, intention to use Mobile Banking. The precedence for the correlations based on the path coefficient value (Beta) were effort expectancy (0.289), facilitating conditions (0.116), habit (0.109), interface design quality (0.239), hedonic motivation (0. 0.158), perceived risk (−0.079), social influence (−0.079) and performance expectancy (0.115). Price value was not significantly related to intention to use mobile banking; the precedence for the correlations based on the path coefficient value (Beta) for price value was (0.044). As shown in Figure 2, one correlation was rejected, and thirteen hypotheses were accepted at the common significance level of 5%.\n\nThe effective size of the performance expectancy, effort expectancy, habit, facilitating conditions and interface design quality on intention to use mobile banking variables was satisfactory, with a level range between 0.016 and 0.032. The variables social influence, hedonic motivation, price value, and perceived risk had an effective size with less than 0.007. In addition, the variables habit, facilitating conditions, interface design quality, perceived risk, and intention to use mobile banking had a satisfactory level of effective size on mobile banking use, with a level range between 0.018 and 0.060.\n\n\nDiscussion\n\nThe final dataset was examined for reliability and validity, as well as loading, convergence, and discriminate measures. Regarding the first outcome variable mobile banking use, the R-square value was 0.553, and the Q-square value was 0.473. The explanatory variables habit, facilitating conditions, interface design quality, perceived risk, and intention to use mobile banking could predict 55.3% and rebuild 47.3% of the mobile banking use variance. Regarding the second outcome variable, intention to use mobile banking, the R-square value was 0.603, and the Q-square value was 0.585. The explanatory variables performance expectancy, effort expectancy, social influence, hedonic motivation, price value, habit, facilitating conditions, interface design quality and perceived risk, could predict 60.3% and rebuild 58.5% of the variance in intention to use mobile banking.\n\nIn general, we can conclude that the model presented in this study is a successful tool for predicting young people’s (generation Y) actual use and intention to use mobile banking services in Malaysia. However, the complementary percentages (approximately 44.7% for actual use and 39.7% for intentional use) show that another determinant, not covered in this study, explains this significant percentage. For mobile banking use, all variables were significantly related to mobile banking use: the habit variable showed correlation results consistent with prior studies (Venkatesh et al., 2012; Kit et al., 2014; Baabdullah et al., 2019); the facilitating conditions variable also showed a similar effect on the response variable compared to prior studies (Venkatesh et al., 2003; Raman and Don, 2013; Slade et al., 2013; Alalwan et al., 2015; Baabdullah et al., 2019). Interface design quality yielded correlation results consistent with prior studies (Fung and Lee, 1999; Everard and Galletta, 2005; Lin, 2013; Al-Otaibi et al., 2018). The perceived risk variable yielded consistent results with prior studies (Venkatesh et al., 2003; Raman and Don, 2013; Slade et al., 2013; Alalwan et al., 2015; Zhou et al., 2010).\n\nFor intention to use mobile banking, all variables were significantly related to intention to use mobile banking, except for price value: the performance expectancy variable showed results consistent with prior studies (Venkatesh et al., 2003; Davis, 1989; Baabdullah et al., 2014; AbuShanab and Pearson, 2007; Tan and Leby Lau, 2016; Alalwan et al., 2015, 2017), the relationship between effort expectancy and intention to use mobile bankingwas consistent with findings from prior studies (Venkatesh et al., 2003; Davis, 1989; Baabdullah et al., 2014; AbuShanab and Pearson, 2007; Tan and Leby Lau, 2016; Alalwan et al., 2015, 2017). The effect of social influence was also consistent with findings from prior studies (Venkatesh et al., 2003; AbuShanab and Pearson, 2007; Tan and Leby Lau, 2016; Abbas et al., 2018; Farah et al., 2018). Similarly, hedonic motivation showed consistent results with prior studies (Venkatesh et al., 2003; Alalwan et al., 2015, 2017; KIT et al., 2014; Gharaibeh & Arshad, 2018; Farah et al., 2018). The habit variable showed similar results as reported in prior studies (Venkatesh et al., 2012; KIT et al., 2014; Farah et al., 2018; Baabdullah et al., 2019). The facilitating conditions (Venkatesh et al., 2003; Raman and Don, 2013; Alalwan et al., 2015; Farah et al., 2018; Baabdullah et al., 2019), perceived risk (Featherman and Pavlou, 2003; Al Khasawneh et al., 2018; Kavita et al., 2018; Moorthy M. et al., 2018), and interface design quality variables also showed correlation results consistent with findings from prior research (Fung and Lee, 1999; Everard and Galletta, 2006; Lin, 2013; Al-Otaibi et al., 2018).\n\nResults show that interface design quality is the highest predictor of mobile banking use and the second predictor of the intentional use of mobile banking in Malaysia. Interface design quality supports the importance of the application’s appearance and design in appealing to users and directing them towards mobile banking use. Effort expectancy was the best predictor of intentional use; the ease of use of mobile banking applications, represented by the effort expectancy, is related to interface design quality as well. Therefore, effort expectancy and interface design quality are important for making mobile banking appealing to users.\n\nIn addition, perceived risk was found to impact intention to use and actual use of mobile banking in Malaysia. While this variable showed the weakest influence on intention and use, it is supposed that people become familiar with advanced technologies and do not feel threatened by mobile applications use. Therefore, specific efforts should be made by mobile application designers to make the mobile banking applications easier and effortless.\n\nThe study findings suggest that price value is not a determining factor, and social influence has a weak, negative impact on intention to use mobile banking in Malaysia. While the effect of price value can be explained logically, because banks do not add any extra charges for using the offered mobile services and some even provide promotions to motivate users, social influence is a questionable matter because financial transactions are more personal than using online shopping, or joining social media. Young people’s social circles (family, friends) have a slight influence on the decision to use mobile banking.\n\nTherefore, further studies may conduct qualitative research by using interviews to explain why social influence and price value do not predicting intention in mobile banking. Moreover, the empirical findings show that perceived risk is the variable affecting intention to use or actual use of mobile banking the least. Further interview-based research may also be conducted to explain why perceived risk has a minor effect on mobile banking. Additionally, this study was restricted to people living in Malaysia as well as designed specifically for Generation Y citizens. So, other groups in various countries could have different circumstances which may affect the results. Further studies may also need to focus on exploring additional, undiscovered variables of real use of mobile phone banking.\n\n\nData availability\n\nFigshare: Mobile Banking Adoption and Usage among Malaysians of Generation Y, https://doi.org/10.6084/m9.figshare.14882307 (Al Tarawneh et al., 2021).\n\nThis project contains the following underlying data:\n\n- Dataset_Mobile Banking Adoption and Usage among Malaysians of Generation Y.xlsx (final data set summarising the answers from 504 questionnaire respondents).",
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}
|
[
{
"id": "138145",
"date": "14 Jun 2022",
"name": "Salamata Loaba",
"expertise": [
"Reviewer Expertise banking",
"digital financial",
"gender"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 analyzes the determinants of mobile banking use and intention to use of the 1981-1996 generation in Malaysia. Using survey data and the PLS-SEM method, results indicate that the main determinants of use and intention to use are habit, facilitating condition, and interface design quality. In contrast, perceived risk and intention to use were found to only have significant impacts on the use of mobile banking, while effort expectancy was found to only have a significant impact on the intention to use.\nThe article analyses an important and current issue and we would like to make some comments to improve the quality of the article\nAbstract\nAuthors can give the main policy implication of these results.\n\nIntroduction\nGives the references of this statistics « The growth of fintech start-ups shows that in 2006 alone, their numbers had doubled by more than 2,000. »\n\nIn paragraph 3 of the introduction, you should insist on the advantages of mobile banking. In addition to flexibility and ease of use, you can add \"reduced transaction costs, secure operations, traceability and trust (the fact that you can follow your banking movements creates trust between customers and the bank).\n\nThe statistics in the following paragraph need to be updated (at least 2020 statistics) « According to the 2018 report issued by the Bank Negara of Malaysia, among the amounts of money transferred through various payment channels such as Internet banking, mobile banking, ATM payment transaction, credit card, charge card and debit card between 2005 to 2018, the Internet banking channel had the highest-value transaction channel in 2018, i.e., RM607.5 billion (equivalent to USD146.24 million). In comparison, mobile banking had the third-ranking overpayment channel value, with RM 78.36 billion in the same year.»\n\nThe issue needs to be strengthened. The author discusses the quality of the interface and the trust problem associated with mobile banking. It would be interesting if the author could show some stylized facts about these problems in Malaysia. For example, do the banking structures point out fraud, do consumers complain? For example, in the case of my region, the problem that is often cited is the difficulty related to the internet connection.\n\nReview the following paragraph « Currently, there is a lack of research on the framework for evaluating the quality of interface design for mobile banking. The evaluation of information quality on mobile interface design for banking services is unclear (Zamzami et al., 2012). The interface design quality of mobile banking services is examined in this research. »\nBe more specific. The research was never conducted or the work is unclear. (There are some studies. See 1,2).\n\nThe following sentence « This work investigated the phenomenon of the inefficient use of mobile banking service among Malaysian citizens; this study will emphasize the roles of perceived risk and interface design quality, among other technical and human factors. Hence, this study aims to bridge the gaps in previous literature and provide valuable guidelines to determine the factors that influence the intention to use mobile banking among banking users in Malaysia » - Do you analyze the inefficiency? Or the risk or the determinants of the use of mobile banking?\nBut in the introduction you develop as if it is the problem of quality that is your objective because you say that the literature gap is at this level, and your research is interested in this question. See next sentence « Currently, there is a lack of research on the framework for evaluating the quality of interface design for mobile banking. The evaluation of information quality on mobile interface design for banking services is unclear (Zamzami et al., 2012). The interface design quality of mobile banking services is examined in this research. »\nIn your results you discuss the determinants. If your concern is the quality of the interface the discussions should be focused on this outcome. Review your objectives in accordance with the title of the article « Mobile banking adoption and usage among Generation Y Malaysians » or change the title of the article.\n\nConceptual framework\nH10: Perceived risk has a positive influence on behavioral intention.\nBetter express this hypothesis. The perception of low or high risk?\n\nFigure 1 should be improved. You need to show how the different factors influence adoption. Does it facilitate the use or not. Moreover, when we talk about use, it implies that we already have access to the technology. The authors would benefit from integrating this aspect in their analysis.\n\nMethods\nWhy the choice of generation Y? The justification given is insufficient. And the 2000 generation? Today this generation is part of the fintech star up. More justification is needed. For me, I would opt for a comparative analysis in terms of adoption between two generations before drawing conclusions.\n\nReview your descriptive statistics « For the respondents' profile, 52.2% of the respondents were female, 53.6% of the respondents were male ». For me, the total must be 100%. Check\n\nAfter the presentation of the conceptual framework, it is important in the methods section to present the empirical model with the definition and measurement of the different variables.\n\nIt is also important that you highlight the econometric problems, and justify the choice of the PLS-SEM method.\n\nDiscussion\nYour discussion needs improvement. You should explain why such a result in Malaysia. The result may be similar to other countries but the explanation of this result is not the same, depending on the context.\n\nThe following result « In addition, perceived risk was found to impact intention to use and actual use of mobile banking in Malaysia. » is not accurate. Perceived risk increases or decreases intent to use?\n\nThe authors should include a concluding section showing the economic policy implications of their results.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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": "311235",
"date": "26 Aug 2024",
"name": "Zahoor Ur Rehman",
"expertise": [
"Reviewer Expertise Marketing",
"consumer behavior",
"sustainable products",
"mobile banking",
"internet banking."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 abstract, the authors mention that 2018 is too outdated, please search for the latest reports. You mentioned the qualitative method and in the data collection, you collected data and analyze it through SPSS. How is that possible? The conclusion part does not present what is supposed to be presented. please rewrite. The statement \"According to the 2018 report issued by the Bank Negara of Malaysia\" it is outdated please have a look over the latest reports it is already mid-2024. You used the term \"conceptual framework\" although your framework is purely based on theories. please use the terms Proposed framework or just study model. I do not agree with the development of the hypothesis. please explain each variable in detail and then write about the relationships and justify why are you going to find this relationship as there are already many studies with such relationships. How can Klang Valley represent the whole Malaysia Generation Y? Please justify and write it in Paper. Why you use the purposive sampling technique? please justify. You mentioned \"All respondents were aged between 18-27 years\" so what about the other age group? The respondents' profile discussion is too missy please rewrite in a proper way i.e define the age group 1st, then ethnicity, income level. The discussion section is mostly like the authors compared the results with the previous studies. I think this study is not like a comparative study. Please discuss the results in detail and then you can cite the previous studies. Some of the relationships are negative and significant, that is the real contribution of your study so I couldn't see any discussion related to it. Please justify the results. The conclusion section is missing so how can the authors conclude their study?\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1170
|
https://f1000research.com/articles/10-1168/v1
|
17 Nov 21
|
{
"type": "Research Article",
"title": "WBC-based segmentation and classification on microscopic images: a minor improvement",
"authors": [
"Xin-Hui Lam",
"Kok-Why Ng",
"Yih-Jian Yoong",
"Seng-Beng Ng",
"Xin-Hui Lam",
"Yih-Jian Yoong",
"Seng-Beng Ng"
],
"abstract": "Introduction White blood cells (WBCs) are immunity cells which fight against viruses and bacteria in the human body. Microscope images of captured WBCs for processing and analysis are important to interpret the body condition. At present, there is no robust automated method to segment and classify WBCs images with high accuracy. This paper aims to improve on WBCs image segmentation and classification method. Methods A triple thresholding method was proposed to segment the WBCs; meanwhile, a convolutional neural network (CNN)-based binary classification model that adopts transfer learning technique was proposed to detect and classify WBCs as a healthy or a malignant. The input dataset of this research work is the Acute Lymphoblastic Leukemia Image Database (ALL-IDB). The process first converts the captured microscope images into HSV format for obtaining the H component. Otsu thresholding is applied to segment the WBC area. A 13 × 13 kernel with two iterations was used to apply morphological opening on image to ameliorate output results. Collected cell masks were used to detect the contour of each cell on the original image. To classify WBCs into a healthy or a malignant category, characteristics and conditions of WBCs are to be examined. A transfer learning technique and pre-trained InceptionV3 model were employed to extract the features from the images for classification. Results The proposed WBCs segmentation method yields 90.45% accuracy, 83.81% of the structural similarity index, 76.25% of the dice similarity coefficient, and is computationally efficient. The accuracy of fine-tuned classifier model for training, validation and test sets are 93.27%, 92.31% and 96.15% respectively. The obtained results are high in accuracy and precision are over 96% and with lower loss value. Discussion Triple thresholding outperforms K-means clustering in segmenting smaller dataset. Pre-trained InceptionV3 model and transfer learning improve the flexibility and ability of classifier.",
"keywords": [
"Microscopic Images",
"White Blood Cells",
"Image Processing",
"Image Segmentation",
"Image Classification",
"Convolutional Neural Network"
],
"content": "Introduction\n\nAccording to,1 peripheral blood (PB) or whole blood is the circulating fluid through the entire human body. PB delivers oxygen and nutrients to all the body cells, tissues, and organs, and removes the carbon dioxide and other waste products. It consists of erythrocytes (red blood cells, RBCs), leukocytes (white blood cells, WBCs) and thrombocytes (platelets). RBCs transport oxygen from the lungs to all the body tissues; WBCs fight against the harmful bacteria, parasitic and fungal infections; while platelets clot the blood in wounds on surfaces of the tissue layers. WBCs with a single granulocyte are the monocyte and lymphocyte; while basophil, eosinophil, neutrophil are the WBCs with more than one granulocyte. Lymphocyte can be affected by acute lymphoblastic leukemia (ALL).\n\nLeukemia is a disease formed in tissues that produce large portions of malfunctional and abnormal WBCs that spreads from bone marrow. Based on findings of,2 chronic lymphoblastic leukemia (CLL) (35%) and acute myelogenous leukemia (AML) (32%) are the most common leukemias for adults, while ALL (75%) affects children and teens the most. The World Health Organization (WHO) once stated that ALL is one of the six cancers for children that requires extra attention.3\n\nALL, AML, CLL and chronic myelogenous leukemia (CML) are leukemia subtypes. Fast-growing cancer in lymphoid cells results in the formation of ALL,2 as opposed to CML; while fast-growing cancer in myeloid cells resulted in the formation of AML, as opposed to CLL. Those over 50 years old and children below 5 years old are the main affected populations of ALL, and the disease can be fatal if not treated earlier.4\n\nPB smear analysis can detect potential disorders and inform health status, while pathology tests can help in tracking the ongoing status of infections, allergies, cancers etc.5 A WBC test is one sub-element of a complete blood count (CBC), one of the pathology tests that helps doctors discovers the unexposed infections. The University of Roschester Medical Center (UMRC) has declared that the normal range of WBCs per microliter of blood is 4,000 to 11,000; if WBCs exceed 11,000 per microliter, it is termed as leukocytosis.\n\nTraditional PB smear analysis and CBCs are based on the human inspection. It is laboriously suffered from the intra-observer variability and is not time-efficient or cost efficient. Today, computer-aided diagnosis (CADx) systems are employed and contain four main steps: preprocessing, segmentation, feature extraction, and classification.\n\nPrevious work gained 99.14% and 94.12% accuracy for the nucleus segmentation and cell segmentation respectively, while classification accuracy was over 90%. Cell segmentation and binary classification works can be improved further.\n\nStudies by6,7 summarized WBC segmentation works into pattern recognition-based, deformable model-based, threshold-based, morphological operations-based, and clustering-based segmentation.7 suggested a combination of dual-threshold and morphological operations which achieved 97.85% accuracy. Dual-threshold, binarization, and morphological opening were applied on both preprocessed contrast-stretched grey and H components images. A threshold method was also proposed by other researchers.8–12 recommended a watershed-based and Otsu threshold-based segmentation which resulted in 99.3% and 93.3% accuracy, respectively.\n\nK-means clustering was another famous segmentation approach.13–16,20,32 applied K-means clustering-based segmentation on the G component of RGB image for two datasets and gained 99.51% and 99.74% accuracy respectively; when applied to a CMYK image, 98.89% accuracy was obtained.16\n\nDeep learning (DL) performed object class prediction by recognizing and learning patterns in visual inputs, making it the state-of-the-art method today. Region of interest (ROI) and neural networks were two other parts of machine learning that were popular nowadays.17 Recommended semantic segmentation that performed whole-slide WBCs segmentation and received 93.34% accuracy.18 Used four-moment statistical features and artificial neural networks (ANN) to segment based on local pixel information, and the overall accuracy was 97%. Work done by19 included WBC localization and Grabcut to perform WBCs segmentation. Edge density (ED) and color contrast (CC) were measured. DL gains high segmentation accuracy; however, it has complex architecture, making it challenging to be a robust and generalized DL model.\n\nFor the WBCs classification works,20–22 employed a deep convolutional neural network (DCNN); 29 suggested two methods, neural network (NN) combined with the autoencoders, and a convolutional neural network (CNN); 23–25 also proposed CNN; 26,27 suggested the support vector machine (SVM); 28 suggested the combination of K-means neighbours and social spider optimization. Works of23,29,24,21 yielded great outputs.24 used DCNN to classify WBCs into monocytes, neutrophils, eosinophils, and lymphocytes with accuracy of 92.14%, 94.72%, 91.25%, and 94.61% respectively.\n\nThis research project is a continuing work that aims to gain improved results for both the WBCs segmentation and classification works. The cell segmentation from the previous work has achieved high accuracy for the nucleus segmentation.\n\n\nMethod\n\nThe input dataset was the ALL-IDB2 dataset provided by the Department of Information Technology at University degli Studi di Milano.30 ALL-IDB2 contains a total of 260 normal and blasts WBCs images collected from blood samples of ALL patients which were designed to test the cell classification efficiency. Classification and labelling process to get the ground truth images was done by the expert oncologists. This dataset was captured using an optical laboratory microscope coupled with a Canon PowerShot G5 camera, saved as JPG format.\n\nFigure 1 shows the overall flowchart of the proposed cell segmentation. H component is extracted from the transformed HSV formatted microscopic image (Figure 2 and Figure 3). Subsequently, Gaussian filtering and Otsu thresholding31,11,32 are applied three times to remove RBCs, RBCs boundaries, and to segment the WBCs. Results for each round can be viewed in Figure 4. Then, a 13 × 13 morphological opening is employed to remove small objects from the foreground to get better results as shown in Figure 5. Finally, cell masks are collected to detect the cell contour from the original RGB formatted image as shown in Figure 6.\n\nFigure 7 shows the flowchart of the formation of the proposed binary WBCs classifier model. Characteristics and conditions of WBCs are crucial for this work.\n\nA pre-trained InceptionV3 model is employed.33–35 It is used to extract features in a data preprocessing step which was inspired by.12 Also, the transfer learning technique is adopted. Dataset is divided into training, validation and testing sets, 208 images for training set, while validation and test sets each contains 26 images. All the input images are re-sized to 150 × 150 pixels and are normalized to (−1, 1) to fit into InceptionV3 model.\n\nFirst, a new classifier is built and its architecture is shown in Figure 8. It has 2049 trainable parameters, global average pooling that forms a feature map to prevent overfitting, and a dense layer that applies sigmoid activation to do the binary classification. The pre-trained InceptionV3 model extracts all the features from the training and validation sets. Next, the model is trained for 300 epochs. The training learning curves graph (accuracy and loss) of the newly defined classifier are shown in Figure 9 and Figure 10. The point of interception has the highest validation accuracy and smaller differences between training and validation accuracy. Hence, the epoch value along with the lead of intersection between the two curve lines is the best epoch chosen as a final classifier. New classifier will then be combined with the pre-trained InceptionV3 to form the final classifier. As shown in Figure 11, out of 21,804,833 parameters, the final classifier had a total of 6,321,857 trainable parameters.\n\nData augmentation increases the diversity of data using various techniques such as flipping, rotation, translation etc. The benefit that comes along with this technique is reducing the model bias tendency towards a particular class of data. Thus, it is applied to both the training and validation sets to allow the model to learn better and to reduce the overfitting consequences. The training learning curves graph (accuracy and loss) of the fine-tuned classifier model can be viewed in Figure 12 and Figure 13. Epoch with the highest validation accuracy and lowest validation loss is chosen as the final classifier.\n\n\nResults\n\nFigure 14 shows some results of the proposed cell segmentation that attained 90.45%, 93.91%, 76.25% and 0.0186 seconds for the average accuracy, structural similarity, dice similarity coefficient and computational time respectively. The final results achieve high accuracy and similarity, over the average overlapping between the ground truth and the original images with short computation time. In short, the proposed cell segmentation method makes a performance.\n\nThe sample results shown in Figure 14 demostrate that the first row yields an excellent segmentation outcomes while the following rows of images weren’t. This may be due to the undesirable illuminations and blur levels. In addition, the inconspicuous difference between the foreground (WBC) and the background caused by the uneven acquisition can be another factor that affects the final results.\n\nTable 1 and the bar chart in Figure 15 show the comparison between the K-means clustering and the proposed triple thresholding method. This work obtained higher accuracy in a shorter time.\n\nTable 2 shows the performance of the newly defined classifier; while Table 3 shows the performance of the fine-tuned classifier.\n\nIt is observed that the accuracy, precision, recall, true positive and true negative for all the three sets of data increased while loss, false positive and false negative results decreased after the fine-tuned stage. This indicates that the fine-tuned classifier is a robust and good fitted classifier that can accurately predict and make fewer errors.\n\nFigure 16 and Figure 17 are the samples of the binary classification results. If the prediction value is over 0.5, they are considered as healthy WBCs; otherwise, they are ALL WBCs. Results of the predicted label by the classifier and the actual label are the same. Both the sample images are classified correctly.\n\nComparisons between the previous works and the proposed work for the binary classification are shown in Table 4 and the bar chart in Figure 18. The proposed binary classification work outperforms previous works with the highest accuracy, 96.15%. The proposed work is able to classify the WBCs into healthy and malignant groups accurately.\n\n\nDiscussion\n\nThe proposed method in this study shows a new possible approach or direction for the future research work on WBC cell segmentation and binary classification.\n\nIn the comparison table between the previous works and the proposed work for the cell segmentation, it is proven that the threshold-based segmentation can outperform the K-means clustering when dealing with a small dataset. Otsu thresholding uses the global thresholding while the K-means clustering uses the local thresholding to perform the segmentation. Otsu thresholding calculates the optimum thresholding after distributing the pixels into foreground and background classes. K-means clustering determines the k centroids, evaluates pixels and groups the similar pixels into the same cluster. Most images of the ALL-IDB2 contain large foreground (WBC) size leading to a good bimodal distribution of the histogram where Otsu thresholding is more capable and expertise than K-means clustering to perform segmentation due to the thresholding technique used. The pre-processing and post-processing are crucial as they can very much affect the final output of the Otsu thresholding.\n\nOn the other hand, the proposed binary WBC classification that uses the pre-trained InceptionV3 and transfer learning technique yields 96% of accuracy. The pre-trained classifier model is trained with a large dataset, hence, it eliminates the need to build a classifier model from scratch. This makes it able to extract features better than VGGNet or SSOA in previous works. Transfer learning technique reuses pre-trained model on a different but similar problem is a noble approach. This gives the model a higher learning rate during the training. It is not only more intelligent but also able to accomplish works in higher performance. Using pre-trained and transfer learning approaches, the binary classifier model is more brilliant and flexible than the previous research. It can adapt quickly and use the best-fitted methods to perform classification on the dataset. Also, the InceptionV3 model requires fewer generated parameters of networks as compared with VGGNet. Hence, the final results are better than the previous works when combined with the binary WBCs classification. From Table 4, it is observed that the proposed work has a potential to be considered for the future application.\n\n\nConclusions\n\nThis research focuses on improving the WBC cell segmentation and binary classification works. A public dataset, ALL-IDB2 is used to perform the cell segmentation and binary classification. Triple thresholding method is proposed to achieve the first objective of this research and the results are 90.45%, 83.81%, 76.25%, and 0.0186 seconds for the accuracy, structural similarity index, dice similarity coefficient, and computation time respectively. Combining the pre-trained InceptionV3 model and the transfer learning technique produce over 96% accuracy and the precision with a lower loss value was suggested to accomplish the second objective of this research. The overall performance for both the segmentation and classification works have been improved.\n\n\nAuthor contributions\n\nLamXH, NgKW, YoongYJ and NgSB conceived the presented idea. LamXH carried out the experiment and wrote the manuscript. NgKW, YoongYJ and NgSB supervised the project and provided feedback.\n\n\nEthics\n\nEthical Approval Body: Research Ethic Committee 2021, Multimedia University\n\nEthical Approval Number: EA1552021\n\n\nData availability\n\nData were obtained from Acute Lymphoblastic Leukemia Image Database for Image Processing (ALL-IDB) (https://homes.di.unimi.it/scotti/all/).\n\nThis dataset was not generated nor is it owned by the authors of this article; the listed owners is the Department of Computer Science - Università degli Studi di Milano. Therefore, neither the authors nor F1000Research are responsible for the content of this dataset and cannot provide information about data collection.",
"appendix": "Acknowledgements\n\nWe thank the anonymous reviewers for their careful reading of our manuscript and their insightful comments and suggestions.\n\n\nReferences\n\nMandal N: What is Peripheral Blood?. Retrieved July 7, 2020.Reference Source\n\nHuang A: Immunotherapy for leukemia.2020, September. Retrieved April 05, 2021.Reference Source\n\nChildhood cancer: 2021, February 12. Retrieved April 05, 2021.Reference Source\n\nBennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukemias. French–American–British (FAB) co-operative group. Br. J. Haematol. 1976; 33: 451–458. PubMed Abstract | Publisher Full Text\n\nBlood and pathology tests: 2017, September 15. Retrieved July 9, 2020.Reference Source\n\nAndrade AR, Vogado LH, Veras RD, et al.: Recent computational methods for white blood cell nuclei segmentation: A comparative study. Comput. Methods Prog. Biomed. 2019; 173: 1–14. PubMed Abstract | Publisher Full Text\n\nLi Y, Zhu R, Mi L, et al.: Segmentation of White Blood Cell from Acute Lymphoblastic Leukemia Images Using Dual-Threshold Method. Comput. Math. Methods Med. 2016; 2016: 1–12. Publisher Full Text\n\nBhavnani LA, Jaliya UK, Joshi MJ: Segmentation and Counting of WBCs and RBCs from Microscopic Blood Sample Images. International Journal of Image, Graphics and Signal Processing. 2016; 8(11): 32–40. Publisher Full Text\n\nQuinones VV, Macawile MJ, Ballado A, et al.: Leukocyte segmentation and counting based on microscopic blood images using HSV saturation component with blob analysis. 2018 3rd International Conference on Control and Robotics Engineering (ICCRE). 2018. Publisher Full Text\n\nSafuan SN, Tomari MR, Zakaria WN: White blood cell (WBC) counting analysis in blood smear images using various color segmentation methods. Measurement. 2018; 116: 543–555. Publisher Full Text\n\nSalem N, Sobhy NM, Dosoky ME: A Comparative Study of White Blood cells Segmentation using Otsu Threshold and Watershed Transformation. Journal of Biomedical Engineering and Medical Imaging. 2016; 3(3): Publisher Full Text\n\nSahlol AT, Kollmannsberger P: All-sessa deep feature optimization.2020, February 10. Retrieved March 11, 2021.Reference Source\n\nFerdosi BJ, Nowshin S, Sabera FA, Habiba: White Blood Cell Detection and Segmentation from Fluorescent Images with an Improved Algorithm using K-means Clustering and Morphological Operators. 2018 4th International Conference on Electrical Engineering and Information & Communication Technology (iCEEiCT). 2018. Publisher Full Text\n\nNegm AS, Hassan OA, Kandil AH: A decision support system for Acute Leukaemia classification based on digital microscopic images. Alex. Eng. J. 2018; 57(4): 2319–2332. Publisher Full Text\n\nSavkare SS, Narote SP: Blood cell segmentation from microscopic blood images. 2015 International Conference on Information Processing (ICIP). 2015. Publisher Full Text\n\nSavkare SS, Narote AS, Narote SP: Automatic Blood CellSegmentation Using K-Mean Clustering from Microscopic Thin Blood Images. Proceedings of the Third International Symposium on Computer Vision and the Internet - VisionNet'16. 2016. Publisher Full Text\n\nShahzad M, Umar AI, Khan MA, et al.: Robust Method for Semantic Segmentation of Whole-Slide Blood Cell Microscopic Images. Comput. Math. Methods Med. 2020; 2020: 1–13. Publisher Full Text\n\nAl-Jaboriy SS, Sjarif NN, Chuprat S, et al.: Acute lymphoblastic leukemia segmentation using local pixel information. Pattern Recogn. Lett. 2019; 125: 85–90. Publisher Full Text\n\nLiu Y, Cao F, Zhao J, et al.: Segmentation of white blood cells image using adaptive location and iteration. IEEE J. Biomed. Health Inform. 2017; 21(6): 1644–1655. PubMed Abstract | Publisher Full Text\n\nShafique S, Tehsin S: Acute Lymphoblastic Leukemia Detection and Classification of Its Subtypes Using Pretrained Deep Convolutional Neural Networks. Technol. Cancer Res. Treat. 2018; 17: 153303381880278. Publisher Full Text\n\nThrongnumchai K, Lomvisai P, Tantasirin C, Phasukkit P: Classification of White blood cell using Deep Convolutional Neural Network. 2019 12th Biomedical Engineering International Conference (BMEiCON). 2019. Publisher Full Text\n\nOng K, Haw S-C, Ng K-W: Deep Learning Based-Recommendation System: An Overview on Models, Datasets, Evaluation Metrics, and Future Trends. Proceedings of the 2019 2nd International Conference on Computational Intelligence and Intelligent Systems. 2019; pp. 6–11. Publisher Full Text\n\nBanik PP, Saha R, Kim K: An Automatic Nucleus Segmentation and CNN Model based Classification Method of White Blood Cell. Expert Syst. Appl. 2020; 149: 113211. Publisher Full Text\n\nThanh TT, Vununu C, Atoev S, et al.: Leukemia Blood Cell Image Classification Using Convolutional Neural Network. International Journal of Computer Theory and Engineering. 2018; 10(2): 54–58. Publisher Full Text\n\nAng J-S, Ng K-W, Chua F-F: Modeling Time Series Data with Deep Learning - A Review, Analysis, Evaluation and Future Trend. 8th International Conference on Information Technology and Multimedia (ICIMμ 2020), 24-25 August, 2020. 2020. Publisher Full Text\n\nElen A, Turan MK: Classifying White Blood Cells Using Machine Learning Algorithms. Uluslararası Muhendislik Arastirma Ve Gelistirme Dergisi. 2019; 141–152. Publisher Full Text\n\nSetiawan A, Harjoko A, Ratnaningsih T, et al.: Classification of cell types in Acute Myeloid Leukemia (AML) of M4, M5 and M7 subtypes with support vector machine classifier. 2018 International Conference on Information and Communications Technology (ICOIACT). 2018. Publisher Full Text\n\nSahlol AT, Abdeldaim AM, Hassanien AE: Automatic acute lymphoblastic leukemia classification model using social spider optimization algorithm. Soft. Comput. 2018; 23(15): 6345–6360. Publisher Full Text\n\nHegde RB, Prasad K, Hebbar H, et al.: Comparison of traditional image processing and deep learning approaches for classification of white blood cells in peripheral blood smear images. Biocybernetics and Biomedical Engineering. 2019; 39(2): 382–392. Publisher Full Text\n\nLabati RD, Piuri V, Scotti F: All-IDB: The acute lymphoblastic leukemia image database for image processing. 2011 18th IEEE International Conference on Image Processing. 2011, September; (pp. 2045–2048). IEEE.\n\nMahdy LN, Ezzat KA, Darwish A, et al.: Automatic Counting of Infected White Blood Cells Using Multi-Level Thresholding. 2019 Ninth International Conference on Intelligent Computing and Information Systems (ICICIS). 2019. Publisher Full Text\n\nVard A, Ghane N, Talebi A, et al.: Segmentation of White Blood Cells From Microscopic Images Using a Novel Combination of K-Means Clustering and Modified Watershed Algorithm. Journal of Medical Signals & Sensors. 2017; 7(2): 92–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBianco S, Cadene R, Celona L, et al.: IEEE Access. Benchmark Analysis of Representative Deep Neural Network Architectures. 2018; 4: 64270–64277. Publisher Full Text\n\nGramener: Compare pre-trained ImageNet models for classification. Retrieved March 11, 2021. 2020.Reference Source\n\nHow to choose the best keras pre-trained model fdaor image classification: 2021, January 27. Retrieved March 11, 2021.Reference Source\n\nPrellberg J, Kramer O: Acute Lymphoblastic Leukemia Classification from Microscopic Images Using Convolutional Neural Networks. Lecture Notes in Bioengineering ISBI 2019 C-NMC Challenge: Classification in Cancer Cell Imaging. 2019; 53–61. Publisher Full Text"
}
|
[
{
"id": "100625",
"date": "23 Dec 2021",
"name": "Naresh Babu Muppalaneni",
"expertise": [
"Reviewer Expertise Myself working in the area of machine learning",
"deep learning and made good number of publications in bioinformatics",
"machine learning."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have used a novel methodology for White Blood Cell (WBC) segmentation and classification. They have proposed a new classifier and fine-tune the classifier for better accuracy. The results are prominent as the accuracy is high compared to the existing methods in Hedge et al. (2019)1, Prellberg et al. (2019)2 and Sahlol et al. (2020) (references 29, 36, and 12 respectively in the article). The results are tabulated and represented in the form of graphs and charts.\nThe authors have used Gaussian filtering with Otsu thresholding for three times with a 13 x 13 filter for segmentation of WBC and to remove Red Blood Cells (RBC). What is the significance of the 13 x 13 filter? The reason is not found in the paper.\nThe authors experimented with neural networks combined with autoencoders for improved accuracy. The authors have used various pre-trained models for classification and also performed comparative studies with the existing techniques from the literature.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
},
{
"id": "120327",
"date": "01 Apr 2022",
"name": "Chiung Ching Ho",
"expertise": [
"Reviewer Expertise Deep Learning",
"Machine Learning"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper reports on an effort to segment and classify microscopic images.\nI wonder how the authors define \"a minor improvement\"? The baseline results on the original dataset should be listed, if applicable.\n\nPerhaps authors should consider if the listed publications at https://homes.di.unimi.it/scotti/all/ are necessary to be cited.\n\nWhy was InceptionV3 selected and not any other pre-trained model?\n\nCan the authors comment on the work entitled \"IoT Application of Transfer Learning in Hybrid Artificial Intelligence Systems for Acute Lymphoblastic Leukemia Classification\"1? It uses low power IoT devices with an encoder and a classification head. And achieves higher accuracy - what would be a fair comparison between this work and the author's 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? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1168
|
https://f1000research.com/articles/10-105/v1
|
11 Feb 21
|
{
"type": "Research Article",
"title": "Seroprevalence and characterisation of herpes simplex virus from human immunodeficiency virus in samples collected from the North-West and KwaZulu-Natal Provinces: a retrospective study",
"authors": [
"Oluwafemi Samuel Obisesan",
"Nomathamsanqa Patricia Sithebe",
"Hazel Tumelo Mufhandu",
"Nomathamsanqa Patricia Sithebe",
"Hazel Tumelo Mufhandu"
],
"abstract": "Background: Herpes simplex viruses (HSVs) are highly pervasive and show a strong synergistic interaction with human immunodeficiency virus (HIV). High prevalence of HSV type 1 (HSV-1) has been reported in Africa with a prevalence rate of 20-80% in women and 10-50% in men. Studies on the prevalence of HSV in South Africa are few considering the rate of HIV infection in the country. Our focus was to determine the molecular prevalence of HSV-DNA in HIV-1 sera. Methods: In total, 44 convenience samples were screened for HSV and HIV-1 using the highly sensitive enzyme-linked immunosorbent assay (ELISA). The ELISA positive samples were characterized using polymerase chain reaction (PCR) to confirm the positivity of both viruses and to further differentiate HSV into HSV-1 and -2. Thereafter, the samples were analysed for relatedness using phylogenetic analysis. Results: Of 44 samples, 36 (81.8%) were positive for HIV-1, while 35 (79.5%) were positive for HSV when screened with ELISA kits. The results of PCR with type specific primers showed that 4/35 (11.4%) samples were specific for HSV-1 while 30/35 (85.7%) were specific for HSV-2. Statistical analysis performed using chi-squared goodness-of-fit test showed that there is a significant relationship between HSV-2 and HIV-1 transmission. Conclusions: High prevalence of HSV-2 recorded in HIV-1 sera corroborate with similar studies conducted within different cohorts in the continent. SPSS Pearson’s chi-squared test established that there is a significant relationship between HSV-2 and HIV-1 transmission.",
"keywords": [
"Co-infection",
"Enzyme Linked Immunosorbent Assay",
"Herpes Simplex Virus",
"Human Immunodeficiency Virus",
"Polymerase Chain Reaction."
],
"content": "Introduction\n\nHerpes simplex virus (HSV) is a prevalent organism that belongs to the sub-family of alpha Herpesviridae (Greninger et al., 2018). The majority of HSV transmission is asymptomatic because carriers are not aware of their infection, a factor that is partly responsible for the high prevalence of HSV infection worldwide. On the other hand, HSV transmission can produce symptomatic lesions in the infected host (Looker et al., 2015). When symptoms appear, there is an increase in the virus titre (Mazzarello et al., 2018). Exposure to an infected person or cell fuels the transmission of the virus (Jaishankar & Shukla, 2016). Transmission of this herpetic virus can be through oral or genital contact with the lesion. These routes of transmission berth HSV differentiation into two types, HSV-1 and HSV-2, respectively (Looker et al., 2008; Schiffer et al., 2014). HSV-1 is the cause of blisters and sores around the mouth, while HSV-2 is traditionally associated with blisters around the genitals, although, both viruses can cause infection at both sites (Grinde, 2013; Modi et al., 2008).\n\nThe prevalence of HSV-1 and HSV-2 infection in the United States from a survey conducted in 2018 was reported as 47.8% and 11.9%, respectively (McQuillan et al., 2018). In Africa, the rate of occurrence of HSV-2 is 20–80% in women, 10–50% in men, while that of HSV-1 is 49.7% in women and 50.3% in men (Looker et al., 2015; WHO, 2015). HSV-2 is the most common virus responsible for genital ulcer diseases (Johnston & Corey, 2016). Feng et al. (2013) stated that genital ulcerations caused by these viruses is a burden globally with a worldwide estimate of >500,000,000 people (15% prevalence) infected with genital herpes between the ages of 15–49 years. In South Africa, a study conducted in KwaZulu-Natal by Rajagopal et al. (2014), showed a 84% incidence of HSV-2 among commercial sex workers.\n\nRecently, HSV-1 has become a major factor influencing genital herpes in most industrialised nations with about 140 million people, aged 15–49 years, infected with genital HSV-1 (WHO, 2015). The change in virus causing genital herpes is due to the downward shift in trend of HSV-1 acquisition before sexual relations. In addition, children who do not have HSV-1 antibodies at the early stage are vulnerable to genital HSV-1 infection when exposed (Bradley et al., 2014; Forward & Lee, 2003).\n\nAccording to UNAIDS (2019), HIV-1 prevalence in South Africa was estimated at 7.7 million in 2018 making it the highest epidemic in the world. Considering the high prevalence of human immunodeficiency virus (HIV) in South Africa and the role that HSV plays in its transmission, the need to determine the prevalence of HSV and HIV-1 co-infection is of great importance. HSV is an important co-factor in HIV acquisition due to physical disruption of the epithelial surface at the infection site. This serves as a port of entry for HIV recruitment and can facilitate its transmission by two to three fold (Looker et al., 2017; Munawwar & Singh, 2016). HSV makes the transmission of HIV effortless by causing frequent replication of HSV; hence, causing disease progression. The effect of HSV in HIV acquisition has been observed in Western Asia, Europe and Africa where the prevalence of HSV-2 in HIV infected populations was 60–90%, 30–70% and 50–90%, respectively, which is three times the rate of infection in normal populations (Anaedobe & Ajani, 2019; Des Jarlais et al., 2014; Mohraz et al., 2018).\n\nIt is apparent that a well-built interaction exists between HSV-2 and HIV-1 infection (Barnabas & Celum, 2012; Kolawole et al., 2016; Todd et al., 2013), although there are few contrasting opinions. In 2006, Freeman and colleagues conducted a systematic review on gender-based effect of HSV-2 in the transmission of HIV infection (Freeman et al., 2006). In their study, they discovered that HSV-2 is a significant facilitator for HIV transmission in men and women. In addition, there is a three-fold risk of HIV-1 acquisition in HSV-2 infected persons in sub-Saharan Africa (Barnabas & Celum, 2012). Most research that recognises the association between HSV-2 and HIV-1 has been conducted outside South Africa. However, the incidence of HSV-2 and HIV-1 co-infection reported in South African women was 41% (Abbai et al., 2015).\n\nThe focus of this study was to establish the prevalence of HSV antibodies and HSV-DNA in HIV-1 sera collected from National Health Laboratory Service (NHLS) laboratories. In addition, HSV-2 and HIV-1 co-infections were examined in the samples.\n\n\nMethods\n\nSamples from patients who attended a NHLS clinic in the North-West Province and KwaZulu-Natal Province for HIV screening and management were used. Convenience sampling was used. Patients had attended the laboratories with health conditions that were discrete from HSV infection. From the laboratories, 44 sera samples were collected over a period of one year (July 2017 – May 2018); 20 sera samples from North-West and 24 from KwaZulu-Natal Provinces. The samples were collected blindly from the two clinical laboratories with no additional data except for the age and sex of the participants. Sera were kept in sterile vials and stored at -80°C until they were ready for use.\n\nKasubi (2006) has stated that the majority of the screening on Africa sera samples are biased because of their high false positive results. In addition, Satpathy et al. (2018) has stated that “EIA and PCR are more reliable and accurate detection techniques for HSV and HIV-1”. These two statements were considered while selecting the laboratory technique to assess HSV. The statements informed our decision to use enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) techniques to analyse the samples. ELISA was used to detect the presence of viral antibodies (HSV and HIV-1) in the sera samples and PCR was used to confirm the positivity of the samples and differentiate HSV samples into types 1 and 2.\n\nA highly sensitive but non-specific ELISA test kit, Platelia HSV (1+2) (Bio-Rad, Marnes-la-Coquette, Paris, France) and Genscreen Ultra HIV Ag-Ab test kit (Bio-Rad, Marnes-la-Coquette, Paris, France) were used to detect the presence of HSV-1 and -2 and HIV-1 antibodies, respectively. The two kits were used to test all 44 samples. The manufacturer’s instructions were strictly followed with little modifications where necessary, as reported in our previous work, Obisesan (2019).\n\nDNA and RNA were extracted from the sera samples using QIAamp® MinElute® Virus Spin kit and QIAamp® Viral RNA Mini kit (Whitehead Scientific, Cape Town, South Africa), respectively, following the manufacturer’s protocols. The extracted material was aliquoted and stored at -80°C until further use.\n\nPCR was run on each ELISA positive sample (HSV types 1 and 2 and HIV-1) using viral gene specific primers. The primers were selected based on previous studies (Nie et al., 2011; Schmutzhard et al., 2004; Victória et al., 2005), for the detection of HSV-1, HSV-2 and HIV-1, respectively, as outlined in the Extended data (Table A). Briefly, 25 µl PCR reaction mixture of Quick-Load® Taq 2X Master Mix kit (Biolabs) with each primer set targeting the different regions was prepared (Extended data, Table B) and amplification was performed on a T100TM thermal cycler (Bio-Rad, Hercules, California, United States). HSV-1 and -2 amplification was completed with primer annealing temperature at 55°C for first round PCR and 61.4°C for nested PCR, with a total of 35 cycles for both, as outlined in the Extended data (Table B). A two-step reverse transcription PCR was used to amplify the HIV-1 gene of interest from the extracted RNA material. This was achieved with a primer annealing temperature of 50°C for 30 cycles, as outlined in the Extended data (Table C). The PCR products were electrophoresed on a 2% agarose gel, stained with ethidium bromide and identified by UV light transilluminator (MUV26 Series, Major Science, California, USA).\n\nNext-generation sequencing (NGS) was used to validate the detected viral genomes of the clinical samples. Only the samples that exhibited high titers of the two individual viruses (HSV-2 and HIV-1) were processed through to sequencing. DNA sequencing was performed on four HSV-2/HIV-1 co-infected samples with the highest titre as identified with ELISA. The samples were annotated as G13, G15 and G34, and G20. HSV-2 primers were used to sequence G13, G15 and G34 while the G20 sequencing was done using HIV-1 primers. The next generation sequencing was carried out on the Illumina MiSeq NGS platform at Inqaba Biotec (Inqaba Biotechnical Industries (Pty) Ltd, Johannesburg, SA). The phylogenetic analysis was performed by trimming and aligning the sequences using BowTie 2 v 2.3.2 (Langmead & Salzberg, 2012). All aligned data were further annotated to determine the viral genome using Prokka v 1.12 (Seemann, 2014). The sequence data, after trimming and annotation, was subjected to Molecular Evolutionary Genetics Analysis (MEGA 7) against HIV-1 and HSV-2 reference genomes (see Results) obtained from National Centre for Biotechnology Information (NCBI).\n\nData analyses were carried out on Statistical Package of Social Sciences (SPSS) software (version 25). The chi-squared goodness-of-fit test (x2) was used to evaluate for an association between the categorical variables. Relationship between the demographics and the viruses was tested using Pearson correlation coefficient. The 5% significance level was considered as significant p value in this study\n\nThe study received ethical approval from the North-West University Research Ethics Regulatory Committee (NWU-00068-15-A9) prior to the study. Also, we received permissions from NHLS to make use of the samples of those patients who gave their verbal consent for use of their samples in the study.\n\n\nResults\n\nThe demographics of the study population showed that majority of the study participants were female (79.5%) and a lesser percentage (20.5%) of the population were male (Table 1). The sample size is considered as one of the study limitations. The mean age and standard deviation of the study population were 33.09 ±11.94 years.\n\nELISA screening of the samples showed that 36/44 (81.8%) were seropositive for HIV-1 (Figure 1 and Extended data, Figure A) while 35/44 (79.5%) were positive for either HSV-1/2 antibody (Figure 1). Notably, the study participants within the age group of 41–50 years had the highest HSV and HIV-1 infection rates, as depicted in Figure 1.\n\nThe amplification of glycoprotein B region of HSV using PCR showed that 4/35 (11.4%) of the HSV positive samples tested positive for HSV-1. Similarly, in order to differentiate the HSV positive samples into HSV-2, PCR amplification of glycoprotein G region of HSV positive samples was done. The result showed that 30/35 (85.7%) were HSV-2 positive. The gender distribution of these viruses in the study participants are shown in the Extended data (Figure B and C) for HSV-1 and HSV-2, respectively. Another finding from the study was that 1/44 (2.3%) males and 2/44 (4.5% ) females from the study population were HSV-1/HIV-1 co-infected. Furthermore, a significant proportion of the population, 6/44 (13.6%) males and 24/44 (54.5%) females were HSV-2/HIV-1 co-infected.\n\nNGS was performed to detect and confirm the genomes of the viral isolates (HSV-2 and HIV-1) from the clinical samples. The sequenced data was compared with reference genomes of HSV-2 and HIV-1 obtained from NCBI. The reference genomes were selected based on the amplified targeted regions, that is, glycoprotein G for HSV-2 and integrase for HIV-1. The selected HSV-2 reference genomes are HSV-2 SD90e (KF781518), HSV-2 strain 333 (M15118) and glycoprotein G-2 (AF141858); and for HIV-1 they are HIV-1 LC022388, HIV-1 LC201873, HIV-1 isolate 3792/15 KU609388 and HIV-1 isolate KU609428.\n\nPhylogenetic analysis was performed on the sequence data to check the evolutionary relatedness of the sequenced data and the selected reference genomes. We decided to use a maximum likelihood method of analysis with a bootstrap phylogeny method (1,000 bootstrap replicates), that generated evolutionary trees as illustrated in Figure 2 and Figure 3 for HSV-2 and HIV-1, respectively.\n\nThe HSV-2 phylogeny tree (Figure 2) clearly showed that nucleotide sequence 13 is closely related to sequence 15 more than sequence 34, with 98–99% similarity to glycoprotein G2 reference strain.\n\nThe HIV-1 phylogeny tree in Figure 3 showed that the G20 sequence is 77% closely related to HIV LC201873 and HIV-1 isolate 4533/11 KU609428; and distantly related to the other HIV-1 reference genomes (HIV-1 LC022388 and HIV-1 isolate 3793/15 KU609388) used in constructing the phylogenetic tree.\n\nSPSS v25 was used to establish that a possible relationship exists between age, HSV, and HIV-1. SPSS was also utilized to evaluate the association between HSV and HIV-1 positive samples. The two-tailed correlation test exhibited a statistical link between age and HSV-1 (0.366**), HSV-2 and HIV-1 samples (0.690**) and an inverse relationship between HSV-1 and HSV-2 samples (-0.463**), as shown in Table 2.\n\n**Correlation is significant at 0.01 level (2-tailed)\n\nThe SPSS chi-square goodness-of-fit test was also used to assess association between HSV positive samples and HIV-1 sera. The data showed that there was no significant association between HSV-1 and HIV-1 (X2 (1) = 0.138, p>0.05). However, there was a strong statistical association between HSV-2 and HIV-1 (X2 (1) = 20.952, p< 0.05), as shown in Table 3.\n\n*Significant at 0.05 level (2-tailed).\n\n\nDiscussion\n\nThere are insufficient data to recount the prevalence of HSV genotypes among HIV-1 infected individuals in the Republic of South Africa. This study provides insight into an existing interrelation between HSV and HIV-1 and the potential risk that one of the viruses may have on the other. Our focus was to determine the seroprevalence of HSV among HIV-1 sample cohort. The study also assessed for possible co-infections (HSV-1/HIV-1 or HSV-2/HIV-1). The study detected 81.8% HIV-1 and 79.5% HSV positive samples, with 85.7% of the HSV samples being positive for HSV-2. Conversely, HSV-1, which is the most prevalent type of HSV, as recorded by previous studies, was not highly prevalent in this study population (11.4%). The study also revealed a higher co-infection rate of HSV-2/HIV-1 (13.6% males, 54.5% females) compared with HSV-1/HIV-1 (2.3% males, 4.5% females).\n\nOne of the few trends drawn from this study was that the prevalence of HSV-2 as compared to HSV-1 in HIV-1 co-infection was relatively high. The validity of the high prevalence of HSV-2/HIV-1 co-infection in this study is further supported by previous studies (Looker et al., 2017; Patel et al., 2012). Furthermore, it was discovered that females were more susceptible to HSV infection 30/35 (85.7%) than their male counterparts 4/35 (11.4%) in this population. This auspiciously matches with findings of Pebody et al. (2004) and Smith & Robinson (2002), who reported that women are more at risk of acquiring HSV-2 infection compared with men. This was also observed by the findings of Celum et al. (2004), that more than half of the female population who are HIV-1 positive suffer from HSV-2 infection. This might be due to their early exposure to sexual relations than their male counterpart (Schiffer et al., 2014). Moreover, the highest number of HSV and HIV-1 prevalence was observed in the age group of 41–50 years. However, only 3/44 (6.8%) HSV-1/HIV-1 co-infected samples were recorded in this study. Of note is that the rate of co-infection increased with age, which correlates with the steady rise by age for HSV-2/HIV-1 co-infection, as recorded by Beydoun et al. (2010).\n\nPCR was performed to confirm the positivity of the ELISA screened samples and differentiate the HSV samples into types 1 and 2. The results (11.4% HSV-1 and 85.7% HSV-2) correlate with the high rate of HSV-2 infection in Africa. HSV-2 infection rates were previously reported in Zimbabwe (68%), Uganda (58%), Zambia (55%) and Gambia (28%) (Debrah et al., 2018; Looker et al., 2015; Paz-Bailey et al., 2007). The decline in the prevalence rate of HSV-1 in this study is in contrast with the high HSV-1 prevalence observed by Cunningham et al. (2006) with 80% in women and 71% in men. This decline was also stated by Ayoub et al. (2019), who added that more children will reach the age of sexual debut with no antibody protection against HSV-1. In addition, the decline is attributable to the change in disease spread in the current population owing to the fact that there are reduced viral HSV-1 antibodies at a very young age, a factor influencing HSV-2 acquisition.\n\nPhylogenetic analysis revealed that HSV-2 samples 13 and 15 from this study do not share the same ancestral lineage with a more virulent clinical isolate SD90e (accession number KF781518) and the HSV-2 laboratory strain 333 (M15118). A previous study by Newman et al. (2015) showed that SD90e viral sequence originated from South Africa. However, the distant relation between SD90e reference genome and samples 13 and 15 may suggest geographical diversity in viral transmission (Szpara et al., 2014). Furthermore, a close relation of the two samples (G13 and G15) was observed with the less virulent glycoprotein G-2 strain originating from Scotland, which is attributed to international migration. A study with a larger sample cohort is encouraged to confirm this claim.\n\nThe HIV-1 phylogenetic analysis demonstrated that there is a close relationship between the G20 sequence and HIV-1 LC201873, a resistant integrase strand transfer inhibitor (INSTI) strain found in Japan and the HIV-1 isolate 4533/11 KU609428 from Morocco. This may be a reflection of another instance of international migration (Lurie et al., 2003). The three sequences were observed to be distantly related to HIV-1 isolate 3792/15 KU609388 and HIV-1 LC022388, both from Morocco.\n\nA previous study on the relationship between age and HSV-1 prevalence by Smith & Robinson (2002) reports that global HSV-1 prevalence increases with age. The statistical relationship between age, HSV and HIV-1 infection in our study revealed a similar significant relationship between age and HSV-1 (p = 0.366*). In the same vein, we discovered a discreet relationship between age, HSV-2 and HIV-1. HSV-1 showed an inverse correlation with HSV-2 (p = -0.463**). This suggests that an increase in HSV-2 prevalence in the population will result in a drastic decline of HSV-1. It was also discovered that a robust significant relationship exists between HSV-2 and HIV-1 (p =0.690**) suggesting that a steady rise in HSV-2 leads to a rise in HIV-1 infection in the population. A probable reason for this relationship is that the viruses share a similar route of entry and the impact of one is significant on the other as seen in the micro-ulceration of the genitalia in HSV-2 patients, which provides a port of entry for HIV-1 (Sheth et al., 2008).\n\nThe association between HIV-1 and HSV was analysed using chi-square goodness-of-fit test and it was discovered that no significant association exist between HSV-1 and HIV-1 (X2 (1) = 0.138, p >0.05) but a strong statistical association was found between HSV-2 and HIV-1 (X2 (1) = 20.952, p <0.05). Although, there has been contrasting opinions on the association of HSV-2 and HIV-1, the current study is consistent with Sudenga et al. (2012) and Omori & Abu-Raddad (2017) who suggested that the infection of one virus may fuel the transmission of the other. In their study, Sudenga et al. (2012) observed that HIV-1 positive individuals with higher CD4+ counts at baseline and those with lower viral load were associated with HSV-2 acquisition, while Omori & Abu-Raddad (2017) used the sexual network determinants as components to determine the prevalence of HIV/ HSV-2. However, they deduced that HIV is an agent of HSV-2 transmission in the population. The data from this study suggests that contracting one virus (either HSV-2 or HIV-1) will influence the acquisition of the other. A recent study led by Kouyoumjian et al. (2018) and his group discovered a robust association between HSV-2 and HIV-1, with HSV-2 prevalence being consistently higher than that of HIV-1 in the global population. This accentuates the importance for data collation on HSV-2 and HIV-1 infected persons in South Africa\n\nThis study is a retrospective study with the aim to determine the prevalence of HSV-DNA in HIV-1 sera. The study contributed widely to the literature by exploring a broad group (participants between 14 to 49 years) within a small population, but there were certain limitations. First, the study population was small when compared to the size of the general population. Second, the samples were collected exclusively from North-West and KwaZulu-Natal Provinces, hence, it is difficult to generalize the outcomes of the study to the South African populace.\n\n\nConclusion\n\nThis study showed that HSV is highly prevalent with women being largely affected. Moreover, HSV-2 infection in the study cohort was robustly associated with HIV-1. This suggests that if HSV-2 infection is not properly managed in a setting with generalized HIV epidemic, it may add a burden to the already deteriorating health status of the affected persons leading to high mortality and morbidity. To acknowledge that a relationship exists between these two viruses, and to identify how the transmission of one could affect the other, requires a large cohort at risk for HIV that is well described with longitudinal measurements of HSV-1, HSV-2 and HIV-1 as well as measurements of potential confounders such as condom use, partner change and other sexually transmitted diseases. This will aid in reducing the rate of disease recurrence in the population and possibly prevent impending co-infections. In spite of the study limitations, the data adds to the body of knowledge on HSV infection and its co-infection with HIV-1.\n\n\nData availability\n\nSRA: gG sequencing of HSV-2 (sample G15), Accession number SRX9590097: https://www.ncbi.nlm.nih.gov/sra/?term=SRX9590097\n\nSRA: gG sequencing of HSV-2 (sample G34), Accession number SRX9590139: https://www.ncbi.nlm.nih.gov/sra/?term=SRX9590139\n\nSRA: gG sequence (sample G13), Accession number SRX9590098: https://www.ncbi.nlm.nih.gov/sra/?term=SRX9590098\n\nSRA: HIV-1 sequencing targeting integrase region (sample G20), Accession number SRX9531105: https://www.ncbi.nlm.nih.gov/sra/?term=SRX9531105\n\nDryad: HSV AND HIV RAW DATA, https://doi.org/10.5061/dryad.zs7h44j7g (Obisesan et al., 2020).\n\nThis project contains the following underlying data:\n\n- CSV spreadsheet containing demographics and ELISA and PCR results for all 44 sera samples.\n\nDryad: F1000 SUPPLEMENTARY FILE, https://doi.org/10.5061/dryad.zs7h44j7g (Obisesan et al., 2020).\n\nThis project contains the following extended data:\n\n- Table A: Primers for the detection of HSV-1, HSV-2 and HIV-1.\n\n- Table B: PCR reaction mixture and thermocycling conditions for HSV-1 and -2.\n\n- Table C: Thermocycling conditions for HIV-1 PCR.\n\n- Figure A: ELISA results of HSV as recorded on the microplate reader.\n\n- Figure B: Age variation and the frequency distribution of HSV-1 in the study population\n\n- Figure C: Age variation and the frequency distribution of HSV-2 in the study population\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\nThis research was supported by the Department of Microbiology, North-West University, South Africa. We would also like to appreciate Dr P. Moodley and Dr K. Msomi, University of KwaZulu-Natal for their immense support with sample collection, Dr L. Makhado, North-West University for his guidance with literature review.\n\n\nReferences\n\nAbbai NS, Wand H, Ramjee G: Socio-demographic and behavioural characteristics associated with HSV-2 sero-prevalence in high risk women in KwaZulu-Natal. BMC Res Notes. 2015; 8: 185. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAnaedobe CG, Ajani TA: Co-infection of herpes simplex virus type 2 and HIV infections among pregnant women in Ibadan, Nigeria. J Glob Infect Dis. 2019; 11(1): 19–24. PubMed Abstract | Free Full Text\n\nAyoub HH, Chemaitelly H, Abu-Raddad LJ: Characterizing the transitioning epidemiology of herpes simplex virus type 1 in the USA: model-based predictions. BMC Med. 2019; 17(1): 57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarnabas RV, Celum C: Infectious co-factors in HIV-1 transmission herpes simplex virus type-2 and HIV-1: new insights and interventions. Curr HIV Res. 2012; 10(3): 228–237. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBeydoun HA, Dail J, Ugwu B, et al.: Socio-demographic and behavioral correlates of herpes simplex virus type 1 and 2 infections and co-infections among adults in the USA. Int J Infect Dis. 2010; 14 Suppl 3: e154–e160. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBradley H, Markowitz LE, Gibson T, et al.: Seroprevalence of herpes simplex virus types 1 and 2––United States, 1999–2010. J Infect Dis. 2014; 209(3): 325–333. PubMed Abstract | Publisher Full Text\n\nCelum C, Levine R, Weaver M, et al.: Genital herpes and human immunodeficiency virus: double trouble. Bull World Health Organ. 2004; 82(6): 447–453. PubMed Abstract | Free Full Text\n\nCunningham AL, Diefenbach RJ, Miranda-Saksena M, et al.: The cycle of human herpes simplex virus infection: virus transport and immune control. J Infect Dis. 2006; 194(Suppl 1): S11–S18. PubMed Abstract | Publisher Full Text\n\nDebrah O, Agyemang-Yeboah F, Asmah RH, et al.: SERO-prevalence of herpes simplex virus type 1 and type 2 among women attending routine Cervicare clinics in Ghana. BMC Infect Dis. 2018; 18(1): 378. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDes Jarlais DC, Arasteh K, McKnight C, et al.: HSV-2 co-infection as a driver of HIV transmission among heterosexual non-injecting drug users in New York City. PLoS One. 2014; 9(1): e87993. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFeng Z, Qiu Z, Sang Z, et al.: Modeling the synergy between HSV-2 and HIV and potential impact of HSV-2 therapy. Math Biosci. 2013; 245(2): 171–187. PubMed Abstract | Publisher Full Text\n\nForward KR, Lee SH: Predeominace of Herpes Simplex Virus Type 1 from Patients with Genital Herpes in Nova Scotia. Can J Infect Dis. 2003; 14(2): 94–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFreeman EE, Weiss HA, Glynn JR, et al.: Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006; 20(1): 73–83. PubMed Abstract | Publisher Full Text\n\nGreninger AL, Roychoudhury P, Xie H, et al.: Ultrasensitive capture of human herpes simplex virus genomes directly from clinical samples reveals extraordinarily limited evolution in cell culture. mSphere. 2018; 3(3): e00283–18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrinde B: Herpesviruses: latency and reactivation–viral strategies and host response. J Oral Microbiol. 2013; 5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJaishankar D, Shukla D: Genital herpes: insights into sexually transmitted infectious disease. Microb Cell. 2016; 3(9): 438–450. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohnston C, Corey L: Current concepts for genital herpes simplex virus infection: diagnostics and pathogenesis of genital tract shedding. Clin Microbiol Rev. 2016; 29(1): 149–161. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKasubi MJ: Detection and molecular characterization of herpes simplex virus from Tanzania and Norway. 2006. Reference Source\n\nKolawole OM, Amuda OO, Nzurumike C, et al.: Seroprevalence and co-infection of human immunodeficiency virus (HIV) and herpes simplex virus (HSV) among pregnant women in Lokoja, North-Central Nigeria. Iran Red Crescent Med J. 2016; 18(10): e25284. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKouyoumjian SP, Heijnen M, Chaabna K, et al.: Global population-level association between herpes simplex virus 2 prevalence and HIV prevalence. AIDS. 2018; 32(10): 1343–1352. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLangmead B, Salzberg SL: Fast gapped-read alignment with Bowtie 2. Nat Methods. 2012; 9(4): 357–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLooker KJ, Elmes JA, Gottlieb SL, et al.: Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis. Lancet Infect Dis. 2017; 17(12): 1303–1316. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLooker KJ, Garnett GP, Schmid GP: An estimate of the global prevalence and incidence of herpes simplex virus type 2 infection. Bull World Health Organ. 2008; 86(10): 805–812. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLooker KJ, Magaret AS, Turner KME, et al.: Global Estimates of Prevalent and Incident Herpes Simplex Virus Type 2 Infections in 2012. PLoS One. 2015; 10(5): e0128615. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLurie MN, Williams BG, Zuma K, et al.: The impact of migration on HIV-1 transmission in South Africa: a study of migrant and nonmigrant men and their partners. Sex Transm Dis. 2003; 30(2): 149–156. PubMed Abstract | Publisher Full Text\n\nMazzarello V, Ferrari M, Decandia S, et al.: Sunlight and herpes virus. In Human Herpesvirus Infection-Biological Features, Transmission, Symptoms, Diagnosis and Treatment. IntechOpen. 2018. Publisher Full Text\n\nMcQuillan GM, Kruszon-Moran D, Flagg EW, et al.: Prevalence of herpes simplex virus type 1 and type 2 in persons aged 14-49: United States, 2015-2016. NCHS Data Brief. 2018; (304): 1–8. PubMed Abstract\n\nModi S, Van L, Gewirtzman A, et al.: Single-day treatment for orolabial and genital herpes: a brief review of pathogenesis and pharmacology. Ther Clin Risk Manag. 2008; 4(2): 409–17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMohraz M, Aghakhani A, Moayedi-Nia S, et al.: No role of herpes simplex virus type 2 (HSV-2) infection on HIV progression in naïve HIV patients. Iran Biomed J. 2018; 22(2): 123–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMunawwar A, Singh S: Human herpesviruses as copathogens of HIV infection, their role in HIV transmission, and disease progression. J Lab Pysicians. 2016; 8(1): 5–18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNewman RM, Lamers SL, Weiner B, et al.: Genome sequencing and analysis of geographically diverse clinical isolates of herpes simplex virus 2. J Virol. 2015; 89(16): 8219–8232. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNie T, Detorio M, Schinazi RF: Universal profiling of HIV-1 pol for genotypic study and resistance analysis across subtypes. Antivir Ther. 2011; 16(8): 1267–75. PubMed Abstract | Publisher Full Text | Free Full Text\n\nObisesan OS: Molecular Prevalence of HSV1/2 from HIV-1 Positive and HIV-1 Negative sera collected from North-West and KwaZulu-Natal Provinces. (Doctoral dissertation, North-West University (South Africa)). 2019. Reference Source\n\nObisesan O, Sithebe NP, Mufhandu HT, et al.: Hsv And Hiv Raw Data. Dryad (dataset). 2020. http://www.doi.org/10.5061/dryad.zs7h44j7g\n\nOmori R, Abu-Raddad LJ: Sexual network drivers of HIV and herpes simplex virus type 2 transmission. AIDS. 2017; 31(12): 1721–1732. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPatel P, Bush T, Mayer KH, et al.: Prevalence and risk factors associated with herpes simplex virus-2 infection in a contemporary cohort of HIV-infected persons in the United States. Sex Transm Dis. 2012; 39(2): 154–60. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPaz-Bailey G, Ramaswamy M, Hawkes SJ, et al.: Herpes simplex virus type 2: epidemiology and management options in developing countries. Sex Transm Infect. 2007; 83(1): 16–22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPebody RG, Andrews N, Brown D, et al.: The seroepidemiology of herpes simplex virus type 1 and 2 in Europe. Sex Transm Infect. 2004; 80(3): 185–191. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRajagopal S, Magaret A, Mugo N, et al.: Incidence of herpes simplex virus type 2 infections in Africa: a systematic review. Open Forum Infect Dis. Oxford University Press. 2014; 1(2): ofu043. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSatpathy G, Behera HS, Sharma A, et al.: A 20-year experience of ocular herpes virus detection using immunofluorescence and polymerase chain reaction. Clin Exp Optom. 2018; 101(5): 648–651. PubMed Abstract | Publisher Full Text\n\nSchiffer JT, Mayer BT, Fong Y, et al.: Herpes simplex virus-2 transmission probability estimates based on quantity of viral shedding. J R Soc Interface. 2014; 11(95): 20140160. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchmutzhard J, Riedel HM, Wirgart BZ, et al.: Detection of herpes simplex virus type 1, herpes simplex virus type 2 and varicella-zoster virus in skin lesions. Comparison of real-time PCR, nested PCR and virus isolation. J Clin Virol. 2004; 29(2): 120–126. PubMed Abstract | Publisher Full Text\n\nSeemann T: Prokka: rapid prokaryotic genome annotation. Bioinformatics. 2014; 30(14): 2068–2069. PubMed Abstract | Publisher Full Text\n\nSheth PM, Sunderji S, Shin LYY, et al.: Coinfection with herpes simplex virus type 2 is associated with reduced HIV-specific T cell responses and systemic immune activation. J Infect Dis. 2008; 197(10): 1394–1401. PubMed Abstract | Publisher Full Text\n\nSmith JS, Robinson NJ: Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review. J Infect Dis. 2002; 186(Suppl 1): S3–S28. PubMed Abstract | Publisher Full Text\n\nSudenga SL, Kempf MC, McGwin G Jr, et al.: Incidence, prevalence and epidemiology of herpes simplex virus-2 in HIV-1-positive and HIV-1-negative adolescents. Sex Transm Dis. 2012; 39(4): 300–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSzpara ML, Gatherer D, Ochoa A, et al.: Evolution and diversity in human herpes simplex virus genomes. J Virol. 2014; 88(2): 1209–1227. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTodd J, Riedner G, Maboko L, et al.: Effect of genital herpes on cervicovaginal HIV shedding in women co-infected with HIV AND HSV-2 in Tanzania. PLoS One. 2013; 8(3): e59037. PubMed Abstract | Publisher Full Text | Free Full Text\n\nUnited Nations Programme on HIV/AIDS Data. 2019; (Accessed September 22 2020). Reference Source\n\nVictória JMN, Guimarães ALS, da Silva LM, et al.: Polymerase chain reaction for identification of herpes simplex virus (HSV-1), cytomegalovirus (CMV) and human herpes virus-type 6 (HHV-6) in oral swabs. Microbiol Res. 2005; 160(1): 61–65. PubMed Abstract | Publisher Full Text\n\nWorld Health Organisation: Globally, an estimated two-thirds of the population under 50 are infected with herpes simplex virus type 1. 2015; Accessed August 19 2020. Reference Source"
}
|
[
{
"id": "79452",
"date": "03 Mar 2021",
"name": "Oksana Debrah",
"expertise": [
"Reviewer Expertise Infectious diseases of public health concern",
"medical biochemistry",
"chemical pathology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nGeneral comments:\nMajority of the sentences can be restructured for better representation and understanding of information.\n\nThe text contains some grammatical and punctuation errors, they should be corrected before indexing.\n\nIt is suggested that the authors focus more on the sequencing analysis of the viruses, and present the prevalence of co-infection as side data, due to small sample size.\n\nSpecific comments: Below are more specific comments by section:\nTitle: The title of the article should be revised to make it more specific. For example, the country where the study took place should be included. This is an international journal and it is important to know from the title where these provinces can be found.\n\nAbstract: It is advised to revise the structure of the “Abstract” to improve the quality of the paper (or example, background, conclusion etc.).\n\nIntroduction: Some sentences are very long and can be restructured for better representation and understanding of information (for example, first and second sentence, etc.). Objectives can be better expressed.\n\nMethodology: Generally, this section can be improved. The details can be added to some laboratory analysis, even though the publication was done and the authors used the manufacturer’s instructions.\n\nSample collection criteria and study population: this section needs clarification. According to the authors, there was a retrospective study, but the methodology states that the sample was collected from the patients using convince sampling approach. Where later it was mentioned that the sample was collected blindly from the facilities. Please, kindly write in details the sampling collection approach so that it would be easy to understand. Secondly, why were different numbers of sera samples collected from two provinces (20 sera samples from North-West and 24 from KwaZulu-Natal Provinces)? It would be appropriate to explain the sampling approach that was used.\n\nLaboratory analysis: the structure of this paragraph can be improved.\n\nELISA: It was mentioned that the kits used in research were not specific. This statement needs some clarification, is it applied for HSV test kit or for HIV-1 test kit also?\n\nResults:\n\nTable: Presentation can be improved (for example, in table 1 there was no data for age group less than 10 years and etc.).\n\nTable 1 & figure 1 represent the same data. One should be removed, as it is a duplication of data representation.\n\nIt was mentioned in the methodology section, that the PCR was used to confirm the non-specific ELISA method even for HIV-1. There is no data in the result section. Please, kindly include this data.\n\nSome information on result section should be sent to methodology section.\n\nDiscussion: It is very difficult to draw the conclusion on the co-infection prevalence of HSV type 1 and type 2 and HIV-1, due to the small sample size and small co-infection in the study population.\n\nReferences: Some references in the text were wrongly introduced, for example, Debrah et al., 2018 was cited to present prevalence of HSV in Gambia, whereas Debrah and colleagues did the research in Ghanaian population.\n\nLimitation: The main limitation of the study is small sample size. This section mentioned that the age of study participants is from 14-49 years, whereas the results (table 1) introduce the data up to 60 years.\n\nConclusion: It is very difficult to draw the conclusions with such small sample size. The authors took a risk to make such conclusions.\n\nConclusion: major revision is needed.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "80471",
"date": "14 Apr 2021",
"name": "Bongiwe Ndlovu",
"expertise": [
"Reviewer Expertise 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\nStudy Title: The title of the paper should be revised, it is unclear. The location of samples collected should be removed from the title and properly explained in the Methods section.\n\nThe introduction: The authors should restructure the sentences. Some sentences are long and they have typographical errors. Some statements are inaccurate, for example: they mentioned that transmission is asymptomatic.\n\nMethods: The methods section should be revised. The authors should indicate the type of samples used for the study (blood, plasma, or serum), the country of origin, and the hospitals/ institutions where the samples were collected. They should also define convenience sampling.\n\nLaboratory Analysis: The authors should restructure the sentences. They also used abbreviations like EIA & PCR without describing them first/ writing in full.\nELISA method was not properly described. Which HIV-1/ HSV proteins did they use to measure antibody responses? The authors also did not specify which genes of interest and primers were used to amplify the HIV-1 genome with nested PCR. This should be clearly explained and referred to supplementary information.\nSequencing: It is not clear why G13, G15, G34 were sequenced with HSV-2 primers while G20 was amplified with HIV-1 primers.\n\nResults:\nDid you measure p24 antibody titers?\n\nFigure 1 is confusing, the authors used too many colors. They should consider simplifying the figure by showing a bar graph with positive and negative responses for each age group. The figure legend is too brief.\n\nThe authors did HSV1/2 PCR. However, the results are not shown in the article. The bar graphs are only shown in the supplementary information. These should be simplified and added as figure 2 of the manuscript. Where is the figure that shows HIV-1/HSV co-infections? These can be summarized clearly in a pie chart.\n\nThe interpretation of the sequencing data needs improvement. Which HIV-1 subtypes are HIV LC201873, 4533/11 and KU609428? Are they South African strains? What was the aim of selecting these strains?\n\nHIV-1 LC022388 and 3793/15 KU609388) were used in constructing the phylogenetic tree. However, it is not clear why these strains were selected for analysis.\n\nThe relationships between age and HSV-1, HSV-2, and HIV-1 or HSV-1 and HSV-2 are not clearly explained. Are they positive or negative associations?\n\nDiscussion:\n\nThe authors mentioned that HSV-1 is the most prevalent type of HSV as recorded by previous studies. However, they did not cite those studies.\n\nIn this study, they only found 4 patients with HSV-1. They should explain the differences between these studies that could lead to this difference in the findings.\n\nThe differences in HSV prevalence between males and females, could be due to their anatomy? It is unclear whether the studies conducted by Cunningham 2006 and Ayoub 2019 were done on South African participants or not.\n\nConclusion: The conclusion should be revised. The study was done on a small sample size.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-105
|
https://f1000research.com/articles/10-1045/v1
|
15 Oct 21
|
{
"type": "Research Article",
"title": "2-DOF robot modelling by SimMechanics and PD-FL integrated controller for position control and trajectory tracking",
"authors": [
"Tian Soon Lee",
"Esmail Ali Alandoli",
"V Vijayakumar",
"Esmail Ali Alandoli",
"V Vijayakumar"
],
"abstract": "Background Due to the high demand of robots to perform several industrial tasks, such as welding, machining, pick and place, position control in robotics has attracted high attention recently. Controllers’ improvement is also continuous specifically in terms of design simplicity and performance accuracy. This research plans to obtain the SimMechanics model of a two-degree of freedom (DOF) robot and to propose an integrated controller of a proportional–derivative (PD) controller and a fuzzy logic (FL) controller. Methodology The SimMechanics model of the 2-DOF robot is obtained using MATLAB SimMechanics toolbox from a CAD assembly design of the 2-DOF robot. Then, the proposed PD-FL integrated controller is designed and simulated in MATLAB Simulink. The PD controller is widely used for its simplicity, but it doesn’t have a satisfactory performance in difficult tasks. Furthermore, the FL controller is also easy for design and implementation even by non-experts in control theory, but it has the disadvantage of long computational time for multi-input systems due to the increased fuzzy rules. Results The FL controller is integrated with the PD controller for enhanced performance of the 2-DOF robot. The PD-FL integrated controller is developed and tested to control the 2-DOF robot for point-to-point position control and also tip trajectory tracking (TTT) such as triangular TTT and rhombic TTT. Conclusion The PD-FL integrated controller demonstrates enhanced performance compared to the conventional PD controller in both point-to-point position control and TTT. Furthermore, the PD-FL integrated controller has the advantage of less fuzzy rules which helps to overcome the computational time issue of the FL controller.",
"keywords": [
"2-DOF robot",
"SimMechanics model",
"PD-FL integrated controller",
"position control",
"tip trajectory tracking."
],
"content": "Introduction\n\nThere is a wide use of planar robots in industries to achieve several required tasks, such as welding, handling, machining, polishing, pick and place, etc. Meanwhile, there is a high demand of fast and precise position control for such robots in industries1. A dynamic model is required for several types of controllers in order to obtain the optimal parameters of a controller for satisfactory performance. There are many mathematical modelling methods, such as the kinematics method2, Newtonian method3, Lagrange’s equation4,5, and Hamilton's principle6. However, mathematical modelling is difficult and requires long calculations especially for nonlinear systems; critical and deep discussion of mathematical modelling methods is given in reference7. A numerical modelling method was used to obtain SimMechanics models of robots using Simulink and Simscape toolboxes from CAD assemblies8–10. SimMechanics models are easily obtained and can be simulated and controlled, so they are preferable.\n\nA proportional–derivative (PD) controller was tuned using root locus11,12 and manually tuned13,14 for position control of such robots. The manual tuning method helps to dispense about the mathematical model of a system which one of its advantages. However, the PD controller is not perfect for nonlinear and complex systems. A 2-DOF robot was controlled by a proportional–integral–derivative controller (PID) due to its simple structure, but it is not easy to obtain optimal PID parameters to give a satisfactory performance15. The linear quadratic regulator (LQR) is an optimal classical control technique and was utilized to control a planar robot with the necessity of a system mathematical model in order to calculate the controller gain16,17. The fuzzy logic controller (FLC) is a common control technique in robotics and has continuous increasing interest due to its robustness performance for nonlinear systems and does not require a mathematical model to tune its membership functions and rules18. FLC has the disadvantage of computational time due to the fuzzy rules explosion for controlling multi-input systems19,20.\n\nNeural network (NN) is an intelligent control technique and can be developed with simple knowledge of the system behavior without a need for a dynamic model which assists to avert the complexity of the mathematical modelling21. NN was used to control a 2-DOF robot in terms of links’ position22. However, NN require many hidden layers in its network to provide an accurate position control which needs long time for training23. Sliding mode controller (SMC) is a robust controller and was employed for position control of a 2-DOF robot24,25. However, sliding mode controller has the chattering issue which is a serious disadvantage26,27. Integrated controllers which consist of more than on control technique were also used for position control of 2-DOF robots such as FLC-SMC28,29, FLC-PID30, and FLC-NN31. There are many other control techniques were critically discussed in the literature32.\n\nBased on the discussed previous studies, the mathematical modelling of robots is a serious problem faces researchers and control engineers either the difficulty of mathematical operations or the challenge of obtaining accurate models. Therefore, the first objective is to obtain the SimMechanics model of the 2-DOF robot from the CAD assembly design via SimMechanics environment in MATLAB (RRID:SCR_001622); an open access alternative is GNU Octave (RRID:SCR_014398). The second objective is to design the PD-FL integrated controller to control the 2-DOF robot in terms of point-to-point position control of the links, triangular TTT and rhombic TTT. The remaining sections of this paper are as follows: section 2 describes the system and the SimMechanics model. Section 3 explains the proposed controller design. Section 4 presents the results and discussion. Section 5 is the conclusion.\n\n\nSystem and the SimMechanics model\n\nA schematic diagram of the 2-DOF robot is shown in Figure 1 which consists of two links with 50-cm length of each link and a 4.5 cm2 cross-sectional area. The movement of this robot is only on the horizontal plane. The tip position of the robot is computed based on Equation 1.\n\n\n\nThe CAD assembly of the 2-DOF is designed as shown in Figure 2. The CAD assembly is used to generate the SimMechanics model of the 2-DOF robot. The SimMechanics model is obtained starting by building the CAD assembly design of the robot and export the CAD assembly and save it in the format of ‘XML’ file. Then, the assembly ‘XML’ file is imported to the MATLAB SimMechanics toolbox using the ‘smimport’ function. The steps of generation the SimMechanics model is explained in detail in Figure 3. The SimMechanics model of the 2-DOF robot is presented in Figure 4. The SimMechanics model was generated and used in previous research such as in reference 9 and reference 10.\n\n\nControl design\n\nThe 2-DOF robot is controlled by the PD-FL integrated controller. The PD controller is selected due to its simplicity of design and it is widely used. The PD parameters can be easily tuned based on trial and error13,14, Equation 2 shown the PD control transfer function. Two PD controllers are designed as the PD controller is single input single output. The parameters of the two PD controllers are manually tuned and the better performance is achieved by the parameters tabulated in Table 1.\n\n\n\nFL controller is an intelligence control technique that depends on expressing the system behaviour. FL uses errors as its input variables and assigns the input into partial degrees of membership functions (MFs)33. The MF amplitude varies between 0 and 1. The fuzzy rules are expressed in the form of IF-THEN to describe the relation between inputs and outputs depended on the MFs. The MFs are designed and tuned in terms of range, numbers, and shape as shown in Figure 5 for the two inputs and outputs, they are described by “positive big” (PB), “positive medium” (PM), “positive small” (PS), “zero” (ZE), “negative big” (NB), “negative medium” (NM), and “negative small” (NS). Then, the fuzzy rules are tuned to describe the system errors depended on the MFs and to decide what fuzzy output should be, Table 2 describes the fuzzy rule-base. Table 2 shows the fuzzy rules reduction from 49 rules to 25 rules. The fuzzy rules reduction improves the computational time and simplifies the FL controller design.\n\nThe 2-DOF robot model and proposed PD-FL controller is shown in Figure 6. The outputs of the two PD controllers are the fuzzy inputs, and the fuzzy outputs are the robot inputs. The first PD controller controls link 1 and the second PD controller control link 2. The two PD controllers initially control the robot and minimize the errors, which do not reach NM and NB regions. Thus, there is no effectiveness of the fuzzy rules for NM and NB of errors which helps to minimize the fuzzy rules number from 49 to 25. This fuzzy rules’ reduction solves the issue of the computational time and also simplifies the FL controller design. The proposed PD-FL integrated controller\n\n\nResults and discussion\n\nThis section presents and discusses the results of point-to-point position control and the TTT.\n\nThe performance of the PD-FL integrated controller and the conventional PD controller is shown in Figure 7 for the first link of the 2-DOF robot by the blue line and the red line, respectively. The PD-FL integrated controller demonstrated great improvement in terms of “rise time” (Tr), “settling time” (Ts), “overshoot” (OS), and “steady state error” (ess) compared with the PD controller alone as analyzed in Table 3.\n\nThe PD controller has better performance for link 2 than link 1 as shown in Figure 8, this is because link 2 is a load to link 1 which makes the control of link 2 easier than control link 1 for the PD controller. However, the PD-FL integrated controller has better performance than the PD controller for link 2 as it has shorter rise time (Tr) and settling time (Ts), also it has less overshoot as described in Table 4. Based on the results of point-to-point position control of the 2-DOF robot, it is obvious that the PD-FL integrated controller is better than the conventional PD controller as it has shorter rise time (Tr), shorter settling time (Ts), and less overshoot for link 1 and link 2.\n\nThe PD-FL integrated controller is tested for TTT of the 2-DOF robot for triangular TTT and rhombic TTT as follows.\n\nThe triangular TTT of the 2-DOF is shown in Figure 9 for the PD-FL controller and the PD controller, The triangular TTT starts and ends based on the following trajectory points (X,Y): (1.0,0.0), (0.9,−0.1), (0.9,0.1), (1.0,0.0). It can be seen that the TTT of the PD-FL controller trajectory is nearer to the reference than the TTT of the PD controller. Based on the X and Y errors of both controllers in Figure 10, the improvement of the PD-FL integrated controller for the triangular TTT is also noticeable. The maximum Y error of the PD-FL integrated controller is less than 6 millimeters, but it is more than 9 millimeters for the PD controller. The X error of the PD-FL integrated controller is also smaller than the X error of the PD controller as presented in Figure 10.\n\nThe rhombic TTT starts and ends based on the following trajectory points (X,Y): (1.0,0.0), (0.9,−0.1), (0.8,0.0), (0.9,0.1), (1.0,0.0). Figure 11 shows the rhombic TTT of the 2-DOF robot. It is clearly shown that the PD-FL integrated controller is better than the PD controller in tracking the tip of the 2-DOF robot as it is closer to the tip reference trajectory. Furthermore, the maximum Y error of the PD controller tracking is about 8 millimeters while the maximum Y error of the PD-FL controller is less than 4 millimeters as shown in Figure 12. The X error of the PD controller is also larger than the X error of the PD-FL integrated controller as presented in Figure 12. Thus, the PD-FL integrated controller performance for the rhombic TTT of the 2-DOF robot is better than the PD controller.\n\nThe discussed results of the point-to-point position control and the TTT demonstrate the improvement of the proposed controller in terms of fast response and accuracy. Normally, the faster response is the more overshoot and larger tip position error. However, the proposed PD-FL integrated controller has a faster response and reduces the overshoot and the tip position error of the 2-DOF robot. Furthermore, the proposed controller has the advantage of design simplicity compared with other integrated controllers.\n\n\nConclusion\n\nThe aim of this research was to obtain the SimMechanics model of the 2-DOF robot using MATLAB SimMechanics Toolbox from the CAD assembly design. Then, the PD-FL integrated controller was designed to control the 2-DOF robot in terms of point-to-point position control and TTT. This proposed integration technique of the PD controller and the FL controller improves the position control performance and reduces the fuzzy rules which results in avoiding the computational time drawback. The PD-FL integrated controller was used to control the 2-DOF robot for point-to-point position control which demonstrates enhanced performance compared with the conventional PD controller. Moreover, the 2-DOF robot was controlled for triangular TTT and rhombic TTT by the PD-FL integrated controller which has better performance than the PD controller.\n\n\nData availability\n\nFigshare: Data are available under the term of the ‘2-DOF robot data of position control and tip trajectory tracking’ and has the following DOI: https://doi.org/10.6084/m9.figshare.16706458.\n\nFigshare: The model of the 2-DOF robot and control is available under the term of the ‘2-DOF robot model’ and has the following DOI: https://doi.org/10.6084/m9.figshare.16714324.",
"appendix": "Author contributions\n\n\n\nAll authors equally contributed to this research.\n\n\nReferences\n\nChi J, Yu H, Yu J: Hybrid Tracking Control of 2-DOF SCARA Robot via Port-Controlled Hamiltonian and Backstepping. IEEE Access. 2018; 6: 17354–17360. Publisher Full Text\n\nZhang B, Wu J, Wang L, et al.: Accurate dynamic modeling and control parameters design of an industrial hybrid spray-painting robot. Robot Comput Integr Manuf. 2020; 63: 101923. Publisher Full Text\n\nLee SH, Kim J, Park FC, et al.: Newton-Type Algorithms for Dynamics-Based Robot Movement Optimization. IEEE Trans Robot. 2005; 21(4): 657–667. Publisher Full Text\n\nAlandoli EA, Lee TS, My CA, et al.: Robust P-H∞ Integrated Controller for Flexible Link Manipulator System in the Presence of Disturbance. J Appl Comput Mech. 2021; 7(2): 646–654. Publisher Full Text\n\nAmin ATM, Ab Rahim AH, Low CY: Adaptive controller algorithm for 2-DOF humanoid robot arm. Procedia Technol. 2014; 15: 765–774. Publisher Full Text\n\nCao F, Liu J: Optimal trajectory control for a two-link rigid-flexible manipulator with ODE-PDE model. Optim Control Appl Methods. 2018; 39(4): 1515–1529. Publisher Full Text\n\nLee TS, Alandoli EA: A critical review of modelling methods for flexible and rigid link manipulators. J Braz Soc Mech Sci Eng. 2020; 42(10): 508. Publisher Full Text\n\nBoujnah F, Knani J: Motion simulation of a manipulator robot modeled by a CAD software. In: Proceedings of the 7th Int. Conf. Model. Identif. Control. 2015; 1–6. Publisher Full Text\n\nWest C, Montazeri A, Monk SD, et al.: A genetic algorithm approach for parameter optimization of a 7DOF robotic manipulator. IFAC-PapersOnLine. 2016; 49(12): 1261–1266. Publisher Full Text\n\nAlandoli EA, Lee TS, Lin YJ, et al.: Dynamic model and intelligent optimal controller of flexible link manipulator system with payload uncertainty. Arab J Sci Eng. 2021; 46: 7423–7433. Publisher Full Text\n\nAli SA, Miskon MF, Shukor AZH, et al.: The Effect of Parameters Variation on Bilateral Controller. Int J Power Electron Drive Syst. 2018; 9(2): 648–659. Reference Source\n\nAli SA, Miskon MF, Shukor AZH, et al.: Single Link Bilateral Haptics Control with PD Controller and Geared DC-Motor in Robotic Rehabilitation Technology. Int J Mech Mechatronics Eng. 2019; 17(5): 148–155.\n\nAlandoli EA, Shah HNM, Sulaiman M, et al.: PD/H-∞ Integrated Controller for Position Tracking and Vibration Suppression of Flexible Link Manipulator System. Int J Mech Mechatronics Eng. 2018; 18(3): 54–61. Reference Source\n\nAlandoli EA, Sulaiman M, Rashid MZA: Robustness and Disturbance Rejection of PD/H-∞ Integrated Controller for Flexible. J Eng Sci Technol Rev. 2019; 12(1): 27–36. Publisher Full Text\n\nBingül Z, Karahan O: A Fuzzy Logic Controller tuned with PSO for 2 DOF robot trajectory control. Expert Syst Appl. 2011; 38(1): 1017–1031. Publisher Full Text\n\nLeines MT, Yang JS: LQR control of an under actuated planar biped robot. In: Proceedings of the 6th IEEE Conf. Ind. Electron. Appl.. 2011; 1684–1689. Publisher Full Text\n\nAjwad SA, Iqbal J, Islam RU, et al.: Optimal and Robust Control of Multi DOF Robotic Manipulator: Design and Hardware Realization. Cybern Syst. 2018; 49(1): 77–93. Publisher Full Text\n\nKumar A, Kumar V: Hybridized ABC-GA optimized fractional order fuzzy pre-compensated FOPID Control design for 2-DOF robot manipulator. Int J Electron Commun. 2017; 79: 219–233. Publisher Full Text\n\nFarah N, Talib MHN, Ibrahim Z, et al.: Self-Tuned Output Scaling Factor of Fuzzy Logic Speed Control of Induction Motor Drive. In: Proceedings of the 2017 7th IEEE International Conference on System Engineering and Technology (ICSET) 2017; 134–139. Publisher Full Text\n\nFarah N, Talib MHN, Ibrahim Z, et al.: Self-tuning fuzzy logic control based on mras for induction motor drives. In: Proceedings of the 5th IET International Conference on Clean Energy and Technology (CEAT2018). 2018; 61–67. Publisher Full Text\n\nKiang CT, Spowage A, Yoong CK: Review of Control and Sensor System of Flexible Manipulator. J Intell Robot Syst Theory Appl. 2015; 77(1): 187–213. Publisher Full Text\n\nHe W, Chen Y, Yin Z: Adaptive Neural Network Control of an Uncertain Robot with Full-State Constraints. IEEE Trans Cybern. 2016; 46(3): 620–629. PubMed Abstract | Publisher Full Text\n\nTavoosi J, Jokandan AS, Daneshwar MA: A new method for position control of a 2-DOF robot arm using neuro-fuzzy controller. Indian J Sci Technol. 2012; 5(3): 1–5. Publisher Full Text\n\nIslam S, Liu XP: Robust sliding mode control for robot manipulators. IEEE Trans Ind Electron. 2011; 58(6): 2444–2453. Publisher Full Text\n\nKuo TC, Huang YJ, Hong BW: Design of Adaptive Sliding Mode Controller for Robotic Manipulators Tracking Control. Int J Comput Electr Autom Control Inf Eng. 2011; 5(5): 453–457. Publisher Full Text\n\nPiltan F, Sulaiman NB: Review of Sliding Mode Control of Robotic Manipulator. World Appl Sci J. 2012; 18(12): 1855–1869. Reference Source\n\nCapisani LM, Ferrara A: Trajectory Planning and Second-Order Sliding Mode Motion/Interaction Control for Robot Manipulators in Unknown Environments. IEEE Trans Ind Electron. 2012; 59(8): 3189–3198. Publisher Full Text\n\nLi TS, Huang Y: MIMO adaptive fuzzy terminal sliding-mode controller for robotic manipulators. Inf Sci. 2010; 180(23): 4641–4660. Publisher Full Text\n\nSoltanpour MR, Khooban MH: A particle swarm optimization approach for fuzzy sliding mode control for tracking the robot manipulator. Nonlinear Dyn. 2013; 74(1): 467–478. Publisher Full Text\n\nSharma R, Rana KPS, Kumar V: Performance analysis of fractional order fuzzy PID controllers applied to a robotic manipulator. Expert Syst Appl. 2014; 41(9): 4274–4289. Publisher Full Text\n\nGierlak P, Muszyńska M, Żylski W: Neuro-fuzzy control of a robotic manipulator. Int J Appl Mech Eng. 2014; 19(3): 575–584. Publisher Full Text\n\nAlandoli EA, Lee TS: A Critical Review of Control Techniques for Flexible and Rigid Link Manipulators. Robotica. 2020; 38(12): 2239–2265. Publisher Full Text\n\nFarah N, Talib MHN, Shah NSM, et al.: A Novel Self-Tuning Fuzzy Logic Controller Based Induction Motor Drive System: An Experimental Approach. IEEE Access. 2019; 7: 68172–68184. Publisher Full Text"
}
|
[
{
"id": "97077",
"date": "02 Nov 2021",
"name": "Xuan Bien Duong",
"expertise": [
"Reviewer Expertise CAD/CAM/CNC Technology",
"Robotics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nReviewer Comment for Authors 1. Comment No. 1\nThis paper implements modeling a planar two links robot with rotational joints based on 3D CAD model and SIMMECHANICS Toolbox in MATLAB software. This model retains the basic connections of the joints in the design environment. The PD-FL hybrid control system is designed to control the position and trajectory of the end-effector point. The control quality is compared with the traditional PD control system. The results show that the quality of the hybrid control system is much better than that of the PD system.\n2. Comment No. 2\nThe article has not shown new points in terms of robot model because the 2DOF robot model is quite simple, common and not a model that is widely applied in industrial production.\n\nEstablishing and converting 3D models from CAD design environment to MATLAB environment is not prominent because this problem has been done for a long time and with more complex robot models, more degrees of freedom.\n3. Comment No. 3\nThe concern point of the article is the position control and trajectory control problem of the end-effect point in the workspace, but it seems to only stop at the control for the kinematics model, not considering the factors dynamics, if any. The author should to add more information to the article.\n4. Comment No. 4\nThe position control problem is presented quite clearly. However, the control trajectory problem needs to include more specific information, such as how the author describes the trajectory of the end-effector point in the workspace - the equation describing the trajectory should to be clearly shown.\n5. Comment No. 5\nThe paper should to be further developed with consideration of the trajectory planning of the end-effector point in the workspace with more specific constraints on velocity and acceleration as well as the dynamic factors of the robot.\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? Yes",
"responses": [
{
"c_id": "7439",
"date": "17 Nov 2021",
"name": "tian lee",
"role": "Author Response",
"response": "The following points are the comments from Dr. Xuan Bien Duong and the authors' responses. Reviewer Comment No. 1 This paper implements modeling a planar two links robot with rotational joints based on 3D CAD model and SIMMECHANICS Toolbox in MATLAB software. This model retains the basic connections of the joints in the design environment. The PD-FL hybrid control system is designed to control the position and trajectory of the end-effector point. The control quality is compared with the traditional PD control system. The results show that the quality of the hybrid control system is much better than that of the PD system. Reviewer Comment No. 2 The article has not shown new points in terms of robot model because the 2DOF robot model is quite simple, common and not a model that is widely applied in industrial production. Establishing and converting 3D models from CAD design environment to MATLAB environment is not prominent because this problem has been done for a long time and with more complex robot models, more degrees of freedom. Authors’ response: The SimMechanics model can be obtained easier than the derivation of a mathematical model and might be more accurate to present the system. Thus, the SimMechanics model of the 2-DOF robot is obtained in this research in order to test the proposed PD-FL integrated controller in terms of position control and tip trajectory tracking. The main concern of this research is the PD-FL integrated controller design and it demonstrates significant enhancement in terms of the point-to-point position control of the links and the tip trajectory tracking. Reviewer Comment No. 3 The concern point of the article is the position control and trajectory control problem of the end-effect point in the workspace, but it seems to only stop at the control for the kinematics model, not considering the factors dynamics, if any. The author should to add more information to the article. Authors’ response: The SimMechanics model includes all the parameters of the 2-DOF robot which were identified in the CAD assembly design such as the material density, the weights, the cross-sectional area of the links, and the links’ lengths. In addition, the motion of the SimMechanics model is based on the torques actuation to the joints. Therefore, the position control of the 2-DOF robot is based on the dynamic motion. Such information is recently added to the article for more clarification of the model. Reviewer Comment No. 4 The position control problem is presented quite clearly. However, the control trajectory problem needs to include more specific information, such as how the author describes the trajectory of the end-effector point in the workspace - the equation describing the trajectory should to be clearly shown. Authors’ response: The tip trajectory of the 2-DOF robot is achieved by specific reference paths for the two joints simultaneously, the data of the joints’ references are available in the link provided in the “Data availability” section. The accurate position control of the joints related to the desired references will lead to an accurate tip trajectory of any demanded tip trajectory. From the position control output of the joints can obtain the tip position based on Equation 1 and compute the error. Reviewer Comment No. 5 The paper should to be further developed with consideration of the trajectory planning of the end-effector point in the workspace with more specific constraints on velocity and acceleration as well as the dynamic factors of the robot. Authors’ response: The velocity and acceleration for the position control response and the tip trajectory tracking are added to the article."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1045
|
https://f1000research.com/articles/10-1167/v1
|
17 Nov 21
|
{
"type": "Brief Report",
"title": "Does COVID-19 infection change the need for future surgical interventions? An exploratory analysis.",
"authors": [
"Blayne Welk",
"Lucie Richard",
"Lucie Richard"
],
"abstract": "Background: It is unknown whether recovery from coronavirus disease 2019 (COVID-19) infection leads to an increased need for common surgical procedures. Our objective was to conduct an exploratory analysis of surgical procedures performed after a documented COVID-19 infection. Methods: We conducted a retrospective cohort study using routinely collected data from the province of Ontario, Canada. We identified individuals with a positive COVID-19 test between February 1 2020 and May 31 2020, and matched them 1:2 with individuals who had a negative COVID-19 test during the same period. We used physician billing codes to identify the ten most frequent surgical procedures in the COVID-19 cohort. An at-risk period 30 days after the first positive COVID-19 swab (or matched index date in the control group) until November 30 2020 was used. Cox proportional hazard models (adjusted for important baseline differences) are reported with hazard ratios (HR) and 95% confidence intervals.\n\nResults: After exclusions and matching, we had 19,143 people in the COVID-19 cohort, and 38,286 people in the control cohort. The top ten surgical procedures were hand/wrist fracture fixation, cesarean-section, ureteral stent placement, cholecystectomy, treatment of an upper tract urinary stone, hysterectomy, femur fracture repair, hip replacement, transurethral prostatectomy, and appendectomy. There was a significantly reduced hazard of requiring upper tract renal stone surgery (adjusted hazard ratio [aHR] 0.50, 95% confidence interval [CI] 0.29-0.87) or ureteral stent placement (aHR 0.54, 95%CI 0.36-0.82), or undergoing a cholecystectomy (aHR 0.43, 95%CI 0.26-0.71) among those with a prior positive COVID-19 test.\n\nConclusions: After a COVID-19 infection there is not an increased risk of needing several common surgical procedures. There appears to be a reduced risk of renal stone disease treatment and ureteral stent placement, and a reduced risk of cholecystectomy, however understanding the reasons for this will require further study.",
"keywords": [
"Surgery",
"SARS-CoV-2",
"Covid-19",
"Renal stone disease"
],
"content": "Introduction\n\nThe coronavirus disease 2019 (COVID-19) global pandemic has led to fundamental shifts in everyday life around the world. Immense amounts of clinical research have examined the potential mechanisms and sequela of COVID-19 complications.1 This includes a significant volume of research on acute, and long-term complications of COVID-19. As a previously unknown disease, an important part of this research process is exploratory analyses to determine which health conditions may be more prominent after a COVID-19 infection; this led to important studies which have identified the risk of long-term sequela such as neurologic, metabolic, cardiovascular and gastrointestinal disorders that are now recognized as being part of long-COVID-19.2,3\n\nFor surgeons, most of the early study of COVID-19 centered around how surgical practices changed in response to the pandemic,4 safe operating room practices,5 or the abnormally high surgical mortality rate associated with operating on a COVID-19 patient.6 However, little research has examined if COVID-19 puts patients at increased risk of requiring specific surgical procedures after the period of acute infection. Given the wide-ranging impact of COVID-19 across several different organs, and the fact there is still much to be understood about long COVID-19, it is possible that patients with a previous COVID-19 infection are at an elevated risk of diseases that are managed operatively. Knowledge of this would be important for patients, physicians treating COVID-19 patients, and the surgical community.\n\nOur objective was to use routinely collected administrative data to conduct an exploratory analysis of surgical procedures performed after a documented COVID-19 infection.\n\n\nMethods\n\nThis is a retrospective cohort study. We made use of routinely collected data from the province of Ontario, Canada. All the datasets were linked using an encoded version of a unique patient identifier. All data was analysed at ICES Western. Ontario (Canada’s largest province with a population of 14.7 million people in 2020) has a single universal healthcare system, meaning this data is population based. The use of the data in this study was authorized under Ontario’s Personal Health Information Protection Act (Section 45), which does not require approval by a Research Ethics Board, or patient consent.7 A completed STROBE checklist, data collection plan and example analytic code for this study can be found as Extended data.28\n\nWe made use of several different datasets for this study. First, we used the Ontario Laboratories Information System (OLIS) to determine COVID-19 polymerase chain reaction (PCR) results.8 This dataset contains over 97% of the provincial COVID-19 PCR tests. Second, we used the Ontario Health Insurance Plan (OHIP) records, which contains information for all services provided through the province’s publicly funded health insurance system. Physicians must submit billing codes to this database to be compensated for medical services they provide; these OHIP fee codes have a high accuracy.9 Third, the Discharge Abstract Database (DAD)/Same Day Surgery (SDS)/National Ambulatory Care Reporting System (NACRS) datasets are compiled by the Canadian Institute for Health Information. They receive administrative, clinical (diagnoses and procedures/interventions), and demographic information for patients who have a hospital admission, same day surgery, or emergency room visit (respectively). Re-abstraction studies have demonstrated that diagnostic codes (89% exact match, 95% ICD10 code group match) are quite accurate.10 Finally, the Registered Persons Database (RPDB) provides basic demographic information (such as age and sex) for all people who are permanent citizens of Ontario.\n\nWe first identified all people in Ontario who had a positive COVID-19 nasopharyngeal PCR test between February 1 2020-May 31 2020 (COVID-19 cohort) using OLIS. We used the date of the positive nasopharyngeal swab as the index date of the infection. Using OLIS and RPDB, we excluded patients who were less than 18 years of age, those that had evidence of a previous positive COVID-19 PCR test in the 3 months prior, and those that died within 30 days of the COVID-19 diagnosis (as we were only interested in the period after acute COVID-19 infection). We also excluded residents of long-term care, as they were disproportionally affected by COVID-19,11 and in many instances have an intrinsic bias against surgical interventions due to competing medical issues, and advance care directives.\n\nTo create a comparison group (control cohort), we started by identifying all people that were alive in Ontario as of February 1, 2020, and had at least one negative COVID-19 nasopharyngeal PCR test between February 1 2020-May 31 2020. We used those with documented negative COVID-19 PCR tests for comparison, as there are systemic differences in the types of people that had access to and underwent COVID-19 testing, and this can introduce collider bias.12 For each of the people who met these inclusion criteria, we used the negative test date as their index date. We excluded people who had evidence of a COVID-19 infection between February 1 2020-May 31 2020, and then used the same exclusion criteria as we did for the COVID-19 cohort (age <18 years, those that died during the first 30 days following the index date and those residing in long-term care).\n\nWe matched (without replacement) one person from the COVID-19 cohort to two people from the control cohort based on the index date (±1 week), age (±1 year), and sex. We used two years of data from our datasets prior to the index date and three validated datasets (to identify patients with chronic obstructive pulmonary disease,13 hypertension,14 and diabetes15) to measure several baseline characteristics relevant to COVID-19 infection16 (coding details have been previously described17).\n\nOur primary outcome was the occurrence of surgical procedures 30 days after the index date. As this was an exploratory analysis, we did not identify specific surgical procedures a priori, but instead examined the top ten most frequent surgical procedures that occurred in the COVID-19 cohort during the follow-up period. These procedures were identified using OHIP fee codes (listed in the results table for the ten surgeries of interest). Each patient was observed for surgical procedures from the index date + 30 days, until November 30 2020 (with a follow-up period of six to ten months). Patients were censored if they died, or in the case of the control patients, if they were diagnosed with COVID-19 between May 31 and November 30 2020.\n\nWe compared baseline characteristics between the matched COVID-19 and the control cohorts using standardized differences; >10% is a potentially meaningful difference.18 We used PROC PHREG (SAS 9.4, SAS institute, Cary, NC, USA) to create Cox proportional hazards models with robust variance estimation to account for the correlation introduced with matching. We adjusted statistical models for any differences in the baseline characteristics which had a standardised difference >10%. Results are reported as hazard ratios (HR) and 95% confidence intervals (CI), and we considered two-tailed p-values <0.05 statistically significant.\n\n\nResults\n\nWe identified 30,284 people who had a positive COVID-19 test during the four-month study accrual period; of these 19,143 remained after our exclusion criteria. There were 528,581 people who had a negative COVID-19 test during the four-month study accrual period; 436,396 remained after applying the exclusion criteria, and 38,286 were matched to our COVID-19 positive patients (details in Figure 1).\n\nThe COVID-19 and control cohorts had similar age ranges and sex composition due to the matching. Other baseline variables were generally similar, other than a higher rate of chronic obstructive lung disease and heart disease among the control cohort (Table 1). The top ten surgical procedures that were identified were hand/wrist fracture fixation, Cesarean-section, ureteral stent placement, cholecystectomy, treatment of an upper tract urinary stone, hysterectomy, femur fracture repair, hip replacement, transurethral prostatectomy, and appendectomy. After adjusting for COPD cancer, and heart disease, there was a significantly reduced hazard of requiring upper tract renal stone surgery or ureteral stent placement, or undergoing a cholecystectomy among people who had a history of a positive COVID-19 test (Table 2).\n\nSD = standard deviation.\n\naHR = adjusted hazard ratio; CI = confidence interval.\n\na Results adjusted for the binary variables of chronic obstructive pulmonary disease (COPD), cancer and heart disease.\n\nb For privacy reasons, groups of people with an n < 6 are not reported.\n\n* p < 0.05.\n\nTwo post-hoc analyses were carried out after seeing our initial exploratory results. The first was measuring the use of nephrostomy tube insertions (OHIP code J046) during the same at-risk period as our primary outcomes (30 days after the index date until the end of follow-up). The COVID-19 cohort was significantly less likely to undergo this procedure (adjusted HR 0.251 (95% CI 0.075-0.840). The second was the frequency of requiring upper tract renal stone surgery or ureteral stent placement in the immediate 30 days after the index date; the adjusted HR for these outcomes during this earlier period were also significantly lower for the COVID-19 cohort (Table 2).\n\n\nDiscussion\n\nIn this study, we determined the relative risk of common operative procedures beyond the first 30 days of COVID-19 infection. For most of the surgical procedures, there was no significant increased risk, and many of these hazard ratios were close to one. We did however identify three surgical procedures that were significantly less likely to be carried out in patients who had a history of COVID-19 infection. To our knowledge, this has not been previously described.\n\nA reduced risk of upper tract renal stone surgery or ureteral stent placement (HRs of approximately 0.50 for each) was observed. After seeing this result, we explored whether this could be due to an increased reliance on nephrostomy tube insertions (which generally only require sedation rather than a general anesthetic), however this procedure was rare and also significantly lower among COVID-19 patients. Similarly, the results were not explained by increased stone disease in the 30 days immediately after COVID-19 infection. Therefore, our results could be due to a reduced presentation of renal stones, a reluctance from urologists to intervene on stones after COVID-19 infection, or a lower propensity to form stones or have symptomatic renal stone disease after COVID-19. In general, the COVID-19 pandemic reduced the frequency of emergency room presentations of renal colic, and many hospitals setup triage procedures that precluded treatment of any non-urgent stone disease.19 This however should have impacted both the COVID-19 and control cohort. During this time period of the pandemic, people in general were less likely to go to the emergency room with renal colic and were more likely to avoid operative intervention.20 This may have been amplified in post COVID-19 patients. It is likely that non-acute renal stone interventions were avoided among patients with a recent history of COVID-19 due to uncertainties about patient and operating room personnel safety, and due to the provincial operating room procedures.21 It is also possible that the specific renal effects of COVID-19 (mediated through the ACE receptors in the kidney) led to a lower propensity to develop kidney stones; the resulting kidney injury may have led to an increased focus on hydration after COVID-19 infection, patients may have experienced favorable anti-lithogenic electrolyte shifts during the acute infection, or care processes around post-COVID-19 infection follow-up may have decreased the risk of renal stone development and subsequent intervention.22,23 Magnetic resonance imaging (MRI) abnormalities have also been detect in the kidney after COVID-19 infection, and these changes may impact renal stone risk.24\n\nThe reduced risk of cholecystectomy was an interesting finding. Abdominal imaging in COVID-19 patients is more likely to detect biliary sludge and gallstones,25 which would lead to a hypothetically increased risk of future complications and need for cholecystectomy (contrary to our findings). Similar to renal stones, it is possible that conservative management was the goal for the initial period after COVID-19, and surgical interventions were deferred for the same reasons previously discussed.26\n\nSome limitations of our study are important to acknowledge. The pandemic started in Canada in February of 2020, therefore our period of follow-up after COVID-19 infection is limited in our study to at most 10 months. Many hospitals in Ontario instituted surgical triage protocols which affected the delivery of elective care; however, our surgical procedure list does contain a mix of procedures which are traditionally elective and others that are more urgent. The time period of the study was characterized primarily by COVID-19 wildtype infections, and it is possible that the subsequent variants have different effects. People can have asymptomatic COVID-19, and early in 2020 testing for COVID-19 was limited to those who met specific criteria; therefore, some people with a prior COVID-19 infection may have been misclassified and included in the control group. The risk of this should be low, as a study of healthcare workers (a group that did have early access to testing and more stringent screening for symptoms) found that 3% had COVID-19 antibodies in the absence of a documented COVID-19 positive test.27 Finally, all observational studies may have residual confounding.\n\n\nConclusions\n\nAfter a COVID-19 infection there is not an increased risk of needing common surgical procedures. There appears to be a reduced risk of renal stone disease treatment and ureteral stent placement, and a reduced risk of cholecystectomy, however understanding the reasons for this will require more study.\n\n\nData availability\n\nThe dataset from this study is held securely in coded form at ICES. While legal data sharing agreements between ICES and data providers (e.g., healthcare organizations and government) prohibit ICES from making the dataset publicly available, access may be granted to those who meet pre-specified criteria for confidential access, available at www.ices.on.ca/DAS (email: das@ices.on.ca). Further details about the process can be found here.\n\nOpen Science Framework: Supplementary information for Welk B, Richards L. Does CoVID-19 infection change the need for future surgical interventions? An exploratory analysis. https://doi.org/10.17605/OSF.IO/GHDB9.28\n\nThis project contains the following extended data:\n\n- STROBE/RECORD checklist\n\n- Data collection plan\n\n- Example analytic code\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).\n\nThe full underlying analytic code are available from the authors upon request after approval for access to the data from the Data Analytic Services at ICES (see data availability statement). Users must understand that the computer programs may rely upon coding templates or macros that are unique to ICES and are therefore are either inaccessible or they may require modification.",
"appendix": "Acknowledgements\n\nParts of this material are based on data and/or information compiled and provided by CIHI. However, the analyses, conclusions, opinions and statements expressed in the material are those of the author(s), and not necessarily those of CIHI. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File.\n\n\n\n\nThe study was funded by the St. Joseph’s Health Care Foundation’s Health Crisis Fund. The study was carried out by ICES Western. ICES is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). Core funding for ICES Western is provided by several partners including the Academic Medical Organization of Southwestern Ontario (AMOSO), the Schulich School of Medicine and Dentistry (SSMD), Western University, and the Lawson Health Research Institute (LHRI). The opinions, results and conclusions are those of the authors and are independent from the funding sources. No endorsement by ICES, AMOSO, SSMD, LHRI, or the MOHLTC is intended or should be inferred.\n\n\nReferences\n\nElse H: How a torrent of COVID science changed research publishing — in seven charts. Nature. 2020; 588(7839): 553–553. PubMed Abstract | Publisher Full Text\n\nAl-Aly Z, Xie Y, Bowe B: High-dimensional characterization of post-acute sequalae of COVID-19. Nature. 2021; 594(7862): 259–264. Publisher Full Text\n\nNasserie T, Hittle M, Goodman SN: Assessment of the Frequency and Variety of Persistent Symptoms Among Patients With COVID-19. JAMA Netw. Open. 2021; 4(5): e2111417. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGomez D, Simpson AN, Sue-Chue-Lam C, et al.: A population-based analysis of the impact of the COVID-19 pandemic on common abdominal and gynecological emergency department visits. CMAJ. 2021; 193(21): E753–E760. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKibbe MR: Surgery and COVID-19. JAMA. 2020; 324(12): 1151–1152. PubMed Abstract | Publisher Full Text\n\nWelk B, Richard L, Rodriguez-Elizalde S: The requirement for surgery and subsequent 30-day mortality in patients with COVID-19. Can. J. Surg. 2021; 64(2): E246–E248. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPrivacy at ICES: [cited 2021 Oct 29]. Reference Source\n\nHuang C, et al.: COVID-19 Laboratory Testing in Ontario: Patterns of Testing and Characteristics of Individuals Tested, as of April 30, 2020.Reference Source\n\nRaina P, Torrance-Rynard V, Wong M, et al.: Agreement between self-reported and routinely collected health-care utilization data among seniors. Health Serv. Res. 2002 Jun; 37(3): 751–774. Publisher Full Text\n\nCIHI: Data Quality Study of the 2009–2010 Discharge Abstract Database.1–139. Accessed 2012 Apr 4. Reference Source\n\nLiu M, Maxwell CJ, Armstrong P, et al.: COVID-19 in long-term care homes in Ontario and British Columbia. CMAJ. 2020; 192(47): E1540–E1546. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGriffith GJ, Morris TT, Tudball MJ, et al.: Collider bias undermines our understanding of COVID-19 disease risk and severity. Nat. Commun. 2020; 11(1): 5749. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGershon AS, Wang C, Guan J, et al.: Identifying Patients with Physician-Diagnosed Asthma in Health Administrative Databases. Can. Respir. J. 2009; 16(6): 183–188. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTu K, Campbell NR, Chen Z-L, et al.: Accuracy of administrative databases in identifying patients with hypertension. Open Medicine Peer-Reviewed Indep Open-Access J. 2007; 1(1): e18–e26.\n\nHux JE, Ivis F, Flintoft V, et al.: Diabetes in Ontario: determination of prevalence and incidence using a validated administrative data algorithm. Diabetes Care. 2002 Mar; 25(3): 512–516. Publisher Full Text\n\nRichardson S, Hirsch JS, Narasimhan M, et al.: Presenting Characteristics, Comorbidities, and Outcomes Among 5700 Patients Hospitalized With COVID-19 in the New York City Area. JAMA. 2020; 323(20): 2052–2059. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWelk B, Richard L, Braschi E, et al.: Is coronavirus disease 2019 associated with indicators of long-term bladder dysfunction?. Neurourol. Urodyn. 2021; 40: 1200–1206. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAustin PC: Using the Standardized Difference to Compare the Prevalence of a Binary Variable Between Two Groups in Observational Research. Commun. Stat. Simul. Comput. 2009; 38(6): 1228–1234. Publisher Full Text\n\nCastellani D, Ragonese M, Rosa MD, et al.: An Italian multicenter analysis of emergency admissions and treatment of upper tract urolithiasis during the lockdown and reopening phases of the COVID-19 pandemic: Are we ready for a second wave of the outbreak?. Int. J. Urol. 2021; 28(9): 950–954. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJiang T, Osadchiy V, Weinberger JM, et al.: Impact of the COVID-19 Pandemic on Patient Preferences and Decision Making for Symptomatic Urolithiasis. J. Endourol. 2021; 35(8): 1250–1256. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarrett K, Khan YA, Mac S, et al.: Estimation of COVID-19–induced depletion of hospital resources in Ontario, Canada. CMAJ. 2020; 192(24): E640–E646. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGupta A, Madhavan MV, Sehgal K, et al.: Extrapulmonary manifestations of COVID-19. Nat. Med. 2020; 26(7): 1017–1032. PubMed Abstract | Publisher Full Text\n\nCortinovis M, Perico N, Remuzzi G: Long-term follow-up of recovered patients with COVID-19. Lancet. 2021; 397(10270): 173–175. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKorompoki E, Gavriatopoulou M, Hicklen RS, et al.: Epidemiology and organ specific sequelae of post-acute COVID19: A Narrative Review. J. Infect. 2021; 83(1): 1–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBoraschi P, Giugliano L, Mercogliano G, et al.: Abdominal and gastrointestinal manifestations in COVID-19 patients: Is imaging useful?. World J Gastroentero. 2021; 27(26): 4143–4159. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNarvaez JRF, Cooper C, Brewer JJ, et al.: Do We “Do No Harm” in the Management of Acute Cholecystitis in COVID-19 Patients?. Am. Surg. 2020; 86(7): 748–750. PubMed Abstract | Publisher Full Text\n\nScience M, Bolotin S, Silverman M, et al.: SARS-CoV-2 antibodies in Ontario health care workers during and after the first wave of the pandemic: a cohort study. Can Medical Assoc Open Access J. 2021; 9(4): E929–E939. Publisher Full Text\n\nWelk B: Supplementary information for Welk B, Richards L. Does CoVID-19 infection change the need for future surgical interventions? An exploratory analysis.2021, November 9. Publisher Full Text"
}
|
[
{
"id": "100488",
"date": "03 Dec 2021",
"name": "Henry Tran",
"expertise": [
"Reviewer Expertise Reconstructive Urology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis paper is a retrospective cohort study looking at whether COVID-19 infection increases chances of needing surgical procedures after the period of acute infection.\nThe authors used the Ontario Laboratories Information System (OLIS) to determine COVID-19 PCR results, in addition to Ontario Health Insurance Plan (OHIP) records to identify all people in Ontario with a positive COVID 19 nasopharyngeal PCR test between February 1 to May 31, 2020. Control cohort was generated by identifying people who had one negative COVID nasopharyngeal PCR test between February 1-May 31, 2020. Long term care residents and patients < 18 years of age were excluded. Primary outcome was occurrence of surgical procedures 30 days after index date, identified using OHIP fee codes.\nThe top 10 surgical procedures in the COVID-19 cohort were analyzed and there was no significant increased risk of needing those specific surgical procedures in the COVID-19 group. They found a reduced risk of having renal stone disease treatment and ureteral stent placement and cholecystectomy.\nThe authors do a good job comparing the COVID-19 cohort with the control cohort and have a high number of patients in their analysis. They correctly identify limitations to their study, including the potential for misclassification of COVID-19 positive and negative patients due to possibility of patients with asymptomatic disease and COVID-19 testing errors.\nOverall, I feel that the paper is ready for indexing. This study addresses an important question of whether or not there is an increased risk of surgical diseases in COVID-19 patients.\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": []
},
{
"id": "115400",
"date": "24 Jan 2022",
"name": "Jorge Moreno-Palacios",
"expertise": [
"Reviewer Expertise Urologist",
"Endourology",
"Functional Urology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors report regarding surgical procedures during the COVID-19 pandemic in a province of Canada. Interestingly, they found that there appears to be a reduced risk of renal stone disease treatment and ureteral stent placement, and a reduced risk of cholecystectomy. The data obtained are well presented, and although the information is new regarding the COVID-19 literature, it could not be applied to all medical systems (they acknowledge this as one of the limitations of the study), but give us the idea that due to COVID-19, surgical procedures changed according to each specific site, pandemic situation, and resources. New triage protocols for surgical procedures were developed in the hospitals and they are now performed on a regular basis.\n\nDifferent protocols1 had been suggested to ensure the surgical treatment of patients with and without the infection. Although the focus will be on treating the epidemic, patients will continue to need emergency and elective procedures so research models as the one presented in this article could help similar health systems to plan how surgical services will operate during this health crisis.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1167
|
https://f1000research.com/articles/10-1163/v1
|
16 Nov 21
|
{
"type": "Research Article",
"title": "Effectiveness of strengthening exercise plus activities of daily living instructions in reducing pain in patients with lumbar disc herniation: a randomized controlled trial",
"authors": [
"Shabbir Ahmed Sany",
"MD Imam Shahriar",
"Zannatun Nyme",
"Taukir Tanjim",
"MD Imam Shahriar",
"Zannatun Nyme",
"Taukir Tanjim"
],
"abstract": "Background: Lumbar disc herniation (LDH) is one of the most common causes of chronic low back pain (CLBP) with sciatica. The exercise intervention was found effective in improving CLBP, although a paucity of research evaluated the effectiveness of exercise intervention to alleviate CLBP due to LDH. This study aimed to evaluate the effectiveness of the combination of back and hip strengthening exercises and activities of daily living instructions (ADLIs) to improve CLBP with sciatica due to LDH. Method: This assessor-blinded randomized clinical trial was conducted on 70 patients with CLBP with sciatica due to LDH. The patients were randomly allocated either in the intervention group (IG) or control group (CG). Patients in IG received both back and hip strengthening exercises five days a week for six weeks. Patients in CG received pharmacological therapy for three weeks, followed by hot moist compression for another three weeks. Patients of both groups followed the ADLIs at the time of the intervention and at least three months after the intervention. Back pain intensity and perceived pain due to sciatica were measured by the Visual Analogue Scale and range of hip flexion during the Straight Leg Raising Test, respectively, at three weeks and six weeks of intervention, and three months after the intervention. Results: Back pain and sciatica improved significantly (p < 0.05) in both groups at the end of the intervention and follow-up, while the IG showed significantly better improvements (p < 0.05) at the end of the intervention. However, only ADLIs were not adequate to sustain the improvements after the intervention. Conclusion: The combination of back and hip strengthening exercises and ADLIs improves CLBP with sciatica due to LDH. Nevertheless, it is required to instruct patients to follow ADLIs and perform strengthening exercises regularly to maintain the improvements. Trial registration: ClinicalTrials.gov, NCT05021718.",
"keywords": [
"Back pain",
"Daily living instructions",
"Lumbar disc herniation",
"Sciatica",
"Strengthening exercise."
],
"content": "Introduction\n\nLow back pain (LBP) is the pain, muscle tension, or stiffness localized below the costal margin and above the inferior gluteal folds with or without leg pain.1 Around 70-80% of people experience LBP at least once during their lifetime,2,3 while 18% of the people suffer from LBP at any given time.4 LBP prevalence is also high in middle and low-income countries,5 including Bangladesh.6–9 Nearly 97% of patients have LBP due to mechanical factors, while 2% are due to visceral disease and 1% non-mechanical reasons.10,11 Intervertebral disc herniation is the most common cause of LBP in adults, and that accounts for 4% of mechanical LBP.11–13 Intervertebral disc herniation is defined as a focal displacement of disc material beyond the limits of the intervertebral disc space.14 The lower lumbar spine (L4/5 and L5/S1 level) is the most common site of disc herniation.15 In addition, about 60% of patients with LBP presented with radiating leg pain, which is also known as sciatica.16 Nerve root compression by the herniated lumbar intervertebral disc (LDH) is considered the most common cause of sciatica, although there are many possible causes.17\n\nMost of the patients recover spontaneously within two to four weeks from the acute phase of LBP without receiving any treatment.18 However, about 10 – 20% of patients develop chronic low back pain (CLBP) that may lead to significant disability.19,20 Exercise is regarded as the first-line treatment of CLBP.21 Different types of exercise, including strengthening exercise, flexibility training, aerobic exercise, resistance training, and stretching exercise, effectively gain short-term and long-term improvements in patients with CLBP.22–25\n\nStrengthening exercise is frequently included in the exercise program as it enhances the lumbar extensor muscle strength of LBP patients.26,27 Research showed that strengthening exercise was more effective than aerobic exercise and other exercises to improve CLBP.28,29 In addition, strengthening exercise is also safe for the elderly, and it helps regain muscle strength.26 Ishak et al. showed in their systemic review that strengthening exercise effectively alleviates pain and prevents disability in the elderly with CLBP.26 However, a paucity of research evaluated the effectiveness of strengthening exercise to improve pain in patients with CLBP due to LDH. In addition, activities-of-daily-living instruction (ADLI) is a useful tool that enables patients with LBP to perform daily tasks efficiently without increasing direct demand on injured areas.30 It helps to enhance spinal stability and limit LBP and, consequently, intensifies the recovery.30\n\nThis study aimed to evaluate the effectiveness of combined back and hip strengthening exercises and ADLIs to improve pain intensity in patients with CLBP due to LDH. In addition, we also investigated whether only ADLIs were sufficient to sustain improvements after the intervention. To our best knowledge, it is the first research that assessed the effectiveness of combined strengthening exercises and ADLIs to improve CLBP due to LDH. We hypothesized that this combined therapy would alleviate pain significantly after the end of the intervention, and only ADLIs would be adequate to maintain the progress at follow-up.\n\n\nMethods\n\nThe sample size was determined as 34 in each group using OpenEpi version 3.1, assuming 7.74% as the estimated prevalence rate31 at a 95% confidence level with 9% precision. Outpatients with CLBP caused by one or more lumbar discs herniation attending the Department of Physical Medicine & Rehabilitation, Chittagong Medical College Hospital, were recruited for the study. The recruitment was done from July 2018 to February 2019. Initially, the patients were clinically re-examined by a physical medicine consultant of Chittagong Medical College Hospital, and then the diagnosis was confirmed by magnetic resonance imaging (MRI).\n\nPatients aged 18 – 59 years and with a history of pain for the last three months, or more were included in the study. Patients with pregnancy, cauda equina syndrome and other pathological conditions of the spine were excluded. Details of inclusion and exclusion criteria are presented in Table 1. All participants received detailed information about the research project. Informed consent, both in written and oral form, was obtained from each subject to participate in the study. Demographic characteristics of the participants, including age, weight, and height, were recorded at the hospital before the commencement of the intervention.\n\nLDH: Lumbar disc herniation; MRI: magnetic resonance imaging.\n\n\n\n• Age: 18-59 years\n\n• Clinically diagnosed LDH that was confirmed by MRI.\n\n• Duration of the pain: ≥3 months\n\n\n\n• Painful spinal deformity\n\n• Cauda equina syndrome\n\n• Progressive neurological signs and/or muscle-wasting\n\n• History of spinal surgery, spine fracture, scoliosis, tuberculosis, and tumors.\n\n• Treated with epidural injections.\n\n• Pregnancy\n\nThis parallel-group randomized controlled trial was reported following the Consolidated Standards for Reporting Trials (CONSORT) guidelines. The CONSORT diagram is shown in Figure 1. No changes were made to methods after trial commencement.\n\nAll eligible patients were randomly allocated to either the intervention group (IG) or control group (CG). Randomization was done by lottery method using the unique identification number of the participants. An independent person who was not part of the research was involved in randomization. Both researchers and assessors were unaware of randomization.\n\nPatients in IG received different back and hip strengthening exercises for six weeks, five days a week, once a day, for a total of 30 sessions. Under the supervision of the researchers, a trained physiotherapist instructed the patients at the hospital. The exercises were initiated from a basic level and were gradually progressed. The intensity of exercises, including the cycle and repetition of exercise, was controlled depending on the individual subject's exercise tolerance and pain thresholds. The details of back and hip strengthening exercises are presented in Table 2.\n\n\n\n• 1st week:\n\nPelvic tilt exercise: The patients were instructed to lie on the back with the knees bent and feet flat on the floor. Then they were asked to tighten the buttocks and abdomen so that they tip up slightly. Afterward, they are asked to press the lower back to the floor and hold for six seconds while breathing evenly.\n\n• 2nd and 3rd week:\n\nBack strengthening exercise: In the prone position, the patients were instructed to lift their upper body off the ground while keeping their legs on the floor. They were asked to hold the position for about three to four seconds.\n\nHip strengthening exercise: In the prone position, the patients were trained to perform alternate hip extension.\n\n• 4th and 5th week:\n\nThe patients were instructed to raise their head and shoulders and extend their hips in the prone position. They were asked to maintain the position for five to six seconds.\n\n• 6th week:\n\nIn the prone kneeling position, the patients were instructed to lift the opposite arm and leg simultaneously until the body is in a straight line and to hold the position for four to five seconds. Then they were asked to do the same movement on the other side.\n\n\n\n• Week 1 to week 3:\n\nNaproxen (500 mg) and Baclofen (10 mg) tablet twice a day for three weeks.\n\n• Week 4 to week 6:\n\nHot moist compression for the next three weeks, five days a week, once a day for a total of 15 sessions.\n\n\n\n✓ Avoid forward bending.\n\n✓ Avoid heavy weightlifting.\n\n✓ Avoid prolonged standing.\n\n✓ Avoid prolonged sitting.\n\n✓ Use a plain, firm bed.\n\n✓ Lie down in a supine position.\n\nThe patients in CG received pharmacological therapy and hot moist compression as suggested in previous studies.32 They were treated with Naproxen (500 mg) and Baclofen (10 mg) tablet twice a day for three weeks, followed by hot moist compression for the next three weeks, five days a week, once a day for a total of 15 sessions. Patients were asked to take drugs regularly at home, while hot moist compression was given by a physiotherapist at the hospital. In addition, the patients in both groups were instructed to follow the activities in daily living instructions (ADLIs) during the intervention and at least three months after the intervention. Details of ADLIs are demonstrated in Table 2.\n\nEvaluation of the intensity of back pain of the patients was the primary outcome of the intervention. In addition, the patient's perceived pain due to sciatica was also assessed as the secondary outcome. The severity of perceived back pain was evaluated using a Visual Analogue Scale (VAS). VAS is regarded as valid and reliable for rating back pain.33 Patients were asked to rate their perceived pain on a 0-to-10-point scale, where 0 indicated no pain at all and 10 indicated the most severe imaginable pain.\n\nIn addition, the straight leg raising test (SLRT) was performed for clinical assessment and to evaluate the progression of sciatica. SLRT is an important clinical test for assessing sciatica or the lumbar root irritation caused by disc herniation.34–36 The SLRT has high sensitivity but low specificity to diagnose LDH.37,38 The SLRT was performed with the patients lying in the supine position without any pillow under their heads. Then the examiner gently lifted the patient's leg by the posterior ankle while keeping the knee fully extended position. The examiner stopped raising the leg when the patient felt pain, or the maximum flexion was obtained. Then the range of hip flexion (RHF) without pain was measured by a hand-held goniometer. The test was done for both affected and unaffected legs.\n\nOutcomes were evaluated at baseline, at three weeks, and at six weeks of the intervention. Patients were followed up after three months of the intervention. All measurements were performed at the hospital by an independent assessor who was unaware of group allocation and intervention.\n\nData analysis was performed using the Statistical Package for the Social Sciences (SPSS Inc, Chicago, IL), version 26. Descriptive statistics were generated, and results were presented as mean ± SD. Continuous variables were non-normally distributed. Hence, differences between the groups at baseline, at three months, post-intervention, and at follow-up were analyzed by the Mann-Whitney U test. Differences in outcomes at different time points in the same group were analyzed with Wilcoxon's signed-rank test. A p-value less than 0.05 was considered statistically significant.\n\nThe research protocol was approved by the ethics committee of Chittagong Medical College (Approval number: CMC/PG/2018/226) and was registered at ClinicalTrials.gov (Identifier: NCT05021718). The original protocol was strictly maintained.\n\n\nResults\n\nA total of 72 participants met all the inclusion criteria and were confirmed to have LDH by MRI images. However, two participants declined to participate in the study before the start of the intervention. Hence, 70 subjects were finally included in the study who were equally allocated to either in IG or CG. The mean age of the participants in IG was 42.37 ± 10.32 years and in CG was 38.94 ± 8.33 years. At the same time, the mean BMI of participants in IG and CG was 26.14 ± 4.49 kg/m2 and 24.58 ± 4.15 kg/m2, respectively. Table 3 shows the baseline demographic and clinical characteristics of the patients. Baseline assessment of demographic and clinical characteristics of patients did not show any significant differences (p > 0.05) between the two groups.\n\nThe within-group analysis demonstrated that back pain intensity decreased significantly in both groups at all time points compared to baseline.\n\nFrom baseline to three weeks of intervention, back pain intensity reduced by 59.17% (7.20 ± 0.90 to 2.94 ± 1.11, p < 0.05) in IG, and 59.07% (7.11 ± 0.80 to 2.91 ± 0.82, p < 0.05) in CG. However, no significant differences (p = 0.951) between groups were observed.\n\nFrom baseline to the end of the intervention, back pain intensity decreased by 85.69% (7.20 ± 0.90 to 1.03 ± 1.00, p < 0.005) in IG, and 79.89% (7.11 ± 0.80 to 1.43 ± 0.88, p < 0.005) in CG. Moreover, between group analysis showed significant differences between groups (p = 0.049).\n\nFrom baseline to follow-up, back pain intensity reduced by 51.53% (7.20 ± 0.90 to 3.49 ± 1.84, p < 0.005) and 54.57% (7.11 ± 0.80 to 3.23 ± 1.85, p < 0.005) in IG and CG, respectively, without any significant differences between groups (p = 0.515). Whereas from the end of the intervention to follow-up back pain was increased significantly both in IG (1.03 ± 0.92 to 3.49 ± 1.84, p < 0.005) and CG (1.43 ± 0.88 to 3.23 ± 1.85, p < 0.005) (Figure 2).\n\n(* indicates statistically significant difference, VAS = Visual Analogue Scale).\n\nResults of within analysis of both groups and between analysis of groups are presented in Tables 4 and 5, respectively.\n\nThe within-group analysis showed that RHF during SLRT of the affected leg increased significantly in both groups at all time points compared to baseline.\n\nFrom baseline to three weeks of the intervention, RHF during SLRT of affected leg increased by 40.82% (48.29 ± 12.30° to 68 ± 10.66°, p < 0.005) in IG, and 32.49% (50.14 ± 11.73° to 66.43 ± 11.48°, p < 0.005) in CG. In contrast, the between-group analysis showed no significant differences between groups (p = 0.560).\n\nFrom baseline to the end of the intervention, RHF during SLRT of affected leg improved by 66.85% (48.29 ± 12.30° to 80.57 ± 8.47°, p < 0.005) in IG, and 48.44% (50.14 ± 11.73° to 74.43 ± 9.53°, p < 0.005) in CG. In addition, the between-group analysis showed significant differences between groups (p = 0.002).\n\nFrom baseline to follow-up, RHF during SLRT of affected leg enhanced by 49.1% (48.29 ± 12.30° to 72 ± 14.76°, p < 0.005) and 39.33% (50.14 ± 11.73° to 69.86 ± 15.07°, p < 0.005) in IG and CG, respectively, without any significant differences between groups (p = 0.549). However, from the end of the intervention to follow-up, RHF during SLRT of affected leg decreased significantly in IG (80.57 ± 8.47° to 72 ± 14.76°, p < 0.005), whereas in CG it was decreased, but the difference was not significant (74.43 ± 9.53° to 69.86 ± 15.07°, p = 0.072) (Figure 3).\n\n(* indicates statistically significant difference, RHF = Range of hip flexion, SLRT = Straight leg raising test).\n\nAdditionally, RHF during SLRT of unaffected leg enhanced significantly (p < 0.001) in both groups without any significant differences between groups (p > 0.150) at all time points compared to baseline. Results of within-group analysis of both groups and between analysis of groups are presented in Tables 4 and 5, respectively.\n\n\nDiscussion\n\nDeep abdominal muscles, including the superficial muscles, transversus abdominis, and multifidus, are essential for lumbar segmental stability.39 Reduction in the strength of these muscles causes lumbar instability and inflexibility, which eventually lead to CLBP.40,41 Research demonstrated that strengthening exercises enhance these muscles' strength and endurance, consequently improving the spine stability and reducing LBP.42–45 Strengthening exercise is a safe and low-cost intervention to improve pain and disability in patients with LBP.46 Lumbar extensor strengthening exercise is an effective therapeutic tool as it provides measurable physiologic adaption to the therapy.46,47\n\nIn addition, strength deficits in hip muscle are frequently reported in patients with LBP.48,49 Researchers showed that hip strengthening exercise was beneficial for improving pain and disability in patients with LBP.48,50,51 Jeong et al. showed that hip strengthening exercise plus lumbar stabilization exercises were more effective in improving CLBP than lumbar stabilization alone exercise.51 In another study, Chang et al.52 suggested to add hip strengthening exercise with trunk muscle strengthening exercise to train patients with LBP. In this study, patients in IG received six weeks of back and hip strengthening exercises. Results showed that back pain intensity reduced significantly at three weeks and the end of intervention compared to baseline.\n\nMoreover, researchers showed a strong correlation between SLRT and various parameters that signify the patients' pain level.35 SLRT reflects the severity of LDH and the degree of nerve root compression.35 SLRT also indicates the extent of the outcome as research showed that a positive postoperative SLRT was associated with an inferior outcome.35 If the patient feels radiating pain along the course of the sciatic nerve and below the knee between 30 and 70 degrees of hip flexion, then the SLRT is considered positive.17 In this research, RHF during SLRT of both affected and unaffected legs increased significantly in IG in all time points that indicated the improvement in sciatica due to nerve compression.\n\nActivities-of-daily-living instruction (ADLI) is a useful tool to train patients with LBP to meet the daily demands with proper ADL technique and enables them to perform tasks efficiently without increasing direct demand on injured areas.30 Therefore, it helps to increase spinal stability, limit LBP, and improve their recovery.30 In this study, patients in both IG and CG were instructed to follow ADLIs during the intervention and at least three months after the intervention. Results demonstrated that back pain intensity and RHF during SLRT improved significantly in both groups at all time points. However, patients in both groups followed ADLIs in combination with other interventions; hence we could not establish the effectiveness of ADLIs alone to improve back pain and sciatica due to LDH. In addition, after the intervention, the patients were asked to follow the ADLIs for at least three months. Outcomes evaluated at follow-up indicated that VAS scores increased and RHF decreased in both groups compared to the end of the intervention, which indicated that only ADLIs were insufficient to sustain the improvements. Nevertheless, after the intervention, the patients were neither supervised nor instructed. Therefore, we could not confirm whether the patients followed the ADLIs as they were trained.\n\nFurthermore, it is also essential to evaluate whether the improvements achieve the minimally clinically significant difference (MCID) to be regarded as clinically relevant and justify whether the patients can perceive the effects of an intervention as a benefit.53,54 MCID is regarded as the minimal change in score in the domain of interest, which correlates with the patient's perception of beneficial change or recovery.55,56 Any improvement is considered meaningful if the amount of change exceeds the MCID threshold.57 A minimum change of 30% in pain intensity measured with VAS is usually considered as MCID when the difference is compared with the baseline.58–60 In this study, VAS score changes in both IG and CG in all time points compared to baseline attained MCID threshold to be regarded as clinically significant.\n\n\nLimitations\n\nThe major limitations of this study are the relatively small sample size and the absence of long-term follow-up. Moreover, in this study, we evaluated only pain intensity and RHF during SLRT outcomes. Other measurements, including functional disabilities, quality of life, fear-avoidance belief of patients, and intervention cost-effectiveness, were missed. In addition, as we conducted the study at one medical institution, it is difficult to generalize the findings to every LDH patient.\n\n\nConclusion\n\nThis study showed that back and hip strengthening exercises combined with ADLIs were effective in alleviating back pain and sciatica due to LDH. However, only ADLIs did not seem to be adequate to sustain improvements after the intervention. Therefore, it is required to suggest the patients follow ADLIs and perform strengthening exercises regularly. However, due to the limitations of the study, we are unable to unambiguously state the effectiveness of the therapy. Future studies with larger sample sizes and long-term follow-up are needed to justify the effectiveness of this therapy to obtain clinically significant changes. Moreover, assessment of other outcomes and cost-effectiveness of the therapy is also required. The pre-and post-intervention MRI and ultrasound images can be evaluated to observe the changes in muscle function, size, symmetry, and fatty infiltration, which can clinically prove the effectiveness of the therapy.\n\n\nData availability\n\nMendeley Data: Effectiveness of strengthening exercise plus activities of daily living instructions in reducing pain in patients with lumbar disc herniation. https://doi.org/10.17632/mzsnj6nnsw.361\n\nThe project contains the following underlying data:\n\n• Main Raw Data.xlsx\n\nMendeley Data: CONSORT checklist for ‘Effectiveness of strengthening exercise plus activities of daily living instructions in reducing pain in patients with lumbar disc herniation’. https://doi.org/10.17632/mzsnj6nnsw.3.61\n\nThe project contains the following data:\n\n• CONSORT Checklist.doc\n\n• CONSORT Flow Chart.jpg\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 are grateful to the participants, physiotherapists, and supervisors of the study. The authors are indebted to Dr. Wahid for his kind contribution.\n\n\nReferences\n\nChou R: Low back pain (chronic). BMJ Clin. Evid. 2010; 2010.\n\nMaher C, Underwood M, Buchbinder R: Non-specific low back pain. Lancet. 2017 February 18; 389: 736–747. Publisher Full Text\n\nNguyen TH, Randolph DC: Nonspecific low back pain and return to work. Am. Fam. Physician. 2007; 76.\n\nVujcic I, Stojilovic N, Dubljanin E, et al.: Low Back Pain among Medical Students in Belgrade (Serbia): A Cross-Sectional Study. Pain Res. Manag. 2018; 2018: 1–6. Publisher Full Text\n\nHartvigsen J, Hancock MJ, Kongsted A, et al.: What low back pain is and why we need to pay attention. Lancet. 2018 June 1; 391: 2356–2367. Publisher Full Text\n\nSany SA, Tanjim T, Hossain MI: Low back pain and associated risk factors among medical students in Bangladesh: a cross-sectional study. F1000Res. 2021 July 30; 10: 698. Publisher Full Text\n\nMondal R, Sarker RC, Akter S, et al.: Prevalence of low back pain and its associated factors among physiotherapists in Dhaka city of Bangladesh in 2016. J. Occup. Heal. Epidemiol. 2018 April 1; 7: 70–74. Publisher Full Text\n\nAli M, Ahsan GU, Hossain A: Prevalence and associated occupational factors of low back pain among the bank employees in Dhaka City. J. Occup. Health. 2020 January 1; 62: 12131. Publisher Full Text\n\nHossain MD, Aftab A, Al IMH, et al.: Prevalence of work related musculoskeletal disorders (WMSDs) and ergonomic risk assessment among readymade garment workers of Bangladesh: A cross sectional study. PLoS One. 2018 July 1; 13: e0200122. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChien JJ, Bajwa ZH: What is mechanical back pain and how best to treat it?. Curr. Pain Headache Rep. 2008; 12: 406–411. PubMed Abstract | Publisher Full Text\n\nBakhtiary AH, Safavi-Farokhi Z, Rezasoltani A: Lumbar stabilizing exercises improve activities of daily living in patients with lumbar disc herniation. J. Back Musculoskelet. Rehabil. 2005; 18: 55–60. Publisher Full Text\n\nDeyo RA, Weinstein JN: Low back pain. N. Engl. J. Med. 2001 February 1; 344: 363–370. Publisher Full Text\n\nDePalma MJ, Ketchum JM, Saullo T: What is the source of chronic low back pain and does age play a role?. Pain Med. 2011; 12: 224–233. PubMed Abstract | Publisher Full Text\n\nFardon DF, Milette PC: Nomenclature and classification of lumbar disc pathology. Recommendations of the Combined task Forces of the North American Spine Society, American Society of Spine Radiology, and American Society of Neuroradiology. Spine (Phila Pa 1976). 2001; 26: E93–E113. Publisher Full Text\n\nJordon J, Konstantinou K, O’Dowd J: Herniated lumbar disc. BMJ Clin. Evid. 2009; 2009.\n\nKonstantinou K, Dunn KM, Ogollah R, et al.: Characteristics of patients with low back and leg pain seeking treatment in primary care: baseline results from the ATLAS cohort study. BMC Musculoskelet. Disord. 2015 November 4; 16: 332. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRopper AH, Zafonte RD: Sciatica Longo DL, editor. N. Engl. J. Med. 2015 March 26; 372: 1240–1248. Publisher Full Text\n\nHoy D, Bain C, Williams G, et al.: A systematic review of the global prevalence of low back pain. Arthritis Rheum. 2012 June; 64: 2028–2037. PubMed Abstract | Publisher Full Text\n\nBalagué F, Mannion AF, Pellisé F, et al.: Clinical update: low back pain. Lancet. 2007 March 3; 369: 726–728. Publisher Full Text\n\nBurton AK, Balagué F, Cardon G, et al.: Chapter 2: European guidelines for prevention in low back pain November 2004. Eur. Spine J. 2006 March; 15: s136–s168. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAiraksinen O, Brox JI, Cedraschi C, et al.: Chapter 4: European guidelines for the management of chronic nonspecific low back pain. Eur. Spine J. 2006 March; 15: s192–s300. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHayden JA, Cartwright JL, Riley RD, et al.: Exercise therapy for chronic low back pain: protocol for an individual participant data meta-analysis. Syst. Rev. 2012 December 21; 1: 64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGordon R, Bloxham S: A Systematic Review of the Effects of Exercise and Physical Activity on Non-Specific Chronic Low Back Pain. Healthcare. 2016; 4: 22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSearle A, Spink M, Ho A, et al.: Exercise interventions for the treatment of chronic low back pain: A systematic review and meta-analysis of randomised controlled trials. Clin. Rehabil. 2015; 29: 1155–1167. PubMed Abstract | Publisher Full Text\n\nMody GM, Brooks PM: Improving musculoskeletal health: Global issues. Best Pract. Res. Clin. Rheumatol. 2012; 26: 237–249. PubMed Abstract | Publisher Full Text\n\nIshak NA, Zahari Z, Justine M: Effectiveness of Strengthening Exercises for the Elderly with Low Back Pain to Improve Symptoms and Functions: A Systematic Review. Scientifica (Cairo). 2016; 2016: 1–10. Publisher Full Text\n\nHyoung H-K: Effects of a strengthening program for lower back in older women with chronic low back pain. J. Korean Acad. Nurs. 2008; 38: 902–913. PubMed Abstract | Publisher Full Text\n\nShnayderman I, Katz-Leurer M: An aerobic walking programme versus muscle strengthening programme for chronic low back pain: A randomized controlled trial. Clin. Rehabil. 2013; 27: 207–214. PubMed Abstract | Publisher Full Text\n\nSlade SC, Keating JL: Trunk-strengthening exercises for chronic low back pain: a systematic review. J. Manip. Physiol. Ther. 2006 February; 29: 163–173. PubMed Abstract | Publisher Full Text\n\nSpeicher T, Martin RD, DeSimone RM: Managing low back pain through activities-of-daily-living education. Athl. Ther. Today. 2006; 11: 74–77. Publisher Full Text\n\nAl Hasan S, Rahim MA, Siddiq MAB, et al.: Study of Spectrum of Rheumatic Diseases in the Department of Physical Medicine & Rehabilitation, Chittagong Medical College Hospital, Bangladesh. J. Chittagong Med. Coll. Teach. Assoc. 2009; 20: 6–11. Publisher Full Text\n\nQaseem A, Wilt TJ, McLean RM, et al.: Noninvasive treatments for acute, subacute, and chronic low back pain: A clinical practice guideline from the American College of Physicians. Ann. Intern. Med. 2017 April 4; 166: 514–530. PubMed Abstract | Publisher Full Text\n\nOlaogun MOB, Adedoyin RA, Ikem IC, et al.: Reliability of rating low back pain with a visual analogue scale and a semantic differential scale. Physiother. Theory Pract. 2004 June; 20: 135–142. Publisher Full Text\n\nKosteljanetz M, Bang F, Schmidt-Olsen S: The clinical significance of straight-leg raising (Lasègue’s sign) in the diagnosis of prolapsed lumbar disc. Interobserver variation and correlation with surgical finding. Spine (Phila Pa 1976). 1988; 13: 393–395. PubMed Abstract | Publisher Full Text\n\nJönsson B, Strömqvist B: The straight leg raising test and the severity of symptoms in lumbar disc herniation. A preoperative evaluation. Spine (Phila Pa 1976). 1995; 20: 27–30. PubMed Abstract | Publisher Full Text\n\nPesonen J, Shacklock M, Rantanen P, et al.: Extending the straight leg raise test for improved clinical evaluation of sciatica: reliability of hip internal rotation or ankle dorsiflexion. BMC Musculoskelet. Disord. 2021 March 24; 22: 1–8. Publisher Full Text 2021 221.\n\nvan der Windt DA , Simons E, Riphagen II, et al.: Physical examination for lumbar radiculopathy due to disc herniation in patients with low-back pain. Cochrane Database Syst. Rev. 2010 February 17. Publisher Full Text\n\nEkedahl H, Jönsson B, Annertz M, et al.: Accuracy of Clinical Tests in Detecting Disk Herniation and Nerve Root Compression in Subjects With Lumbar Radicular Symptoms. Arch. Phys. Med. Rehabil. 2018 April 1; 99: 726–735. PubMed Abstract | Publisher Full Text\n\nMcGill SM, Grenier S, Kavcic N, et al.: Coordination of muscle activity to assure stability of the lumbar spine. J. Electromyogr. Kinesiol. 2003; 13: 353–359. PubMed Abstract | Publisher Full Text\n\nCho H-Y, Kim E-H, Kim J: Effects of the CORE Exercise Program on Pain and Active Range of Motion in Patients with Chronic Low Back Pain. J. Phys. Ther. Sci. 2014; 26: 1237–1240. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWillson JD, Dougherty CP, Ireland ML, et al.: Core stability and its relationship to lower extremity function and injury. J. Am. Acad. Orthop. Surg. 2005; 13: 316–325. Publisher Full Text\n\nKavcic N, Grenier S, McGill SM: Determining the stabilizing role of individual torso muscles during rehabilitation exercises. Spine (Phila Pa 1976). 2004; 29: 1254–1265. PubMed Abstract | Publisher Full Text\n\nArokoski JP, Valta T, Airaksinen O, et al.: Back and abdominal muscle function during stabilization exercises. Arch. Phys. Med. Rehabil. 2001; 82: 1089–1098. PubMed Abstract | Publisher Full Text\n\nInani SB, Selkar SP: Effect of core stabilization exercises versus conventional exercises on pain and functional status in patients with non-specific low back pain: A randomized clinical trial. J. Back Musculoskelet. Rehabil. 2013; 26: 37–43. PubMed Abstract | Publisher Full Text\n\nYou JH, Kim SY, Oh DW, et al.: The effect of a novel core stabilization technique on managing patients with chronic low back pain: A randomized, controlled, experimenter-blinded study. Clin. Rehabil. 2014; 28: 460–469. PubMed Abstract | Publisher Full Text\n\nDreisinger TE: Exercise in the Management of Chronic Back Pain. Ochsner J. 2014; 14: 101.\n\nHelmhout PH, Harts CC, Staal JB, et al.: Comparison of a high-intensity and a low-intensity lumbar extensor training program as minimal intervention treatment in low back pain: a randomized trial. Eur. Spine J. 2004 October; 13: 537–547. Publisher Full Text\n\nde Jesus FLA , Fukuda TY, Souza C, et al.: Addition of specific hip strengthening exercises to conventional rehabilitation therapy for low back pain: a systematic review and meta-analysis. Clin. Rehabil. 2020 November 1; 34: 1368–1377. PubMed Abstract | Publisher Full Text\n\nde Sousa CS , de Jesus FLA , Machado MB, et al.: Lower limb muscle strength in patients with low back pain: a systematic review and meta-analysis. J. Musculoskelet. Neuronal Interact. 2019 March 1; 19: 69.\n\nBade M, Cobo-Estevez M, Neeley D, et al.: Effects of manual therapy and exercise targeting the hips in patients with low-back pain-A randomized controlled trial. J. Eval. Clin. Pract. 2017 August 1; 23: 734–740. Publisher Full Text\n\nJeong U-C, Sim J-H, Kim C-Y, et al.: The effects of gluteus muscle strengthening exercise and lumbar stabilization exercise on lumbar muscle strength and balance in chronic low back pain patients. J. Phys. Ther. Sci. 2015 December 28; 27: 3813–3816. Publisher Full Text\n\nChang W-D, Lin H-Y, Lai P-T: Core strength training for patients with chronic low backpain. J. Phys. Ther. Sci. 2015 March 1; 27: 619–622. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRai SK, Yazdany J, Fortin PR, et al.: Approaches for estimating minimal clinically important differences in systemic lupus erythematosus. Arthritis Res. Ther. 2015 June 3; 17: 143. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTroosters T: How important is a minimal difference?. Eur. Respir. J. 2011 April 1; 37: 755–756. Publisher Full Text\n\nCook CE: Clinimetrics Corner: The Minimal Clinically Important Change Score (MCID): A Necessary Pretense. J. Man. Manip. Ther. 2008 October; 16: 82E–83E. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRocchi MBL, Sisti D, Benedetti P, et al.: Critical comparison of nine different self-administered questionnaires for the evaluation of disability caused by low back pain. Eura. Medicophys. 2005 December 1; 41: 275–281. PubMed Abstract\n\nWang YC, Hart DL, Stratford PW, et al.: Baseline dependency of minimal clinically important improvement. Phys. Ther. 2011 May; 91: 675–688. PubMed Abstract | Publisher Full Text\n\nFarrar JT, Young JP, LaMoreaux L, et al.: Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001; 94: 149–158. PubMed Abstract | Publisher Full Text\n\nChilds JD, Piva SR, Fritz JM: Responsiveness of the numeric pain rating scale in patients with low back pain. Spine (Phila Pa 1976). 2005 June 1; 30: 1331–1334. PubMed Abstract | Publisher Full Text\n\nOstelo RWJG, Deyo RA, Stratford P, et al.: Interpreting change scores for pain and functional status in low back pain: Towards international consensus regarding minimal important change. Spine (Phila Pa 1976). 2008 January; 33: 90–94. PubMed Abstract | Publisher Full Text\n\nSany SA, Shahriar MDI, Nyme Z, et al.: Effectiveness of strengthening exercise plus activities of daily living instructions in reducing pain in patients with lumbar disc herniation: a randomized controlled trial. Mendeley Data. 2021; V3. Publisher Full Text"
}
|
[
{
"id": "140933",
"date": "21 Jul 2022",
"name": "Fareeha Amjad",
"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\nI want to appreciate the authors for this excellent effort. Overall the manuscript is well written.\n\nReferences are needed after few sentences e.g.: After ADLIs details etc. (It has been mentioned inside the annotated copy of the manuscript).\n\nIn the methodology section, pictures of patients are required while performing each exercise.\n\nThe rest of the comments have been mentioned inside the annotated copy of the manuscript which can be viewed 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?\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": "290582",
"date": "20 Jun 2024",
"name": "Gopal Nambi",
"expertise": [
"Reviewer Expertise Musculoskeletal and sports physiotherapist"
],
"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\nAbstract:\nThe background and objective of the study is not clear. There are huge studies in the same field.\n\nMention the study duration and study setting. Mention the character of study participants. Mention the randomization and allocation procedure in short. The outcome measures used are not clearly mentioned. Mention the statistical tests used for the study. Mention the demographic details in the results in short. Present the results part with p values and 95% CI (Upper – Lower) limits. The conclusion should be drawn on the basis of study reports.\n\nManuscript:\nMention in detail about the type of LBP, it s features and common management. Mention the role of exercises in LBP patients’ with recent reference. Mention the merits and demerits of Pilates exercise in burns patients’ with recent reference. Please elaborate the introduction part as it is not scientifically written. The need for the study is not mentioned clearly in recent references. Mention the gaps monitored by the researcher in the previous studies. Include the clinical significance of the study for the researchers, clinicians and patients. Present the study as per the CONSORT guidelines. Mention the study design, study duration and study setting. Include the ICD classification of the disease. Mention who has diagnosed the participants and their qualification and experience. Mention the randomization and allocation procedure in detail. Mention the blinding procedure in detail. – Is the independent reviewer is included in application of the intervention Give the latest reference for using these exercise protocol for LBP patients. Mention the detail description of the exercise intervention. Provide real figures for study replication and make sure there is no need of copy right for using the figures. Mention the duration of measuring the outcome measures. Include the sample size calculation with a suitable reference. The statistical tests included in the study are not apt to this study. Mention the Intention to treat analysis, and how it was managed? Mention how the variables are controlled and how the homogeneity is measured. Present the results part with p values and 95% CI (Upper – Lower) limits for all the variables. Mention the effect size and MCID values of all the variables. Please elaborate the discussion part and explain the mechanism how these interventions helpful to change these outcome variables in these patients. Mention the real time limitations faced by the researcher and how it affects the study reports. The conclusion should be drawn on the basis of study reports.\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": []
}
] | 1
|
https://f1000research.com/articles/10-1163
|
https://f1000research.com/articles/10-1162/v1
|
16 Nov 21
|
{
"type": "Data Note",
"title": "Ribo-Seq and RNA-Seq of TMA46 (DFRP1) and GIR2 (DFRP2) knockout yeast strains",
"authors": [
"Artyom A. Egorov",
"Desislava S. Makeeva",
"Nadezhda E. Makarova",
"Dmitri A. Bykov",
"Yanislav S. Hrytseniuk",
"Olga V. Mitkevich",
"Valery N. Urakov",
"Alexander I. Alexandrov",
"Ivan V. Kulakovskiy",
"Sergey E. Dmitriev",
"Artyom A. Egorov",
"Desislava S. Makeeva",
"Nadezhda E. Makarova",
"Dmitri A. Bykov",
"Yanislav S. Hrytseniuk",
"Olga V. Mitkevich",
"Valery N. Urakov",
"Alexander I. Alexandrov"
],
"abstract": "In eukaryotes, stalled and collided ribosomes are recognized by several conserved multicomponent systems, which either block protein synthesis in situ and resolve the collision locally, or trigger a general stress response. Yeast ribosome-binding GTPases RBG1 (DRG1 in mammals) and RBG2 (DRG2) form two distinct heterodimers with TMA46 (DFRP1) and GIR2 (DFRP2), respectively, both involved in mRNA translation. Accumulated evidence suggests that the dimers play partially redundant roles in elongation processivity and resolution of ribosome stalling and collision events, as well as in the regulation of GCN1-mediated signaling involved in ribosome-associated quality control (RQC). They also genetically interact with SLH1 (ASCC3) helicase, a key component of RQC trigger (RQT) complex disassembling collided ribosomes. Here, we present RNA-Seq and ribosome profiling (Ribo-Seq) data from S. cerevisiae strains with individual deletions of the TMA46 and GIR2 genes. Raw RNA-Seq and Ribo-Seq data as well as gene-level read counts are available in NCBI Gene Expression Omnibus (GEO) repository under GEO accession GSE185458 and GSE185286.",
"keywords": [
"Transcriptome",
"translatome",
"ribosome profiling",
"ribosome stalling",
"ribosome collision",
"Saccharomyces cerevisiae",
"TMA46",
"GIR2",
"GCN1/GCN20",
"eIF2A",
"YGR054W",
"STM1",
"PUB1"
],
"content": "Introduction\n\nHere, we present Ribo-Seq and RNA-Seq data for S. cerevisiae strains lacking translation-associated proteins Tma46 and Gir2, as well as for the wild type BY4742 parent strain. Tma46 and Gir2 are yeast orthologs of two mammalian DRG family regulatory proteins: DFRP1 and DFRP2, respectively.1–3 Mammalian DFRP1 and DFRP2 are binding partners of two closely related proteins, developmentally regulated GTPases DRG1 and DRG2,1,4 while yeast Tma46 and Gir2 dimerize with their orthologs, the ribosome-binding GTPases Rbg1 and Rbg2, respectively.2,3,5 Thus, in both yeast and mammals, two distinct heterodimers exist, RBG1•TMA46 (DRG1•DFRP1) and RBG2•GIR2 (DRG1•DFRP1), although under some conditions RBG1 may interact with GIR2 as well.5 The RBG1 (DRG1) containing complexes associate with mono- and polysomes.2,3,5–7 Using 5P-Seq, it was recently shown that RBG1•TMA46 promotes efficient translation in yeast, alleviating ribosome pausing at Arg/Lys-rich regions.7 In contrast, the RBG2 (DRG2) containing dimers are not bound to ribosomes under normal conditions.3,6 However, they are also clearly related to translation, as GIR2 interacts with the ribosome-bound GCN1, and RBG2•GIR2 is responsible for efficient cell growth under amino acid starvation.5,8 GCN1 is a large protein necessary for activation of GCN2, the evolutionary conserved eIF2 kinase.9 Recently, the RBG2•GIR2 complex was detected on the leading stalled ribosome on the Cryo-EM reconstruction of a GCN1-disome complex.10 These results suggest that GIR2 is a physical linker between RBG2 and GCN1 and that this interaction could prevent excessive activation of the GCN2 pathway upon incidental ribosome stalling.\n\nInterestingly, neither the yeast rbg1Δ or rbg2Δ knockout strains nor the double rbg1Δrbg2Δ mutants display any defects in translation or cell growth.3 However, a genetic screen for triple synthetic interaction demonstrates that RBGs have redundant function with SLH1,3 an RNA helicase involved in ribosome-associated quality control (RQC). SLH1 is an ortholog of mammalian ATCC3, a component of the ASC-1 complex that disassembles collided ribosomes (see 11 and references therein).\n\nTaken together, the above data suggest that the RBG1•TMA46 (DRG1•DFRP1) and RBG2•GIR2 (DRG1•DFRP1) complexes play a role in elongation processivity and resolution of ribosome stalling and collision events, as well as in control of GCN1-mediated signaling accompanying these processes. However, many questions remain unanswered. In particular, the individual roles of the two distinct complexes are still unclear. To improve our understanding of their functions, we systematically characterized translational defects in S. cerevisiae strains with individual deletions of the TMA46 or GIR2 genes using ribosome profiling.12 We present RNA-Seq and Ribo-Seq data for the yeast tma46Δ and gir2Δ knockout strains. For comparison, we also provide corresponding data for three strains bearing deletions of other translation-related genes: STM1, PUB1 and YGR054W (encoding translation factor eIF2A), as well as for the wild type BY4742 parent strain. Raw sequencing data are available online in the NCBI Gene Expression Omnibus (GEO accession: GSE185458 and GSE185286).\n\n\nMaterials and methods\n\nRNA-Seq and Ribo-Seq сDNA libraries were prepared from total RNA samples or ribosome-bound RNA samples, respectively, for the wild-type BY4742 (MATα his3Δ1 leu2Δ0 lys2Δ0 ura3Δ0) yeast strain and five knockout strains. The data were obtained in two independent series. The first one included the wild-type BY4742 yeast strain (wt) and strains with individually deleted YGR054W (eIF2A), STM1, and TMA46 genes, which were obtained from the Yeast Gene Deletion Collection.13 The second one included the wild-type BY4742 yeast strain and strains lacking GIR2 and PUB1, which were created during this study. KanMX disruption cassettes were obtained via polymerase chain reaction (PCR) using the primers (GIR2 - 5′-CAATTGTAAAATCAGCAGGCA-3′; 5′-AAACTTGTCTATTTCCTTCTTC-3′; PUB1 - 5′-TTGTCCTTCATTTTCCTCTCGT-3′; 5′-AGGCCCTTTTATTTTTCGAGC-3′) and genomic DNA of the corresponding deletion collection strains as a template. Phusion HF polymerase (TFS F-530L) was used as recommended by the supplier. PCR protocol: 95°С – 5 min, [95°С – 30 sec, 64°С – 30 sec, 72°С – 60 sec] x 28 cycles, 72°С – 90 sec. The resulting cassettes were used to transform the BY4742 strain. The correctness of the integration was checked using pairs of verification primers (GIR2-5′-GAAAAAGAAAGAAGAAAAATTTGGG-3′; PUB1-5′-ACGACCACAAAGGATCCAGGGCTT-3′; Universal primer inside the KanMX cassette - 5′-CTGCAGCGAGGAGCCGTAAT-3′).\n\nHere we focus on wt, tma46Δ, and gir2Δ strains. The data from the other strains were used to correct for batch effects within each series. The libraries were sequenced, resulting in 31 RNA-Seq and 28 Ribo-Seq data sets, including 18 RNA-Seq and 16 Ribo-Seq data sets for wt, gir2Δ, and tma46Δ strains. Supplementary Table 1 in the Extended data14 summarizes information about the sequencing experiments.\n\nThe experimental procedure followed the ribosome profiling protocol described in.15 Briefly, yeast cells were grown to exponential phase (OD = 0.5-0.6) in yeast extract peptone dextrose (YPD) media (1% yeast extract, 2% peptone, 2% glucose). Cells were harvested by filtration, scraped into liquid nitrogen, and ground using a liquid nitrogen-cooled mortar and pestle with drop-by-drop addition of polysome lysis buffer (20 mM Tris-HCl pH 8.0, 140 mM KCl, 1.5 mM MgCl2, 0.1 mg/ml cycloheximide, 1% Triton). Cell lysates were clarified by two sequential centrifugation steps - 3000g, 5 minutes, 4°С, and 20000g, 10 minutes, 4°С. The cell lysate was partially used for mRNA isolation using oligo (dT) beads. Another portion was treated with ribonuclease I for polysome disassembly and applied to a linear 10-50% sucrose gradient in fractionation buffer (20 mM Tris pH 8.0, 140 mM KCl, 15 mM MgCl2, 1 mM DTT, 0.1 mg/ml cycloheximide, 1% Triton) and separated on a SW-41 rotor (Beckman) at 35000 rpm, 3 hours, 4°С. Subsequently, ribosome-bound RNA fragments were collected from the monosome fraction. Ribosome-bound RNA was isolated using acidic-phenol extraction. Further Ribo-Seq and RNA-Seq library preparations were performed as described previously.12\n\nReads were trimmed using cutadapt v. 2.1016 with the following parameters for RNA-Seq (-a AGATCGGAAGAGCACACGTCTGAACTCCAGTCAC –minimum-length 20 -q 20) and Ribo-Seq samples (-a CTGTAGGCACCATCAATAGATCGGAAGAGCACACGTCTGAACTCCAGTCAC –trimmed-only -q 20). Additionally, for Ribo-Seq, the reads were deduplicated with seqkit rmdup v. 0.10.1,17 and unique barcodes were then removed with cutadapt v. 2.10 (-q 20 –minimum-length 20 -u -4). Afterwards, reads were aligned against eukaryotic rRNA sequence set obtained from silva-euk18 and rfam19 databases using bowtie2 v. 1.2.3.20 Only unmapped non-rRNA reads were used in the further analysis. Read mapping and counting against the Saccharomyces_cerevisiae.R64-1-1.95 (Ensembl)21 genome assembly was performed with STAR v. 2.7.9a.22 We estimated the position of the P-site for each dataset from the 5′ end of the reads on the basis of the length of each footprint using plastid v0.5.1.23 Fraction of reads in each phase and read length distribution were also obtained with plastid, see Figure S1 in the Extended data.24 The results show that almost 90% 28nt reads are in 0 phase through the annotated coding sequences (CDSs). Then we produced BedGraph profiles from SAM data with samtools v. 1.1025 and bedtools v2.27.1.26 Coverage profiles were normalized using normalization factor and library size estimates from differential expression analysis (see below) separately for each bedGraph profile. Finally, we visualized coverage tracks in the modified genomic loci using svist4get.27 Figure S2 in the Extended data24 shows that the read counts originating from the mRNA encoded by the knockout gene in the corresponding strain are negligible. The coverage of the neighboring genes remains unaltered, i.e. there are no indications of the so-called neighboring gene effect (NGE).28\n\nStatistical analyses were performed in R v. 4.1.2 using edgeR Bioconductor package.29 As mentioned above, the data were produced in two independent series which were analyzed separately. Genes not reaching 10 read count per million (CPM) in at least 4 RNA-Seq and 4 Ribo-Seq libraries were excluded from the analysis. Then, we performed the batch correction using ComBat-seq R package.30 Principal component analysis (PCA) plots of the raw and batch corrected expression profiles are shown in Figure S3 in the Extended data.24 A generalized linear model (glmQLFit, glmQLFTest of the edgeR package) was used to detect differentially expressed genes (for RNA-Seq, Ribo-Seq, and ribosome occupancy (RO) defined as the Ribo-Seq coverage of a CDS normalized to its RNA-Seq coverage) with the strain as a categorical variable. The false discovery rate (FDR < 0.05) was used for identification of differential expressed genes. We also performed Gene Ontology (GO) enrichment analysis for upregulated and downregulated genes with yeastmine.31 The results are shown in Figure 1.\n\n(A) Total number of differentially expressed genes (passing FDR < 0.05) in each test. (B) and (C) Scatter plots illustrating expression changes at the level of transcription (X-axis, RNA-Seq) and translation (Y-Axis, Ribo-Seq) in the gir2Δ and tma46Δ strains, respectively. Translationally upregulated or downregulated (FDR < 0.05) genes marked in pink/blue, respectively. (D-G) Results of Gene Ontology (GO) enrichment analysis of RNA-Seq (D-E) and ribosome occupancy (RO) (F-G) considering upregulated (D, F) and downregulated (E, G) genes in gir2Δ vs. wt comparison. The numbers of differentially expressed genes with particular GO terms are shown in labels. X-axes show the enrichment P-value in log-scale.\n\n\nData availability\n\nNCBI Gene Expression Omnibus: RNA Sequencing and Ribosome profiling of TMA46, STM1 and YGR054W knockout yeast strains. Accession number GSE185458; https://identifiers.org/geo:GSE185458.\n\nNCBI Gene Expression Omnibus: RNA Sequencing and Ribosome profiling of GIR2 and PUB1 knockout yeast strains. Accession number GSE185286; https://identifiers.org/geo:GSE185286.\n\nFigshare: Supplementary Table 1.csv https://doi.org/10.6084/m9.figshare.16818505.14\n\nThis project contains the following extended data:\n\n- Supplementary Table 1.csv (Table with information about sequencing experiments)\n\nFigshare: Supplementary Figures. https://doi.org/10.6084/m9.figshare.16818610.v1.24\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\nA.A.E., N.E.M., D.A.B., and S.E.D. are members of the Interdisciplinary Scientific and Educational School of Moscow University “Molecular Technologies of the Living Systems and Synthetic Biology”.\n\n\nReferences\n\nIshikawa K, Azuma S, Ikawa S, et al.: Identification of DRG family regulatory proteins (DFRPs): specific regulation of DRG1 and DRG2. Genes Cells. 2005; 10: 139–150. PubMed Abstract | Publisher Full Text\n\nFleischer TC, Weaver CM, McAfee KJ, et al.: Systematic identification and functional screens of uncharacterized proteins associated with eukaryotic ribosomal complexes. Genes Dev. 2006; 20: 1294–1307. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDaugeron MC, Prouteau M, Lacroute F, et al.: The highly conserved eukaryotic DRG factors are required for efficient translation in a manner redundant with the putative RNA helicase Slh1. Nucleic Acids Res. 2011; 39: 2221–2233. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLi B, Trueb B: DRG represents a family of two closely related GTP-binding proteins. Biochim. Biophys. Acta. 2000; 1491: 196–204. PubMed Abstract | Publisher Full Text\n\nWout PK, Sattlegger E, Sullivan SM, et al.: Saccharomyces cerevisiae Rbg1 protein and its binding partner Gir2 interact on Polyribosomes with Gcn1. Eukaryot. Cell. 2009; 8: 1061–1071. PubMed Abstract | Publisher Full Text | Free Full Text\n\nIshikawa K, Akiyama T, Ito K, et al.: Independent stabilizations of polysomal Drg1/Dfrp1 complex and non-polysomal Drg2/Dfrp2 complex in mammalian cells. Biochem. Biophys. Res. Commun. 2009; 390: 552–556. PubMed Abstract | Publisher Full Text\n\nZeng F, Li X, Pires-Alves M, et al.: Conserved heterodimeric GTPase Rbg1/Tma46 promotes efficient translation in eukaryotic cells. bioRxiv. 2021. 2020.2007.2006.190082.\n\nIshikawa K, Ito K, Inoue J, et al.: Cell growth control by stable Rbg2/Gir2 complex formation under amino acid starvation. Genes Cells. 2013; 18: 859–872. PubMed Abstract | Publisher Full Text\n\nCastilho BA, Shanmugam R, Silva RC, et al.: Keeping the eIF2 alpha kinase Gcn2 in check. Biochim. Biophys. Acta. 2014; 1843: 1948–1968. PubMed Abstract | Publisher Full Text\n\nPochopien AA, Beckert B, Kasvandik S, et al.: Structure of Gcn1 bound to stalled and colliding 80S ribosomes. Proc. Natl. Acad. Sci. U. S. A. 2021; 118: e2022756118. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJuszkiewicz S, Speldewinde SH, Wan L, et al.: The ASC-1 Complex Disassembles Collided Ribosomes. Mol. Cell. 2020; 79: 603–614 e608. Publisher Full Text\n\nIngolia NT, Ghaemmaghami S, Newman JR, et al.: Genome-wide analysis in vivo of translation with nucleotide resolution using ribosome profiling. Science. 2009; 324: 218–223. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGiaever G, Nislow C: The yeast deletion collection: a decade of functional genomics. Genetics. 2014; 197: 451–465. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEgorov A: Supplementary Table 1.csv. figshare. Dataset. 2021. Publisher Full Text\n\nKasari V, Pochopien AA, Margus T, et al.: A role for the Saccharomyces cerevisiae ABCF protein New1 in translation termination/recycling. Nucleic Acids Res. 2019; 47: 8807–8820. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMartin M: Cutadapt removes adapter sequences from high-throughput sequencing reads.2011; 17: 3. 2011.\n\nShen W, Le S, Li Y, et al.: SeqKit: A Cross-Platform and Ultrafast Toolkit for FASTA/Q File Manipulation. PloS One. 2016; 11: e0163962. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuast C, Pruesse E, Yilmaz P, et al.: The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res. 2013; 41: D590–D596. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKalvari I, Nawrocki EP, Ontiveros-Palacios N, et al.: Rfam 14: expanded coverage of metagenomic, viral and microRNA families. Nucleic Acids Res. 2021; 49: D192–D200. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLangmead B, Salzberg SL: Fast gapped-read alignment with Bowtie 2. Nat. Methods. 2012; 9: 357–359. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZerbino DR, Achuthan P, Akanni W, et al.: Ensembl 2018. Nucleic Acids Res. 2018; 46: D754–D761. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDobin A, Davis CA, Schlesinger F, et al.: STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013; 29: 15–21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDunn JG, Weissman JS: Plastid: nucleotide-resolution analysis of next-generation sequencing and genomics data. BMC Genom. 2016; 17: 958. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEgorov A: Supplementary Figures. figshare. Figure. 2021. Publisher Full Text\n\nLi H, Handsaker B, Wysoker A, et al.: The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009; 25: 2078–2079. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuinlan AR, Hall IM: BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics. 2010; 26: 841–842. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEgorov AA, Sakharova EA, Anisimova AS, et al.: svist4get: a simple visualization tool for genomic tracks from sequencing experiments. BMC Bioinform. 2019; 20: 113. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEgorov AA, Alexandrov AI, Urakov VN, et al.: A standard knockout procedure alters expression of adjacent loci at the translational level. Nucleic Acids Res. 2021; 49: 11134–11144. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRobinson MD, McCarthy DJ, Smyth GK: edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010; 26: 139–140. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang Y, Parmigiani G, Johnson WE: ComBat-seq: batch effect adjustment for RNA-seq count data. NAR Genom. Bioinform. 2020; 2: lqaa078. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBalakrishnan R, Park J, Karra K, et al.: YeastMine–an integrated data warehouse for Saccharomyces cerevisiae data as a multipurpose tool-kit. Database (Oxford). 2012; 2012: bar062."
}
|
[
{
"id": "100403",
"date": "30 Nov 2021",
"name": "Anton A. Komar",
"expertise": [
"Reviewer Expertise Translational control of gene expression"
],
"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 manuscript, Egorov and co-authors presented transcriptome and ribosome profiling data for Saccharomyces cerevisiae strains with individual deletions of the TMA46 and GIR2 genes. The interest in the protein products encoded by these genes has increased substantially in recent years, as these protein products have been shown to be involved in translation elongation and ribosome stalling. However, to date, there were limited “omics” data available from the respective knockout strains that could help shed additional light on the function of these genes. Particularly, ribosomal profiling of the knockout strains has not been performed. The present study fills in this gap and presents comparative ribosome profiling data obtained using the wild-type and knockout yeast strains. The ribosome profiling was followed by the standard quality checks and some basic downstream analysis, i.e. analysis of the differentially expressed genes and Gene Ontology (GO) enrichment analysis. Overall, these data will be useful for further research on TMA46 and GIR2 genes’ functions.\nThe sample preparation was performed using the standard protocols. The raw and processed data were deposited in the relevant open access repositories such as the Gene Expression Omnibus (GEO). Data processing has been described with reasonable detail (including the description of the command-line tools options and adapter sequences). The reliability of Ribo-Seq data has been demonstrated by read length distribution and the corresponding fraction of reads in each frame (Supplementary figure 1). All in all, the data seem to be technically sound and accurately described, but I would suggest adding illustrative plots showing triplet periodicity of the ribosome footprints.\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": "100401",
"date": "01 Dec 2021",
"name": "Olivier Namy",
"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\nIn this manuscript Egorov A.A and colleagues aim to understand the translational consequences of the inactivation of two genes TMA46 and GIR2 in yeast S. cerevisiae. The experiments are clearly detailed and basic quality controls have been done for the RiboSeq analysis. It is not clear for me why the authors provided data for STM1, PUB1, and YGR054W without showing or analyzing them. I have several comments:\nThe authors should justify why they have used a generalized linear model to calculate differential expression instead of a robust and well established negative binomial distribution (DESeq2). Why the authors used two different databases (silva-euk and rfam) to align reads to the rRNA? Did they use sequences specific to S. cerevisiae?\n\nLegend of Supplementary Fig1 needs to be improved. In the actual format, it is not obvious how the authors calculate the phasing of their RiboSeq data. Moreover, it is a pity that the analyses were not pursued a little further. For example, triplet periodicity could be shown, ribosome collision, and/or ribosome occupancy calculated. These additional qualitative analyses would strengthen the manuscript.\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? Yes",
"responses": []
},
{
"id": "100404",
"date": "07 Dec 2021",
"name": "Nikolay E. Shirokikh",
"expertise": [
"Reviewer Expertise Molecular biology",
"biochemistry",
"cell biology",
"genetics and gene expression",
"RNA",
"protein biosynthesis",
"ribosome profiling"
],
"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 work by Artyom Egorov and others touches upon proteins implicated in the processivity of translation of mRNA into polypeptides by eukaryotic ribosomes, specifically in resolving the stalled (or ‘collided’) translational intermediates. Research in this area is accelerating with many new studies uncovering unforeseen depths of the cells’ mechanisms of translation fidelity control. Not too many datasets exist in this space to date and few are multi-target studies that provide a package of data obtained in a highly similar fashion for several translation-related genes, which is the rationale that justifies well the generated datasets.\nIn a series of yeast knock-out strains, the authors accurately employ common approaches of RNA sequencing and RNA-sequencing-based ribosome (translation) footprint profiling, to provide high-throughput short-read sequencing data resulting from the individual gene knock-out effects. The data are provided for the wild-type yeast of BY4742 strain used as a control, the GIR2 and TMA46 knock-out mutant strains which are in the focus of the dataset, and additionally the YGR054W (eIF2A), STM1, and PUB1 knock-out mutant strains, either commercially purchased or generated in the work.\nThe methods are written succinctly but capture most of the relevant detail where it matters. Perhaps, expanding on the particulars of the method used to isolate mRNA with oligo(dT) beads could add to the better understanding of the RNA-seq data (including any information about the other treatments and purifications used, such as RNA fragmentation and size cut-offs). Regarding the ribosomal material isolation, although not strictly necessary, it would add to the value of the datasets by outlining their applicability if the authors could provide more detail on the intensity of the digestion with RNase I to generate the footprints, the homogeneity of the resultant sedimentation profiles, and the boundaries used to define the monosomal fraction. For the lysate clarification, the second spin uses very high acceleration; comments about whether the spin does or does not result in any loss of the heavy polysomes (e.g., if a suitably long particle sedimentation path was employed) could be beneficial. Although the authors are referring to the prior works, to bolster the applicability of the datasets and make their uptake convenient, any information about the additional size selection of the ribosome-protected fragments used (biochemical and/or bioinformatic) would be very helpful.\nThe data appears as accurate. The authors provide some differential abundance and GO term enrichment information for the more and less abundant gene categories within the pairwise comparisons, to characterise the datasets. This is very useful information; more information regarding the general properties of the datasets (such as total read/mappable/unique read number tables or histograms, gene coverage saturation plots etc.) could be further attractive in the main figure. The replicated datasets are validated through principal component analysis plots in Supplementary Figure 3, which show generally good groupings between the replicated sample types. The validity of the ribo-seq data is confirmed by Supplementary Figure 1 through demonstrating triplet periodicity of the dominant-length footprint fraction usually attributed to the cycloheximide-stabilised ribosomal protection extent (28 nt; although this is shown only for the wild-type, GIR2 and TMA46 knock-out strains). The datasets are most definitely usable, presented accessibly including uploads to the NCBI Gene Expression Omnibus, and are of a high utility.\nAltogether, the authors provide an excellent resource to the field, which perfectly fits the scope of F1000Research Data Note publication, and will likely be cited.\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/10-1162
|
https://f1000research.com/articles/10-1160/v1
|
16 Nov 21
|
{
"type": "Research Article",
"title": "Pedagogy of Success: Perception in undergraduate and postgraduate students at a Peruvian university",
"authors": [
"Silvia Ana Valverde-Zavaleta",
"Ray Harvey Mellin Rubio",
"Aurea Elizabeth Rafael Sánchez",
"Martha Gonzales Loli",
"Enaidy Reynosa Navarro",
"Silvia Ana Valverde-Zavaleta",
"Ray Harvey Mellin Rubio",
"Aurea Elizabeth Rafael Sánchez",
"Martha Gonzales Loli"
],
"abstract": "Background: The study's objective was to compare whether there are differences in the perception of undergraduate and postgraduate students about the pedagogy of success.\n\nMethods: This is non-experimental research with a comparative descriptive design, and a hypothetical deductive method was used. The perception of success pedagogy questionnaire was applied as a data collection technique with a sample of 50 university students with 23 items based on three dimensions: opportunity to learn (nine items), feedback (eight items), and consideration of the person (six items), with the following qualitative value scale, always = high, sometimes = middle, and never = low; the scale of quantitative value was from two to zero. To find the instrument's validity, it was subjected to expert judgment, calculating the content validity ratio for each item and considering the criteria of clarity and relevance. The instrument's reliability was determined using Cronbach's alpha, which found a high consistency between the items. For the questionnaire application, Google Forms was used to obtain fast, timely, and reliable answers. The data were processed through the SPSS V. 25.\n\nResults: The pedagogical support of the postgraduate teacher is more effective than that of the undergraduate. The undergraduate teacher stands out for listening and being more empathic. Didactics is crucial for students to develop their cognitive and human potential. Academic success is related to the teacher's pedagogical skills and the student's motivation. In addition, teachers and students can develop cognitive skills through effective communication and socialization. Finally, the affective dimension allows students to achieve personal and professional goals. Conclusions: There are significant differences in the perception of the pedagogy of success among undergraduate and postgraduate university students; therefore, the application of this methodology is more promoted towards postgraduate students than to their undergraduate peers.",
"keywords": [
"Pedagogy",
"Success",
"Perception",
"Undergraduate",
"Postgraduate",
"Affectivity"
],
"content": "Introduction\n\nAn essential part of the purpose of university education is ensuring that students can know how to be, know how to know, and learn how to do.1 Teachers must generate improved didactics in their pedagogical work,2 allowing students to develop these educational competencies.3\n\nTheoretically, this study is based on Juan Amos Comenius’ research on pedagogy. Comenius argued that pedagogy is a science with a strict educational purpose that integrates educational materials to achieve quality teaching that impacts the person and the surrounding society. He also argued that academic success was guaranteed from horizontal and effective communication with his students4, allowing them to develop their potential cognitive abilities, interrelate, collaborate and interconnect.5\n\nThe pedagogy of success is based on didactic strategies that motivate the learner to manage their learning, promoting; respect for diversity, empathy, harmonious coexistence, and the use of ICT6 to avoid failure or the feeling of academic loss.7 For this, teachers trained in emotional intelligence issues (motivation, self-regulation, self-knowledge, empathy, and social skills) are needed.8 In conclusion, educators must be capable of forming tolerant, respectful, democratic, caring, and competent citizens that can perform professionally in a complex and changing world.9\n\nIn the pedagogical task, educators focus on achieving two basic pedagogical principles.10 The first principle is based on providing a supportive environment where the learners can get involved; the second is based on developing practical classroom activities. In this regard, the following aspects are systematized: a) Errors resulting from experimentation are a part of learning. Therefore, the teacher must assist the student in overcoming mistakes. b) Outstanding achievements are reinforced to improve the student's self-esteem and motivate them to continue learning. c) Importance should be given to general activities without preventing the learner from excelling in specific activities. d) Self-correction helps the learner to be critical of their work and to be independent. e) The teacher must address competitiveness as a central point of the training process and generate a collaborative work environment where they share their successes. f) Parents, teachers, tutors, classmates, and socio-cultural space, intervene in the formative process of the student. g) The educational content that the teacher develops with their students must be attractive and, at the same time, reflect the socio-cultural reality of the student. h) Students actively participate in the learning process to achieve their goals. i) Classroom activities must involve everyone without neglecting the rhythm and learning style of each person. j) Work must be evaluated on an individual basis, and evaluation techniques must be adapted with the learning objectives.\n\nLearning allows students to discover their passions and goals. The teacher accompanies the students in this process of discovery and encourages them to build their future using the knowledge gained and applying it to current societal problems. Thus, successful teaching is correlated with the quality of teacher training.11 Teaching is a real challenge, especially when teachers do not have the required skills to implement change.12\n\n\nLiterature review\n\nRompelmann (2002) proposes three components to strengthen the pedagogy of success: 1) opportunity for response, 2) feedback, and 3) consideration for the person.13 The first component considers equity in the opportunity to respond, individual support for the student, latency, deepening, and high expectations in reasoning. The second involves evaluating, correcting, praising, providing reasons for the recognition, and active listening. The latter includes proximity, courtesy, respect, a caring approach, and limits to behavior. The correlational and multiple regression analysis developed by Ali Roohani and Shahrzad Haghparast (2020) showed a significant and positive relationship between critical pedagogy and teachers' reflective thinking. Both variables were predictors of pedagogical success from the evaluation of the students.11 The research by Galbán Lozano and Ortega Barba (2021) highlights that a fundamental quality of the teacher is the vocation for teaching and the confidence and concern that they demonstrate for the student's academic development. The study also points out that students feel satisfied and identify better with those teachers who, without neglecting the theoretical-practical link, promote environments for active learning.14\n\nUniversity teachers, above all, must be specialists in their subject area. They must also be motivated to develop teaching and scientific research with enthusiasm, interest, and vocation and show tolerance, empathy, justice, openness, creativity, flexibility, availability, and curiosity in otherness. They must possess social skills for effective communication and management of difficult emotions. Organization and effective structuring of knowledge is also crucial, along with short and long-term planning and promoting independent and critical thinking. They should demonstrate an acute and reflective attitude about their performance and be innovative and adaptable.15\n\nThe student’s journey is characterized by their cognitive and motivational development and the challenges of university life. Faced with this, the educator needs the pedagogical tools to accompany them in complex issues such as lack of motivation, communication problems, stress management, teamwork deficiencies, and accepting change. The student needs an approach to the modern educational reality to understand, reflect and merge the acquired knowledge, forming values that promote solidarity, friendship, respect, cooperation, and joint creation as fundamental learning.\n\nThe present investigation is justified from a set of theoretical antecedents and epistemological arguments that allow us to understand undergraduate and postgraduate students' perceptions of the teacher's pedagogical development. It presents a design that will enable the results to be interpreted, statistically processed, and replicated in other educational contexts. From the practical point of view, it provides new knowledge and approaches that help the comprehensive professional training of undergraduate and postgraduate students, regardless of their perception. Likewise, it offers pedagogical and personal development reflections relevant to minimizing the difficulties that affect students' desirable academic skills: knowing, doing, and acting, allowing them to align their potential intellectual development with aspirations for success. Overall, this research highlights the relevance of the pedagogy of success in the comprehensive training of teachers and students.\n\nThe study's objective was to compare whether there are differences in the perception of undergraduate and postgraduate university students about the pedagogy of success. The general hypothesis holds that there are differences in the perception of success among undergraduate and postgraduate university students.\n\n\nMethods\n\nThis study was non-experimental with a comparative descriptive design. The hypothetical-deductive method was used, whereby the variable's dimensions are known through observation, deduction, verification, or factual verification of the facts.16 The pedagogy of success variable was structured by three dimensions: opportunity to learn, feedback, and consideration of the person. Participants were undergraduate and postgraduate students enrolled at the Universidad Católica de Trujillo, Peru (UCT, Peru).\n\nStudents were approached to take part in the study via institutional email and social networks. Those who agreed to participate were then invited to a meeting held via Zoom, in which they were formally invited to the study. All participants were informed about the importance of the study, the anonymous nature of the instrument, and the theoretical, methodological, and practical procedures that would be used to answer the research question. It was also explained that the results of the said study would serve as the basis for developing quality education focused on improving the perception of success of undergraduate and graduate university students at UCT Peru. The population was 50 students: 20 undergraduates, X cycle (fifth year, professional career of Initial Education, Faculty of Humanities, UCT, Peru), and 30 postgraduates, IV cycle (second year, Master of Education Postgraduate School, UCT, Peru); total sample: 100% of the population. The inclusion criteria for participants were: Undergraduate students pursuing the professional career of Initial Education and postgraduate students pursuing a Master of Education. All participants had to be enrolled at UCT, Peru. In the case of undergraduate students, they had to be studying the tenth cycle of studies, and postgraduate students, the second cycle. The sample was non-probabilistic for convenience; it was selected in this way, taking into account restrictions on in-person meetings in the COVID-19 context. All participants were enrolled at UCT, Peru, located on North Panamericana Avenue. 555, Moche 13600, Trujillo, La Libertad, Peru.\n\nWe successfully used 100% of the sample data after recruiting all participants in a short space of time and processing the data immediately. All participants gave their informed and signed consent as an essential requirement to participate in the study.\n\nThe data collection technique was a questionnaire.22 As the study instrument, the Perception of Success Pedagogy questionnaire was administered, which consisted of 23 items distributed in three dimensions: opportunity to learn (nine items), feedback (eight items), and consideration of the person (six items). The qualitative value scale used was: high, middle, and low; likewise, the quantitative value scale was two to zero. To test the general hypothesis, the nonparametric Mann-Whitney U test was used. Due to social distancing, the decision was made to distribute the questionnaire through Google Forms. The reasons for this decision were communicated to the participants through a meeting held on February 25, 2021, via Zoom. This meeting was called and directed by the team of researchers. Subsequently, the questionnaire was sent to all participants through their institutional emails so that they could respond to them within approximately 20 days. The data collection period began March 1, 2021, and ended April 22, 2021.\n\nThe data sources were: 1). Enrollment records of undergraduate and postgraduate students, UCT, Peru; cycles X (undergraduate) and IV (graduate). 2). Results of the applied questionnaire. To avoid potential biases, the instrument was validated. First, pilot testing was carried out, then it was submitted for expert assessment. The instrument's reliability was performed using the Cronbach's Alpha test, obtaining (0.887). The pilot test was subjected to expert judgment to calculate the content validity for each item, considering the criteria of clarity, belonging, and relevance. The experts concluded that the test was valid. Therefore, they recommended not to delete any item and apply it. To compare the pedagogy of success between the undergraduate and postgraduate groups, the parametric student's t-test was used for independent samples.\n\nAll data were processed using SPSS V.26 statistical software. The specific processes were carried out as follows: in the Validity and Reliability tests of the instrument, the calculation of the content validity ratio was with the maximum evaluation score of 1 for each item, which was subjected to the validity of V for Aitken. The reliability of the instrument was performed using the Cronbach's Alpha test, obtaining (0.887). To determine normality, the Shapiro-Wilk test was used in the Pedagogy of success variable with p> 0.05; therefore, the null hypothesis was accepted, and the alternative hypothesis was rejected. After contrasting the specific hypotheses in each of them, the results are less than 0.05 with a confidence level of 95%. Regarding the specific hypothesis, for each one, the Mann-Whitney U test was used, the result of which was less than 0.05 with a confidence level of 95%. A copy of the accompanying dataset can be found here.22\n\nThe research assumed two fundamental ethical principles: 1. Informed consent, 2. confidentiality and anonymity.17 Before signing the consent letter, the participants received a talk via Zoom, where the study's objective, importance, and scope were explained to them. Participants were informed that the research results would be used strictly for research purposes to improve pedagogical processes. The consent letter was shared with participants via Google Drive and could only be accessed with an institutional email address. This research complies with the Ethical Principles of the teaching staff, provided in Article 6 of the Code of Ethics, Version 1.0; Approved by University Council Resolution No. 143-2019/UCT-CU, dated December 30, 2019, Catholic University of Trujillo, Peru.18\n\n\nResults\n\nIn Table 1, it can be observed that there are significant differences at p < 0.005 when applying the nonparametric Mann-Whitney U test to the items related to the opportunity to learn dimension.\n\nIn the comparison of frequencies of the levels of perception of pedagogy of success in the dimension of opportunity to learn among undergraduate and postgraduate students, it is observed that most (65%) undergraduate university students score in the medium level, with the other 35% scoring in the high level. Among postgraduate students, a higher percentage of 86.7% score in the high level for this dimension and 13.3% in the intermediate level. According to the Mann-Whitney U test results, z = −4.685 and p = 0.000 (<0.05), the alternative hypothesis is accepted, concluding that there are significant differences. This suggests that postgraduate students are given more opportunities to learn from the teacher than undergraduate students.\n\nIn Table 3, it can be observed that there are significant differences (p <0.05) when applying the nonparametric Mann-Whitney U test to the items related to the feedback dimension.\n\nIn the comparison of frequencies of the levels of perception of pedagogy of success in the feedback dimension among undergraduate and postgraduate students, it is observed that most (85%) undergraduate university students score in the high level and 15% score in the intermediate level, while among postgraduate students a higher percentage (53.3%) score in the middle level for this dimension, and 46.7% score in the high level. According to the Mann-Whitney U test results, z = −4.009 and p = 0.000 (<0.05), the alternative hypothesis is accepted, concluding that there are significant differences. This suggests that undergraduate teachers provide better feedback on students’ learning compared to postgraduate teachers.\n\nIt can be observed that there are significant differences (p < 0.05) when applying the nonparametric Mann-Whitney U test to the items related to the consideration for people dimension.\n\nIn the comparison of frequencies of the levels of perception of the pedagogy of success in the consideration towards people dimension among undergraduate and postgraduate students, it is observed that most (55%) undergraduate university students score in the high level, and 45% score in the intermediate level, while among postgraduate students a higher percentage of 93.3% score in the high level for this dimension, and 6.7% score in the intermediate level. According to the Mann-Whitney U test results, z = −2.634 and p = 0.008 (<0.05), the alternative hypothesis is accepted, concluding that there are significant differences. This suggests that postgraduate teachers have greater consideration for students than undergraduate teachers.\n\nIn comparing frequencies of the levels of perception of pedagogy of success among undergraduate and postgraduate students, it is observed that the most significant proportion (50%) of undergraduate university students score in the high level and 20% score in the medium level. In comparison, 96.7% score in the high level for this dimension among postgraduate students and 3.3% score in the medium level. According to the results of the students’ t-test, −3.270 and p = 0.002 (<0.05), the alternative hypothesis is accepted, concluding that there are significant differences. This suggests that the pedagogy of success is promoted more in postgraduate students than in undergraduates.\n\n\nDiscussion\n\nHigher education teachers must guide their pedagogical performance to help students achieve the general and specific competencies needed for their professional careers. However, to achieve these competencies with undergraduate or postgraduate students, educators must demonstrate didactic qualities, motivate and integrate the student; likewise, they must establish a teacher-student relationship that encourages lifelong learning.\n\nTable 1 indicates that the comparison of frequencies of the levels of perception of the pedagogy of success for the opportunity to learn dimension, there are significant differences (p = 0.000, <0.05); for undergraduate students (65%) with a medium level, and postgraduate students (86.7%) qualify as high level. Galbán Lozano supports these data, and Ortega Barba stated that teachers are professionals who establish connections with students to provide essential support for academic achievement. Only through this method are adequate conditions and academic results created with high well-being and personal satisfaction levels.13 Active listening, learning from mistakes, and evaluating their successes are also emphasized. Similarly, Roohani and Haghparast argued that the quality of teacher training is related to successful teaching.11 These results are theoretically corroborated in previous research that argues that teachers must promote change in their pedagogical practice to create interest in learning.2 It can be seen that academic success is related to the teacher's pedagogical skills and the student's motivation to assimilate new knowledge.19\n\nAccording to Table 2, the results suggest that in comparing frequencies of the levels of perception of success pedagogy for the feedback dimension, there are highly significant differences (p = 0.000, <0.05). 85% of undergraduate students scored in the high level for feedback, while 53.3% of postgraduate university students scored in the medium level. The teacher must develop didactic strategies that motivate the student in their learning.14 This corresponds with a recent study that considered the teacher's didactic capacity essential to the teacher profile. It emphasizes that university higher education students will succeed if they apply a reinforcing, communicative pedagogy that addresses their doubts and expectations for learning.20 The results are theoretically corroborated. The techniques for achieving pedagogical objectives should consider the student's learning rhythm, the reinforcement of their achievements to improve their self-esteem, and encouragement for the continuity of their studies, emphasizing the students' work. Students value these techniques, and they increase their enthusiasm for other activities.9\n\nTable 3 indicates that, in comparing frequencies of the levels of perception of the success pedagogy for the consideration towards people dimension, the data present highly significant differences (p = 0.008, <0.05); 55% of undergraduate students scored in the high level for consideration for people, and 93.3% of postgraduate college students scored in the high level. The findings confirm that teachers and students have the opportunity to develop practical skills through socialization and communication.21 This result is mainly due to the attitude that the teacher has towards the student. If this relationship is appropriate, adequate, and optimal, the probability of achieving affective learning is high. It is also vital to highlight the communication strategies that the teacher applies; the teacher must be passionate about their pedagogical activity. It is not only the application of techniques and instruments, the student must also be considered. The affective dimension is essential for learning because the teacher supports the learner, fosters confidence, professional progress, and enables them to achieve important goals.13\n\nThe results in Table 4 show that in comparing frequencies of the levels of perception of success pedagogy, the data present highly significant differences (p = 0.02, <0.05). 80% of undergraduate students scored high for applying the pedagogy of success, whereas 96.7% of postgraduate university students scored high. These results are also found in a recent study where it was suggested that teachers require personal qualities and skills as university professionals.14 The teacher who pushes for success has a high command of their specialty, is competent in the use of methodological strategies to engage the student and commit them to their learning, has a sense of connection to the student that allows them to mobilize, motivate, and awaken their interest in knowledge and success. All this demonstrates trust, respect, constructive criticism, and support for the optimal learning environment. It should be noted that the pedagogy of success is aimed at avoiding all kinds of educational failure or feelings of academic frustration. It is not necessarily about applying didactic techniques and strategies but also the teacher's way of managing students of varying levels. It is, therefore, necessary for teachers to develop empathy towards students, that is, develop the ability to understand their difficulties in the learning process and give the student the confidence required to overcome adversity.9\n\nIn sum, this research considers an education focused on developing the learner's attitude, motivation, and autonomy, improving the current pedagogy perception in undergraduate and postgraduate students. It provides a relevant theoretical contribution for future research that addresses this issue.\n\n\nConclusions\n\nOnce the statistical analysis was carried out, it was determined that there are significant differences in the levels of the Pedagogy of Success for the dimension Opportunity to learn among undergraduate and postgraduate university students; therefore, the postgraduate teacher provides the student with more excellent pedagogical support to improve her learning than the undergraduate teacher. When performing the comparative analysis of the perception of success of Pedagogy in the Feedback dimension, significant differences were found between undergraduate and postgraduate university students; therefore, the undergraduate teacher clarifies, broadens, strengthens knowledge, and gives students more extraordinary listening skills than the postgraduate teacher. In the dimension of Consideration towards people in the perception of successful Pedagogy, significant differences were found between undergraduate and postgraduate university students. Postgraduate teachers were confirmed to provide students with more excellent courtesy, respect, and affection than undergraduate teachers. Finally, it has been shown that there are significant differences in the perception of pedagogical success between undergraduate and postgraduate university students; therefore, in the application of the pedagogy of success as a formal learning process, teaching and personal inspiration of achievements in knowledge management are promoted more to postgraduate students than to undergraduates.\n\n\nData availability\n\nZenodo: Pedagogy of success: Perception in undergraduate and postgraduate students at a Peruvian university. https://doi.org/10.5281/zenodo.5307057.22\n\nThis project contains the following underlying data:\n\n‐ Statistical Results.xlsx\n\n‐ Processed data.pdf\n\nThis project contains the following extended data:\n\n- Pedagogy of success questionnaire.docx\n\n- Success pedagogy questionnaire (Technical sheet).docx\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nTobón S: Comprehensive training and skills. Complex thinking, curriculum, didactics, and assessment. Bogotá:ECOE;4th ed.2013 [cited 2021 Aug 17]. Reference Source\n\nBarrón Tirado MC: Online education. Transitions and disruptions. Education and pandemic: an academic vision. Ciudad de México:Universidad Nacional Autónoma de México, Instituto de Investigaciones sobre la Universidad y la Educación;1st ed.2020 [cited 2021 Jul 2]; p. 66–74.Reference Source\n\nEspín Álvarez GA, Alpízar Fernández R: Bibliographic references on the formation of pedagogical competencies of university teachers. Conrado J. 2020 Jun 9 [cited 2021 Jul 2]; 16(74): 215–224.Reference Source\n\nComenius JA: The Great Didactic. London:A & C Black;1st ed.1896 [cited 2021 Aug 22]; 1–468.Reference Source\n\nGleason B: Expanding interaction in online courses: integrating critical humanizing pedagogy for learner success. Educ Technol Res Dev. 2021 Feb 1 [cited 2021 Jun 29]; 69(1): 51–54. Publisher Full Text\n\nEarly M, Kendrick M: Inquiry-based pedagogies, multimodalities, and multilingualism: opportunities and challenges in supporting english learner success. Can Mod Lang Rev. 2020 May 1 [cited 2021 Jun 29]; 76(2): 139–154. Publisher Full Text Reference Source\n\nComenius JA: Magna Didactics. Madrid:Ediciones Akal, S. A.;1st ed.2012 [cited 2021 Jul 2]; 1–269.Reference Source\n\nIllouz E: Frozen Intimacies: Emotions in Capitalism. Katz editores;1st ed.2007 [cited 2021 July 2]. undefined-244.Reference Source\n\nCalvo Soto M, Gertrúdix Romero de Ávila S: The pedagogy of success. Aula Libr. 2006 [cited 2021 Jul 2]; 84: 17–19.Reference Source\n\nMendoza N: Rethinking Student Success: History Pedagogy and the Promise of Social Change across the K-16 Continuum. J Am Hist. 2020 March 1 [cited 2021 July 2]; 106(4): 1016–1019. Publisher Full Text Reference Source\n\nRoohani A, Haghparast S: Relationship between critical pedagogy and reflective thinking with l2 teachers’ pedagogical success. J Asia TEFL. 2020 Mar 1 [cited 2021 Jul 2]; 17(1): 105–123. Publisher Full Text Reference Source\n\nBilican K, Akerson V, Nargund V: Learning by Teaching: a Case Study of Co-teaching to Enhance Nature of Science Pedagogy, Successes, and Challenges. Int J Sci Math Educ. 2020 [cited 2021 July 2]; 19: 957–976. Publisher Full Text\n\nRompelmann L: Affective Teaching. MD:University Press of America, Inc.;2002.\n\nGalbán Lozano SE, Ortega Barba CF: Qualities and competencies of the university professor: The teachers’ vision summary. Rev Panam Pedagog. 2021 Jun 23 [cited 2021 Jul 2]; 31: 97–112.Reference Source\n\nSanz Blas S, Ruiz C, Pérez Pérez I: The university professor and her role as a teacher. Rev Divulg Científica y Cult - Multidiscip. 2014 [cited 2021 Aug 24]; 3(5): 97–112. Publisher Full Text Reference Source\n\nHernández Sampieri R, Mendoza Torres C: Metodología de la investigación: Las rutas de la investigación cuantitativa, cualitativa y mixta. Hill MG, editor.México:McGraw-Hill Interamericana Editores;2018 [cited 2021 Jul 12]; 1–752 p. Publisher Full Text Reference Source\n\nWorld Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Clin Rev Educ. 2013 [cited 2021 May 30]; 310(20): 2191–2194. Publisher Full Text Reference Source\n\nCatholic University of Trujillo. Code of Ethics Version 1.0: Resolución de Consejo Universitario N° 143-2019/UCT-CU Catholic University of Trujillo.2019; p. 1–9.Reference Source\n\nJiménez L, Corona J, Maldonado T: Necesidad de éxito del estudiante de posgrado.2014 [cited 2021 Jul 2].Reference Source\n\nQuijije-Anchundia PJ: El docente universitario frente al perfil didáctico profesional. Rev Científica Arbitr Investig en Comun Mark y Empres Reicomunicar. 2021 Jan 11 [cited 2021 Jul 2]; 4(7): 2–14. Publisher Full Text\n\nEscalante Z, Castillo Á, Duarte M: Affective learning in Higher Education virtual of Venezuela. Revecitec Urbe. 2012 [cited 2020 Oct 7]; 2(2): 35–45.Reference Source\n\nValverde-Zavaleta SA, Mellin Rubio RH, Rafael Sánchez AE, et al.: Pedagogy of success: Perception in undergraduate and postgraduate students at a Peruvian university. Zenodo. 2021 [cited 2021 Sep 23].Reference Source"
}
|
[
{
"id": "100442",
"date": "22 Dec 2021",
"name": "Betsi Josefina Fernández",
"expertise": [
"Reviewer Expertise Pedagogy",
"Education Curriculum"
],
"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 suggested that the following aspects be reviewed and clarified:\n(a) It is necessary to provide more details of the method applied, differentiating the technique (survey) used according to the instrument designed (questionnaire) and the analysis carried out to facilitate its replicability.\nAmong the details related to the method applied, it should be indicated which research paradigm was used, which approach predominated in the methodological approach, and which phases or stages were developed during the fieldwork, which will allow a broad assessment and understanding of the work carried out, since the method indicates the path followed to arrive at the results or findings and its description facilitates the understanding and contextualization of the problem addressed.\nWith the complete visualization of the research, being that the technique reflects the procedure in the collection of data and the instrument the one with which the data were collected, and how its validity and reliability of said instrument was carried out.\nb) The statistical analysis (very well developed) is adequate, but not sufficient; it is suggested to refine its interpretation: describe, infer and conclude in each of the tables. However, all the data in the article were tested in the Zenodo open access repository, where it is described1.\nStatistical analysis is the key to visualize the relevance of the results, so it is recommended to describe each table, infer from the data shown and close with a conclusion from each table to then generalize.\n(c) The conclusions drawn are adequately supported by the results, but can be further strengthened if they are confronted with the theoretical elements developed with the objectives of the study, i.e., produce a discussion of the results confronting them with the proposed objectives.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "100440",
"date": "23 Dec 2021",
"name": "Enrique Renteria",
"expertise": [
"Reviewer Expertise Pedagogy",
"quality of education",
"evaluation and curriculum design",
"development of teaching skills",
"coordination of academic leaders. Currently the general director of the Institute for Educational Evaluation and Development",
"and President of the Board of Directors of CLUB UNESCO COMPSE."
],
"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 defines the pedagogy of success with the following characteristics: didactic strategies that motivate the learner to manage his learning; promoting respect for diversity, empathy, and harmonious coexistence; and the use of Information and Communication Technologies (TIC). The instrument used confirms that the work achieved by teachers is not done in isolation, but through collegiate work that allows to define a socialized joint work. The questionnaire applied shows that university students perceive this joint work that is defined as teaching. I agree with the conclusion of the objective proposed by the authors in their research, and which is to highlight the relevance of the pedagogy of success in the integral training of teachers and students.\nTeaching as a professional activity has been transformed, like all social practices, significantly with the impact of the conditions of the development of computer and communication technologies, as detailed in my article, \"Renteria Castro, Enrique. (2012) Distance education, the use of new technologies and didactics of university teaching. Ibero-American Journal of Educational Research and Development\". In addition it has moved from a fluctuating dynamic between an empirical and isolated practice, which is perfected with experience, to be considered as a practice intimately articulated to intellectual processes, supported by the previous training and pedagogical didactic training and mainly with the socialization of the analysis of the teaching exercise.\n\nUniversity teaching becomes a practice based on the reflective and proactive planning of teaching to achieve the design and implementation of strategies for learning, an activity that must be carried out by all teachers, this work of reflection and proposals in the group of teachers is conceptually defined as teaching; and its main action is to be the articulator between theory and social praxis, based on a solid vision of joint work, articulated by two axes; evaluation and processes of continuous improvements.\nThis means, according to the authors, that the undergraduate teacher clarifies, broadens, strengthens knowledge and gives students way more extraordinary listening skills than the graduate teacher. With the above, we can lead to a discussion and conclusion that the pedagogy of success consists of achieving with the students the fifth pillar of knowledge of education; learning to transform (UNESCO, 2021, Dialogues on the Futures of Education). Learning that is achieved throughout the formative trajectory of the students and that the motivational level of the graduate students must be considered because of the pedagogical didactic intervention implemented during the undergraduate school cycles.\nIt is suggested to consider in the text of Table 4 to refer to the result that consists of the distribution of percentage frequencies according to the perception of success in pedagogy that corresponds to the factor called feedback among university students, which undergraduate students obtain a high score with respect to graduate students.\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": "100438",
"date": "10 Jan 2022",
"name": "Iris Agustina Jiménez Pitre",
"expertise": [
"Reviewer Expertise Science and Technology",
"Science and Technology Project Management",
"didactics and educational pedagogy."
],
"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, on the pedagogy of success and the perception of the participating students regarding this pedagogy; is scientifically sound, it is supported by well-established theoretical and methodological arguments and procedures. The paradigm, approach, and design it presents allow the research to be statistically processed, interpreted and replicated in other educational contexts. The data of this investigation were opportunely shared in open access (https://doi.org/10.5281/zenodo.5307057).\nOne of the main strengths of the study is that it raises an appropriate academic debate to address the significant differences found in the perception of the pedagogy of success among undergraduate and graduate university students. In this sense, delving into this problem will allow students to align their potential intellectual development with their aspirations for success, starting from fundamental pillars such as knowing how to be, knowing how to know, and knowing how to do.\nIt is recommended to strengthen the Conclusions of the research because, although they are concise, clear, orderly, and carry an academic language according to scientific requirements; they do not indicate what were the main limitations that were found throughout the investigative process.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1160
|
https://f1000research.com/articles/10-1158/v1
|
15 Nov 21
|
{
"type": "Research Article",
"title": "Protofibril formation: decreased total glutathione concentration as an early indicator of neuron damage in the brainstems of Wistar rats treated with rotenone",
"authors": [
"Arief Budi Yulianti",
"Sony Heru Sumarsono",
"Ahmad Ridwan",
"Ayda T Yusuf",
"Sony Heru Sumarsono",
"Ahmad Ridwan",
"Ayda T Yusuf"
],
"abstract": "Background: Rotenone treatment causes oxidative stress in neurons and forms the basis of animal models of Parkinson's disease. The reduced form of glutathione is predicted to detoxify rotenone from neurons in the brainstem. This study aims to measure the concentration of total glutathione and analyze the formation of protofibril in the brainstem of Wistar rats treated with rotenone. Methods: Seventy-two male Wistar rats aged 8–9 weeks weighing 200–250 g were divided into two investigations: total glutathione determination and protofibril analysis. The independent variables were treatment group, observation time, and location in the brainstem. The dependent variables were the concentration of total glutathione and protofibril density. Results: The concentration of total glutathione was not significantly different among treatment groups (p: 0.084), observation time (p: 0.608), or the location in the brainstem (p: 0.372). Protofibril density was different in the treatment groups (p: 0.001), observation time (p: 0.001), and between the upper and lower brainstem (p: 0.001). Rotenone treatment subcortically induced the concentration of total glutathione in the brainstem to decrease, but protofibril density tended to increase. Conclusions: The total glutathione concentration is inversely proportional to protofibril density. Total glutathione might be an early marker of neuronal damage.",
"keywords": [
"Brainstem",
"early markers",
"neuron damage",
"protofibrils",
"rotenone",
"total glutathione"
],
"content": "Introduction\n\nGlutathione (GSH) is a tripeptide of glutamic acid, cysteine, and glycine. GSH functions in cells as a cellular antioxidant, a cofactor of glutathione peroxidase, and a redox system regulator. Another role of GSH is in protecting cells, especially from toxic substances.1 GSH can conjugate to a protein and protect it from oxidation.2-4 GSH is also involved in detoxification in phase II drug metabolism.5 Most GSH is present in its reduced thiol tripeptide form, whereas the rest is oxidized as glutathione disulfide (GSSG). The equilibrium between GSH and GSSG is a function of the redox status of a cell, and specifically, the ratio of GSSG to GSH is an index of oxidative stress. It can therefore be said that the redox status is inversely related to the oxidative stress index. The sum of reduced GSH and oxidized GSSG is referred to as “total glutathione”.5-8 The concentration of total glutathione describes the capacity of the redox state in the cell. An increase in concentration of total glutathione indicates an increased ability of a cell to scavenge free radicals and protect the redox system, thereby protecting the cell from exposure to toxins.9,10 The typical concentration of GSH in a cell is 1–2 mM, except in hepatocytes, in which the concentration can be as high as 10 mM.9 In general, the more active a cell is, the higher the concentration of GSH is in that cell, and vice versa. In unhealthy cells, the concentration of GSH tends to be lower than in their healthy counterparts.9\n\nNeurons are highly active cells and are responsible for up to 20% of the body's oxygen consumption, despite the brain being only 2% of body mass.2 Neuronal activities cause an increase in the concentration of reactive oxygen species (ROS), such as hydrogen peroxide, which is strongly oxidizing and thus harmful to cells.10 Physiologically, hydrogen peroxide is produced in the processes of signal transduction, oxidative stress, growth, cell proliferation, and apoptosis.11,12 The enzyme glutathione peroxidase, in the presence of its cofactor GSH, catalyzes the breakdown of hydrogen peroxide into water and oxygen. This is part of the system of redox equilibrium in a cell.4 If the redox equilibrium is perturbed, cells are said to be under oxidative stress and this causes biomolecules, such as proteins, to be oxidized.13,14 In neurons, one such protein is alpha-synuclein, and changes in its structure resulting from oxidation create insoluble protofibrils.15,16\n\nInsoluble protofibrils tend to undergo aggregation in cytoplasm because cytoplasm is 70% water. Protofibrils are toxic, and the mechanism of the cell to prevent the toxicity is to form inclusion bodies.17 In the pathogenesis of neurodegenerative diseases, protofibrils are the precursors of Lewy bodies in Parkinson's disease and senile plaques in Alzheimer's disease.15\n\nThe process of protofibril formation and their deposition in cells and tissues varies between the neurodegenerative diseases.1 In Parkinson's disease, one of the causative factors for the formation of protofibrils from alpha-synuclein is exposure to neurotoxic pesticides, which induces oxidative stress pathways. The formation of protofibrils from alpha-synuclein can be prevented if cellular antioxidant activity is high, that is, if the concentration of GSH is high.18\n\nStudies on GSH are numerous, particularly those examining the role of GSH as a redox buffer in cells, and also as a cellular and extracellular antioxidant nutritional supplement.1 Nevertheless, studies related to total glutathione are scarce and the importance of total glutathione in neurons is unclear. In this study, the total glutathione concentration in the brainstems of rats treated with rotenone was analyzed. Rotenone (a natural pesticide from the root of Derris sp.) is lipophilic and readily penetrates cell membranes,19,20 causing neurons to undergo oxidative stress.8 The aims of this research were to determine the total glutathione concentration in the upper and lower brainstems of Wistar rats treated with rotenone, and whether the sub-chronic exposure of rotenone causes the formation of protofibrils that, in humans, leads to the formation of Lewy bodies, as occurs in Parkinson's disease. The results reinforce the concept of pathogenesis of sporadic Parkinson's disease in rats treated with rotenone.\n\n\nMethods\n\nSeventy-two male Wistar rats aged 8–9 weeks and weighing 200–250 g were selected randomly from the animal house at SITH ITB. Breeding, maintenance, treatment, and sacrifice protocols were adapted to the provisions of the Health Research Ethics Committee, Faculty of Medicine, UNPAD–RSUP Dr. Hasan Sadikin Central General Hospital, Bandung, Indonesia (214/FKUP-RSHS/KEPK/Kep./EC/2010).8\n\nRotenone (R8875), sunflower seed oil (S5007), 5,5′-dithiobis (2-nitrobenzoic acid) (DTNB, D8130), reduced L-glutathione (G4251), glutathione reductase (G3664), NADPH (N5130) and thioflavin S (T1892) were purchased from Sigma–Aldrich or Merck.\n\nThe selected rats were divided equally into two studies—determination of total glutathione and protofibril examination. Four independent variables were examined: 1) rat treatment group: blank (not treated), solvent-rotenone (intraperitoneally administered sunflower seed oil at a dose of 1 mL/kg body weight/day),8,21 and rotenone (intraperitoneally administered rotenone at a dose of 2.5 mg/kg body weight/day) groups18; 2) duration of rotenone treatment to examine subacute and subchronic exposure (9, 19 and 28 days); 3) observation time (days 10, 20, 30, 40, 50, and 60); and 4) the location in the brainstem (upper and lower brainstem).22 The concentrations of total glutathione and protofibrils were dependent variables (https://figshare.com/articles/dataset/Arrive-ten-aby/16880536).\n\nThirty-six male rats weighing more than 200 g were sacrificed by decapitation.23 The brainstems were isolated and separated between the upper and the lower regions and stored in liquid nitrogen. Samples were thawed at 4°C and washed three times with phosphate-buffered saline (PBS) containing 0.16% heparin, then homogenized using a homogenizer. The samples were diluted with 0.1 M phosphate buffer (pH 7) to a volume of 2 mL.21 Homogenates were centrifuged at 14,000 rpm for 10 min at 4°C. The obtained supernatant was stored as aliquots at −80°C.\n\nThe total glutathione measurement is defined as the concentration of GSH after glutathione reductase and NADPH are added to ensure all glutathione exists in the reduced form. In brief, the supernatant was thawed at 4°C, treated with 25% trichloroacetic acid and then centrifuged at 2000 × g for 15 min. Another supernatant was added GSH reductase and NADPH with the corresponding volume. DTNB was added and the absorbance of the solution was measured at λ = 412 nm (the by-product formed from the reaction of GSH and DTNB is yellow in solution) using a UV–vis spectrophotometer.8\n\nThirty-six male rats were sacrificed according to the cardiac perfusion method using ketamine (90mg/kg body weight) and xylazine (10 mg/kg body weight) administered by intraperitoneal injection (27-gauge needle and 1-mL syringe). A cardiac perfusion with ice-cold PBS was performed followed by perfusion of a 4% paraformaldehyde solution containing 0.1% glutaraldehyde. The brainstem was isolated, and the lower and upper brainstems were separated before being immersed into the fixative for less than 48 h, then embedded in a paraffin block. To facilitate embedding, first the brainstem specimens were dehydrated in ethanol at increasing concentrations (30%, 50%, 70%, 80%, 96%, and 100%). Then, the specimens were cleared using a toluene solution and infiltrated using a toluene/paraffin solution (1:1 v/v). Finally, the specimens were embedded in a paraffin block.24\n\nSlicing was performed at the Histopathology Laboratory, Faculty of Veterinary Science, Bogor Agriculture Institute, Bogor (Indonesia). Both serial coronal sections of the upper brainstem and longitudinal sections of the lower brainstem were made with thicknesses of 4 μm. Based on a previous study, 10 serial sections showed no differences in histological profile. Thus, the serial sections 1–10, 11–20, 21–30, 31–40, 41–5021,25 were stained using thioflavin S.26\n\nPreserved samples were deparaffinized using xylol followed by rehydration using ethanol, and the preparations were immersed into PBS solution containing 0.01% thioflavin S for 10 min. Protofibrils were identified using fluorescence microscopy and quantified using an unbiased stereological method.27 These experiments were repeated on days 20, 30, 40, 50, and 60.8\n\nThe protofibrils in brainstem slices were stained with thioflavin S and their density was measured by using a fluorescence microscope (Nikon Eclipse E800) equipped with a Nikon DXM1200F digital camera with a 450–550 nm filter. Yellow-green luminescence reveals the presence of protofibrils.28 The intensity of the emission was calculated using ImageJ 1.53a (NIH; Figure 1).29\n\nThe brainstems of Wistar rats were stained using thioflavin S and observed using a fluorescence microscope at 400× magnification. Protofibrils were identified by yellow-green fluorescence, the intensity of which was determined by corrected density.\n\nData were analyzed using IBM SPSS 21 and are reported as the mean ± SEM (standard error of the mean). The relationships between the independent and dependent variables were analyzed by using two-way analysis of variance (ANOVA) with a significance level of 5%.\n\n\nResults\n\nThe average concentrations of total glutathione in the upper brainstems of Wistar rats in the blank, solvent-rotenone, and rotenone-treated groups were 7.78 ± 1.44, 7.05 ± 1.57, and 7.58 ± 1.32 μmol/mg brain wet weight, respectively (Figure 2). Total glutathione concentration was at its highest on day 20 in the blank group and on day 50 in the rotenone-treated rats. The lowest total glutathione concentrations were measured on days 10 and 20 in the blank and rotenone groups, respectively. In the lower brainstems of Wistar rats, the average concentrations of total glutathione in the blank, solvent-rotenone, and rotenone groups were 8.37 ± 0.73, 6.90 ± 1.14, and 5.77 ± 0.79 μmol/mg brain wet weight, respectively (Figure 3). The highest total glutathione concentration in the blank group was measured on day 50, and on day 10 in the rotenone-treated rats. The lowest total glutathione concentrations were measured on days 30 and 50 in the blank and rotenone groups, respectively.40 Total glutathione was different in the treated rats, especially in the rotenone group, albeit not statistically significant (p: 0.084). With respect to observation time, the concentration of total glutathione was not statistically significant (p: 0.608). Differences between upper and lower brainstems were also not significant (p: 0.372), although the concentration of total glutathione was higher in the upper brainstem.\n\nThe concentration of total glutathione in the blank group (dots) was highest on day 20. The concentration of total glutathione in the solvent-rotenone group (vertical lines) was highest on day 60. The concentration of total glutathione in the rotenone group (horizontal lines) was highest on day 50.\n\nThe concentration of total glutathione in the blank group (dots) was highest on day 50 after acute exposure. The concentration of total glutathione in solvent-rotenone group (vertical lines) was highest on day 40. The concentration of total glutathione in the rotenone group (horizontal lines) was highest on day 10 after acute exposure.\n\nTo examine the existence of protofibrils, the sliced brainstem was immersed into a solution of thioflavin S and observed using a fluorescence microscope at 400x magnification. The average densities of protofibrils in upper brainstems in blank, solvent-rotenone, and rotenone-treated rats were 2076.45 ± 144.14, 2538.11 ± 224.96, and 2784.71 ± 289.98 protofibrils per μm2, respectively (Figure 4). The highest protofibril densities in the blank and rotenone-treated groups were measured on day 50 (Figure 5).\n\nThe protofibril density in the blank group (dots) was highest on day 50, the solvent-rotenone group (vertical lines) was highest on day 3, and in the rotenone group (horizontal lines) on day 50.\n\nObserved at 400× magnification, yellow-green fluorescence indicates the presence of protofibril (black arrows). The highest protofibril densities were found in the blank group (A), solvent-rotenone group (B), and rotenone group (C) at days 50, 30, and 50, respectively.\n\nhttps://figshare.com/articles/figure/Protofibril-ABY/16879819.\n\nIn the lower brainstem of rats in the blank, solvent-rotenone, and rotenone groups, the average protofibril densities were 2844.92 ± 220.98, 2931.85 ± 224.96, and 3122.08 ± 229.23 protofibrils per μm2, respectively (Figure 6) (https://doi.org/10.6084/m9.figshare.16528659). The highest protofibril density in the blank group was measured on day 50, and on day 30 in the rotenone group (Figures 6 and 7). Based on ANOVA, the differences in protofibril density within the observation time and treatment groups were significant (p: 0.001), as were differences between the upper and lower brainstem (p: 0.001). The protofibril density was higher in the lower brainstem than in the upper region\n\nThe protofibril density in the blank group (dots) was highest on day 50, and that in the solvent-rotenone group (vertical lines) was highest on day 30. The highest protofibril density in the rotenone group (horizontal lines) was measured on day 30.\n\nObserved at 400× magnification, yellow-green fluorescence indicates the presence of protofibril (black arrows). The highest protofibril densities were found in the blank group (A), solvent-rotenone group (B), and rotenone group (C) at days 50, 30, and 30, respectively.\n\nhttps://figshare.com/articles/figure/Protofibril-ABY/16879819.\n\n\nDiscussion\n\nGSH is a cellular antioxidant that acts as a free-radical scavenger. It is produced as a metabolic by-product in mitochondria. An increase in cell activity increases the production of free radicals, particularly ROS.1 The concentration of total glutathione indicates the ability of a cell to prevent the harmful effects of free radicals. Brain oxygen consumption is higher than in other organs, so ROS levels are typically higher in the brain. Conversely, the concentration of GSH is relatively lower in the brain than in other organs, such as kidney and liver. A decrease in GSH levels in the brain will cause the level of oxidative stress to increase, resulting in lipid oxidation that can cause neuronal death.30 Depletion of the total glutathione in the substantia nigra is indicative of neurodegeneration, such as in Parkinson's disease.31 Pharmacokinetically, GSH plays a role in phase II drug metabolism, becoming sequestered by conjugation through its thiol group such that it cannot traverse the cell membrane. An interaction between rotenone and GSH has not been reported. Previous studies have suggested that rotenone inhibits mitochondrial complex I, which decreases GSH concentration,7,8 indicating that cellular free radicals increase in abundance, resulting in oxidative stress. This condition can be prevented by monitoring the changing concentration of total glutathione.\n\nThe brainstem was selected for study as it is closely associated with neurogenerative diseases, particularly sporadic Parkinson's disease. The pathogenesis of Parkinson's disease originates from damage to the 10th cranial nerve (vagus nerve) where its pathway crosses the brainstem. Thus, measuring the total glutathione in the brainstem might be an initial indicator of neurodegenerative disease. In the present study, the concentration of total glutathione in the upper brainstem was higher than in the lower brainstem. This might indicate that neuronal damage had occurred in the lower brainstems of these rats.22\n\nThe concentration of total glutathione in the upper brainstems of rotenone-treated rats on day 60 was higher than that in the blank group. The concentration of total glutathione in the upper brainstems of rats treated with rotenone was 7.58 μM and that in the lower brainstem was 5.77 μM. To make the comparison with humans, these concentrations can be multiplied by a factor of 67.30,31 This estimates the concentrations in humans to be 0.5 mM (upper brainstem) and 0.38 mM (lower brainstem). In humans, the normal concentration of total glutathione is in the range 1–2 mM.1,30 Therefore, we conclude that sub-chronic exposure to rotenone decreases the concentration of total glutathione in brainstem.\n\nThe concentration of total glutathione in all the treatment groups fluctuated over time. This indicates that the homeostasis of neurons remained stable. However, our data indicates that rotenone exposure causes the concentration of total glutathione to decline. Thus, it might be predicted that GSH could be used as an indicator of exposure to a specific toxic substance that induces oxidative stress in neurons. Meanwhile, the concentration of GSH was obtained from 60% of total glutathione.32 Applying this to our results, the concentrations of GSH in the rotenone-treated rats were 4.5 μM (upper brainstem) and 3.4 μM (lower brainstem).\n\nA reduction in GSH concentration causes oxidative stress resulting in the oxidation of intracellular biomolecules, such as proteins, lipids, and nucleic acids. In neurons, alpha-synuclein protein is readily oxidized. The physiological role of this protein is unknown, but it is well known that oxidation due to neurotoxic exposure results in structural changes that cause aggregation and formation of protofibrils.15 Thus, the measurement of protofibrils might serve as a marker of neurotoxic exposure, in this case to rotenone that causes oxidative stress in neurons.\n\nProteins can function as receptors, enzymes, or transporters, and the structure of a protein determines its function, particularly water-soluble proteins.14 If a protein is oxidized, its structure can change. Water-soluble proteins can become insoluble and aggregate. Such aggregates can form inclusion bodies for 20 days after exposure to a neurotoxin.33,34 Inclusion bodies can spread to other parts of the brain and cause clinical symptoms. In this study, the sub-chronic exposure of a neurotoxin was repeated daily for 9, 19, and 28 days. These rats were observed every 10 days for 60 days. Over this time course, the concentration of total glutathione fluctuated and tended to decrease, whereas protofibril density tended to increase. There is a weak correlation between the increase of total glutathione and the formation of protofibrils at 0.3 (sig: 0.001). Furthermore, the formation of protofibrils can influence neuron activities. Protofibrils formed in neurons can cause damage that ultimately leads to cell death.35,36 These dead cells cannot be replaced with new neurons, so the size of the brain will decrease.37\n\nThe measured protofibrils are likely alpha-synuclein protein aggregates, although only a specific labelling protocol would confirm this. The density of protofibrils in brainstem tends to increase over the time course of observation, indicating an increase in protein aggregation, particularly in rotenone-treated rats. The lower brainstem is more abundant with protofibrils than the upper brainstem. This is consistent with the pathogenesis of those neurodegenerative diseases38 that originate from damage to the 10th cranial nerve, which is followed by specific clinical symptoms, particularly gastrointestinal tract disorders. The pathway of the 10th cranial nerve starts in the lower brainstem and travels to the upper brainstem in the substantia nigra.22 If dopaminergic neurons are damaged, symptoms of Parkinson's disease present. This also applies to Alzheimer's disease, in which the protein beta-amyloid forms aggregates in any part of the brain.38,39\n\nThioflavin-S-labeled protofibrils were measured by their fluorescence intensity.29 Image analysis showed that the density of protofibrils in the lower brainstem is higher than that in the upper region. Protofibrils were also distributed around the neurons and extracellular matrix, specifically in neurofibrils (Figures 5 and 7). To conclude, the process of neurodegeneration can be prevented by avoiding oxidative stress condition.\n\nIn this study, we propose measurement of total glutathione for identifying the capacity of neurons to avoid oxidative stress. If the concentration of total glutathione is high, neurons are in a homeostatic condition and have the ability to self-recover by shifting the steady state of the redox system. Therefore, water-soluble proteins are not oxidized and do not form protofibrils. The development of GSH as the indicator of oxidative stress cannot be applied in humans. Other studies are investigating alpha-synuclein in erythrocytes. It is hoped that a marker for the early detection of neurogenesis process could be developed, and thus, neurodegenerative diseases might be slowed or even prevented as early as possible to improve quality of life.\n\n\nConclusion\n\nRotenone exposure subcortically causes the concentration of total glutathione in brainstem to decrease and concentrations of total glutathione in the lower brainstem were lower than in the upper region. Conversely, protofibril density tended to increase with rotenone treatment. The concentration of total glutathione is inversely proportional to the density of protofibrils. Decreased GSH might be an early indicator of neuronal damage.\n\n\nAuthor contributions\n\nThe author is Arief Budi Yulianti, from Medical biology Department, Faculty of Medicine, Universitas Islam Bandung (UNISBA), Indonesia. My contribution in this paper are in introduction, methods, result, and discussion.\n\nThe first co-author is Sony Heru Sumarsono, from Research Group of Physiology, Developmental Biology and Biomedical Science, School of Life Science and Technology, Institut Teknologi Bandung (ITB), Indonesia. His contribution in this paper are in introduction and discussion.\n\nThe second co-author is Ahmad Ridwan from from Research Group of Physiology, Developmental Biology and Biomedical Science, School of Life Science and Technology, Institut Teknologi Bandung (ITB), Indonesia. His contribution in this paper are in introduction and methods.\n\nThe third co-author is Ayda T Yusuf from Research Group of Physiology, Developmental Biology and Biomedical Science, School of Life Science and Technology, Institut Teknologi Bandung (ITB), Indonesia. Her contribution in this paper are in introduction, result and discussion.\n\n\nData availability\n\nFigshare: Glutathione total concentration in upper and lower rats Wistar brainstem treated rotenone, https://doi.org/10.6084/m9.figshare.16528659.\n\nThis project contains the following underlying data:\n\n- Data-aby-gsh.xlsx (The data presented is total glutathione concentration in the brainstem.)\n\n- Data-aby-protofibril.xlsx (The data presented is density of protofibrils in the brainstem.)\n\nFigshare: Protofibril-ABY, https://doi.org/10.6084/m9.figshare.16879819.\n\nThis project contains the following underlying data:\n\n- Fig. 5A.jpg\n\n- Fig. 5B.jpg\n\n- Fig. 5C.jpg\n\n- Fig. 7A.jpg\n\n- Fig. 7B.jpg\n\n- Fig. 7C.jpg\n\nThe data presented is flouresence photomicrogrph brainstem with thioflavin staining.\n\nFigshare: Arrive ten checklist-aby.pdf, https://doi.org/10.6084/m9.figshare.16880536.\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\nThis article does not report studies involving human participants. Animals were handled according to the requirements of the Health Research Ethics Committee, Faculty of Medicine, UNPAD–RSUP Dr. Hasan Sadikin Central General Hospital, Bandung, Indonesia (214/FKUP-RSHS/KEPK/Kep./EC/2010).",
"appendix": "Acknowledgements\n\nThis research was funded by a grant from the Faculty of Medicine, Universitas Islam Bandung. We are grateful to the Dean and staff of Universitas Islam Bandung for supporting this research, to the Rector and staff of Universitas Islam Bandung who led the Paper Camp activities, and also to Research Gate Fondation (RSF) who facilitated the writing of this paper.\n\n\nReferences\n\nAoyama K, Nakaki T: Impaired Glutathione Synthesis in Neurodegeneration. Int. J. Mol. Sci. 2013; 14: 21021–21044. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAshtiani HRA, Bakhshandi AK, Rahbar M, et al.: Glutathione, cell proliferation and differentiation. Afr. J. Biotechnol. 2011; 10(34): 6348–6361.\n\nDeponte M: Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Biochim Biophys Acta - Gen Subj. 2013; 1830(5): 3217–3266. 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}
|
[
{
"id": "122047",
"date": "04 Feb 2022",
"name": "Toshio Nakaki",
"expertise": [
"Reviewer Expertise Neuronal glutathione and neurodegenerative 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\nThis manuscript describes brain stem GSH content and accumulation of protofibrils after subchronic exposure to rotenone and potentially contributes to making rotenone-treated rats more useful as an animal model for Parkinson’s disease (PD). There are several issues to be considered by the authors.\nMajor issues\nIt is rather odd to assume the major pathogenesis of PD is invoked in the vagal nerve nucleus in the lower brain stem. The nigro-striatal pathway is still widely believed to be compromised neurons in PD, if not the only hypothesis. Therefore, at least the authors should have included this pathway to analyze GSH content and protofibril accumulation.\n\nThe readers may have an impression, with which Lewy bodies containing alpha-synuclein cause PD. This is not correct, although we understand it for now to be an attractive working hypothesis. The cause-effect relationship is not established yet. The same story holds true with Alzheimer's disease. It is not unequivocally proved in humans that amyloid-beta is the cause of Alzheimer's disease. Therefore, the authors should rewrite the introduction section to have the background presentation more balanced.\n\nThe timing of sampling of brain tissues to quantify GSH should be clearly stated because GSH level is known to show a circadian rhythm. In other words, GSH and GSSG content varies within a day and, therefore, the data obtained depends on time points during the day.\n\nIn the discussion section, the authors calculate GSH concentrations based on data shown in the figures in the report. However, the labeling of the ordinate in figures should read “content” instead of “concentration”, because the wet weight of each brain sample was measured in this report but not the intracellular concentration, and wet weight contains intra- and extracellular fluid. Since biologically important GSH is intracellular not extracellular one and micromolar calculation is not warranted and misleading.\n\nWhat is the reason for solvent-treated rats showing elevated levels of protofibrils along with rotenone-treated ones? This issue might undermine the credibility of the authors’ conclusion.\n\nIf some antioxidants are able to inhibit or reverse the effect of rotenone, these data will strengthen the current manuscript.\n\nMinor issues\nIn the introduction, “pathogenesis of sporadic Parkinson’s disease in rats”. This should be rewritten because PD is a human disease. Rotenone is used to make a rat PD model.\n\nWhat is the definition of the upper and lower brain stem in this report?\n\nThere are no indications of the number of rats used for each column in the figures.\n\nAs the authors mention in the discussion, the component of the stained material is unknown but it is in fact an important issue in order to confirm the rotenone-administered rats to be really a good model for PD.\n\nIn the conclusion section, the expression “rotenone exposure subcortically“ should read as “rotenone exposure subchronically”.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "120707",
"date": "14 Mar 2022",
"name": "Mahesh Ramalingam,",
"expertise": [
"Reviewer Expertise Parkinson's disease",
"Rotenone",
"alpha-synuclein",
"tyrosine hydroxylase."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAs the authors mentioned “the ratio of GSSG to GSH is an index of oxidative stress”, authors can measure ‘reduced glutathione’ also and can compare with ‘total glutathione’. The authors found that ‘total glutathione was not statistically different'. Confusing that the readers and reviewers need to verify each time points text and graphs. As data were analyzed ‘two-way analysis of variance’ using SPSS, authors must include statistical significance in the graphs (* or ** or ***) to understand easily.\nFigure 3, ‘Y axis’ name must be in ‘English’ language.\nAs rotenone is known to induce Parkinson’s disease, the authors could include ‘tyrosine hydroxylase (TH)’ immunostaining at the highest observation day.\nThe authors used a fluorescence microscope for protofibril measurement, they can directly stain for alpha-synculein instead of thioflavin S. Authors must explain the reason for this.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNo\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1158
|
https://f1000research.com/articles/10-545/v1
|
07 Jul 21
|
{
"type": "Research Article",
"title": "The effects of telenutrition in overweight and obese adults in a nutritional center in Lima, Peru.",
"authors": [
"Carolina Castrillón Liñan",
"Jimy Henry Alvarez Mayorga",
"Michelle Lozada-Urbano",
"Carolina Castrillón Liñan",
"Jimy Henry Alvarez Mayorga"
],
"abstract": "Background: COVID-19 pandemic has been challenging for health services and systems around the world, including Peru. A viable alternative in the telemedicine field to guarantee patient nutritional care is telenutrition. Telenutrition involves the interactive use of electronic information and telecommunications technologies to implement the nutrition care process with patients at a remote location. Information regarding the experience with this methodology and its potential effect on patients’ nutritional goals, does not exist in Peru. The aim of the study was to report the effect of the evaluation type (telenutrition vs. in-person) on anthropometric parameters weight, body mass index (BMI), waist circumference (WC) and relative fat mass (RFM) in overweight and obese adult patients. Methods: This retrospective study included 100 eligible patients in a single nutritional center, from January 2019 to March 2021. Results: There was a significant difference in weight, BMI, WC and RFM at the end of the three-month follow-up period, in both evaluation modalities. Patients on the telenutrition group had a mean decrease of 6.80 ± 4.87 cm in their WC, whereas the mean difference observed for the in-person group was 6.74 ± 4.55 cm. There were no statistically significant differences in the changes of any anthropometric parameters when comparing both systems. Reductions were observed in weight (5.93 ± 3.88 kg vs. 4.92 ± 3.29 kg), BMI (2.23 ± 1.39 kg/ m2 vs. 1.83 ± 1.23 kg/ m2), WC (6.80 ± 4.87 cm vs. 6.74 ± 4.55 cm) and RFM (2.43 ± 1.78 vs. 2.63 ± 1.73) in telenutrition and in-person evaluation, respectively. Conclusions: Telenutrition may be regarded as an alternative to in-person evaluation offering anthropometric changes and nutritional goals similar to those reported through the in-person modality, in overweight and obese adult people.",
"keywords": [
"Overweight",
"Obesity",
"Telemedicine",
"Waist Circumference",
"Nutrition Assessment"
],
"content": "Introduction\n\nClinical practice has gone through adaptative processes during the COVID-19 pandemic due to isolation and social distancing policies to reduce virus transmission. Telemedicine, a discipline that has been developing for many years,1 provides an alternative to ensure continued patients’ access to health services, while minimizing the risks for health workers.2\n\nTelehealth is the use of electronic information and telecommunication technology to facilitate clinical healthcare and patient education remotely. Whereas telenutrition is defined as a modality of Telehealth that provides an opportunity for a registered dietitian nutritionist to implement patients’ nutritional care remotely.3\n\nStudies in Western China have shown that telemedicine practices are feasible, acceptable, effective and improves health care outcomes,4 by providing the healthcare worker with information about the patient’s surroundings and how homecare is maintained. In New Mexico, USA, telemedicine-related barriers were identified through a survey that included 2016 nutrition professionals.5 In this study, 29% of the professionals reported lack of client interest, 26% reported not having internet access, and 28% mentioned not being able to perform client assessment or monitor activities by this modality. In regard to the benefits of telemedicine, 66% of the professionals stated that it contributed to social distancing compliance, while 50% acknowledged the flexibility in arranging appointments.5\n\nAustralian nutrition professionals regard telehealth evaluations as profitable and well-received by patients. They report that this practice improved healthcare access for people with chronic diseases.6\n\nRegarding potential obstacles in telenutrition practices, anthropometric parameters are key for nutritional assessment and are widely discussed when comparing this modality to in-person evaluation. It is known that standard anthropometric assessment involves direct contact, however, there is evidence that self-reported weight and height measurements may have adequate precision.7 Besides, reports state that self-reported WC measurement may be reliable in cases where scales are not available.8,9 Precise measurement can be achieved by providing video instructions for the patient.10,11\n\nIn Lima, Peru we are facing these challenges as well. In 2020, the Allikay nutritional center started providing virtual appointments for nutritional care to patients, guaranteeing safe conditions based on the COVID-19 pandemic-related recommendations. There is no information regarding the impact of this modality on the patients’ nutritional status measured by anthropometric parameters in Lima, Peru. The aim of this study was to report the effect of the evaluation type (telenutrition vs. in-person) on anthropometric parameters such as weight, body mass index (BMI), waist circumference (WC) and relative fat mass (RFM), in overweight and obese adult patients in a nutritional center in Lima.\n\n\nMethods\n\nThis is an observational retrospective study that took place between January 2019-March 2021. This study included overweight and obese patients that were assessed by a Registered Dietitian Nutritionist through in-person or virtual appointment, in a nutritional center in Lima.\n\nThe samples were obtained through a non-probability convenience sampling. Due to the type of sampling, it is acknowledged that bias is possible and considering this, authors recommend caution when interpreting results in terms of generalization. The final sample size was 100 patients which was arrived by assessing eligibility in every patient evaluated during the established study period (January 2019-March 2021). There were 50 patients evaluated with telenutrition and 50 with in-person assessment. This study included overweight or obese males and females aged 18 years and older, who had both their baseline and three-month assessment data available. Overweight (BMI ≥ 25) and obesity (BMI ≥ 30) was defined as proposed by the World Health Organization (WHO).12 Patients that had bariatric surgery before the recruitment period or were on weight-loss medication at the time of the recruitment, were excluded. All anthropometric parameters were collected twice, at baseline and during the three-month follow-up measurements.\n\nAssessment modalities were either in-person or by telenutrition. The in-person appointment starts with a thorough examination of food habits including two nutritional questionnaires: food consumption frequency and 24-hour dietary recall (Extended data: https://doi.org/10.6084/m9.figshare.14832345.v2).13\n\nHeight measurement is self-reported, WC measurement is performed by the nutritionist following standard procedures (middle area between the lower edge of the rib cage and the upper edge of the iliac crest) with a Lufkin measurement tape. Weight measurement was taken by the Inbody 120 scale.14 Body fat percentage was calculated with the use of the following RFM formula described by Woolcott OO and Bergman RN:15\n\nMale adults: 64−(20 × (height cm/waist circumference (cm))\n\nRFM ≥ 22.8 for obesity in males.\n\nFemale adults: 76−(20 × (height cm/waist circumference cm))\n\nRFM ≥ 33.9 for obesity in females.\n\nOnce the anthropometric data is taken, the nutritionist creates a personalized nutritional plan adapted to the patients’ nutritional status, food habits and preferences. The follow-up and monitoring are performed through e-mail or by the multimedia messaging application (WhatsApp), once a week. Standard follow-up appointments are performed every 20 days. The three-month follow up assessment includes WC, weight measurements and RFM.\n\nTelenutrition assessment starts one day before the actual appointment by sending an infographic that includes fasting anthropometric measurement instructions to the patient based on the local recommendations.14 This is done in order to standardize weight and WC measurements for remote assessments (Figure 1). During the appointment, height value is self-reported and the nutritionist requests the self-measured values (weight and WC) for the RFM calculation. Following this, the nutritional plan adapted to the patients’ nutritional status, food habits and preferences is sent to the patient by e-mail. The follow-up and monitoring are once a week and it is done by e-mail or WhatsApp. Standard follow-up appointments are performed every 20 days. The three-month follow -up assessment includes self-reported WC, weight measurements and RFM calculation.\n\nData analysis was performed with the use of Stata/SE 12.0 for Windows (https://www.stata.com/). Continuous variables were examined for outliers with graphic (box plot) and analytic techniques (interquartile ranges). Normality was assessed with graphic (histograms) and analytic techniques for skewness and kurtosis (Shapiro Wilk test). For univariate analysis, continuous variables were described with means and standard deviations or medians and ranges. Categorical variables were reported as frequencies. For bivariate analysis, baseline and follow-up continuous variables were compared with paired-samples t-test or Wilcoxon Rank-sum test. Telenutrition and in-person continuous variable values were compared with independent samples t-test or U Mann-Whitney test. Categorical variables were compared with the chi-square test. P-value < 0.05 is considered statistically significant.\n\nDataset created and analyzed for the study is available as underlying data: https://doi.org/10.6084/m9.figshare.14710296.v1.16\n\nThis study was conducted according to the Declaration of Helsinki principles. Patients were deidentified by being assigned to code numbers, without any reference to the patient information, therefore keeping the data confidential. Patient information was only accessible to the Registered Dietitian Nutritionist who evaluated the patients. Informed consent was not needed for this retrospective study as the data had been anonymized and this was confirmed by the Ethics Committee which approved the study. Ethical approval was obtained from the Institutional Ethics Committee for Research of the Norbert Wiener University with Exp. No 526-2021.\n\n\nResults\n\nMean baseline BMI was in the obesity range (31.91 ± 5.53 and 30.36 ± 4.35 kg/m2 for telenutrition and in-person group respectively), while the mean final BMI was in the overweight range (29.68 ± 5.02 and 28.53 ± 4.12 kg/m2 for telenutrition and in-person group respectively) (Table 1).\n\nThe baseline and three-month follow-up weight, BMI and WC values were not statistically different between the two assessment groups. However, significant differences were observed in the mean baseline RFM (41.03 ± 5.30 vs. 37.85 ± 6.53) and mean three-month follow-up RFM (38.60 ± 5.53 vs 35.23 ± 6.73), between the assessment groups (Table 1).\n\nSignificant differences between baseline and three-month follow -up weight, BMI, WC and RFM within the assessment groups (p = 0.0000) were identified, the greatest difference reported was in WC, which decreased by 6.80 ± 4.87 cm and 6.74 ± 4.55 cm in telenutrition and in-person assessment, respectively (Tables 2 and 3).\n\nIn regard to the change in the magnitude of the anthropometric parameter values between the assessment groups, no significant differences were identified for any parameter. Weight (5.93 kg and 4.92 kg), BMI (2.23 kg/m2 and 1.83 kg/m2), WC (6.80 cm and 6.74 cm), and RFM (2.43 and 2.63) reductions were similar in both telenutrition and in-person assessment, respectively (Table 4).\n\n\nDiscussion\n\nThis study was designed to examine variations in the anthropometric parameters of overweight and obese adults treated in a private nutritional center where telenutrition was additionally implemented. The results showed that weight loss was statistically significant in both groups, with no difference in the variation by the three-month follow-up evaluation. Weight loss is a key factor in reducing non-communicable disease risk and COVID-19 complications, the fact that this nutritional goal is achieved through both assessment modalities, offers the patient a viable alternative for health maintenance.\n\nSignificant changes in weight, WC, BMI and RFM were observed within each assessment modality in our study. However, comparing the changes in these anthropometric measures between these two assessment modalities, no significant difference in these values was identified. Kuzmar IE et al., reported similar results, with no significant differences in weight loss, BMI and waist-to-height ratio (WHtR), when comparing the in-person assessment to telenutrition, in obese women.17\n\nOther studies have identified significant changes in anthropometric parameters, such as Huang et al., who had assessed overweight and obese patients with non-communicable diseases by using telenutrition and observed a significant BMI decrease.18 Whereas Beleigoli et al., used a web-based software with patient feedback for 24 weeks in overweight and obese patients in comparison to non-technological interventions to assess weight loss and lifestyle changes, and indicated improvement in food consumption habits, user adherence and significant weight loss.19 Likewise, Ventura Marra et al., in a randomized study in cardiovascular patients observed a significant weight loss in a similar follow-up period of 12 weeks, 4.92 ± 3.29 kg and 5.93 ± 3.88 kg for in-person modality and telenutrition, respectively.20 In five American clinics, a randomized study examined pregnant women to prevent excessive weight gain and promote healthy behavior by comparing telehealth strategies to traditional assessment. Pregnant women assessed traditionally showed an average weekly gestational weight loss of 0.26kg, in comparison to 0.32kg in the telehealth group (the mean difference between the two groups was 0.07 kg per week, CI 95%: −0.09 to −0.04).21\n\nA study that compared video conference health coaching with a focus on physical activity and weight management, to in-person modality for adults with high BMI, showed that the intervention group achieved a significantly greater weight loss (8.23 ± 4.5 kg),22 within 12 weeks.\n\nAnother telehealth program for weight loss that used video conferencing for 12 weeks showed a significant difference between the intervention and control groups in body weight (7.16 ± 4.4 vs. 1.5 ± 4.1%, respectively). The significant weight loss was achieved in nine out of 13 individuals (69.2%) in the intervention group compared to one in 12 (8%) in the control group.23\n\nIt is important to emphasize that in our study, the greatest decrease obtained in the telenutrition assessment was for WC (mean difference 6.80 ± 4.87 cm), which is an anthropometric index significantly associated with increased risk to cardiovascular and metabolic diseases, as reported in the literature.24-27\n\nAdditionally, this study has included RFM which as an anthropometric parameter has not been extensively examined in Lima, Peru. RFM, is a valuable tool for corporal composition evaluation,15,28 and for being a great predictor of dyslipidemia and metabolic syndrome.29 In our study, RFM showed also a significant decrease in both modalities (2.43 ± 1.78 telenutrition vs 2.63 ± 1.73 in-person).\n\nThis study has some limitations, consider the observational and retrospective nature of the study. There may be other variables, such as physical activity, lifestyle changes, previous nutritional consultation or weight-loss concomitant medications, which have not been assessed that could act as confounders. The study was conducted in a private nutritional center and through a convenience sampling strategy which may impact representativity. The follow-up period was three months, so either stabilization or further variations of the assessed parameters may take place which could be observed with longer follow-up periods. Future prospective studies could assess the long-term impact of telenutrition in anthropometric parameters and nutritional health in patients.\n\n\nConclusion\n\nIn the time of pandemic, telenutrition has become a valuable alternative to nutritional care by reducing the transmission risk through social distancing practices. Telenutrition may well be regarded as a useful tool for current situations such as the COVID-19 pandemic, by offering similar outcomes to those reported as the in-person assessments, while providing ongoing nutritional support to overweight and obese adults in times of isolation and social distancing. Health care providers should attempt to adapt their processes to fulfil the patients’ health demands, in order to prevent excessive weight gain and its related comorbidities through interventions like telenutrition.\n\n\nData availability statement\n\nFigshare: The effects of telenutrition in overweight and obese adults in a nutritional center in Lima, Peru.\n\nDOI: https://doi.org/10.6084/m9.figshare.14710296.v1.16\n\nThe project contains the following underlying data:\n\nDatabase: The data includes baseline and 3-month follow up demographic and anthropometric parameters for overweight and obese adults according to assessment modality (telenutrition vs in-person).\n\nFigshare: The effects of telenutrition in overweight and obese adults in a nutritional center in Lima, Peru.\n\nDOI: https://doi.org/10.6084/m9.figshare.14832345.v2.13\n\nThis project contains the following extended data:\n\nFile 1: Consumption Frequency Questionnaire\n\nFile 2: 24-hour Dietary Recall Questionnaire\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication): https://creativecommons.org/publicdomain/zero/1.0/.",
"appendix": "References\n\nContreras CM, Metzger GA, Beane JD, et al.: Telemedicine: Patient-Provider Clinical Engagement During the COVID-19 Pandemic and Beyond. J Gastrointest Surg. julio de. 2020; 24(7): 1692–1697. Epub 2020 May 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Using Telehealth to Expand Access to Essential Health Services during the COVID-19 Pandemic [Internet].2020. Reference Source\n\nEat Right PRO Academy of Nutrition and Dietetics [Internet].2020. Reference Source\n\nHong Z, Li N, Li D, et al.: Telemedicine During the COVID-19 Pandemic: Experiences from Western China. J Med Internet Res. 8 de mayo de 2020; 22(5): e19577. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRozga M, Handu D, Kelley K, et al.: Telehealth During the COVID-19 Pandemic: A Cross-Sectional Survey of Registered Dietitian Nutritionists. J Acad Nutr Diet. enero de 2021; S2212267221000368. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKelly JT, Allman-Farinelli M, Chen J, et al.: Dietitians Australia position statement on telehealth. Nutr Diet. septiembre de 2020; 77(4): 406–15. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPursey K, Burrows TL, Stanwell P, et al.: How Accurate is Web-Based Self-Reported Height, Weight, and Body Mass Index in Young Adults? J Med Internet Res. 7 de enero de 2014; 16(1): e4. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSpencer EA, Roddam AW, Key TJ: Accuracy of self-reported waist and hip measurements in 4492 EPIC–Oxford participants. Public Health Nutr. septiembre de 2004; 7(6): 723–727. PubMed Abstract | Publisher Full Text\n\nRoberts CA, Wilder LB, Jackson RT, et al.: Accuracy of self-measurement of waist and hip circumference in men and women. Public Health Nutr. 1997; 97(5): 534–536. PubMed Abstract | Publisher Full Text\n\nElliott WL: Criterion validity of a computer-based tutorial for teaching waist circumference self-measurement. J Bodywork Movement Therapies. 2008; 12: 133–145. Epub 2007 Dec 26. PubMed Abstract | Publisher Full Text\n\nMcEneaney DF, Lennie SC: Video instructions improve accuracy of self-measures of waist circumference compared with written instructions. Public Health Nutr. julio de 2011; 14(7): 1192–1199. Epub 2011 Mar 31. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Obesidad y sobrepeso [Internet].2020. Reference Source\n\nQuestionnaire Frequency and 24-hour Dietary [Internet]. yesFigshare. Castrillón Liñan, Carolina. . 2021 June – [cited 2021 June 623].;DOI: 10.6084/m9.figshare.14832345.v2\n\nAguilar Esenarro L, Contreras Rojas M, Del Canto y Dorador J, et al.: Guía técnica para la valoración nutricional antropométrica de la persona adulta [Internet]. Instituto Nacional de Salud 2012. Reference Source\n\nWoolcott OO, Bergman RN: Relative fat mass (RFM) as a new estimator of whole-body fat percentage ─ A cross-sectional study in American adult individuals. Sci Rep. 2018; 8: 1–11. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTelenutrition and Anthropometric Parameters [Internet] Figshare. Castrillón Liñan, Carolina. 2021 June – [cited 2021 June 6]. Publisher Full Text\n\nKuzmar IE, Cortés-Castell E, Rizo M: Effectiveness of telenutrition in a women’s weight loss program. PeerJ. 3 de febrero de 2015; 3: e748. eCollection 2015. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang J-W, Lin Y-Y, Wu N-Y: The effectiveness of telemedicine on body mass index: A systematic review and meta-analysis. J Telemed Telecare. 2019; 7: 389–401. Epub 2018 May 28. PubMed Abstract | Publisher Full Text\n\nBeleigoli AM, Andrade AQ, Cançado AG, et al.: Web-Based Digital Health Interventions for Weight Loss and Lifestyle Habit Changes in Overweight and Obese Adults: Systematic Review and Meta-Analysis. J Med Internet Res. 8 de enero de 2019; 21(1): e298. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVentura Marra M, Lilly C, Nelson K, et al.: Pilot Randomized Controlled Trial of a Telenutrition Weight Loss Intervention in Middle-Aged and Older Men with Multiple Risk Factors for Cardiovascular Disease. Nutrients. 22 de enero de 2019; 11(2): 229. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFerrara A, Hedderson MM, Brown SD, et al.: A telehealth lifestyle intervention to reduce excess gestational weight gain in pregnant women with overweight or obesity (GLOW): a randomised, parallel-group, controlled trial. Lancet Diabetes Endocrinol. junio de 2020; 8(6): 490–500. PubMed Abstract | Publisher Full Text\n\nJohnson KE, Alencar MK, Coakley KE, et al.: Telemedicine-Based Health Coaching Is Effective for Inducing Weight Loss and Improving Metabolic Markers. Telemed J E Health. febrero de 2019; 25(2): 85–92. Epub 2018 May 30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAlencar MK, Johnson K, Mullur R, et al.: The efficacy of a telemedicine-based weight loss program with video conference health coaching support. J Telemed Telecare. abril de 2019; 25(3): 151–157. Epub 2017 Dec 3. PubMed Abstract | Publisher Full Text\n\nNicklas BJ, Penninx BW, Ryan AS, et al.: Visceral adipose tissue cutoffs associated wwith metabolic risk factors for coronary heart disease in women. Diabetes Care. mayo de 2003; 26(5): 1413–1420. PubMed Abstract | Publisher Full Text\n\nWang Y, Rimm EB, Stampfer MJ, et al.: Comparison of abdominal adiposity and overall obesity in predicting risk of type 2 diabetes among men. Am J Clin Nutr. 2005; 81: 555–63. PubMed Abstract | Publisher Full Text\n\nBellido D, López de la Torre M, Carreira J, et al.: Índices antropométricos estimadores de la distribución adiposa abdominal y capacidad discriminante para el síndrome metabólico en población española. Clínica e Investigación en Arteriosclerosis. julio de 2013; 25(3): 105–109. Publisher Full Text\n\nBener A, Yousafzai MT, Darwish S, et al.: Obesity Index That Better Predict Metabolic Syndrome: Body Mass Index, Waist Circumference, Waist Hip Ratio, or Waist Height Ratio. J Obes. 2013: 1–9. Epub 2013 Aug 13. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuzmán-León AE, Velarde AG, Vidal-Salas M, et al.: External validation of the relative fat mass (RFM) index in adults from north-west Mexico using different reference methods. PLOS ONE. 31 de diciembre de 2019; 14(12): 1–15. eCollection 2019. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKobo O, Leiba R, Avizohar O, et al.: Relative fat mass is a better predictor of dyslipidemia and metabolic syndrome than body mass index. Cardiovasc Endocrinol Metab. 2019; 8(3): 77–81. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "93552",
"date": "20 Sep 2021",
"name": "María Del Mar Morales Hernández",
"expertise": [
"Reviewer Expertise Endocrinology disorders",
"diabetes technology"
],
"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\nClinically relevant retrospective study about the effects of telenutrition in obese and overweight patients in Lima, Peru. The study includes both study and control groups. The authors used easy-to-follow questionnaires and imaging to guide patient's nutritional care. Also provided good weekly follow-up for patients with aid of the technology. Would have liked to see an example of the nutritional plan utilized and if those were similar to in person vs telemedicine patients. Having no statistical significance in changes on anthropometric parameters between groups will suggest that patients could still receive benefits of nutritional care during the pandemic and expect to have similar results as in person encounters in their weight control. This study showed changes in weight, waist circumference, BMI, and RFM. Improvement of nutrition is key to decrease disease burden in the times of COVID 19 pandemic and this study adds to the usefulness of telemedicine and in this specific case telenutrition to help address risk factors during these challenging times.\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": "92606",
"date": "23 Sep 2021",
"name": "Katherine Curi Quinto",
"expertise": [
"Reviewer Expertise Nutrition 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\nOverall comment:\n\nThis manuscript is an important contribution to inform current practice/strategies and intervention to promote a better nutritional and health status in the current context of the COVID-19 pandemic, although it could be sustained over time as a new strategy in the nutritional practice.\n\nGiven this importance, I highlight the following aspects to clarify in the manuscript. This will help to improve the scientific quality of the document:\n\nAbstract: Add the statistical analysis in methods and specify the group of comparison for the last results presented in brackets (weight, BMI, WC, RFM.)\n\nIn the overall manuscript: Explain why the design of the study is retrospective? according to the flow of this study, it seems a quasi-experimental study with \"prospective\" repeated measurements over the time of the intervention (longitudinal), unless you want to present as a secondary data analysis which could be also adequate mainly because you did not have the inform consent of the participants. If the latter is your case, you must make this clarification in your manuscript.\n\nIn the methods:\n\na) Explain how you did the allocation of the 50 participants per each group of intervention and add the inclusion criteria for eligibility.\n\nb) Give more detailed information about the intervention itself: characteristics of the nutritional plan, how and what indicators did you follow & monitor? in case you did for both groups. You could also specify what kind of messages/mail/text, etc. you included.\nc) In data analysis, add which values you considered outliers and report: how many and how you handled the outliers (based on your results, it appears there were no outliers).\nd) Since this is a convenience sample, it will be contributed to the internal validity of your study if you add information on key sociodemographic factors such as level of education. In case you did not collect this information, this must be reported as a limitation and explain why the impact in the results you could be are reporting.\n\nIn the results:\na) In the footnotes of the tables indicate the test from which you obtained the p-value.\nb) The tables repeat information. It would be better if you avoid these types of repetitions. As a suggestion, you could present in Table 1 only the initial characteristics. Tables 2 and 3 can be joined without presenting the differences between the groups. The reader has enough information to know the differences. Then you could keep table 4 as is.\n\nIn the discussion:\na) The discussion needs to be stronger. Add a possible explanation of your results and discuss it in the context of the previous evidence related to the comparison of traditional and telenutrition intervention. The explanation could be in terms of differences or advantages/disadvantages of the method used and why it could influence the results, or it could be for the difference in the intervention itself (frequency, intensity, different ways to monitor, the same nutritionist give the same intervention, some baseline sociodemographic characteristics such as literacy, etc.).\nb) The greater differences in WC in the telenutrition group could be associated with a measurement error, so how do you control that? Can you make cross-validation with the self-reported weight and BMI data? It is more likely that people with weight loss also have a reduction in WC and other parameters. Discuss a little more about this finding that you highlighted in the manuscript.\nc) Add the clinical implication of the RFM. This is a non-common measure, as you presented in the manuscript, but there is little information about its relevance in the clinical nutrition field. Moreover, consider adding information about the validation in the Peruvian population of the equation you used to estimate the RFM.\nd) In the limitation specify how the no inclusion of confounders could affect your results.\ne) Consider highlighting the strengths of your study, I think it has several. You provide important material in terms of methods to the assessment of the Food intake as well as the Food habits.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7424",
"date": "15 Nov 2021",
"name": "Michelle Lozada-Urbano",
"role": "Author Response",
"response": "Suggestion acknowledged and clarifications described in the Amendments from Version 1 and specified on the manuscript in detail."
}
]
}
] | 1
|
https://f1000research.com/articles/10-545
|
https://f1000research.com/articles/10-781/v1
|
09 Aug 21
|
{
"type": "Review",
"title": "Oligodendrocytes, BK channels and remyelination",
"authors": [
"Maddalena Rupnik",
"David Baker",
"David L. Selwood",
"Maddalena Rupnik",
"David Baker"
],
"abstract": "Oligodendrocytes wrap multiple lamellae of their membrane, myelin, around axons of the central nervous system (CNS), to improve impulse conduction. Myelin synthesis is specialised and dynamic, responsive to local neuronal excitation. Subtle pathological insults are sufficient to cause significant neuronal metabolic impairment, so myelin preservation is necessary to safeguard neural networks. Multiple sclerosis (MS) is the most prevalent demyelinating disease of the CNS. In MS, inflammatory attacks against myelin, proposed to be autoimmune, cause myelin decay and oligodendrocyte loss, leaving neurons vulnerable. Current therapies target the prominent neuroinflammation but are mostly ineffective in protecting from neurodegeneration and the progressive neurological disability. People with MS have substantially higher levels of extracellular glutamate, the main excitatory neurotransmitter. This impairs cellular homeostasis to cause excitotoxic stress. Large conductance Ca2+-activated K+ channels (BK channels) could preserve myelin or allow its recovery by protecting cells from the resulting excessive excitability. This review evaluates the role of excitotoxic stress, myelination and BK channels in MS pathology, and explores the hypothesis that BK channel activation could be a therapeutic strategy to protect oligodendrocytes from excitotoxic stress in MS. This could reduce progression of neurological disability if used in parallel to immunomodulatory therapies.",
"keywords": [
"KCNMA1",
"KCNMB4",
"big conductance Ca2+ activated K+ channel",
"oligodendrocytes",
"remyelination"
],
"content": "\n\nMS is the most prevalent chronic demyelinating disease which affects 2.8 million people worldwide1,2. Its increasing prevalence poses a significant socio-economic burden. The aetiology of the disease is not completely understood, but demyelination pathology predominates alongside inflammation. In demyelinating diseases, like MS, an initial local attack against myelin sheath is proposed to trigger a cascade of neuroinflammatory and degenerative pathways causing damage to oligodendrocytes, myelin, and neurons3. This impairs CNS conduction. Other less common demyelinating conditions such as Neuromyelitis optica (Devic's disease), transverse myelitis, and acute disseminated encephalomyelitis all have an inflammatory component4. Demyelinating diseases may also have a genetic cause such as adrenoleukodystrophy, which is a X-linked genetic disorder where mutation in the ABCD1 gene causes a defect in the corresponding ABCD1 transporter protein and accumulation of very long chain fatty acids in the brain and spinal cord leading to inflammation in the white matter, cerebral demyelination and neurodegeneration5. Fragile X syndrome is a genetic disorder where transcriptional silencing of the FMR1 gene leads to loss of the corresponding fragile X mental retardation protein (FMRP). FMRP acts as a RNA transcriptional regulator affecting the function of hundreds of proteins6. Demyelination is an under-recognised feature of fragile X syndrome7, in model systems FMRP silencing has been found to decrease the degree of myelination8.\n\nMS treatments can be classed as disease modifying therapies, (DMTs), to delay progression, or symptom management treatments. Current DMTs are immunomodulatory, with some specifically preventing myelin attack, notably by blocking peripheral immunity9. Despite positive outcomes for neuroinflammation, underlying pathology is still not completely targeted (Table 1). B cell directed therapies are amongst the most effective treatments; as these reflect the emerging disease understanding placing memory B cells at the centre of the disease mechanism10. Although disability is reduced, neurodegeneration and defects in remyelination and repair still occur. Progression to secondary progressive MS (SPMS) is often not prevented and therapies successful for relapsing remitting MS (RRMS) become ineffective11). With the difficulty of finding strategies to prevent neurodegeneration in general and few DMTs for SPMS, new therapeutic approaches need to target underlying demyelination, to date no remyelination strategies have proved effective12. This unmet clinical need has led to the development of some diverse approaches using both repurposed drugs and novel therapeutics. Some of the most promising ideas are listed in Table 1.\n\nThe aims of this review are: to explain the importance of structurally and functionally intact myelin; to address the current lack of therapies targeting neurodegeneration particularly in MS; to evaluate the role of excitotoxicity in oligodendrocyte pathology and to explore the potential for therapeutic use of large conductance Ca2+ activated K+ channel activators to protect oligodendrocytes from excitotoxic stress, ultimately to preserve myelination.\n\n\nOligodendrocytes and myelin in demyelinating disease\n\nNeuronal impulse conduction is formed by action potentials (APs). These are generated from a momentary change in the ionic gradient across the axon membrane that propagates down and is relayed to the next neuron13. Repeated and synchronised through billions of neurons, these rapidly transmit information across the body. In the CNS oligodendrocytes wrap axons with compact lamellae of their membrane myelin sheath19. The low capacitance, high lipid content of myelin propagates action potentials (APs) directly onto short unmyelinated 1-μm axolemma segments, nodes of Ranvier. Voltage-gated Na+ channels concentrate here to integrate a voltage difference so that APs can “skip” myelin internodes through saltatory conduction to increase velocity of impulses. The diameter of myelinated axons positively correlates with conduction velocity20,21; while myelin thickness inversely correlates with capacitance22. Therefore, myelin provides an energy saving evolutionary adaptation; also because it restricts the number of Na+/K+ ATPases to the nodes, so it decreases the chemical energy ATP required to maintain resting potential19. By myelinating larger axons, above ~2 μm in diameter, myelin allows signals to be transmitted fast over a long range19.\n\nThe brain expends one-fifth of total body energy output, but myelin prevents axons from receiving metabolic support extracellularly, so healthy oligodendrocytes are indispensable for axonal support (Figure 1). Although neurons rely on their own mitochondria to synthesise ATP, these require glial glycolytic products, primarily lactate23. Neuronal death can be induced by inhibiting oligodendrocyte glycolysis or neuronal mitochondrial respiration, but not by inhibiting neuronal glycolysis or oligodendrocyte oxidative phosphorylation24. It was found that deleting the lactate transporter protein MCT1 impaired axons and caused atrophy25. MCT1 being expressed relatively specifically by oligodendrocytes, these results indicate oligodendrocytes are important for healthy neuronal metabolism. However, other studies found that upon electrical stimulation neurons used their own glucose to synthesise energy, which might indicate oligodendrocytes are a primary glycolytic source only for neurons at rest26. MCT1 is lost in neurodegenerative diseases like amyotrophic lateral sclerosis, where motor neuron death at the spinal cord indicates impaired axonal lactate supply25. Neurons may depend on oligodendrocytes for metabolic support to survive and function properly, but the pathological relationship may cause damage before or separate to evident demyelination.\n\nFigure created with BioRender.\n\nMetabolic support to axons requires astrocytes, which transfer glycolytic products to neurons through oligodendrocytes (Figure 1). This by way of connexins on astrocytic processes and on oligodendrocytes which co-localise to form gap junctions27. Astrocytes have glycogen stores and upon hypoxia or hypoglycaemia glycogen is catabolised into lactate for delivery to neurons28. Furthermore, connexins found at paranodes may indicate a cooperation of astrocytes and oligodendrocytes in regulating axon electrical properties27,29 (Figure 1). Astrocytes not only regulate axon activity and deliver metabolites; they also regulate BBB passage with astrocytic end feet that adjust membrane permeability. Healthy myelin preserves axon structure, metabolism and function, and potentially improves the general glia–axon relationship.\n\nDemyelination is the erosion of myelin sheaths, which exposes nerve fibres leading to failure of impulse conduction. It can derive directly from traumatic or ischaemic injury30. Alternatively it originates from attack of myelin related proteins in autoimmune disease31. Loss of myelin does not necessarily lead to neuronal death, but overburdens axons by decreasing efficiency of energy homeostasis, making it harder for neurons to meet metabolic demands. Without myelin for saltatory conduction, energy needed to relay impulses increases. This eventually leads to increased functional impairment and susceptibility to further neurodegeneration.\n\nThe “sclerosis” of MS is the fibrotic lesion that forms in the brain or spinal cord from gliosis of astrocytes and microglia, often located near vasculature. The BBB appears “leaky” as shown by gadolinium-enhanced magnetic resonance imaging (MRI) from infiltration of blood-borne macrophages, T lymphocytes and B cells, which contribute to demyelination31 (Figure 2). After two temporally and spatially distinct acute inflammatory episodes, MS can diagnosed and is classified as relapsing–remitting or primary progressive MS depending on the disease course4. As lesions become chronic, factors determining whether inflammation resolves and remyelination occurs are not fully understood. However, demyelination may share pathways with ischaemia and viral infection4. Persisting inflammation and remyelination failure and nerve loss contribute to progressive MS11. Without tissue repair, permanent loss of function often ensues.\n\nOpsonisation by non-specific IgG activates the cytotoxic complement system and ADCC. The emerging importance of B cells is highlighted by recent findings49. Additional roles include possibly secreting anti-myelin antibodies and acting as APCs to increase T cell activation 50, labelled 1. Cytotoxic CD8+ T cells react against self-antigens expressed by oligodendrocytes. Resident microglia or peripheral macrophages phagocytose myelin residues and debris. Reactive astrocytes, activated microglia and Th cells activated by APCs drive inflammation by secreting pro-inflammatory cytokines (TNFα, IFNγ, interleukins) and neurotoxicity by releasing free radicals (ROS, RNS)31. Subsequently to myelin loss, axons degenerate. Figure created with BioRender.\n\nEpisodes may resolve incompletely and RRMS invariably involves neurological decline. Motor symptoms generally affect all patients eventually during disease course, but can involve sensory system particularly sight, pyramidal tracts, psychological aspects, brainstem and autonomic functions32. Spinal cord lesions typically cause most of the lower limb disability and are both the white and grey matter33, which contribute to the atrophy observed. This is observed early in MS brain and spinal cord when measured by atrophy using MRI, as an indicator of neurodegeneration34. Associated neuroaxonal damage, measured as serum and notably intrathecal neurofilament, correlates with disability severity35. Most patients eventually proceed to SPMS, notably those with significant early disease activity4. SPMS develops when compensation pathways becomes exhausted and is notably associated with neurodegenerative state with progressive atrophy, enlarging lesions, chronic inflammation and remyelination failure.\n\nOligodendrocytes are limited in their ability to respond to damage and at least in part depend on replacement by their precursors, OPCs36. In the adult CNS, NG2+ cells, which include OPCs and neural progenitors, constitute nearly 9% of white matter. Their migration into sites of injury is crucial for remyelination, whereby myelin regenerates spontaneously around demyelinated axons37. Preserving myelin is important because neuroaxonal regeneration is limited. Macrophages have a strong influence, and microglia promote this by clearing myelin debris38. Underlying demyelination and inflammation must resolve before new myelin forms. Remyelination may protect axons from inflammation-mediated neurotoxicity39 and is observed in both acute and chronic lesions, even concomitant to demyelination, and in early MS31.\n\nSuccessful remyelination depends on sufficient OPC pools, their migration and survival, until differentiated into myelinating oligodendrocytes; but this does not guarantee it. In MS, OPCs differentiation may arrest before myelin synthesis completes30. Axonal density is higher in remyelinated than chronic demyelinated plaques. However, demyelination may re-occur more frequently in new myelin because newly differentiated oligodendrocytes may produce thinner and shorter sheaths, possibly from external ischaemic factors of the neuroinflammatory environment impairing proper myelination40. Additionally, lesion remyelination occurs 20% more often in acute than chronic lesions, so remyelination may inversely correlate with disease progression or age41. Therefore, preserving myelin might provide a better neuroprotective strategy than remyelination.\n\n\nCommunication between axons and myelin\n\nAbout one-third of myelin sheath constitutes proteins that determine myelin architecture. Myelin basic protein (MBP) is a final component added to sheaths, responsible for compaction. MBP localises and draws two adjacent membranes together at clusters, where it forms a dense fibrillary network42. This prevents signal dissipation and makes neurons more energy efficient. Downregulation of MBP impairs sheath structure in vivo and knockout decreases axonal calibre43,44. Conversely, 2',3'-Cyclic nucleotide 3'-phosphodiesterase (CNP) regulates cytoplasm quantity within myelin by maintaining actin cytoskeleton. This creates channels and directly counteracts MBP compaction45. Working antagonistically, CNP and MBP can adjust these channel systems, possibly to modulate the type and amount of substrate exchange with axons. In mice, knockout of CNP1 and of the functionally similar myelin proteolipid protein caused loss of fibres, of axonal integrity and axonal swelling by impairing neuronal transport44,46. This indicates that intact microstructure is important to preserve local support by oligodendrocytes and that effective conduction depends on this. Indeed, these properties of myelin microstructure can vary to preserve diverse neural networks, to adjust input latencies in nuclei. A latency of about 2 ms remains constant for thalamocortical signals to reach the sensory cortex despite fibres of different lengths47. Instead of gross insulation, myelin tunes its microstructure to local axon requirements.\n\nElectrically-silenced axons myelinate inadequately48. Maintaining high K+ levels extracellularly reduced myelination by increasing depolarisation duration, so APs are a putative channel of communication with oligodendrocytes51. Recent advances in electron microscopy and myelin preservation revealed structure of the developed myelin sheath around axons52. It is now possible to infer a peri-axonal space, where APs may be relayed by neurotransmitter release. Glutamate is the main excitatory neurotransmitter of the nervous system. Typically, it is released at axon terminals to bind to ligand gated ionotropic receptors found post-synaptically on dendrites. Types of ionotropic receptors are glutamatergic NMDARs, AMPARs and kainate receptors. Upon neurotransmitter binding these open voltage-gated channels for selective cation influx, for AP relay53. In mature oligodendrocytes, glutamate may be released at the axolemma to affect the inner tongue of myelin sheath.\n\nGlutamate release from synaptic vesicles along axons can stimulate MBP production to promote the insulating properties of myelin54. Glutamatergic synapses are a feature of developing OPCs, whereby differentiating oligodendrocytes may depend on glutamate signalling for myelination55. Activity dependent myelination may promote the migration and differentiation of OPCs. Stimulating the premotor cortex resulted in increased OPC migration and myelin thickness only in the optogenetically modified mouse model. This was associated with improved motor skills56. Glutamatergic signalling downregulation may alter myelin thickness because, in mice, reduction of visual stimuli associated with reduced conduction velocity57. When tetanus toxin was used to inhibit glutamate release from the synaptosome, Ca2+ influx into oligodendrocytes did not occur58, supporting mediation by excitatory neurotransmitter release. Although most myelinic ionotropic receptors are removed with differentiation, their use in preserving correct myelination in mature oligodendrocytes might explain the few remaining58. NMDARs at the myelin sheath also gauge glycolytic delivery in response to axon energy demand59. Substrate exchange may be triggered by AMPAR/ NMDAR activation, which induced exosome delivery60. Dysregulation of firing frequency would therefore reduce myelinic neuronal support (Figure 1). In pathology this activity dependent alteration of myelin architecture may be rendered unresponsive, counterproductive or even toxic to neurons, even before overt demyelination. Modulating this glutamatergic signalling may preserve myelin and neurons.\n\n\nExcitotoxic stress\n\nExcitotoxic stress is caused by excessive or prolonged activation of glutamatergic receptors causing Ca2+ overload. This sustains pro-apoptotic pathways involving enzymes and transcription factors like MAPK and NF-κB, which degrade membranes, proteins and intracellular organelles. Increased glutamatergic signalling can be triggered by the energy deficiency from the cellular damage in lesions, mitochondrial dysfunction and oxidative stress61,62. The last involves highly reactive and damaging free radicals: ROS and RNS. These cause mitochondrial membrane damage by lipid peroxidation, which exacerbates cellular burden and glutamatergic signalling63. At high levels glutamate is thought to induce oxidative stress by means of blockade of the glutamate/cystine antiporter (XC–Cys/Glu) that prevents uptake of cystine and synthesis of the anti-oxidant glutathione, in a form of cell death termed ferroptosis or oxytosis64.\n\nDamage to neurons causes axon swelling, where ion channels including voltage-gated sodium channels are upregulated to attempt compensation for impaired conduction65,66. Excitotoxic damage to myelin may cause this upregulation without necessarily causing overt demyelination66. Axon swelling impairs network connectivity in MS, where sustained glutamatergic activation associates significantly with increased neurological disability67.\n\nGlutamate is upregulated in MS CSF (p<0.001) and carrying the polymorphism rs794185 that further increases this associates with neurodegeneration67,68. The major source of glutamate production is difficult to discern, but evidence suggests neuroinflammation is important. Pro-inflammatory cytokines TNFα and IL-1β cause neurotoxicity by downregulating astrocytic glutamate transporter and glutaminase which accumulates glutamate in the extracellular space61,69,70. IL-1β but not TNFα are established as significantly upregulated in MS CSF70,71. Immune activation upregulated the cysteine glutamate exchanger on macrophages and microglia and in MS patients72. To synthesise important antioxidant glutathione this exchanger releases glutamate extracellularly.\n\nTable 2 describes drugs targeting excitotoxicity in MS, highlighting the still unmet clinical need. These therapies are inadequate clinically because antagonists of glutamatergic pathways can downregulate excitatory CNS conduction, which importantly can cause serious adverse events. Selectivity could be improved by targeting receptor subunits specific to glial cells and that are more permeable to pathological Ca2+ accumulation, like NR1 and NR3 NMDAR subunits73. Sodium channel blockers provide an alternative means to control excitotoxicity and some benefit has been noted in the more recent clinical trials, but they are poorly tolerated leading to non-compliance74,75.\n\nOxidative damage to proteins and lipids is substantially increased in acute demyelinating lesions compared to healthy white matter. Hypertrophic astrocytes and foamy macrophages are able to limit this damage by upregulating antioxidant superoxide dismutase, but not other components of lesion tissue including neurons and oligodendrocytes76. Oligodendrocytes have a particularly inefficient antioxidant protection. These have a reduced ability to synthesise glutathione77 and their death positively correlates with concentration of the highly reactive lipid peroxidation product 4-HNE78. Oligodendrocytes are also the main cells that store iron in a balance that is susceptible to conversion to its oxidative divalent form79. Their susceptibility to excess glutamate activation specifically is supported by in vitro studies. Only upon inhibition of glutamatergic receptors in oligodendrocytes-only cultures were the apoptotic indicators DNA fragmentation and caspase-3 abolished70,80.\n\nExperimental autoimmune encephalomyelitis (EAE) is an established MS model induced by adoptive transfer of anti-myelin protein T cells. In EAE mice, 60% more of the oligodendrocytes population was preserved with the AMPA/kainate receptor inhibitor NBQX compared with administering phosphate buffered saline (PBS) only, which also improved neurologic impairment score (p <0.01)81. AMPAR-mediated Ca2+ influx activates a sustained phosphorylation of ERK1/2 to activate proapoptotic pathways in oligodendrocytes and mitochondrial impairment in a manner similar to ischaemia62. Ca2+-permeable AMPARs are upregulated only at MS lesions, but not in regions of healthy tissue89, so Ca2+ permeability might indicate upregulation of excitotoxic responses with demyelination. Considering the complex pathological microenvironment of lesions, glutamatergic receptor inhibition alone might not prevent cytotoxicity locally in MS. Pro-inflammatory damage spreads centrifugally from the lesion centre4, so inhibition might instead prevent spread of excitotoxins.\n\nAMPAR/kainate receptors are mainly expressed on oligodendrocytes soma, while myelin mainly expresses NMDARs90. Excitotoxic stress to myelin can cause decompaction of myelin sheath91, which can impair neuronal metabolism before overt demyelination. Since damaged or degraded myelin sheaths increase neuronal metabolic burden and expose axons to inflammation related toxins, this suggests therapeutically protecting myelin from excitotoxic stress may be neuroprotective in MS. A characteristic feature of MS is a dying back oligodendrogliopathy which, in a similar way to complement activation by direct antibody attack4, might also be caused by activation of catalases and mitochondrial redox damage at myelin processes which retrogradely affects oligodendrocytes.\n\nNMDARs induce weaker Ca2+ currents compared with AMPARs but sustain these for longer53. The small cytosolic compartment of myelin may quickly accumulate Ca2+ concentrations sufficiently high to be toxic. All compartments needed for NMDARs to be functional have been detected with immunoblotting: NR1, NR2 and NR390. These require activation by both glutamate and its co-agonist glycine. Release of only glutamate from myelinated axolemmas has been established58. The Mg2+ block characteristic of NMDARs can be released by a slight depolarisation53, which may justify the expression of AMPARs on myelin at lower concentrations. Especially because AMPARs inhibitors only partially abolished the Ca2+ current through myelin, but completely at oligodendrocytes soma, while non-selective ionotropic receptor inhibitor completely abolished at both locations90. This suggests a mediating effect by AMPAR.\n\nHowever, no significant decrease of NMDAR mediated Ca2+ into oligodendrocytes when their inhibitors, NBQX or D-AP5 respectively, were added after ischaemia91. The authors proposed excitotoxicity does not derive directly from glutamatergic Ca2+ influx, but from the resulting K+ and H+ increase because the NMDA evoked current correlated with K+ increase. The resulting decrease in pH (from K+ and from the hypoxic cell) might activate H+-gated TRP channels which then caused about 70% of the Ca2+ rise91. TRP block reduced myelin decompaction, so it is possible these channels are more responsible for the ischaemic excitotoxicity to oligodendrocytes than direct ionotropic receptor activation. Alternatively, the majority of Ca2+ may derive from a secondary source, such as from subsequently activated voltage gated calcium channels (VGCCs) or the reversal of the Na+/Ca2+ exchanger which can occur in conditions of excessive depolarisation89.\n\nDying oligodendrocytes release high levels of Fe2+ which directly contributes to oxidative injury to neurons79. This accumulates at acute demyelinating lesions, phagocytosed and released through oxidative burst. Ferrous iron, Fe2+, is a mediator of the Fenton reaction that synthesises hydroxyl and H2O2 radicals79. Excitotoxic stress will damage oligodendrocytes, which will in turn release more oxidative stress, although contribution of oligodendrocytes excitotoxicity is still unclear because complex to quantify.\n\n\nBK channels reduce excitotoxic stress\n\nLarge conductance calcium-activated, voltage gated potassium channels (BK channels) are the most diverse within the family of transmembrane protein channels, which also includes small and intermediate K+ conductance (SK and IK) channels92. These are activated by thresholds of voltage or Ca2+ transients and accordingly control membrane potential by mediating efflux of the required amount of hyper-polarising K+93. They can also be activated by other metal ions such as Mg2+, but also by pH, arachidonic acid and nitric oxide. Encoded by the KCNMA1 (or SLO) gene, BK channels constitute a heterodimer of pore-forming α-subunits and a monomer comprising a voltage-sensing and a calcium-sensing module94. Ubiquitous, BK channels are overexpressed in regions of high Ca2+ concentrations95. By mediating K+ transients out of cells, BK channels can also regulate K+ homeostasis, cell volume, and therefore have various functions including neuronal excitability, smooth muscle relaxation, blood pressure control and electrical tuning of cochlear hair cells96.\n\nThe highly dynamic physiological properties of BK channels are partly due to the numerous α-subunit splice variants, which makes their translated protein structure highly versatile physiologically. For example, a cysteine-rich 59-amino-acid insert between RCK domains called STREX variant can be added to the C-terminus97, resulting in increased sensitivity to activation, inducing higher neuronal firing frequencies. Additionally, BK channels assemble auxiliary subunits, such as β subunits (β1–4)98. These can modify activity, including modifying sensitivity to its activators, voltage or Ca2+, or by activating protein kinases99. Furthermore, the association with γ subunits, which are leucine rich repeat containing proteins, can increase stimulability of the BK channel by decreasing the negative voltage difference threshold100. Ultimately, this increases the range of pharmacological applications of these channels.\n\nIn the CNS, BK channels are abundantly expressed on axons, dendrites, soma and synaptic terminals in widespread CNS regions. Here, these can control the fast phase of after-hyperpolarisation. Additionally, these can control AP output by changing the magnitude and duration of incoming Ca2+ spikes at dendrites101. This will determine AP duration and firing frequency102. BK channels can mediate their activities and their responses specifically for their cellular location and type of neuronal cell by co-localising with functionally distinct VGCCs102. BK channels have been shown to co-localise with L-/, P/Q-, or N-/ types of VGCCs103,104. Depending on the frequency of basal firing, the BK channels at that neuronal cell will typically provide the opposite effect to modulate and re-set the phase, ultimately to flatten the frequency-current curve and control neuronal excitability. This would occur in a manner similar to hyperpolarisation activated by cyclic nucleotide gated channels, that set the “pacemaker” firing frequency in the brain105. Overall, studies of BK channels indicate these tune the neuronal signal by amplifying it if weak or reducing it if too strong, rather than stringently enhance inhibition or excitation106–108.\n\nBK channels also have an important role in directly mediating neurotransmitter release, this is supported by their co-localisation to VGCCs with those of the P/Q-type being most frequently observed. This co-localisation occurs predominantly at dendrites where it regulates dendritic spike generation relative to neurotransmitter release109. This is consistent with localisation of the BK α subunits at presynaptic terminals in functionally important axon tracts110. At these locations, BK channels limited the Ca2+ mediated neurotransmitter release by decreasing presynaptic APs duration110. Indeed, release of neurotransmitter from vesicles is triggered by Ca2+ elevated locally through VGCCs, once the propagated AP reaches the terminal111. Typically, BK channels would reduce neurotransmitter release, because these are able to reduce the amplitude of the presynaptic AP. An important demonstration of this is the effect on neurotransmitter release by CA3 hippocampal neurons and associated APs upon addition of BK channel blockers. The resulting spontaneous EPSCs increased in amplitude and frequency110. This inhibition ultimately reduces release of glutamate, but does not occur for inhibitory neurotransmitter GABA112. Therefore, BK channels are key to avert overexcitation of the post synaptic neuron.\n\nPhysiologically, BK channels can prevent too much neurotransmitter from causing excessive depolarisation and Ca2+ accumulation post-synaptically. In mice where acute focal cerebral ischemia was induced by middle cerebral artery occlusion, the neurological symptoms were significantly higher with knockout of the BK α subunit compared to wild type113. This may imply glutamate-induced oxidative stress, and consequences for acute and chronic neurodegeneration. This negative feedback by BK channels might only occur if propagated APs are high enough to induce levels of intracellular Ca2+ and neurotransmitter similar to those observed in pathological conditions. For example, only upon addition of 4-AP, a non-specific inhibitor of voltage gated K+ channels, were BK channels activated to decrease AP amplitude post-synaptically and decrease neurotransmitter release114. No amplified repolarisation or reduced neurotransmitter release by BK channels was observed without 4-AP. This is specific to excitatory neurotransmitter release, because a concentration dependent reduction in ischaemia mediated by NMDAR correlated with increased opening of BK channels by the activator NS1619115. By creating a negative feedback control to disproportionate neurotransmitter release, BK channels may be an emergency break to prevent hyperexcitability and subsequent toxicity.\n\nMuch of the available evidence relates to neurons, but if there is a functional link between the role of BK channels and oligodendrocytes in mediating this excitotoxic stress, targeting this could possibly provide an avenue for disease modifying therapy in MS.\n\nAlthough big conductance, calcium-activated potassium (BKCa) channels, notably KCNMB4 isoforms are neuronally expressed116, it is evident that KCNMB4 is also present and differentially expressed by oligodendrocytes117,118. OPCs were associated with high expression of KCNMA1 and KCNMB2 (Figure 3A. 3B), at a time when they express many ion channels perhaps as part of the pre-myelination glial-neuronal synapse119. However, it is evident that oligodendrocyte maturation and myelination was associated with their relative loss and the upregulation of the KCNMB4 BK isoform (Figure 3A, 3B). In addition transcriptomic expression of KCNMA1 and KCNMB4 in NG2+ cells has been found120.\n\nThe expression of: BK channels; platelet-derived growth factor receptor alpha (PDGFRA) and chondroitin sulphate proteoglycan four (CSPG4/NG2) as markers for oligodendrocyte precursor cells (OPC) and committed oligodendrocyte precursors ((COP); myelin oligodendrocyte glycoprotein (MOG) and proteolipid protein one (PLP1) as markers of mature oliogdendrocytes (OL); human glutamatergic neurons (Neuro2 GAD2 0.02, SLC17A7 2.11 (Jäkel et al. 2019); and aquaporin 4 (AQP4) and glial fibrillary acidic protein (GFAP) as markers for astrocytes channels was extracted from public data bases (A) Expression of BK channels in human cells in human white matter tissues extracted from the oligointernode (https://ki.se/en/mbb/oligointernode117. (B) Expression of human and mouse BK channels from cortical brain tissue using 10X single cell RNAseq from the Allen Brain Atlas (www.portal.brain-map.org) (C) BK expression in OPC and mature oligodendrocytes from RNAseq data from the Oligointernode portal126 and the Brain RNA-Seq portal (www.brainrnaseq.org127). Data is expressed as fragments per kilobase of transcript per million mapped reads (FPKM). * = data values reduced 10 times ** = data values reduced 100 times.\n\nHuman KCNMB4 expression increases as OPCs mature into oligodendrocytes and was increased in myelinating oligodendrocytes (Figure 3A). This is perhaps consistent with elevated KCNMB4 expression in chronic inactive multiple sclerosis lesions117. In contrast mouse OPC and oligodendrocytes do not seem to express much Kcnmb2 (Figure 3B, 3C). However, as occurs in humans, Kcnma1 is most marked in the OPC and is down-regulated as oligodendrocytes mature and myelinate (Figure 3C). Likewise, Kcnmb4 can sometimes be found at higher levels in OPCs, but persists in mature oligodendrocytes to be the dominant BK channel isoform (Figure 3B, 3C). Kcnmb4 is expressed on the cell membrane and is also expressed in mitochondria121. Loss of Kcnma1 message during development is consistent with protein expression and functional calcium-induced signalling activity118 and may play a role in oligodendrocyte differentiation.\n\nAdditionally, electrophysiological recordings of increased oligodendrocytes depolarisation corresponded to the increased intracellular fluorescence from labelled Ca2+ upon glutamate-induced stimulation; which occurred only when the BK channel blocker iberiotoxin was added118. This suggests a role of BK channels to regulate Ca2+ influx to protect oligodendrocytes from excitotoxic stress. Other evidence indirectly supports this. As such the fundamental subunits of the NMDARs, NR1, NR2 and NR3 co-localise with myelin protein from primary optic nerve oligodendrocytes upon immunohistochemical staining90. Blocking NMDARs substantially blocked myelin damage upon chemically induced ischaemia in vitro90. This was the first evidence of axo-myelinic signalling, indicating that glutamate released from the axon can cause Ca2+ to enter oligodendrocytes through the myelin sheath. Importantly, it has been found that mature oligodendrocytes express NMDARs, and that small quantities of excitatory neurotransmitters diffusing between axon and myelin could form sufficiently high concentrations to give rise to large Ca2+ transients within mature oligodendrocytes122. In health, oligodendrocytes already communicate with axons through NMDAR for trophic support59 and BK channels form complexes with this receptor123. Therefore, when activated, BK channels could protect oligodendrocytes from axon-induced excitotoxicity by increasing hyperpolarisation. Prolonging APs may increase the duration of the desensitised state of ionotropic channels and VGCCs to limit Ca2+ influx. In demyelinating pathology, the excessive excitotoxicity could inhibit the endogenous protection by BK channels to oligodendrocytes. The addition of an activator could re-open these, re-establishing protective effects. A counter argument is that high extracellular potassium is primarily responsible by increasing length of neuronal depolarised state. Damaged oligodendrocytes may have a dysfunctional inward rectifier potassium channel, so K+ clearance is faulty124. Large levels of excitatory stimulation of myelin may result because when neurons are demyelinated or damaged they upregulate sodium channels, and subunits which maintain the depolarised state65. In this scenario, BK channel activators might be counter-productive by increasing extracellular K+, but possibly only if K+ clearance is faulty.\n\nBK channel activators could be used therapeutically to preserve function in demyelinating diseases, particularly MS. As described above, currently the standard treatment for MS targets inflammation, but curbing the pathological attack by the immune system does not protect from demyelination or excitotoxicity. Therefore, it does not prevent neurodegeneration or restore functionality lost11. In MS, BK channels are expressed in both myelin and the axons it covers. Crucially, in chronically injured white matter, their activation upon Ca2+ influx was observed only upon axon exposure subsequent to chronic spinal cord injury125. Addition of the BK channel activator isopimaric acid preserved myelination after spinal cord injury in rats50, where functionality correlated with preserved myelinated tracts. This suggests that a BK channel activator could target demyelination to preserve functionality in MS.\n\nOnly a few BK channel activators have been studied in the clinic, BMS-204352 (Maxipost) was developed for stroke while andolast is reported to be in phase III for asthma128,129. Unoprostone isopropyl is an atypical prostanoid used topically in the treatment of glaucoma130. VSN16R was recently trialled in people with MS for muscle spasticity116,131,132. This trial focussed on spasticity endpoints up to a week after administration of the drug and no remyelination parameters were studied132.\n\n\nConclusion\n\nThere are numerous ways excessive glutamate may cause oligodendrocytes toxicity in demyelinating pathology. Neuroinflammation increases neuronal signalling which will damage neurons, that will release even more glutamate. The vicious cycle of damage by oxidative stress to cellular metabolism will exacerbate pathology. Close proximity to neurons, glutamatergic receptor expression and high vulnerability to oxidative stress makes oligodendrocytes particularly susceptible to excitotoxicity compared to other lesion tissue61,62. Oligodendrocytes perivascular location, as part of white matter, further increases this susceptibility, especially in MS where neuroinflammatory oxidative stress is central to demyelination.\n\nBK channels can modulate cellular excitability and are even proposed to protect cells from release of excessive levels of excitatory neurotransmitters, by pairing with ionotropic glutamate receptors and VGCCs. It is plausible that BK channels could protect oligodendrocytes from excitotoxicity, supported by their expression in these cells118. With high levels of glutamate BK channels become inactivated, possibly explaining their inability to protect cells in models of demyelination50. It is therefore feasible that BK channel activators might protect pathological oligodendrocytes from excitotoxic stress. Considering oligodendrocytes primary function is axon myelination, then if BK channels preserve oligodendrocytes integrity myelination would also be preserved.\n\nThere is still little evidence of the functions of BK channels on oligodendrocytes and the involvement of BK channels in MS is an angle of research that has yet to be explored extensively. Therefore, in vitro tests are fundamental to establish a first functional link between BK channels, oligodendrocytes, oxidative stress and myelin production, to verify the importance of conducting these investigations and possibly prompt more. Crucially, it is important to determine whether BK channels are expressed by oligodendrocytes, whether this expression depends on developmental stage, but also effects of glutamate-induced excitotoxicity in the context of myelination and the ability to target BK channels in vivo. This would define whether increasing the open conformation of BK channels with activating agents is a promising neuroprotective therapy to be used in parallel to immunosuppressive agents for the treatment of MS.\n\n\nAbbreviations\n\nADCC: antibody- dependent cellular cytotoxicity\n\nAMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor\n\nAP: action potential\n\nAPC: antigen presenting cell\n\nATP: adenosine triphosphate\n\nBBB: blood brain barrier\n\nBK: big conductance Ca2+ activated K+ (channel)\n\nCD: cluster of differentiation\n\nCNP: 2',3'-cyclic nucleotide 3'-phosphodiesterase\n\nCNS: central nervous system\n\nCSF: cerebrospinal fluid\n\nCx: connexin\n\nDMEM: modified minimal essential medium\n\nDMT: disease modifying therapy\n\nDNA: deoxyribonucleic acid\n\nEAE: experimental autoimmune encephalomyelitis\n\nERK: extracellular-signal regulated kinase\n\nFBS: foetal bovine serum\n\nGABA: gamma-aminobutyric acid\n\nGAPDH: glyceraldehyde 3-phosphate dehydrogenase\n\nGFAP: glial fibrillary acidic protein\n\nGLUT1: glucose transporter 1\n\nGM-CSF: granulocyte- macrophage colony stimulating factor\n\nIFNγ: interferon gamma\n\nIgG: immunoglobulin G\n\nIL: interleukin\n\nKCNM: Ca2+-activated-K+ channel subunit\n\nKir: inward rectifying K+ channel\n\nKO: knockout\n\nKv1: voltage gated K+ channel\n\nMAG: myelin- associated glycoprotein\n\nMAPK: mitogen- activated protein kinase\n\nMBP: myelin basic protein\n\nMCT: monocarboxylate transporter\n\nMDA: malondialdehyde\n\nMOG: myelin oligodendrocyte glycoprotein\n\nMRI: magnetic resonance imaging\n\nMS: multiple sclerosis\n\nNav1: voltage gated Na+ channel\n\nNFκB: nuclear factor kappa-light-chain-enhancer of activated B cells\n\nNMDA(R): N-methyl-D-aspartate (receptor)\n\nOPC: oligodendrocyte progenitor cell\n\nPBS: phosphate-buffered saline\n\nqPCR: quantitative polymerase chain reaction\n\nRNS: reactive nitrogen species\n\nROS: reactive oxygen species\n\nRRMS: relapsing- remitting multiple sclerosis\n\nSPMS: secondary progressive multiple sclerosis\n\nSTREX: stress-axis regulated exon\n\nTBARs: thiobarbituric acid reactive substance assay\n\nTh: T helper (cell)\n\nTNFα: tumour necrosis factor alpha\n\nTNFβ: tumour necrosis factor beta\n\nTRP: transient receptor potential (channel)\n\nVGCC: voltage gated Ca2+ channel\n\n4-AP: 4-aminopyrimidine\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\nRaffaelli G, Saviane C, Mohajerani MH, et al.: BK potassium channels control transmitter release at CA3-CA3 synapses in the rat hippocampus. J Physiol. 2004; 557(1): 147–57. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFon EA, Edwards RH: Molecular mechanisms of neurotransmitter release. Muscle Nerve. 2001; 24(5): 581–601. PubMed Abstract | Publisher Full Text\n\nSamengo I, Currò D, Barrese V, et al.: Large conductance calcium-activated potassium channels: Their expression and modulation of glutamate release from nerve terminals isolated from rat trigeminal caudal nucleus and cerebral cortex. Neurochem Res. 2014; 39(5): 901–10. PubMed Abstract | Publisher Full Text\n\nLiao Y, Kristiansen AM, Oksvold CP, et al.: Neuronal Ca2+-activated K+ channels limit brain infarction and promote survival. PLoS One. 2010; 5(12): e15601. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHu H, Shao LR, Chavoshy S, et al.: Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release. J Neurosci. 2001; 21(24): 9585–97. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMancini M, Soldovieri MV, Gessner G, et al.: Calcium-Activated Potassium Channels in Leptin-. 2015; 80–6.\n\nBaker D, Pryce G, Visintin C, et al.: Big conductance calcium-activated potassium channel openers control spasticity without sedation. Br J Pharmacol. 2017; 174(16): 2662–81. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJäkel S, Agirre E, Mendanha Falcão A, et al.: Altered human oligodendrocyte heterogeneity in multiple sclerosis. Nature. 2019; 566(7745): 543–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nButtigieg J, Eftekharpour E, Karimi-Abdolrezaee S, et al.: Molecular and electrophysiological evidence for the expression of BK channels in oligodendroglial precursor cells. Eur J Neurosci. 2011; 34(4): 538–47. PubMed Abstract | Publisher Full Text\n\nKrasnow AM, Attwell D: NMDA Receptors: Power Switches for Oligodendrocytes. Neuron. 2016; 91(1): 3–5. PubMed Abstract | Publisher Full Text\n\nLarson VA, Zhang Y, Bergles DE: Electrophysiological properties of NG2(+) cells: Matching physiological studies with gene expression profiles. Brain Res. 2016; 1638(Pt B): 138–60. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBalderas E, Zhang J, Stefani E, et al.: Mitochondrial BKCa channel. Front Physiol. 2015; 6: 104. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKáradóttir R, Cavelier P, Bergersen LH, et al.: NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature. 2005; 438(7071): 1162–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang J, Guan X, Li Q, et al.: Glutamate-activated BK channel complexes formed with NMDA receptors. Proc Natl Acad Sci U S A. 2018; 115(38): E9006–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNeusch C, Rozengurt N, Jacobs RE, et al.: Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001; 21(15): 5429–38. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYe H, Buttigieg J, Wan Y, et al.: Expression and functional role of BK channels in chronically injured spinal cord white matter. Neurobiol Dis. 2012; 47(2): 225–36. PubMed Abstract | Publisher Full Text\n\nFalcão AM, van Bruggen D, Marques S, et al.: Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis. Nat Med. 2018; 24(12): 1837–44. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang Y, Chen K, Sloan SA, et al.: An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34(36): 11929–47. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJensen BS: BMS-204352: A potassium channel opener developed for the treatment of stroke. CNS Drug Rev. 2002; 8(4): 353–60. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMalerba M, Amato MD, Radaeli A, et al.: Efficacy of Andolast in Mild to Moderate Asthma: A Randomized, Controlled, Double-Blind Multicenter Study (The Andast Trial). Curr Pharm Des. 2015; 21(26): 3835–43. PubMed Abstract | Publisher Full Text\n\nCuppoletti J, Malinowska DH, Tewari KP, et al.: Unoprostone isopropyl and metabolite M1 activate BK channels and prevent ET-1-induced [Ca2+]i increases in human trabecular meshwork and smooth muscle. Invest Ophthalmol Vis Sci. 2012; 53(9): 5178–89. PubMed Abstract | Publisher Full Text\n\nTabatabaee S, Baker D, Selwood DL, et al.: The cannabinoid-like compound, vsn16r, acts on large conductance, ca 2+-activated k + channels to modulate hippocampal ca1 pyramidal neuron firing. Pharmaceuticals (Basel). 2019; 12(3): 104. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFarrell RA, Selwood DL, Baker D: Results from a phase II proof of concept trial of VSN16R to treat multiple sclerosis related spasticity. 2018. Reference Source"
}
|
[
{
"id": "91531",
"date": "26 Aug 2021",
"name": "Enrique Balderas-Angeles",
"expertise": [
"Reviewer Expertise MaxiK",
"BK",
"mitochondrial ion channels",
"cardiac disorders",
"cardiovascular disease",
"vascular tone",
"immunotherapy",
"Ca2+ handling",
"ROS",
"cellular volume",
"cell death."
],
"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\nIs the topic of the review discussed comprehensively in the context of the current literature?\nIn the review by Rupnik et al., the role of excitotoxicity in oligodendrocytes was approached through a physiological, clinical, and biophysical perspective, which allows the reader to understand the basics on the origin, progression, and possible therapies for diseases associated with demyelination.\nAre all factual statements correct and adequately supported by citations?\nIn the manuscript by Rupnik et al., the statements were adequately supported by citations which included some classic works (Hursh, 19391; Waxman et al., 19772; Waxman et al., 19843) and articles published in the last ten years.\nIs the review written in accessible language?\nThe review was written fluently, clearly and the topics were discussed deeply enough. The structure of the paper was clearly defined at the beginning of the text (page 3).\nAre the conclusions drawn appropriate in the context of the current research literature?\nThe authors summarized the causes and effects of oligodendrocytes toxicity and proposed an alternative therapy to treat pathologies associated with demyelination. One strategy involves modulation of the large conductance, Ca2+ and voltage-activated BKCa channel, which activation might prevent Ca2+ overload to protect oligodendrocytes from excitotoxic stress. Of note, a similar mechanism has been observed in cardiac mitochondria in rodents, where the BKCa channel expresses and its activation reduces the driving force for Ca2+, preventing overload and cell death (Singh et al., 20134; Balderas et al., 20195). Moreover, as observed in cardiac mitochondria, the functional association of mitoBKCa with regulatory subunits β1 broadens the spectrum of molecular targets suitable for the development of new and more directed therapies.\n\nTargeting the pore forming BKCa channel α-subunit with current and novel drugs needs to overcome the broad localization of the channel in brain cells. Considering that BKCa is expressed ubiquitously in brain cells it is essential to establish the differential and perhaps localized expression of BKCa channels and/or its regulatory subunits (β1-4; γ1-4) in oligodendrocytes. This would allow designing a more specific therapy alternative to immunosuppressive agents.\n\nIn summary, the review presented by Rupnik and coworkers represents a good collection of most recent information in the field of oligodendrocytes and the pathologies associated with demyelination, highlighting a possible role of the BKCa channel in preventing Ca2+ overload and reducing excitotoxic stress. Our main suggestion would be to include a comment on the importance of the expression and association with BKCa-regulatory subunits and their possible use as novel targets for future therapies.\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": "7305",
"date": "13 Oct 2021",
"name": "David Selwood",
"role": "Author Response",
"response": "Response to Enrique Balderas-Angeles, and Veronica Loyo-Celis, We thank the reviewers for their careful reading of the manuscript and useful comments and respond below. A new paragraph expressing some of these points will be added to the final manuscript. Based on the reviewed evidence, there is an association of BK channel subunits with disease. BK channel activation is neuroprotective in animal models of spinal cord injury, ischaemia, and excitotoxic stress (50, 113, 115, 125), which share some pathological similarities with MS. This is confirmed by allele knockout or blockage with the antagonist's iberiotoxin and/ or paxilline that exacerbated injury (113, 115). The agonist isopimaric acid targeted the α subunit to improve motor function in rats with spinal cord injury (50). Similarly, NS1619 activated subunit α1 to effectively increase neuroprotection in rat and mouse cortex when used with leptin (115). Certain subunits may only be activated and therefore effectively targeted in the presence of cellular injury or excitotoxic conditions (114, 125), a quality which could arguably improve the specificity of an agent to injured tissue. However, these studies focused on neuron expression of BK channels and axon rather than oligodendrocyte integrity as an outcome. In clinical trials, BMS-204352 activates KCNMA1 also activates another potassium channel KCNQ. This was trialed as a safer neuroprotective agent to reduce intracellular Ca2+ levels in acute ischaemic stroke but did not significantly improve the outcome in this study (128). Andolast has been shown to significantly improve asthma symptoms compared to placebo, but its subunit targets have not yet been investigated (129). The anti-glaucoma agent unoprostone isopropyl activated iberiotoxin resistant BK channels, therefore likely successfully targeted the β2, or β3, subunits (130). The β regulatory subunit is generally quite tissue-specific and therefore arguably a better target for an agonist than the α- subunit (121). In the CNS, KCNMB4 and KCNMB2 are the main regulatory subunits expressed (131). VSN16R, which is thought to target preferentially the β4 subunit, has shown promise in reducing spasticity at higher doses with few side effects (131, 132). Notably, KCNMB4 is expressed in human mature oligodendrocytes (figure 3) and is possibly more abundant in chronic inactive MS lesions (117). Evidence is needed to ascertain whether an agonist to KCNMB4, or to another regulatory subunit, changes outcome in MS pathogenesis by targeting oligodendrocytes and by preserving myelin. Recently Fragile X syndrome the major genetic cause of intellectual disability has been shown to have a demyelinating component. BK channel activation (specifically alpha1beta4) has been shown to restore both electrophysiological and behavioural functions in experimental Fragile X. A clinical evaluation should examine if remyelination is a component of the response to BK activator therapy."
}
]
},
{
"id": "94510",
"date": "27 Sep 2021",
"name": "Wensheng Lin",
"expertise": [
"Reviewer Expertise oligodendrocyte biology and pathology"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis review summarizes the current literature on the role of excitotoxic stress, myelination, and BK channels in MS pathology. The topic is timely and important. The manuscript is well written. However, there are a couple of concerns:\nThe authors stated that \"preserving myelin might provide a better neuroprotective strategy than remyelination\". In fact, this manuscript concentrates on demyelination, rather than remyelination. It could be better to replace remyelination with demyelination in the title.\n\nThis manuscript concentrates on demyelination, particularly in MS. It is important to summarize the current literature on mechanisms governing mature oligodendrocyte viability in MS and its animal models. Recent studies demonstrate the critical roles of PERK, NF-kB, among other signaling pathways in modulating oligodendrocyte viability and demyelination in MS and its animal models. These studies should be cited and discussed.\n\nIs the topic of the review discussed comprehensively in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nIs the review written in accessible language? Yes\n\nAre the conclusions drawn appropriate in the context of the current research literature? Yes",
"responses": [
{
"c_id": "7376",
"date": "15 Nov 2021",
"name": "David Selwood",
"role": "Author Response",
"response": "We would like to thank Prof Lin for his careful reading of the manuscript and useful comments. Pt 1. The reviewer asks if replacing “remyelination” with “demyelination” in the title would be more reflective of the review. The reviewer is correct in ascribing much of the review subject to demyelination, however, using “demyelination” in the title would make an association of demyelination with BK channels that would not be correct and we would not wish to do this. We think the modified title “Oligodendrocytes, BK channels and the preservation of myelin” could be a better reflection of the subject and aims of the review. Pt 2. It is important to consider other targets that may protect mature oligodendrocytes from demyelinating pathologies like multiple sclerosis. This is to establish whether BK channel activators could be a valid alternative or complement existing approaches. Another strategy could modulate the unfolded protein response (UPR) to preserve cell viability during periods of endoplasmic reticulum stress, like those caused by excessive inflammation, by temporarily halting translation to attempt re-establishing protein homeostasis. We will insert the text below into the final version of the manuscript. Pancreatic endoplasmic reticulum kinase (PERK) is implicated in this. Increasing PERK activation in mouse models of MS protected myelin, in the presence of MS- related cytokine interferon- γ (133). This even improved survival of remyelinating oligodendrocytes and recovery in demyelinated lesions (133). A later study indicated that the PERK protective pathway can be enhanced by nuclear factor κB (NFκB) activation (134). Oligodendrocytes were rescued only in mice with MOG- induced EAE and PERK gene deficiency, whilst healthy oligodendrocytes remained unaffected (134). This might indicate this UPR signalling pathway specifically protects from inflammatory and demyelinating pathology. Studies have replicated these cytoprotective effects, but also indicated the need for targeted activation of NFkB (135, 136, 134). Excessive generalised activation may worsen inflammation by dysregulating immunity and promoting autoimmune reactions, possibly leading to adverse effects (137). Alternatively, the leukaemia inhibitory factor (LIF), of the IL-6 cytokine family, was also proposed to protect mature oligodendrocytes from demyelination. Its levels determine growth and differentiation of inflammatory cells, but also possibly neural cells. Exogenous LIF protected against demyelination in cuprizone induced mouse models of MS with knockout endogenous LIF (138). Since cuprizone is toxic to oligodendrocytes but does not elicit an inflammatory response as seen in the EAE model, the authors indicated this method is directly cytoprotective (138). However, some studies suggest its activation might lead to negative effects on neuroinflammation, and state limited ability to cross the BBB when administered therapeutically; although its delivery and effectiveness significantly improved when using lentiviral vectors for CNS- specific expression in murine models (139, 138). Similarly, agents aimed at attenuating the inflammation were also discovered to have independent neuroprotective effects which can lead to reduced demyelination. For example repurposing the antibiotic minocycline, which is thought to enhance anti-apoptotic signalling and was combined with atorvastatin to achieve an enhanced reduction in EAE severity (140). In a randomised controlled trial, taking minocycline within the first 6 months of the clinically isolated syndrome significantly decreased the risk of developing MS but not after two years, which may suggest a delaying instead of disease- modifying effect (141). Finally, in the MS lesion microenvironment, the excessive inflammation and failure of energy metabolism may lead to acidosis and subsequent activation of acid sensing ion channels (ASICs), which were found upregulated in both axons and oligodendrocytes in active MS lesions (142). These proton gated cation channels are activated in similar conditions of excitotoxicity as the BK channel. Amiloride or psalmotoxin-1, blocking respectively ASICs or ASIC1, protected oligodendrocytes from injury related to this acidosis, and the EAE mouse model with knockout ASIC1 had increased levels of myelin immunostaining compared to wild type (142). References: 133. Lin, Y., Huang, G., Jamison, S. & Li, J. et al. (2014) PERK Activation Preserves the Viability and Function of Remyelinating Oligodendrocytes in Immune-Mediated Demyelinating Diseases. The American Journal of Pathology. [Online] 184 (2), 507-519. Available from: doi:10.1016/j.ajpath.2013.10.009. 134. Lei, Z., Yue, Y., Stone, S. & Wu, S. et al. (2020) NF-κB Activation Accounts for the Cytoprotective Effects of PERK Activation on Oligodendrocytes during EAE. The Journal of Neuroscience. [Online] 40 (33), 6444-6456. Available from: doi:10.1523/jneurosci.1156-20.2020. 135. Stone, S., Jamison, S., Yue, Y. & Durose, W. et al. (2017) NF-κB Activation Protects Oligodendrocytes against Inflammation. The Journal of Neuroscience. [Online] 37 (38), 9332-9344. Available from: doi:10.1523/jneurosci.1608-17.2017. 136. Tanner, D., Campbell, A., O'Banion, K. & Noble, M. et al. (2015) cFLIP is critical for oligodendrocyte protection from inflammation. Cell Death & Differentiation. [Online] 22 (9), 1489-1501. Available from: doi:10.1038/cdd.2014.237. 137. Ellrichmann, G., Thöne, J., Lee, D. & Rupec, R. et al. (2012) Constitutive activity of NF-kappa B in myeloid cells drives pathogenicity of monocytes and macrophages during autoimmune neuroinflammation. Journal of Neuroinflammation. [Online] 9 (1). Available from: doi:10.1186/1742-2094-9-15. 138. Marriott, M., Emery, B., Cate, H. & Binder, M. et al. (2008) Leukemia inhibitory factor signaling modulates both central nervous system demyelination and myelin repair. Glia. [Online] 56 (6), 686-698. Available from: doi:10.1002/glia.20646. 139. Slaets, H., Hendriks, J., Van den Haute, C. & Coun, F. et al. (2010) CNS-targeted LIF Expression Improves Therapeutic Efficacy and Limits Autoimmune-mediated Demyelination in a Model of Multiple Sclerosis. Molecular Therapy. [Online] 18 (4), 684-691. Available from: doi:10.1038/mt.2009.311. 140. Luccarini, I., Ballerini, C., Biagioli, T. & Biamonte, F. et al. (2008) Combined treatment with atorvastatin and minocycline suppresses severity of EAE. Experimental Neurology. [Online] 211 (1), 214-226. Available from: doi:10.1016/j.expneurol.2008.01.022. 141. Metz, L., Li, D., Traboulsee, A. & Duquette, P. et al. (2017) Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. New England Journal of Medicine. [Online] 376 (22), 2122-2133. Available from: doi:10.1056/nejmoa1608889. 142. Vergo, S., Craner, M., Etzensperger, R. & Attfield, K. et al. (2011) Acid-sensing ion channel 1 is involved in both axonal injury and demyelination in multiple sclerosis and its animal model. Brain. [Online] 134 (2), 571-584. Available from: doi:10.1093/brain/awq337."
}
]
}
] | 1
|
https://f1000research.com/articles/10-781
|
https://f1000research.com/articles/10-1155/v1
|
15 Nov 21
|
{
"type": "Research Article",
"title": "An examination of determinants for e-wallet adoption in Malaysia: a combined approach",
"authors": [
"Thai Siew Bee",
"Kuwa Yan Ying",
"Kuwa Yan Ying"
],
"abstract": "Background: In this era of innovation in information technology, everything is embedded with technology, and the financial sector is no exception. The term “FinTech” (Financial Services Technology Consortium) attracted the attention of regulators, consumers and investors in 2014. It was initially applied to the back-end systems of financial and banking institutions. However, Fintech has now become more consumer-oriented, as the combination of financial services and information technology. Specifically, it refers to financial services for consumers through technology. The e-wallet is one of the examples of FinTech in payments and infrastructure that can be freely adopted by everyone. However, the penetration of e-wallet usage in Malaysia is still in its early stages compared to other countries. Methods: The aim of this research is to examine the factors that affect the adoption of e-wallets in Malaysia based on five aspects: perceived ease of use, perceived usefulness, perceived risk, social influence and government support. These variables were adopted from the Technology Acceptance Model (TAM) and Theory of Reasoned Action (TRA). Questionnaires were given to a targeted group of 100 e-wallet users in Malaysia using the convenient sampling method. The contribution of each factor in explaining the adoption of e-wallets was analyzed using multiple regression. Results: The results show that social influence has a significant relationship with the adoption of e-wallets in Malaysia: the majority of the respondents are at their prime age and their behaviours tend to be influenced by the reference group. The results from this study may encourage more small and medium enterprises (SMEs) in Malaysia to provide e-wallet payment options, transforming their conventional business into a digital business and spurring the growth of the digital economy in Malaysia. Conclusions: High levels of adoption of e-wallets moves a country towards a cashless society, resulting in better economic growth and environment.",
"keywords": [
"E-wallet",
"Fintech",
"digital business",
"digital economy"
],
"content": "Introduction\n\nIn this era of innovation in information technology (IT), everything is embedded with technology, and the financial sector is no exception. The term FinTech, short for “Financial Services Technology Consortium”, originated in the late 19th century. According to Arner, Barberis, & Buckley (2015), “FinTech is a project initiated by Citigroup to facilitate technological cooperation”. It only attracted the focused attention of regulators, consumers and investors from 2014 onwards. Fintech was initially applied at the back-end systems of financial and banking institutions, but has now become more consumer-oriented. It can be defined as the combination of financial services and IT. Specifically, FinTech provides financial services for consumers through technology (e.g. software, algorithms, apps) and covers anything from cryptocurrency to mobile wallet apps.\n\nThe evolution of Fintech started in 1886. The first era of FinTech (1886-1967) was focused on infrastructure; the key element is computerization and it remained largely an analogue industry. The development of digital technology in the area of communications and processing of transactions happened from 1967-2008, which was known as FinTech 2.0. This development increasingly transformed finance from an analogue to a digital industry. The launch of ATMs and calculators in 1967 is a strong indicator that marked the beginning of FinTech 2.0 (Arner, Barberis, & Buckley, 2015).\n\nThroughout the 1980s, financial institutions increased the use of IT and gradually replaced most forms of paper-based mechanisms, as computerization proceeded and risk management technology developed to manage internal risks. Bloomberg terminals is one example of FinTech Innovation. In 1981, Michael Bloomberg started Innovation Market Solutions (IMS) after leaving Solomon Brothers, where he had designed in-house computer systems (Arner, Barberis, & Buckley, 2015). From that time, usage of Bloomberg systems among financial institutions was in ever-increasing. However, several questions and risks were present. Security issues were major concerns at that time. People were still not familiar with the technology of the finance industry, and risk management techniques were still in the developing and growing stage.\n\nFinTech 3.0 occurs from 2008, up until the present (Arner, Barberis & Buckley, 2015). The general public has now become the main target audience. According to Gergely (2020), the financial crisis of 2008, which left the global financial system on the brink of systemic collapse, can be viewed as another turning point for the industry. Shortly after the financial crisis of 2008, the Basel Committee on Banking Supervision (BCBS) introduced the Third Basel Accord (Basel III) to mitigate risk within the international banking sector. Due to Basel III, people diverted capital from small and medium enterprises (SMEs) and private individuals, and turned to peer to peer (P2P) lending to fulfil their need for credit. This trend has led to a gradual increase in the P2P industry’s revenue from the year 2008 until now. The global P2P lending market generated $67.9 billion in 2019, and is estimated to reach $558.9 billion by 2027, registering a compound annual growth rate (CAGR) of 29.7% from 2020 to 2027 (Utami & Ekaputra, 2021),\n\nMobile payment is integral to people’s life nowadays, especially during the coronavirus disease (COVID-19) pandemic where contactless payment is encouraged. The e-wallet has become an important component for entrepreneurs and small and medium enterprises (SMEs) in digitalizing their payment avenues and connecting better with their consumers. The move towards cashless methods has incentivized businesses to accept digital payments. However, mobile payment is still not being used by everyone in Malaysia, even though technology and payment solutions exist. This study aims to determine the factors that affect the adoption of e-wallets (AEW) in Malaysia. It is vital for e-wallet service providers to understand people's (lack of) acceptance towards mobile payment, as customer participation and usage is the key to success.\n\nWhile e-wallets are widely adopted in many countries, a previous study showed that the intention to use e-wallets was quite low in Malaysia (Mun, Khalid & Nadarajah, 2017). The primary goals of the current research are to investigate the current prevalence of E-wallet use in Malaysia, and the factors that affect AEW. The findings of this study may provide helpful information on user acceptance and the market prospects of e-wallet payment methods in Malaysia today, and help E-wallet providers to modify their business strategy in order to increase user usage and reduce turnover rate. Moreover, companies that are interested in mobile wallet services can use this paper as reference information during the product planning stage.\n\nImportantly, this research may be beneficial to policy-makers and government agencies planning to implement new initiatives. Looking forward to a move to a cashless society, the Malaysian government has launched a few initiatives to promote mobile payment. However, due to people’s general reluctance to change, the uptake of mobile payment in the country lags quite far behind by some measurements, and the 2020 timeframe seems unlikely. Thus, it becomes sustainable important to have a clear understanding of the factors that affect people's intention toward mobile payment (e-wallet) adoption (Chwah, Goh, Lim, Tai & Tan, 2018).\n\nMobile wallets provide many benefits to Malaysia’s citizens, such as time-saving, convenience, and security. However, the intention to use e-wallets was found to be low in Malaysia (Mun, Khalid & Nadarajah, 2017). Even though e-wallet adoption in Malaysia is showing an upward trend, it is still believed to be low compared to other countries such as China. In the current study, AEW would be the dependent variable, whereas the independent variables are: perceived ease of use, perceived usefulness, perceived risk, social influence, and government support.\n\nAEW\n\nE-wallets (digital wallets) allow users to make transactions through mobile devices. E-wallet payment is viewed as one of the most important transaction methods for the time being. This is due to the advantages of ease, flexibility and protection when using digital wallet in an electronic transaction (Uddin & Akhi, 2014). It is the latest contactless payment method besides credit cards. The digital wallet is in fact an example of FinTech. According to Osakwe and Okeke (2016), e-wallets are also known for their innovative advantages such as customization and instantaneous communication. By using e-wallets, the purchase process can be done easily and quickly with Near-Field Communications (NFC) supported devices. In addition to buyers, the traders/sellers also benefit from this method of payment. A high speed transaction process, effective cash management and less labor charges are the advantages for sellers (Hayashi & Bradford, 2014). E-wallets can be utilised in physical stores by using NFC-enabled devices (e.g. mobile phones) to scan the quick response (QR) code provided by traders (Lu, 2018). As the country is currently moving towards a cashless nation, mobile payments (e-wallets) have been adopted at retail stores, supermarkets, food-courts and even food kiosks along the roadside.\n\nAEW has seen a sharp uptake in Malaysia in 2020 during the COVID-19 pandemic, where contactless payment methods are encouraged by the World Health Organization (WHO) and Kementerian Kesihatan Malaysia (KKM). Malaysians have become markedly responsive towards going cashless with a more favorable reception to the idea, since such a payment method is not only expedient, but can also prevent the spread of the virus. Maybank also reported a sharp increase in the usage of the Maybank e-wallet. The policy-maker (bank) has temporarily relinquished transaction fees to boost and promote contactless payments. Moreover, GrabPay Malaysia also announced that, since the Malaysia movement control order (MCO) in 2020, the adoption of the GrabPay e-wallet has increased 1.7 times.\n\nPerceived ease of use (PEU)\n\nPerceived ease of use is an important factor that influences users in adopting information systems, especially in the technology industry. The Technology Acceptance Model (TAM), developed by Fred Davis in 1989, is one of the most popular research models used to predict the use and acceptance of information systems and technology by individual users. According to Davis (1989), perceived ease of use is defined as “the degree to which a person believes that using the system would be free of effort”. Venkatesh (2003) listed PEU under an effort expectancy category, which refers to the perceived difficulty in using a system.\n\nBased on the Theory of Reasoned Action (TRA), PEU is associated with availability, and influenced by external factors such as users’ attitude, use instruction, system attributes, training, and user consultants. Although TRA does not state the functioning viewpoints for a specific behaviour, it is however the prior theory, and TAM is an influential extension of TRA. The intention to use technology is positively and significantly influenced by perceived ease of use (Jackson, Chow & Leitch, 1997). Therefore, it can be argued that PEU influences user adoption of IT.\n\nKim et al. (2016) suggested that perceived ease of use significantly influences the consumer’s acceptance of IT, and this is supported by various studies. Rigopoulos and Askounis (2007) showed that PEU has a significant indirect positive relationship with electronic payment. However, Cao (2016) reported that PEU is more appropriately considered as a factor in the early adoption stage of a technology or system. Meanwhile, Al-Maroof and Al-Emran (2018) showed that undergraduate students perceive technology (e.g. e-learning) as user-friendly. In sum, PEU has a positive influence on perceived usefulness and behavioral intention.\n\nPerceived usefulness (PU)\n\nAccording to Davis (1989), PU refers to the degree to which a person believes that using a particular system will enhance job performance. In previous studies, some scholars categorized PU as performance expectancy: the extent in which an individual believes that the system is beneficial to them and increases job performance (Venkatesh, 2003).\n\nThe TAM proposed that PU is the main factor that greatly influences the acceptance of new technologies. PU is hypothesized to have a direct relationship with behavioral intention in using technology (Park et al., 2014). Specifically, prior studies found that there is a positive relationship between PU and people’s intention to use e-wallets (Nag and Gilitwala, 2019), e-books (Baker-Eveleth and Stone, 2015), and e-learning platforms (Lin and Wang, 2012). The PU of e-wallets can be described as the efficiency, effectiveness and usefulness of e-wallet as perceived by users. When the system (e.g. e-wallets) is useful and effective to use, people’s intention towards adopting it will increase. Compared to carrying a lot of cash or payment cards, e-wallet users just need to carry a phone and the payment process can be done in a few seconds without physical contact. With e-wallets, users can conduct payment processes in the shortest time by just scanning QR codes. This convenience and usefulness encourage its adoption (Cao, 2016). Although a range of studies found that PU is associated with technology adoption, there are contradictory findings: Wang (2008) proposed that PU is not a significant contribution towards the intention to adopt online payment.\n\nPerceived risk (PR)\n\nIn the process of accepting new technologies or virtual services (e.g. mobile payment services), a main consideration is risk. People are always concerned about security issues in technology-related services, especially involving finance, and this is termed “perceived risk” (Zhou, 2011). Bauer (1960) described perceived risk as uncertainty and the opposed outcome derives from using the new technology, which contradicts the consumers’ expectations. It reflects the user's insight about ambiguous outcomes relating mainly to searching product- or services-related information before making any purchasing decision (Cox, 1967). PR could also refer to uncertainty about potential negative outcomes associated with adopting or purchasing financial technology products (Thakur & Srivastava, 2014). In addition, PR may also refer to privacy and financial concerns related to the adoption of FinTech services (e.g. e-wallets).\n\nFinancial risk is a type of danger that can result in the loss of capital for interested parties. For example, people worry if it is safe for them to put money in their e-wallet. What if the money in the e-wallet is lost? Moreover, privacy risk concerns the disclosure of transaction data, personal data (e.g. phone numbers, home address, identification numbers) and other private information. FinTech services comprise of technologies such as big data, the internet of things, and cloud computing. Receiving and using such services all involve risks. Specifically, when users register to use e-wallets or adopt any FinTech services, they need to provide their personal information to complete the registration process.\n\nAccording to Thakur and Srivastava (2014), there is a negative relationship between PR and adoption of mobile payment services, a finding supported by various other studies (Shin, 2010; Lu et al., 2011; Yang et al., 2012; Liébana-Cabanillas et al., 2015; Slade, Dwivedi, Piercy and Williams, 2015). Perceived risk is believed to be a major factor that brings a negative impact to the adoption of technology-related services (Khedmatgozar and Shahnazi, 2018).\n\nUsers are often worried about the possibility of misuse or exposure of their private information when they talk about adoption of technologies (e.g. e-commerce, e-wallets, and mobile banking), which could lead to serious consequences (e.g. cybercrime). These considerations significantly affect the user’s willingness to accept and adopt e-wallets (Bansal et al., 2010).\n\nSocial influence (SI)\n\nSI is another important factor affecting the adoption of FinTech services such as E-wallet. According to Venkatesh, Morris, Davis and Davis (2003), social influence refers to the degree in which an individual believes that “important others” think that he/she should adopt a new technology. In this new digital and social media era, people rely heavily on social communication. People can easily get feedback and comments from friends or even strangers through social media. People can easily observe behaviors of others, and thereby influencing each other. Indeed, friends or people in the user’s surroundings influence users’ decisions in adopting a new technology such as e-wallets (Nysveen et al., 2005b).\n\nEvery individual has someone around influencing their buying decisions. Key social factors include reference groups, family, role and status (Perreau, 2014). The reference group allows consumers to compare their behavior, lifestyle or habits. Reference groups comprise of anybody from close friends, family, neighbors, work groups; to other people that the consumers are attached with. People’s intention towards AEW (Yang, Lu, Gupta, Cao & Zhang, 2012; Lee, Murphy, & Swilley, 2009; Lu, Liu, Yu, & Wang, 2008; Miao & Jayakar 2016) and e-payments (Slade, Williams, Dwivedi & Piercy, 2015) are both affected by social influences.\n\nGovernment support (GS)\n\nIn Malaysia, government support is one of the main determinants for FinTech acceptance. The government can act as a guarantee and can increase the credibility of products and services. The government, acting as the regulator, has a key responsibility in mitigating any possible undesirable outcomes encountered by its people. According to Kiwanuka (2015), government support positively affects technological adoption and continuous-use intention. Government support is important to the confidence towards FinTech services, especially mobile payment services in Malaysia (Marakarkandy, Yajnik & Dasgupta, 2017).\n\nGovernments can show their support by providing network infrastructure, guarantees in electronic payment, data access and digital incentives (allowance). Malaysia and the rest of the world is currently facing the COVID-19 pandemic. The WHO has advised the public to adopt cashless transactions (e.g. e-wallet) to minimize physical interaction. Thus, the encouragement from the government in using e-wallet for payment transactions is useful in the fight against SARS-Cov2 transmission. Such government advisory may motivate people in the country to use e-wallet (Aji, Berakon & Husin, 2020). In Malaysia, governments show their support directly by increasing the publicity for e-wallet applications, and by providing digital incentives to the public, hoping that users of e-wallets can reach 15 million. A positive relationship is expected between government support and intention to use e-wallets.\n\n\nMethods\n\nBased on the literature review, the theoretical framework (as shown in Figure 1) and the hypotheses have been formulated as follows:\n\n\n\nThere is a significant positive relationship between perceived ease of use and adoption of e-wallets.\n\nThere is a significant positive relationship between perceived usefulness and adoption of e-wallets.\n\nThere is a significant negative relationship between perceived risk and adoption of e-wallets.\n\nThere is a significant positive relationship between social influence and adoption of e-wallets.\n\nThere is a significant positive relationship between government support and adoption of e-wallets.\n\nThe current research aims to assess users’ perception of mobile payment methods (e-wallets) and the factors that affect users’ AEW. The research design utilised convenient sampling: a non-probabilistic sampling technique that collects market research data from a conveniently available pool of respondents. The questionnaires were created via Google Forms to measure “The factors that affect the adoption of E-wallet in Malaysia”. The survey was open to all Malaysian citizens or residents, and not limited to students or employees (Siew Bee, 2021a). The questionnaire consists of two parts: Section A collects the respondent’s demographic and E-wallet usage information, and allows us to identify the most popular e-wallet among the respondents, whereas Section B consists of questions relating to AEW. The current research is a correlational study, examining the relationship between the independent variables (perceived ease of use, perceived usefulness, perceived risk, government support and social influence) and the dependent variable (AEW in Malaysia). The independent variables such as perceived ease of use, perceived usefulness and perceived risk are based on the technology context which was adopted from TAM and TRA, while social influence and government support are based on personal context. The extent of researcher interference was at a minimal level, since the study did not affect the respondent’s normal flow of work. The unit of analysis is the individual: users of e-wallets in Malaysia. The time horizon of the study is cross-sectional. The data was successfully gathered within 2 weeks of the development of the questionnaires (17th January 2021-30th January 2021). This research uses a quantitative approach as the main approach, in which the framework is predetermined from previous works of literature.\n\nThe questionnaire was presented virtually through Google Forms. The Google Forms link was distributed to respondents predominantly via Whatsapp, in addition to Facebook messenger and Wechat. Data collection was completed in 2 weeks, when the number of respondents hit the target of 100. Participation was voluntary, and the survey took only between 5 to 10 minutes to complete. Implied, informed consent was obtained from respondents, as the cover page of the questionnaire stated the objective and the usage of the data from this survey, and responding to the survey was on a voluntary basis.\n\nThe sample population consists of e-wallet users in Malaysia (who use at least one e-wallet application) above the age of 18. A cross-sectional research design was used, where a total targeted sample of 100 were drawn from the population. A non-probabilistic sampling procedure was used for this study (convenient sampling), due to the short project time frame. Respondents filled in the questionnaire after informed consent was obtained.\n\nThe data analysis methods used to test the hypotheses are as followed: descriptive analysis, reliability analysis and Pearson correlation analysis. All these analyses have been run using SPSS version 28. The dependent variable is adoption of e-wallet (AEW). The independent variables comprise of five (5) which are Perceived ease of use (PEU), Perceived usefulness (PU), Perceived risk (PR), Social influence (SI) and Government support (GS). The contributions of each independent variables towards the dependent variable have been examined using the Pearson correlation analysis. Detailed of the results from this analysis are presented in the following sections.\n\nThis article received ethical approval from Multimedia University (EA1052021).\n\n\nResults\n\nTable 1 shows a practically balanced number of male respondents (51%) versus female respondents (49%) (Siew Bee, 2021b).\n\nTable 2 shows that an age of 18-25 years old is the most common among the respondents at 36%, followed by the age of 26-35 years old at 33%, the age of 36-45 years old at 14%, the age of 46-55 years old at 11%, and the age of above 55 years old at 6%.\n\nAs shown in Table 3, race is classified into four categories: Chinese, Malay, Indian and Others. Based on the above data, the majority of respondents are Chinese at 44%, followed by Malay at 29%, Indian at 26% and Others at 1%.\n\nAs shown in Table 4, most of the respondents are bachelor’s degree holders at 53%, followed by 15% with a diploma, 13% with a SPM/O-level, 9% with a master’s degree, 6% with STPM/A-level and 4% with a PhD Degree.\n\nTable 5 shows that the majority of the respondents are employees of private companies (41%) followed by students at 35%, civil servants at 13%, and self-employed at 10%, with only 1% of the respondents classified as other (retired).\n\nTable 6 shows 36% of the respondents earned less than RM 2,000 per month; 28% have income ranging from RM 4,001 to RM 8,000; 20% have income ranging from RM 2,001 to RM 4,000; 10% of the respondents have a monthly income more than RM 10,000; and 6% have income ranging from RM 8,001 to RM 10,000.\n\nFigure 2 shows that the major E-wallet applications available in Malaysia are Touch’n Go, GrabPay, Boost, Wechat Pay MY, BigPay and TransferWise. Overall, 88% of respondents are currently using Touch’n Go, which is the most widely used. GrabPay is the second highest at 55%. Grab services are experiencing an increased demand in Malaysia especially during this COVID-19 pandemic. Meanwhile, Boost usage is at 31%, followed by TransferWise at 13%, and Wechat Pay MY and BigPay both at 7%.\n\nAll mean and standard deviation were generated by using SPSS, where “1 = Strongly Disagree”, “2 = Disagree”, “3 = Neutral”, “4 = Agree”, “5 = Strongly Agree”.\n\nBased on Figure 3 and Table 7, among all the independent variables being analyzed it was found that PEU has the highest mean of 4.362 which shows the greatest influence on intention to adopt e-wallets. This is followed by PU (mean= 4.2425), GS (mean= 4.0425), SI (mean= 3.9775) and PR (mean= 2.196). Meanwhile, the AEW score has a mean of 2.45.\n\nBased on Figure 4, PEU has the lowest standard deviation of 0.7248, followed by SI (S.D.=0.82325), GS (S.D.= 0.82925), PU (S.D.= 0.901) and PR (S.D.= 1.0716).\n\nTable 8 shows the results of the reliability test. The aim of Cronbach’s alpha is to test the internal consistency for dependent and independent variables. For independent variables, PEU has the highest consistency with Cronbach’s alpha of 0.892, followed by PU with 0.884, PR with 0.836, SI with 0.767 and GS with 0.746. The overall Cronbach’s alpha for all variables is 0.897, showing that the model is reliable and there’s a “good” consistency of the results among all variables.\n\nPearson correlation analysis was conducted to identify the correlations between the dependent variable and independent variables (Siew Bee, 2021c).\n\nTable 9 shows the results of Pearson correlation after the analysis was conducted. The results indicate that only SI significantly affects the AEW at p = .012, with a a positive correlation of 0.251. This is followed by GS which shows a nonsignificant positive linear relationship of 0.157; PU which shows a nonsignificant positive correlation of 0.066; PEU has a 0.045 nonsignificant positive relation with AEW. On the other hand, the value of Pearson correlation for AEW with PR is −0.055, which is a nonsignificant negative linear relationship.\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\nAs shown in Table 9, the highest correlation value is 0.251 for SI which is below.9, implying that the effect of multicollinearity is nonsignificant in the regression variate.\n\nA Multiple regression analysis was performed. Table 10 shows that the effect size is rather small at R2 = 0.081. In other words, 8.1% of variance in the AEW can be explained by the five independent variables: PEU, PU, PR, SI and GS. The standard error of the model, 0.690, is also relatively high which indicates that the model’s spread is high, and the sample mean is not close to the population mean.\n\nIn addition, Table 11 indicates that the overall model exhibits a weak fit to data because F-statistic = 1.666 (p = value = 0.151) is not significant at the ɑ=1%, 5%, 10% level.\n\n* = Predictors: (constant), GMGS, GMPR, GMPEU, GMSI, GMPU.\n\nThe variance inflation factor (VIF) measures the impact of collinearity among the variables in a regression model. A VIF closer or equal to 1 means the independent variable is not correlated to the remaining ones, thus there is no multicollinearity existing in the model. Table 12 shows that the VIF for all 5 variables range between 1-5, indicating that all of them are moderately correlated. Therefore, there is a chance multicollinearity exists in the regression model.\n\nFurthermore, the results of multiple regression analysis show that only SI is significant at ɑ= 5% with beta coefficient = 0.282 and p-value of 0.035: a positive relationship with AEW. Therefore, hypothesis H4 is statistically supported while H1, H2, H3 and H5 are rejected.\n\n\nDiscussion\n\nIn this research, PEU and PU were found to have a nonsignificant relationship with AEW in Malaysia, contrary to the assertion of TAM. Moreover, our result contradicts Shankar and Datta (2018), who suggested that PEU and PU have significant influences on mobile payment adoption. In that study, users adopt mobile payment only when they find it easy in comparison with other traditional methods of financial transaction. If the payment process is perceived as uncertain or non-user-friendly for consumers, then the adoption goal will be reduced.\n\nPEU was found to be a nonsignificant contributor to AEW in the current study. This result is similar to Aw, Khalil, Emad and Janejira (2009). One possible explanation is that all respondents have a minimum education level of SPM/O level and the majority of them are millennials, which are believed to be highly tech-savvy. Wu and Wang (2005) proposed that PEU is relevant only when potential users have little or no direct experiences with recent innovations.\n\nPU was found to be nonsignificant in influencing AEW in Malaysia. This finding is supported by Aw, Khalil, Emad and Janejira (2009) and Wang (2008). The relative advantage provided by e-wallet apps may not be prevailing enough to increase the consumer’s intention to use them for their payments. E-wallet payment options are still not widely adopted by shops and stalls in Malaysia. Therefore, the perceived usefulness has less contribution to AEW.\n\nWe found that PR has a negative but nonsignificant relationship with e-wallet adoption. This result contradicts Thakur and Srivastava (2014), but is similar to Teoh, Hoo & Lee (2020) and Kapoor, Dwivedi, and Williams (2014). The majority of the respondents are millennials who tend to try new technology in order to enjoy the benefits of advanced technology, for instance more convenient and efficient methods of paying. Risks associated with the adoption of e-wallets are not taken into consideration when youngsters adopt new technology as convenience is the main key for them.\n\nThis study found that SI has a significant relationship with AEW in Malaysia, which is consistent with the study by Kalafatis et al. (1999). According to the study of Kalafatis et al. (1999), social acts bring internally generated feelings of self-respect or pride, while failure to act in a particular way may invoke the feelings of shame or self-reproach. Indeed, the majority of respondents are in the prime age where their behaviors tend to be affected by reference groups (Slade, Williams, Dwivedi and Piercy, 2015; George, 2004).\n\nRespondents believed that e-wallet providers will act in their best interest, as there is a strong sense of trust towards e-wallets under the backing of the Malaysian government in recent years. However, GS is shown to have a nonsignificant impact on e-wallet adoption in the current study. This contradicts Marakarkandy, Yajnik and Dasgupta (2017), where government support was found to be important in the level of confidence felt towards FinTech services, especially mobile payment services in Malaysia. Despite efforts by the Malaysian government to promote e-wallet applications, government support may still be at an “infancy” stage. Indeed, the e-Tunai Rakyat initiative, which aimed to increase e-wallet use, was only launched rather recently in 2020. More incentives and initiatives by the government may be needed.\n\nA longitudinal study may be beneficial in outlining the changes in consumer’s behaviors and attitudes through time as consumer behaviour may change from time to time and their response might be affected by the pandemic. In addition, respondents in the current study consist only of e-wallet users. Factors such as PEU, PU, PR and GS may have more explanatory power on the non-adoption of e-wallets. Future research may therefore assess attitudes towards these factors among non-E-wallet users.\n\n\nConclusions\n\nE-wallets are increasingly gaining traction among consumers. During the COVID-19 pandemic, in particular, contactless payment is being encouraged by the WHO as the virus can potentially spread through physical banknotes. The current study found that SI significantly influenced AEW in Malaysia. Service providers may therefore capitalize on this factor. Rewarding users for referring others to use the e-wallet apps, is a tactic widely adopted by many e-wallet providers. Importantly, service providers should beware of the word-of-mouth marketing power. They should provide high service quality and efficient customer services to warrant a positive word-of-mouth, specifically among the youth, or risk consumers switching to competitors’ e-wallet apps. The results of the study provide a detailed and clearer way for the banking and government sector to boost the number of users who adopt e-wallets, and helps the government in implementing and moving towards a cashless economy. In addition, the findings from this study may encourage more SMEs in Malaysia to provide e-wallet payment options, transforming their conventional businesses into digital businesses and ultimately spurring the growth of the overall digital economy in Malaysia.\n\n\nData availability\n\nFigshare: Database for E-Wallet Adoption in Malaysia. https://doi.org/10.6084/m9.figshare.15167982 (Siew Bee, 2021b).\n\nThis project contains the following underlying data:\n\n• database for ewallet adoption in malaysia.xlsx (raw data of respondents’ feedback on adoption of e-wallets in Malaysia).\n\nFigshare: An Examination of Determinants for E-Wallet Adoption In Malaysia. https://doi.org/10.6084/m9.figshare.15168033 (Siew Bee, 2021c)\n\nThis project contains the following underlying data:\n\n• Results of Analysis.xlsx (the final result of the analysis based on the dataset that was collected through the online questionnaire).\n\nFigshare: Adoption of E-wallet in Malaysia (Questionnaire). https://doi.org/10.6084/m9.figshare.15167934 (Siew Bee, 2021a)\n\nThis project contains the following extended data:\n\n• Adoption of E-wallet in Malaysia (Questionnaire).pdf (a questionnaire that relates to the adoption of e-wallets)\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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Internet Research: Electronic Networking Applications and Policy. 2004; 14: 198–212. Publisher Full Text\n\nHayashi F, Bradford T: Mobile payments: Merchants’ perspectives. Econ. Rev. 2014; 99: 5–30.\n\nDaoud JI: Multicollinearity and Regression Analysis. J. Phys. Conf. Ser. 2017; 949: 012009. Publisher Full Text\n\nKalafatis S, Pollard M, East R, et al.: Green marketing and Ajzen’s theory of planned behavior: A cross-market examination. J. Consum. Mark. 1999; 16: 441–460. Publisher Full Text\n\nKapoor K, Dwivedi Y, Williams M: Examining the role of three sets of innovation attributes for determining adoption of the interbank mobile payment service. Inf. Syst. Front. 2014; 17: 1039–1056. Publisher Full Text\n\nKhedmatgozar HR, Shahnazi A: The Role of Dimensions of Perceived Risk in Adoption of Corporate Internet Banking by Customers in Iran. Electron. Commer. Res. 2018; 18: 389–412. Publisher Full Text\n\nKim C, Mirusmonov M, Lee I: An empirical examination of factors influencing the intention to use mobile payment. Comput. Hum. Behav. 2010; 26(3): 310–322. Publisher Full Text\n\nKoenig-Lewis N, Marquet M, Palmer A, et al.: Enjoyment and social influence: Predicting mobile payment adoption. Serv. Ind. J. 2015; 35(10): 537–554. Publisher Full Text\n\nLautiainen T: Factors affecting consumers' buying decision in the selection of a coffee brand.2015. Reference Source\n\nLiébana-Cabanillas F, Luna IR, Montoro-Ríos FJ: User behaviour in QR mobile payment system: the QR payment acceptance model. Tech. Anal. Strat. Manag. 2015; 27(9): 1031–1049. Publisher Full Text\n\nLin WS, Wang CH: Antecedences to continued intentions of adopting e-learning system in blended learning instruction: A contingency framework based on models of information system success and task-technology fit. Comput. Educ. 2012; 58(1): 88–99. Publisher Full Text\n\nLuna IR, Montoro-Ríos F, Liébana-Cabanillas F, et al.: NFC technology acceptance for mobile payments: A Brazilian Perspective. Review of Business Management. 2017; 19(63): 82–103. Publisher Full Text\n\nLu L: Decoding alipay: mobile payments, a cashless society and regulatory challenges. Butterworths Journal of International Banking and Financial Law. 2018; 33(1): 40–48.\n\nMarakarkandy B, Yajnik N, Dasgupta C: Enabling Internet Banking Adoption: An Empirical Examination with an Augmented Technology Acceptance Model (Tam). J. Enterp. Inf. Manag. 2017; 30: 263–294. Publisher Full Text\n\nMun YP, Khalid H, Nadarajah D: Millenials’ perception on mobile payment services in Malaysia. Procedia Computer Science. 2017; 124: 397–404. Publisher Full Text\n\nNag A, Gilitwala B: E-Wallet- Factors Affecting Its Intention to Use. International Journal of Recent Technology and Engineering. 2019; 8(4): 3411–3415. Publisher Full Text\n\nNysveen H, Pedersen PE, Helge T: Intentions to Use Mobile Services: Antecedents and Cross-Service Comparisons. J. Acad. Mark. Sci. 2005a; 33(3): 330–346. Publisher Full Text\n\nNysveen H, Pedersen PE, Thorbjørnsen H, et al.: Mobilizing the brand: The effects of mobile services on brand relationships and main channel use. J. Serv. Res. 2005b; 7(3): 257–276. Publisher Full Text\n\nOECD: Report on Consumer Protection in Online and Mobile Payments. Paris: OECD; 2012.\n\nOsakwe CN, Okeke TC: Facilitating mCommerce growth in Nigeria through mMoney usage: A preliminary analysis. Interdiscip. J. Inf. Knowl. Manag. 2016; 11: 115–139. Publisher Full Text\n\nOsborne J: Best practices in quantitative methods: 3 Best Practices in Interrater Reliability Three Common Approaches. Thousand Oaks: SAGE Publications, Inc.; 2008. Publisher Full Text\n\nRigopoulos G, Askounis D: A TAM Framework to Evaluate Users’ Perception towards Online Electronic Payments. J. Internet Bank. Commer. 2007; 12(3): 2–6.\n\nRyu H: What makes users willing or hesitant to use Fintech?: the moderating effect of user type. Ind. Manag. Data Syst. 2018; 118(3): 541–569. Publisher Full Text\n\nShankar A, Datta B: Factors Affecting Mobile Payment Adoption Intention: An Indian Perspective. Glob. Bus. Rev. 2018; 19(3_suppl): S72–S89. Publisher Full Text\n\nShin D-H: Modelling the interaction of users and mobile payment system: Conceptual framework. International Journal of Human-Computer Interaction. 2010; 26: 917–940. Publisher Full Text\n\nSiew Bee T: Adoption of E-wallet in Malaysia (Questionnaire).pdf. figshare. Dataset. 2021a. Publisher Full Text\n\nSiew Bee T: Database For E-Wallet Adoption in Malaysia. figshare. Dataset. 2021b. Publisher Full Text\n\nSiew Bee T: An Examination of Determinants for E-Wallet Adoption In Malaysia. figshare. Dataset. 2021c. Publisher Full Text\n\nSlade EL, Dwivedi YK, Piercy NC, et al.: Modeling Consumers Adoption Intentions of Remote Mobile Payments in the United Kingdom: Extending UTAUT with Innovativeness, Risk, and Trust. Psychol. Mark. 2015; 32: 860–873. Publisher Full Text\n\nTan WH, Ooi KB, Chong SC, et al.: NFC mobile credit card: The next frontier of mobile payment?. Telemat and Informatics. 2014; 31(2): 292–307. Publisher Full Text\n\nTeng T, Tenk M, Yew HC, et al.: E-Wallet Adoption: A Case in Malaysia. International Journal of Research in Commerce and Management Studies. 2020; 2(2): 216–233. 2582-2292.\n\nThakur R, Srivastava M: Adoption readiness, personal innovativeness, perceived risk and usage intention across customer groups for mobile payment services in India. Internet Res. 2014; 24(3): 369–392. Publisher Full Text\n\nUddin MS, Akhi AY: E-wallet system for Bangladesh an electronic payment system. International Journal of Modeling and Optimization. 2014; 4(3): 216–219. Publisher Full Text\n\nUtami AF, Ekaputra IA: A paradigm shift in financial landscape: encouraging collaboration and innovation among Indonesian FinTech lending players. J. Sci. Technol. Policy Manag. 2021; 12(2): 309–330. Publisher Full Text\n\nVenkatesh V, Morris MG, Davis GB, et al.: User acceptance of information technology: Toward a unified view. MIS Q. 2003; 27(3): 425–478. Publisher Full Text\n\nVenkatesh V, Thong JYL, Xu X: Consumer acceptance and use of information technology: extending the unified theory of acceptance and use of technology. MIS Q. 2012; 36(1): 157–178. Publisher Full Text\n\nWang YM: Determinants affecting consumer adoption of contactless credit card: an empirical study. CyberPsychol. Behav. 2008; 11(6): 687–689. PubMed Abstract | Publisher Full Text\n\nWu JH, Wang SC: What drives mobile commerce? an empirical evaluation of the revised technology acceptance model. Inf. Manag. 2005; 42(5): 719–729. Publisher Full Text\n\nYang M, Al Mamun A, Mohiuddin M, et al.: Cashless Transactions: A study onIntention and Adoption of e-Wallet. Sustain. For. 2021; 13: 831. Publisher Full Text\n\nYang S, Lu Y, Gupta S, et al.: Mobile payment services adoption across time: An empirical study of the effects of behavioral beliefs, social influences, and personal traits. Comput. Hum. Behav. 2012; 28(1): 129–142. Publisher Full Text Reference Source\n\nZhou T: The impact of privacy concern on user adoption of location-based services. Ind. Manag. Data Syst. 2011; 111(2): 212–226. Publisher Full Text"
}
|
[
{
"id": "137310",
"date": "09 Aug 2022",
"name": "Elaheh Yadegaridehkordi",
"expertise": [
"Reviewer Expertise Technology adoption",
"Information 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 abstract is too long. A lot of information is not necessary in this section.\n\nInformation provided in the introduction section needs to be moved to the literature review section. It is a history of finance and banking.\n\nWhat are the gaps and what other studies have been done so far should be highlighted in the introduction section.\n\nReferences are too old. Use the latest references from 2021 and 2022.\n\nWhy the adoption of e-wallet is important and why its usage in Malaysia is too slow?\n\nWhat is the theoretical foundation of this study? Why have such factors been selected?\n\nWho were the respondents and how data was collected from them?\n\nA sample of questionnaire needs to be provided with references of questions.\n\nIs a sample of 100 respondents enough?\n\nContributions need to be presented in a separate section after conclusions\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "168460",
"date": "17 Apr 2023",
"name": "Norman Shaw",
"expertise": [
"Reviewer Expertise Technology adoption",
"PLS analysis",
"digital wallet adoption"
],
"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 examines the use of e-wallets in Malaysia.\nThe introduction has too much information about the history of the term ‘FinTech’. This could be covered in one short paragraph. Instead, there should be more information about mobile wallets and their use around the world, in various developed countries and in countries similar to Malaysia. This would provide context for the study, which is the specific use of mobile wallets in Malaysia.\nThe first section of the literature review has the heading \"AEW\" – this should be written out in full, “Adoption of E-Wallets”. This first section should provide justification for the selection of the theoretical foundations of TAM and TRA. The authors should explain why they did not consider UTAUT or UTAUT2, which is a synthesis of 8 theories of adoption, including TAM and TRA. UTAUT is focussed on consumer usage, whereas TAM typically refers to use in a business setting, where adoption is mandatory.\nPEU: many studies have found that PEU has no significance. This is especially so for use of mobile applications, the majority of which have intuitive interfaces. Such studies should be referenced.\nPU: meta-studies have found that PU is the most significant factor for technology adoption. If the innovation is not useful, it will not be used. Such studies should be referenced.\nPerceived risk is associated with financial risk and privacy risk. These constructs should be treated separately. Having only one construct confounds these two risks.\nGovernment support is analogous to Facilitating Conditions, which is a construct used in many theories of adoption. Such a comment should be made.\nMethodology: more details are required with respect to the sample. What were the filters? Age group, education level, income? How were the participants recruited? Why only 100?\nStatistical analysis: a high mean does not indicate that the construct has the highest influence. More details should be provided showing how the constructs are measured with converging indicators. There should also be discriminant analysis indicating that the variables are measuring different constructs. More details should be given showing the statistical analysis: the path coefficients, the path significance, the coefficient of determination.\nThe sample size of 100 is too small to measure significance.\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-1155
|
https://f1000research.com/articles/9-1391/v1
|
03 Dec 20
|
{
"type": "Research Article",
"title": "Standardizing a unique renewable energy supply chain: the SURESC Model",
"authors": [
"Emiliano Finocchi"
],
"abstract": "This study intends to dig into the renewable energy industry and drawing from research on learning curves and energy polices, proposes a way to speed-up the energy shift from our fossil-fuel dependency to a green economy. Even though standard economic frameworks suggest that markets and not policy makers should decide winners and losers, we urge to accelerate renewable energy competitiveness, proposing that by limiting the number of renewable technologies where resources are allocated to at government level, we reduce the time within which renewables will achieve technological price parity with fossil fuels. In turn, by analyzing the energy demand and supply curves, the study suggests that this action will also mediate the relation between quantity and price, shifting only the supply curve, leaving the demand curve unaffected. It continues by proposing the standardization of a unique renewable energy supply chain model, later defined as the SURESC model. For such, a deep analysis on existing green technologies will be performed proposing the implementation of a hydrogen through ammonia economy via ammonia for power as key factor for success. This is a preliminary study, first of its kind, intended to provide a holistic approach to a known problem.",
"keywords": [
"Research and Development",
"Carbon-free Technology",
"Energy Policy",
"Energy Shift",
"Renewable Energy",
"Energy Standards",
"Learning Curve"
],
"content": "Introduction\n\n“Geopolitics is the battle for space and power played out in a geographical setting” [1, p.1].\n\nIn the world’s geopolitical puzzle, energy plays a key role defining each piece and a driver to seek for global prosperity and security2. Not all countries produce enough energy to impact the world's geopolitical scenario, but the global energy industry affects the geopolitical interests of all countries3. In fact, for every 10 percent of oil price reduction, the world’s GDP grows 0.2 percent4. As seen in Figure 15, fuel such as petroleum and coal (fossil-fuels), account for more than half of the entire energy consumption source today, making it a strategic commodity for geopolitical bargains.\n\n(Source: U.S. Energy Information Administration, 2019.)\n\nForecasts for the near future do not seem to foresee any change, as even though renewable energy will largely increase by 150% by 2050, energy consumption will also increase by 50% driven by the Asian market5, thus by 2050 petroleum and coal will still be accounted for 47% of the entire energy consumption source (Figure 1). We need to change this trend!\n\nBy looking at Figure 1 we can understand the size of the economic interests for fossil-fuels behind all major economies and politics, which provide a great incentive to the world’s major conflicts (not necessarily wars) that are today spiked among the world’s biggest oil producers’ countries such as Iraq, Iran, Venezuela, Angola, Nigeria, Sudan, Saudi Arabia among others,1,6. Is no coincidence too that the two major oil producers in the world, US and Russia, have a significant role in these conflicts, both as mitigators or instigators, but always with a strong presence (for more information regarding this matter, consult literature on “The Dutch Disease”). Nigeria gave a name to this phenomenon: “the curse of the black gold”7.\n\nNot least, the impact to the environment for such amounts of fossil-fuel consumptions is well documented8–11 and accounts for today’s climate change11. In fact, Höök and Tang11 suggested that as fossil energy and climate change are strongly correlated, a solution must be found by treating them as “interwoven challenges necessitating a holistic solution” (p.1). Considering Höök and Tang11 work, this study intends to develop a holistic approach towards this well-known phenomenon, and underlines the importance of a common, standardized eco-friendly solution where all major resources should be canalized in order to obtain a faster energy shift (from fossil to renewable) than forecasted nowadays. As we will discuss, no solution is perfect, but we need to balance pros and cons prioritizing global warming mitigation processes, which is one of our major responsibility as a developed society.\n\n“Renewable energy, often referred to as clean energy, comes from natural sources or processes that are constantly replenished” [12, p.2].\n\nClimate change is attributed to high levels of carbon dioxide (CO2) emissions into the atmosphere as a result of the combustion of fossil-fuels for energy purposes8–11 that unbalance the CO2 cycle. Renewables don’t interfere with any natural cycles as are constantly replenished12 (with exception of hydropower), providing Earth to maintain a natural balance. The most common and efficient renewable energies today are solar photovoltaic (PV), concentrated solar power (CSP), wind (onshore and offshore), oceanic (tidal and current), hydroelectric, biomass, and geothermal13. Biomass for example, absorb CO2 from the atmosphere through a natural process, and release it under combustion, keeping the CO2 cycle balanced. Each one present advantages and disadvantages in energy potentials, but solar energy is by far the most abundant renewable energy source on earth14,15. Fact: every hour, the amount of power arriving from the sun to the surface of the earth, could provide for the global energy needs for one year16,17.\n\nFurthermore, with exception of geothermal and tidal energy, all other renewable energies are a transformation of solar energy into mechanical (hydroelectric), kinetic (wind and oceanic) and chemical (biomass) energies15, and for each transformation, an efficiency factor has to be accounted for. A direct usage of the primary source could potentially mean a more efficient way to gather energy, but it depends on the technology used. Later, we will discuss on merits and demerits of each renewable energy source, focusing our work finding evidence to support that solar energy alone can potentially meet the world’s energy demand18. Nevertheless, renewable energies present many technical issues, such as intermittence, geographical availability or engineering hazards, and therefore require green-energy storing facilities and green-energy dispensers. For example, solar energy depends on atmospheric events such as rain and cloudy days, besides earth rotation15 and the energy produced must be stored for stabilization and distribution purposes.\n\n“Even with renewable energy and energy efficiency, markets and not goodwill to arrest climate change, largely determine the path of investment”3.\n\nEven though renewable energy technologies are an extremely attractive energy replacement, as we will determine later in this research, fossil-fuels are hard to die. Business leads the way, and we will require a degree of human resources management similar to the one used in the cold war when this shift will happen3. The randomization nature of the world’s natural resources distribution causes great inequalities and attract states and private organizations to aspire access grants to resources in foreign territories19. In fact, even though many treaties and incentives on renewable energies have been signed widely (e.g. Kyoto protocol), countries don’t seem to reduce their carbon footprint. The US alone, for example, has passed from being the 3rd biggest oil producer in 2008, to be the biggest oil producer in the world in 201920, nearly doubling its production in 10 years.\n\n“The disrupting elements of rapid change can be mitigated by common goals and a clear roadmap where incumbents join new players in implementing a low-carbon global energy transformation roadmap” [13, p. 20].\n\nIn the past years we have seen new renewable technologies and new renewable concepts rising at an astonishing rate. Today, we are producing (or potentially produce) green energy from wind, solar PV, concentrated solar PV, hydropower, biomass, geothermal, oceanic (tidal and current), cellulosic ethanol, artificial photosynthesis21 and more, and yet, we haven’t been able to break our fossil-fuel dependency. This extremely segmented sector, made of endless technological possibilities, each with standalone projects most of the times immerged in regional realities, lacks a holistic approach11 to boost-up and turn into the leading energy feedstock of the future. Standardization could be an important part of this process but is dependent on the maturity of the technology. Quebec’s Normalization Bureau22 define standards as a set of agreements among players of a given industry defining characteristics and rules tailormade for that industry using benchmarks from field’s collective knowledge. Standardization means to understand and approach a problem in an agreed way (as a voluntary action), based on field knowledge and studies, and can leverage an innovation journey that can lead to excellence23. Many studies on standardization have shown how standards are important to enhance the development of the industry involved22, from medicine24–26, to HR27, to Oil&Gas28, to IT29,30, all industries have standardized themselves with time. Moreover, standardization diffuses knowledge, increases predictability and reduces uncertainty and risks23, key strategic factors for small and medium enterprises (SME). But is standardization per se sufficient to incentive a green economy?\n\nThe energy sector is extremely complex, data is sometimes not available31 and economic models depend on geopolitics, R&D advancements, competitive alternatives, subsidies and/or taxes, externalities, industry’s supply and demand elasticity and other factors that rapidly change with time32, thus, are hard to determine. Moreover, the energy sector is heavily politicized, where usually the fossil fuel supply chain is subsidized (from supplier’s governments) and taxed (from demander’s governments) whereas green energy is generally subsidized to help it achieve competitive traits33. Policy makers are trying to incentivize a green economy, but we are far from a real shift, as most forecasts have been missed, and we continue to increment the global usage of carbon energy despite all efforts. In 2017, total subsidies to the renewable energy upstream touched 166B$ globally (between private and public)34, with an increment of 7.09% production from the previous year35, equivalent to 442 TWh of extra power generated, and forecasts aim at 192B$ subsidies for 203034. In the energy context these numbers aren’t even close to sustain an energy shift, as in 2017 global energy demand grew 543 TWh from 201636 driven by the Asian markets, yet renewables alone couldn’t cover this need, lacking 11 TWh of power generation that has been supplied by carbon fuels. As suggested by the US Energy Information Administration37, by following this trend our carbon emissions will continue to rise rather than fall, and our carbon dependency will be maintained1,3,5. Furthermore, standard economic framework suggests policymakers to apply policies seeking for price parity in order to achieve competitiveness among energy sources. Nevertheless, price parity between green and brown energy may not be enough if economic models don’t account for fossil fuel price response to renewables, as governments producers of fossil fuel may use their price buffer created from taxes and royalties as a response to push fossil fuel prices yet lower31. This suggests that in order to shift to a green economy, renewable’s price target should aim lower than the current fossil fuel benchmark and its economic models should foresee a strong economic response from its competitors. Technocrats and economists have spent thousands of hours creating models that would incentivize renewable energy deployment, and despite all our knowledge and efforts, we are behind in our green workplan, and our planet seems to be worming up faster than predicted38. Global warming puts our external models (social, environmental, economic, etc.) under a large dose of stress which will consequently unbalance these systems. In non-stressful situations, it would be correct to leave to markets and time the burden of a “natural selection” of technologies, but in today’s environmental pressure, we can’t afford to wait for a technological breakthrough anymore, governments should model current economies with current technologies and regulations to create non-convex economies with convenience equilibria through R&D and taxes/subsidies. We need to act by maximizing all resources and create a coordinate globalized network of protocols that will help to speed-up this shifting process. This concept is not new to the literature and can be partially found in the Carbon Leakage theory39, which states that in the absence of a global coordinated climate change policy, industries relying on fossil fuels as their primary energy source may relocate their premises in countries with less restrictive policies.\n\n“Extremis malis extrema remedia” (Latin saying). The literature seam to point towards a mix use of renewable energies solution11,13–15,17,40, and even though standard economic framework suggests that markets and not policymakers and energy geeks (like myself) should decide winners and losers, I propose that there is a direct positive relation between the number of renewable technologies subsidized at the government level and the speed with which these technologies can achieve price parity with fossil fuels. In other words, the greater the number of renewable technologies our governments subsidize, the more we increment the time within which these technologies will take to reach price parity with fossil fuels. Diminishing the number of renewable technologies to subsidize will speed-up the renewable deployment and renewable price parity of the selected technology with fossil fuels.\n\n\nLimiting the number of technologies\n\n“Governments have been very creative in imposing price control, what is needed is to show the economic costs of those actions and evaluate fewer damaging alternatives” [41, p. 675].\n\nLearning curves play an important role to understand maturing industries such as renewables, as the sizes of the investment needed for a certain renewable technology to reach technological price parity (leaning investment) with fossil fuels may define the time to achieve this goal42. In this context, research and development (R&D) can diminish learning-by-doing investments in different ways43, pushing the learning curve down by curve-shifting or curve-following (for more references on curve-shifting and curve-following please consult42), diminishing the learning investment. Even R&D innovation catch-up could act as a catalyzer but requires continuous efforts through the establishment and adequate support of competence-creating units44.\n\nLet’s begin by analyzing Shayegh et al.42 learning curve for Solar PV on a learning-by-doing bases (without R&D) represented in Figure 2. Fossil fuel unit cost of generation has been set at a fixed price of 50 USD/MWh, supposing it has reached it maximum learning point where cumulative quantity will not affect unit cost (benchmark). Solar PV has a learning quotient of 23%, intercepting fossil fuel line (price parity) with a future cumulative quantity (power deployed) at over 1000 TWh. On the Solar PV line, the continuous line represents historical data for Solar PV technology, the dot represents status quo, and the dotted line after the dot represent forecasts. The area between the Solar PV line (in all its length) and the fossil fuel line in Figure 3 (ABC¯) is the total amount of learning investment needed to reach price parity. The area within the dotted line and the fossil fuel line represents what yet needs to be invested (Ltot1 = the difference between the total amount to be invested ABC¯ and the total amount invested so far ASD¯):\n\n\n\nABC¯ = Total learning investment to reach price parity\n\nASD¯ = ToFtal learning investment historically allocated\n\nSBCD¯, Ltot1 = Total learning investment that needs allocation\n\nLtot = Sum of the total learning investments among selected technologies that needs allocation (only Solar PV, Ltot = Ltot1)\n\nNow we introduce a second renewable technology, onshore wind (Figure 4):\n\n\n\n\n\nBy introducing n technologies, we have:\n\n\n\nSetting Ltot1 as the smaller area, we have Ltot2 = Ltot1 + C1, where C1 is the difference between Ltot2 and Ltot1 (Ltot2 – Ltot1).\n\nTherefore,\n\n\n\n\n\n∑n−1n−1Cn represent the sum of the area differences between the area SBCD¯ (solar PV learning investment needed) and the other renewable technologies areas, and therefore is a constant and can be simplified as Ctot. n represents the number of technologies.\n\n\n\nCeteris paribus but n and Ltot, so that Ltot becomes a function of n:\n\nWhere Ctot > 0, Ltot1 > 0 and n > 0.\n\nThis function represents the total amount of learning investment required for a set of renewable energy technologies to reach fossil fuels price parity. Usually, learning curves are indeed curves and not straight lines, but to the purpose of this exercise, the result would not change.\n\nContinuing; every year both the private sector and the public sector allocate finite resources into the learning investment of renewable sources. These resources can be in the form of equity, subsidies, credit, loans, studies, etc. and are finite in nature (166B$ only in 2017’s subsidies as per Tylor34). To simplify our calculations, let’s idealize a constant yearly resources allocation (RA) to the learning investment Inv, and an equilibrium in the distribution of resources among technologies. This means that, every year (t), the total learning investment Ltot required to achieve price parity decreases of a value of RA.\n\n\n\n\n\nOn the Inv axes of Figure 5, we have the amounts of resources (manhours, subsidies, quantity control protocols, etc.) converted into equivalent B$ as a function of time (t). The RA line represents the constant resources allocated year by year to the renewable industry by the private and public sector.\n\nIn Figure 5 we can see the amount of possible RA converted in USD as a function of time:\n\nWe now substitute Ltot:\n\nPrice parity will be achieved when Inv = 0, this means when t=LtotRA, and by substituting Ltot:\n\nAs we can see, on a learning-by-doing process, as the number of technologies requiring learning investment increase, time to achieve price parity increases too. There is a direct, positive relation between time and the number of technologies where resources are allocated. Investing into R&D would shift the learning curve down, acting as a negative moderator between t and n. This means that as the sum invested into R&D increases, both time and learning investment decrease. Let’s demonstrate this claim:\n\nFollowing Shayegh et al.42 research, we find that investing in R&D will diminish initial investment costs Ltot and will push our learning curve down (for both curve-following and curve-shifting). In our model, it means that we diminish the initial Ltot by an X amount provided by the R&D process resulting into a new R&DLtot42. Thus:\n\nWe now substitute Ltot with R&DLtot:\n\nAs t is a function of n (t(n)), X will act as a negative moderator to this function. To minimize t, we should allocate resources to R&D for n=1.\n\nTaking into account that we are discussing at government level, another obvious result shown in this equation is that time is negatively related to the size of the resources allocated RA. This means that as more resources governments allocate, faster will parity price be accomplished (and vice versa).\n\nWe have found evidence to support that technological price parity between renewables and fossil fuels will be reached faster if limited government resources would be allocated to a restricted number of technologies. Reaching technological price parity means decreasing unit cost of generation price and increasing cumulative quantities too. We now need to apply this find to demand and supply renewable energy curves and see how the market would react by increasing and decreasing the number of technologies n we allocate resources to. Renewables produce electricity; thus, renewables’ commodity is electricity. General demand and supply linear curves in an ideal market are represented by the following inverted functions for both demand and supply:\n\nDemand: P = a - bQd\n\nSupply: P = α + βQs\n\nIdeal markets require perfect competition, property rights well established, information availability, low externalities and no decreasing average costs as production increases32. We will adapt from Dahl’s32 coal demand and supply curves to electricity as main commodity, where in ideal markets the author describes b and β as the slope (elasticity), and a and α as the sum of the following parameters:\n\nDemand b\n\nPrice of substitutes to electricity (-Pse), such as natural gas used in stoves rather than electric stoves;\n\nPrice of complements to the commodity (Pce), such as electric heaters vs gas heaters;\n\nPrice for the technology for electricity use (+/-Tcu), such as electric cars vs diesel cars. This parameter may be positive or negative depending if the electric technology is cheaper than the alternative technology;\n\nPrice of the output produced (-Pop). Prices of services using electricity as feedstock such as fun-parks, electric go-karts, and others;\n\nEnergy policy (+/-Pol). It depends on the policies in place, positive for subsidies and negative for taxes;\n\nNumber of buyers (-#buy)\n\n*Inverted curve: Qd is the demand quantity and P is the price\n\nParameters in the demand curve has no direct effect with the production technology. Demanders only know supplier’s selling price. The demand curve will not be altered by altering n.\n\nSupply β\n\nPrice of factors for producing electricity, such as labor and capital (-Pf);\n\nPrice of similar goods that power plants could produce (-Psim). If oxygen or chlorine prices increase to a point where using electricity for electrolysis would provide more profit than selling electricity directly, green power plants could be enticed to change production;\n\nPrice of by-products or complements of electricity production (Pb), which in renewables do not apply;\n\nProduction technology (Tc), technical changes should reduce costs and increase production;\n\ngovernment coal policies (+/-Pol), they could incentive or disincentive the industry;\n\nthe number of sellers (#sell);\n\n*Inverted curve: Qs is the supply quantity and P is the price\n\nTc are the technical changes throughout time, representing technology advancement. As previously seen in learning curves, time to achieve technological price parity is directly related to the number of technologies n to allocate limited resources to. This means that by diminishing n, we increase technological advancement of maturing technologies and therefore we diminish the time between each technological change, resulting into an increase of Tc. In conclusion, n is negatively related to Tc, and Tc acts as a moderator to the P(Qs) function.\n\nFigure 6 represents the shift in the supply curve when n varies. By increasing n, the supply curve will shift to the right, and vice versa, by diminishing n, the supply curve will shift to the left (in energy markets, both demand and supply are believed to be inelastic (b <1)32,45,46).\n\nWe stated before that by allocating resources to fewer technologies we diminish the time within which renewables’ technological price parity with fossil fuels is achieved. Moreover, I found evidence to support that resource allocation to renewables’ R&D, will act as a negative moderator between the number of technologies receiving the resources and the time within which they will achieve this parity. Furthermore, adapting from Dahl32 energy demand and supply curves, I found evidence to support that time to achieve technological price parity acts as a positive moderator in between the P(Qs) function. Figure 7 represents the final SURESC model.\n\nIt’s important to underline the fact that there is no perfect solution, that any technology will have its pros and cons, breakthroughs may come from excluded ones, and that economic frameworks strongly suggest a diversified portfolio of technologies. Nevertheless, a SURESC model will speed-up a green economy as it has become a priority due to a fast climate change. This research is a deep reflection to possible paths to follow by analyzing renewable energy streams and its technologies in order to build a first SURESC model.\n\n“Energy can neither be created nor destroyed in a system of constant mass, although it may be converted from one form to another” (first law of thermodynamics).\n\nThe physics of energy is fascinating. It can be manipulated endless of times at our own advantage, converted for specific needs such as transportation, and yet never vanish, it converts. The energy sector (non-renewable and renewable) are categorized into three main streams: upstream, midstream and downstream. EnergyHQ47, supported by the Oklahoma Energy Resource Board, defines these streams as:\n\n• Upstream, which refers to all the processes involving the exploration and production of energy. These include all engineering processes to find and reach the energy source like drilling, seismic, pumping, geological surveys, and all other processes that lead to the energy. In the renewable industry, upstream would be all those processes leading at the first energy transformation: solar to electric, wind to electric, geothermal to vapor, hydropower to electric, plantations to biofuel, oceanic to electric.\n\n• Midstream, which refers to all the operations involving storage and transportation of the energy commodity to its energy transformation facilities (e.g. refineries, thermoelectric facilities, etc.), where is transformed into a usable source of energy intended for the final user (e.g. crude oil into gasoline or coal into electricity). Midstream includes pipelines, tankers, storage facilities, pumping stations and more. In the renewable industry, midstream includes storage and transportation of hydrogen generated by renewable systems, transportation of electricity through high tension lines, and the transportation of biofuel to end users.\n\n• Downstream, which is the final sector of the energy streams, referring to all processes associated with the end usage of this commodity. In the oil sector, downstream would include all processes to produce diesel, gasoline, synthetic rubbers, and many more day-to-day products. In the renewable industry, downstream processes include hydrogen to electricity transformation and its distribution, electricity distribution into homes, industries and vehicles, and biofuels into usable fuels and its distribution.\n\nThere is the need to approach each stream (as shown in Figure 8) separately and understand what type of infrastructures and technologies exist, how these streams are connected to each other, and how energy is produced, transported and delivered into our homes, cars and industries. Energy is a very competitive and inelastic market, where companies have issues gaining market shares, thus, its supply chain must be demand driven and customer centric in order to survive25. This study will have the same approach, a customer centric analyses (bottom-up), by starting to examine the energy flow from the clients’ needs (downstream) and follow the streamline in countercurrent (midstream) to the source (upstream), selecting a best-fit technology for the SURESC model form a client perspective.\n\n\nDiscussion\n\n“Transportation is believed to be currently responsible for nearly 60% of total world oil demand and will be the strongest growing energy demand sector in the future” [48, p.4587].\n\nEIA37 has divided the world energy consumptions into four main sectors: residential, commercial, transportation and industry. The industrial sector has the highest energy consumption, overall using over a third of the global energy production, followed by transportation, commercial and residential37. Energy is delivered to end users in endless manners such as electricity, natural gas, steam, coal, diesel, gasoline, LPG, biofuel, and more. To make these deliveries possible, we have built a network of pipes, cables, trucks, facilities (substations, offices, maintenance centers, etc.) and services, that guarantee a constant flux in a vast geographical area full year-round. There are billions of dollars invested into these energy supply chain infrastructures, and most of them required invasive interventions to properties, land and the environment at a capillary level, and therefore must be taken into serious account before even ponder to replace them. Disrupting these systems would result in disrupting many economic interests, meaning that the financial damage of such operation could be an insurmountable barrier to achieve energy transformation, and needs to be carefully addressed. This is not a matter of goodwill, but a matter of available resources; markets probably can’t absorb such financial damage, especially in a relatively short period of time. Once again, economic resources are limited and should be used on a joint effort to create a competitive green economy, a global action for a global problem. The transportation sector is an exception to this complicated web, as its power system is intrinsic to the mobility nature of transportation, and there are small networks of infrastructures that sustain mobility that can be replaced with a smaller effort. All vehicles are built in factories and are fueled “on-the-run”, requiring a relatively simple network of energy dispensers accessible to mobile vehicles, while homes must have a constant and direct supply of energy, requiring a capillary delivery system that penetrate the entire territory. An energy shift implemented at the residential level would be much more invasive than a shift in the transportation sector, which, by the way, is already taking place, jump-started by Tesla’s success49. We shall therefore not account for the transportation sector in this research as it will shape and adapt by itself according to the external environment and clients’ needs. For example, new car manufacturers such as Tesla are producing only electric cars, and conventional car manufacturers are betting on electric cars too (Toyota, Volvo, GM, Citroen, and others).\n\nFinding a common energy denominator among final users would be a good starting point to identify a potential delivery system that could be integrated, rather than disrupted, into the SURESC model and minimize the number of technologies where resources are attributed to. We said that there are countless ways to deliver energy to factories, homes and offices, but without needing to analyze each and every one of them, we know that one is physically provided and needed to all, and powers most of our equipment and tools: electricity. Even though in some countries, electricity is not available to everyone (over 150 million Indians don’t have access to electricity50), today it is widely used, its environmental impact is dependent exclusively to the production phase and can be converted into any other form of energy on demand (heat, kinetic, piezometric, etc.). Being able to provide clean, cheap and reliable electricity would be the solution to the disruptiveness problem which would require comparable small interventions to the existing systems and subsystems to replace other types of energies (such as natural gas and others), and therefore the impact of such would be minimal. Nevertheless, there are certain industries such as iron and steel, pulp and paper, basic chemicals and some non-metallic minerals51 which require large amounts of direct heat in such a scale that existing electrical infrastructures wouldn’t be close to be able to supply their energy demands.\n\nIn conclusion, SURESC’s downstream solution would be to provide energy under electricity form to all end users by potentiating existing infrastructures and gradually abandon (or divert) other types of energy supply systems like natural gas, diesel or coal. SURESC’s downstream starts (and midstream ends) with the distribution system of electricity to end users, defining the electricity production phase as part of midstream. Next, we need to step-up the energy streamline into midstream, and analyze how the SURESC model could handle the transportation and storage of clean energy in its different form that will feed a clean power plant or energy dispenser. Once again, the use of non-disruptive technologies, or integrable technologies would be highly recommended.\n\n“Electricity storage is considered a key technology to enable low-carbon power systems” [52, p. 81].\n\nWe have identified electricity as downstream energy for our SURESC model, but in midstream things can get a little confusing. In fossil-fueled systems, the production of electricity is a midstream definition, nevertheless, in renewable energy systems the production of electricity is considered to be an upstream, midstream and downstream matter according to the technology used. The difference resides on the primary source of energy exploited, which in fossil-fuels are hydrocarbons (all chemical energy) and sub-products (crude oil, natural gas, coal, etc.), which require extensive engineering processes to extract them from its natural deposits (upstream), later transported, stored and transformed into electricity (in midstream), while in renewables, the primary source varies from solar (PV), kinetic (wind), geothermal (thermic), chemical (biomass), among others, each one producing electricity in different stages. For example, PV, CSP and wind, produce electricity as first energy transformation (upstream), while biomass’ first energy transformation is into chemical energy (biofuel), later on transported, stored and transformed into electricity in midstream, while hydrogen-to-electricity, such as used in some vehicles, is transformed in downstream. This is not a mere definition problem, but a serious structural issue. Electricity has distance restrictions and can’t be transported too far from its source without substations injecting extra power into the grid (I will not dig further into the physics of electrical systems as is out of the scope of this research). This means that if we consider electricity production an upstream process in our SURESC model, it will require a decentralization of the upstream system, where production has to be built near consumption (which is a possibility), prioritizing power over energy, and midstream would comprehend electricity storage for stabilization purposes, with medium-low discharge duration and physical distribution from medium to small scale systems. Today, there are several tentative solutions in such direction, as seen with independent renewable projects in homes, offices and factories around the world, but unfortunately these systems supply less than 1% of the entire energy market. Meanwhile, considering electricity production a midstream process, would mean to collect and store energy at the source (wherever it may be) via an energy carrier, which would be shipped to powerplants around the world, prioritizing energy over power. This strategy would require a more centralized upstream system similar to the one seen in today’s fossil-fuel economy. These similarities are an incredible opportunity to adapt the existing infrastructures and accommodate the new energy carrier, with great financial savings and avoid disrupting many business sectors. If such option is available, existing infrastructures such as pipelines or energy dispensers among others, and logistics such as oil-tankers and gas-tankers among others, could be potentially upgraded to handle this new energy carrier. This process would yet be disruptive but less than a decentralized one, and an argument for further studies.\n\nIdeally, considering a centralized model would largely benefit the finance of an eventual energy shift, but technically, we need to seek for energy parameters key to the centralization strategy and hope to find one that fits these parameters. For example, storing energy into lithium batteries is very efficient (up to 96%), cheap (compared to other technologies) and has no installation challenges. But energy and power separation is not possible with this technology, meaning that, in a centralized model, the entire battery should be transported to final destination, making it too costly and inefficient, and therefore not applicable, nevertheless a good fit for a decentralized one, where electricity can be stored and released on demand near points of consumption. Consequently, before deciding on matters such as centralization or decentralization, we need to analyze existing carbon-free energy storage technologies and energy carriers and compare them for different parameters that will provide us with enough elements to make such decision. For such, I will compare them to seven different parameters from three main areas: financial, technical and environmental. Financially, we need one parameter: the initial investment cost (CAPEX) which is sized based on power requirements to be released and is measured in $/kW. We will purposely dismiss the leverage cost of storage (LCOS) from financials as are too similar among each other52 to be useful in our analyses. Technically, we need four parameters: roundtrip efficiency, lifetime cycles, transportability and installation challenges. Roundtrip efficiency measures how much energy is lost (money is lost) in a complete charging/discharging cycle measured in percentage. The lowest a roundtrip efficiency is, the lowest will be its financial feasibility. Lifetime cycles is the number of times the technology completes a charging/discharging cycle before reaching its physical end-of-life. Transportability is the ability to separate energy and power so that energy can be transported into a power facility elsewhere (transportation costs will be discussed later). Installation challenges are those technical challenges that require high degrees of engineering knowledge. Installation challenges is important parameter for accessibility purposes, as it may create an entry barrier not suitable for emerging economies and SMEs. Environmentally, we need two parameters: geographical availability, as not all environments have the right characteristics to host a technology, and land requirements, as some technologies may require large portion of land that may not be available. These seven parameters will provide us with enough elements to select our strategy (centralized or decentralized) and select our midstream technology for our SURESC model.\n\nWe have selected five main green storage technologies based on real-life models and applications:\n\n• Pumped hydropower storage (PHS): this mature system is very simple, PHS facilities store energy by elevating water form a lower level reservoir, to a higher-level deposit, gaining gravitational potential energy40. When high demand energy peeks arise, the water is let to flow back to the lower reservoir which spins a turbine to produce the needed electricity53. This system is usually used to balance demand peeks on a hydropower dam, but the very same principle could be used to store and manage energy demands for inconstant renewable energies. For example, it could use a portion of the electricity produced by solar panels during daytime, and release it during nighttime, when solar panels don’t produce. On a closed system, where all the energy is stored first, this process will also stabilize the output by adjusting the water flow downstream accordingly to the system’s short-term total production. Despite its high storage efficiency between 70% and 84%40, pumped hydropower requires two major characteristics: large land availability with at least two significant elevation differences between plots, and water availability, which makes potential plant locations unequally distributed around the world40. Moreover, there is a significant engineering work behind it to ensure the performance of the system accompanied by a large land-work activity. This is why this system is usually associated with hydroelectric dams and not built as independent systems. Due to its mature stage, implementing this technology is reasonably cost-effective, with an average CAPEX of 1.129 $/kW52. In PHS energy is prioritized over power, making it ideal for seasonal storage or for medium to large power systems over 100MW40. Transportability is not an option.\n\n• Advanced adiabatic compressed air energy store (AA-CAES): these systems have reservoirs in which air is pumped in and compressed to accumulate potential elastic energy40, that can be returned at any point in time by using the compressed air to spin a turbine and generate electricity. One big challenge of this technology is due to the nature of its reservoirs, as the use of natural caves such as old salt deposit or gas depleted reservoirs can drastically diminish CAPEX and therefore make the investment feasible, where else, if a dedicated reservoir should be built, the CAPEX would spike and the investment could cease to make any economic sense40. Thus, location is indeed a key factor for this technology. Another big issue is derived by the compression and decompression physics, meaning that each time a gas is compressed produces heat, and vice-versa, each time is decompressed cools down. This thermal “ups and downs” not only drastically diminish efficiency, as much of the energy is transformed into heat during loading, but this heat may disrupt the physical elements of the system. Standard CAES systems stabilize temperature releasing heat through a radiator while loading, and injecting heat through normal fossil fuel combustion (producing CO2) while unloading (diabatic process), and this is why this study will not consider standard CAES. In advanced adiabatic processes, the system stores heat in a heat storage facility during loading and release it while unloading40. As heat can’t be stored for long periods, AA-CAES efficiency diminishes with time. Average CAES efficiency is 44%52, but AA-CAES efficiency can reach 72%40. Unfortunately, is hard to estimate installation costs for both CAES and AA-CAES, as only two systems are actually connected to the grid (Huntorf, Germany and McIntosh, Alabama), but if the reservoirs are of natural formation, an average of 871 $/kW can be estimated52. In AA-CAES, as per PHS, energy is prioritized over power, but is limited to the size of the reservoir, making it a good choice for short seasonal storage or for medium to large power systems, between 10MW and 2500MW40. Transportability is not an option.\n\n• Flywheel energy storage systems (FESS): these systems use energy to spin a mass (rotational kinetic energy), which is virtually frictionless due to its magnetic elevated bearing to avoid ground friction and placed in a vacuum to avoid air friction53, and uses its moment of inertia in a later stage to invert the process and retrieve the energy stored [40, p. 58]. The total amount of energy that can be stored in this system is equal to the size of its rotatable mass by the speed in which it can spin; the heaviest and/or fastest, the more energy can store and vice-versa. There are two types of FESS, low-speed (under 10k revolutions per minute) and high-speed (up to 100k revolutions per minute), according to requirements54. The system presents huge advantages: it can be built in factories and assembled in-loco anywhere needed, no special environmental requirements, carbon emission free, durable in time with low maintenance, long life cycles and an efficiency rate of up to 88%52, nevertheless has two negative aspects: idle losses of up to 15% per hour (the system loses energy fast), and the need for strict security measures (a loose component can send tons of high-speed spinning mass out of control)40. Its installation costs are in the lower range if compared to other energy storage technologies at 641 $/kW55. In FESS, power is highly prioritized over energy, where the system needs to use its accumulated energy in short periods of time. It’s ideal for power stabilization purposes within hours for systems between 100 kW to 100 MW40. Transportability is not an option.\n\n• Batteries: it was 1800 when Alessandro Volta was accredited to have invented the first battery. A battery is a device capable of converting stored chemical energy into electrical energy53. Anytime two chemical elements (or components) react together they exchange of electrons, and when these reactions happen in a controlled environment such as batteries, the system is able to direct these electrons to generate electrical power, and each of these reactions uniquely yield a performance, efficiency and safety characteristics40. Based on the countless possible interactions between elements and components, with time we have developed many (or too many) battery systems. Even though batteries have become an essential component to all our electronics, from cell phones to cars, to baby toys, and our world would not be the same without these (portable and stationary) energy storing devices, we will not expand further on batteries’ technical description, as it would exceed the scope of this research. As stated, there are batteries of all “kind and shapes”, thus, to avoid distractions and based on previous studies53,56–58, we have selected three main battery groups that have the potential to satisfy the energy storage requirements for this study: lithium-ion (Li-Ion) batteries, lead-acid batteries and vanadium redox-flow batteries.\n\n◦ The Li-Ion battery group, per se a large group far from being homogenous, exchange Lithium ions (Li+) between the anode (made of “Lithium Metal Oxide”) and the cathode (usually made of graphite)56,58. The Li-Ion group comprise batteries such as Nickel-Manganese-Cobalt (NMC), lithium-Cobalt-Aluminum (NCA), Lithium-Iron Phosphate (LEP), Lithium Titanate (LTO) among others, each with different characteristics. Due to their mass-market usage, the production price of these batteries decreases on a monthly base, widening their implementation span. On average, these batteries have an incredible round-trip efficiency raging between 92% and 96%40, shown to be the most efficient energy storing system seen so far in this study, and with an average CAPEX of 678 $/kW52, makes this technology a front-runner for storing energy. Energy and power are balanced, but inseparable. This means that Li-Ion batteries are a good choice for very small, small and medium size power stations. Ideal for portable devices such as laptops or cars but are efficient with systems up to 100 MW too59. Transportability is a valid option only in small devices.\n\n◦ Lead-acid batteries are one of the oldest batteries on the market with over 150 years of existence. There are two types of these batteries: flooded (vented), which need a periodic water replacement, and valve-regulated (sealed) that use a valve to control inner pressure and prevent any electrolyte loss. Both have a very small lifecycle (sealed led-acid batteries a little longer) and are the heaviest batteries on the market. The electrolyte is made of aqueous sulfuric acid (H2SO4), the positive electrode is lead-oxide (PbO2) and the negative electrode is metallic lead (Pb)40. Their roundtrip efficiency is high, but not as high as Li-Ion batteries, reaching 84%, and their implementation costs are about 625 $/kW52. Like Li-Ion batteries, lead-acid batteries balance power and energy (inseparable) but are not so efficient with large systems. Due to its low price, is a good choice for small power stations up to only 25 MW40. Transportability is a valid option for small systems like cars.\n\n◦ Vanadium redox-flow batteries (VRFB) are a subsystem of the redox-flow batteries (RFB) family, which differ from normal batteries by having its electroactive materials dissolved in a liquid-state electrolyte. Although some designs also consist of having one of the electrolytes in a gaseous state (hydrogen/bromine cells), all reactions occur in ionic species in liquid solutions40. The biggest advantage of these batteries consists in the separation of power and energy, where power can be scaled by scaling its cell stack design (by changing the electrode surface), and energy can be scaled by scaling the amounts of electrolyte stored in tanks40. This provides the opportunity to develop batteries for large scale and long duration systems, which can be integrated into a power grid60. Theoretically, energy could be transported by pumping around the electrolytes, where power can be stationary provided by pinpointing cell stacks according to the geographical needs. In this case the issue would be distance, as VRFB have a very low energy density between 0.081 MJ/Kg and 0.144 MJ/Kg, and therefore too expensive to transport. Transportability is possible but economically not feasible. Even though VRFB has some installation challenges, it also offers a simple heat control mechanism, as the system is fed by pumping the liquid electrolytes into the electrode stack, and in case of a system fault, switching off the pumps will stop all reactions. Moreover, even if more studies are required, the scientific community believes that this battery offers a potential environmentally friendly system, as none of its components present danger to the environment or a threat to humans61. With an average initial investment cost of 829 $/kW52, VRFB are ideal for small to medium size power stations up to about 100 MW40.\n\nBatteries can be built in factories and transported virtually anywhere with limited installation challenges. In VRFBs, energy could be transported separated from power, which can be controlled-released in a second moment. Nevertheless, batteries have some negative traits: they are heavy, can catch fire and their lifetime cycle is very short. For example, heat produced by normal batteries can be so intense that the battery itself can catch fire, as seen in some of the Tesla’s early models49, and therefore are not suitable to transport large power systems. This is not so true for VRFB, as its lifecycle is high, its weight can be managed by managing its tanks and the heat be monitored by controlling the pumps. Worst, due to chemical degradation, batteries’ lifetime cycles are short if compared to any other energy storage technology. Again, this is not so true with Vanadium Redox-Flow batteries, which use liquid electrolytes that, in general terms, has lower chemical degradation.\n\n• Hydrogen: this element has fascinated people for centuries and is considered to be the ultimate solution for energy and the environment62, as with its combustion it releases only heat and pure water. The biggest advantage of this gaseous element consists in having the highest energy density values per mass of all energy carriers (142 MJ/Kg), more than triples crude oil and natural gas, and therefore is ideal for energy storage63,64. Nevertheless, on a volume scale the situation is reversed (8 MJ/Liter in its liquid form), where its values of energy per liter are much lower than of others65. For example, in a confined space with equal environmental conditions, 1 kg of hydrogen has more than three times the energy of 1 kg of natural gas but occupies approximately 11m³ of space compared to approximately 1.1 m³ occupied by natural gas (depending on the composition of the natural gas). To make it more efficient, hydrogen needs to be compressed, but in equal conditions, natural gas will always have approximately 3.2 times more energy per volume than hydrogen and this is why hydrogen has never been a first choice for power generation, requiring large tanks and expensive logistics (even if 11 times lighter than air). Marketwise, hydrogen can yet be competitive as an energy carrier if the production price per volumetric energy density would achieve a cost of 3.2 times less than to exploit natural gas. Furthermore, hydrogen’s boiling temperature is -252,87 ˚C, requiring 45% of energy loss when transported in its liquid form64. To worsen things, having the highest energy density among all energy carriers is its strength but also his curst, as is highly flammable and thus very dangerous to handle, requiring strong and costly security measures. But all is not lost… Studies suggest that by combining hydrogen with nitrogen present in the air, hydrogen can be stored inside the ammonia compound (NH3), a carbon-free substance that can potentially resolve many of hydrogen negative aspects55,59,66. We will analyze ammonia as a sub product of hydrogen later. Hydrogen can be produced from fossil-fuels (grey hydrogen), from fossil-fuels combined with carbon capture (blue hydrogen) and directly from renewable sources (green hydrogen). Both grey and blue hydrogen produce high amounts of carbon dioxide as a byproduct, even though blue hydrogen captures it, yet storage is required64. Unfortunately, 95% of all hydrogen produced today in the world is grey and blue hydrogen64, but due to the scope of this research, we will focus on green hydrogen production only. Green hydrogen production process is simple and well documented63,67, obtained by water electrolysis (available virtually anywhere) and eventually re-electrified by combustion (releasing heat and H2O) or by using fuel cells. Unfortunately, its roundtrip efficiency is very low when compared to other storage technologies, reaching up to 42% with today’s technologies but with a theoretical potential to reach 54%53. CAPEX to use this energy carrier is yet very high, calculated at 5,417 $/kw52, thus having an insignificant market share in the energy industry. Nevertheless, the interest in hydrogen is growing by the day, and his potential role in the energy shift has been recognized by most governments64, and efforts are made to bring CAPEX and LCOS prices down. Hydrogen is very versatile, but due to its low volumetric energy content, must be transported in large quantities, making it an acceptable choice for seasonal storage and large power stations over 50 MW59. Some small applications in vehicles exist, but the market didn’t grow as expected.\n\n◦ Ammonia: the base compound for fertilizers is ammonia, which its industrialized process uses fossil-fuels as feedstock for grey hydrogen production, contributing to approximately 1.3% global carbon emissions66. Hydrogen production is key for these CO2 emissions, which we know can be produced by grey, blue and green processes. Despite this fact, ammonia production is a mature industry with an existing network of infrastructures, which is a great incentive for new implementations. In recent years, green ammonia has attracted international interests from many countries such as Japan, Australia, the US, Netherland and the UK59, due to its ability to efficiently store hydrogen in its carbon-free formula (NH3) and be used as a possible energy carrier. Ammonia has a volumetric energy of 17.35 MJ/Liter, comparable to those of liquified natural gas (LNG), standing at 20.8 MJ/Liter, but with an incredible advantage: it can be liquified at atmospheric temperature through simple compression at 0.8 MPa (LNG requires temperatures of -160°C). The production process gets its name from its inventors, Fritz Haber and Carl Bosh (also known as Haber-Bosh process) and consists in reacting hydrogen with atmospheric nitrogen (accumulated through an air separator) using a metal catalyst under certain pressures and temperatures (we will not dig further into the Haber-Bosh process as will not provide a contribution to this research). The Haber-Bosh process is a carbon free process easy to implement. Security wise, ammonia is very toxic to humans and to the environment (graded 3 out of 4 of the hazardous scale form the US National Fire Protection Association) but has a low flammability with helps the handling. Nevertheless, it requires a constant and costly monitoring measures. Furthermore, other security challenges are derived from the reduction of NOx and unburned ammonia from non-performing power generators, both toxic to life, as NO2 is proven to aggravate cardiovascular and respiratory diseases, but as a consolidated industry, all protocols and safety measures are well tested and successful in both synthesis and combustion59. In terms of its roundtrip efficiency, ammonia is more efficient if used directly to produce electricity (fired or through a fuel cell), avoiding dehydrogenization which requires an additional loss of 13% efficiency64. This process can reach a roundtrip efficiency of up to 72%50, nearly doubling pure hydrogen. In terms of CAPEX, ammonia storage is surprisingly low if compared to hydrogen, with an investment cost between 1,350 $/kW and 1,690 $/kW59. Ammonia balances hydrogen best and worst qualities, providing a good volumetric energy content, and an easy handling logistics. Therefore, is a very good choice for seasonal storage and for medium to large power stations over 10 MW59.\n\nBased on the above characteristics, we can now make assumptions on which strategy is a better choice between centralized or decentralized (as graphical represented in Figure 9). A centralized model would imply prioritizing energy over power, where energy is transformed and stored in a remote location, transported to a power station, which than produces high power electricity for a large-scale distribution. Therefore, a centralized model would require energy over power prioritization and transportability. On a decentralized model, where power generation is brought close to the end user, power is prioritized over energy, as electricity is released and distributed in loco in smaller networks. Therefore, a decentralized model would require power over energy prioritization without the need for energy transportability.\n\nAs stated, transportability (energy and power separation) is another key decisional factor. Table 1 shows two potential energy storing technology for a centralized model, hydrogen and ammonia, and six for a decentralized one, where VRFB could have played a role in both scenarios if its energy density would have been higher. The financial aspect is also a very important part of our analyses, as if too high, all efforts to diminish a financial impact of using existing infrastructures may be vanished by a high CAPEX. Fortunately, this is not the case, as all technologies present a small variance among their CAPEX but hydrogen, which is much higher, whereas ammonia can provide a good alternative. Nevertheless, hydrogen CAPEX can notably diminish with the conversion of existing logistics and storing of natural gas facilities into hydrogen facilities68. Many studies on this matter have concluded that this conversion is possible and not expensive69–73, as hydrogen behaves similar to natural gas, thus it can be handled in the same way with the right cautions. Again, ammonia would be preferred to hydrogen per se as its volumetric energy is greater and transportation much cheaper.\n\nAnother concern is hydrogen’s low roundtrip efficiency at 42%, which with ammonia once again goes up to 72%. Ammonia requires only hydrogen and atmospheric air to be produced, making it available virtually anywhere the upstream source is most available. On the eventuality of a decentralized strategy, Li-Ion batteries and FESS have the best characteristics for power stabilization purposes, while PHS and AA-CAES are restricted by the environment but ideal for seasonal storage.\n\nIn conclusion, choosing a centralized strategy (as shown in Figure 10) over a decentralized one is preferred and possible, where hydrogen per se would not satisfy technical and financial parameter, hydrogen embedded into ammonia will, even if more detailed studies are required. “Hydrogen through ammonia economy via ammonia for power” [59, p. 96], this will be our SURESC’s midstream model. SURESC’s midstream starts (and upstream ends) with the storage of green ammonia, leaving its production to the upstream, followed by transportation to the centralized power station network. Next, we need to step-up once again the energy streamline into upstream and analyze how green ammonia can be produced efficiently and above all, carbon-free. Once again, the use of non-disruptive technologies, or integrable technologies would be highly recommended.\n\n“The dissemination of renewables is related to the development of several individual technologies, besides energy policies and market opportunities. A lot of unused potential is associated with renewables throughout the world”74.\n\nWe have agreed upon a centralized SURESC model that will use (as much as possible) the existing fossil-fueled energy supply chain infrastructures, and our energy carrier, ammonia, would have to be green. As stated, green ammonia is produced using green hydrogen from water electrolysis and nitrogen separated from the atmosphere, therefore requiring two main futures: water and electricity that will power both hydrogen production and the air separator for the nitrogen. As water and air are globally available will not be a matter of concern at this stage. In terms of electricity, its production shall be seen as a mere transit process within the hydrogen production phase, within ammonia production facilities, and it must be green. Selecting the right renewable energy for electricity production in upstream is again key to maximize efficiency and minimize costs to our overall SURESC model. This section will be comparing specific characteristics and parameters (financial, technical and environmental) of existing technologies, as we have done with storage technologies in midstream. For the financial parameters we have to consider CAPEX ($/kW) and the levelized cost of electricity (LCOE, measured in $/kWh). LCOE is a similar concept as LCOS, which is the breakeven cost of operation to produce electricity, often referred to as convenient summery measure to compare generating technologies5. Technically, we need to know how efficient each technology is in converting green energy into electricity, and how complicated would be to achieve this goal (installation challenges). On the environmental side, we need to know the geographical availability, as it will impact logistics, and land requirements, which is today a global environmental issue and may spike CAPEX.\n\nToday, proven renewable technologies are the following:\n\n• Solar, or photovoltaic (PV): this technology uses semiconductors cells (such as silicon) to transform photons (sunlight) directly into electricity, from it the name “photo” meaning light and “voltaic” meaning electricity75. The principle behind is simple, once solar light strikes a PV cell, a portion of its energy is transferred to the semiconductor, which knocks electrons loose75. These cells have a magnetic field which then drive these loose electrons in a flow, producing a current measurable in wattages. Even though sunlight is by far the most abundant energy source on the planet14,15, photovoltaic technology has a low efficiency rate that stands between 15%18 and 30%76. Nevertheless, San Diego University Professor Murphy18 believes that even 15% efficiency is enough for our needs, and has calculated that potentially, up to 44% of sunlight energy arriving to the ground can be recoverable (transformed into electricity) with PV cells. This means that PV cells can potentially increase their efficiency with new technological advancements. Another issue that may arise with PV is that the amount of electricity generated by surface area is low, meaning that the amount of land needed to generate high wattages of electricity is also high, creating a visible impact to the environment. Once more, due to its source availability, these panels can be installed in remote areas with low environmental impact such as deserts, where the strength of sunlight is higher. Another extremely important factor is the price. Based on the 2018 International Renewable Energy Agency report, PV has decreased its cost on average 13% on annual basis, and possibly by the end of 2020 the average cost of electricity produced with PV cells will be compared to the least-cost fossil fuel alternative. The cost per kWh generated is around 0.085 US$, and the initial investment cost is between 793 US$/kW and 2,427 US$/kW depending on location, cell technology and storage capacity13. PV is a simple and modulated technology, that can be engineered, transported and installed easily in most of the regions of the world. This is a great advantage if compared to other renewable energy technologies such as geothermal, where a high degree of knowledge and technology must be applied, or if compared to wind power, where the barrier is not due to the technology per se, but the transportation of giant wind turbines seen as a logistic nightmare;\n\n• Concentrated solar power (CSP): this technology uses the same source as PVs, the sun. Instead of taking advantage of its photons, it uses the thermal energy provided by solar irradiation concentrated on a small area to heat up a thermal energy carrier (usually salts, or water/steam) that will power a turbine to produce electricity17. There are two main advantages of this technology when compared to PV77: first, CSP experiences short term variations in cloudy days17, and second, as a thermal process, heat can be easily stored for energy normalization purposes and to supply electricity during nighttime13. There are four main CSP technologies that differ in how solar irradiation is gathered: solar power towers (SPT), parabolic through collector (PTC), linear Fresnel reflector (LFR), and parabolic dish systems (PDS), and one under development, concentrated solar thermoelectric (CST). We will not enter a detailed discussion for these technologies as it will not provide a contribution to this research. The performance of CSP depends on the amount of direct normal irradiance (DNI) provided in a certain geographical location, which intensity is greater between latitude 45˚S and latitude 45˚N17, meaning that CSP could be globally available. In terms of land use, CSP requires a larger but irrelevant amount of land than PV technology for the same power output. On the negative side, despite installation costs declining on average by 28% on an annual basis13, CSP’s CAPEX is still very high, standing between 3,400 $/kW and 7.000 $/kW13. Moreover, its LCOE is also high if compared to other green technologies, standing at 0.185 $/kWh13. The reason behind these high prices is due to the small installed capacity around the world (mostly Spain and the US)17, which needed to be largely incremented to achieve a competitive financial structure. Last, even though CSP is a simple technology, as any new entry it may come with some technical challenges. Nevertheless, is very similar to PV, including its efficiency that achieves 18.1%, and many obstacles are overcome with the PV experience.\n\n• Wind: approximately 2% of the total energy arriving from the sun to earth is transformed to kinetic energy into wind, and wind turbines convert this energy into electricity with no emissions78. Wind energy is divided into two main sectors: onshore and offshore. The technology is the same, what changes are installation issues and finances. Even though wind energy is frequently present (especially offshore due to tidal winds), the real constrain of this technology is their sizes, as wind speeds grow with higher altitudes, obliging new generation of wind turbines to rise on average 86 meter from the ground78, not only creating serious installation challenges, potentially creating fly zones constrains, killing birds flying by, but also changing the environmental sight around it. In terms of efficiency, even though the theoretical maximum efficiency of a wind turbine has been estimated to be 59% provided by the Betz Equation79, this technology converts up to 50% to electricity with new generation turbines, a high rate but leaving little space for further developments. Cost wise:\n\n◦ Onshore: like in PV cells, onshore wind power generation have seen prices dropping on average 13% on annual base, with today LCOE of 0.056 US$/kWh to produce and between 1,170 US$/kW (China) to 2030 US$/kW (UK) to install depending on location, storage capacity but above all, logistics13.\n\n◦ Offshore: for offshore wind power generation, logistics plays a key role in pricing this technology. Unfortunately, prices have dropped only 5% since 201013, and CAPEX is yet very high, standing at 4,353 $/kW. The same is for LCOE, second only to CSP technology at 0.127 $/kWh.\n\n• Hydroelectric power: this is probably the first renewable technology implemented by humankind, as it takes advantage of a simple process, the kinetic energy released by rain, which is accumulated by dams to spin turbines that produce electricity80. Nevertheless, the implementation of this technology comes with some environmental issues, as dams usually permanently inundate large portion of the upstream territories in order to create the needed reservoirs. On another perspective, these reservoirs can stimulate local economies by providing water to the agriculture sector and be used as water sources for cities. Hydroelectric power is also very efficient, managing to transform up to 90% of its total energy potential into electricity81. Nevertheless, this old technology requires thousands of hours of manpower, as it needs a strong engineering knowledge, long construction timeframes, large amounts of land works and the implementation can be very difficult. These installation challenges bring up the initial investment cost, which can be comparable to any other renewable energy source, between 1,193 US$/kW to 1,492 US$/kW13. But the real advantage is the production price, which is the lowest among all renewables: 0.047 US$/kWh13. Furthermore, this renewable source requires specific naturalistic traits such as rivers (with a certain water flow), availability of inundation areas, and piezometric jumps, which are limited traits in our environment. Most of the hydroelectric power sites in the world have already been located;\n\n• Biomass: also known as biofuel, this renewable energy source is very controversial due to the fact that its feedstock may threaten biodiversity82. Environmentalists are very concerned about the utterly use of this technology, as the plants grown for this purpose, such as switchgrass, willow trees and jatropha, not only damages the quality of the soil, but aren’t native in most of the world. Even the Food and Agriculture Organization of the United Nations (FAO) is very concerned about this issue and have produced a manual for policymakers named “Principles and Criteria for Sustainable Biofuel Production”83. There are three possible energy carriers for which biomass can be transformed into: charcoal, oil or gas, using both thermochemical and biochemical conversion technologies84. The principle is simple, convert the chemical energy stored in carbonaceous materials into a usable energy source. This process requires large amounts of arable land, large irrigation systems and special incentive policies, thus, not suitable for any territory. The initial investment cost is very low, between 950 US$/kW to 1,650 US$/kW depending on land price13. The technology is mature, simple and not expensive, therefore has low installation challenges. Nevertheless, the production cost is more expensive than other renewable energy sources, averaging 0.062 US$/kWh due to its labor-intensive maintenance nature13. In terms of efficiency, according to the Biomass Energy Resource Center85, transforming biomass into electricity will provide a range of efficiency between 20% and 25%, low if compared to other similar resources. Converting municipality waste into energy is also considered to be a biomass process, but it depends on human activities for its feedstock, not from a natural replenished, and therefore will not be considered in this research;\n\n• Geothermal: this technology was first used to produce electricity in Lardarello field in Italy in 191386. The physics is very simple, to reach and use underground steam reservoirs (hydrothermal), heated by the earth’s core, to spin steam turbines to produce electricity87. The difficult part is not the physics, but the drilling. Earth’s core heats our crust uniformly, but in some specific areas with certain geological characteristics, the heat reaches the surface. When this heat encounters a water reservoir, the water may surface as steam (Geysers), as simple heated water (hot springs), or be trapped underground (steam reservoirs). Drilling at these temperatures may be a challenge, which spikes the initial investment cost today being between 2,500 US$/kW86 and 3,976 US$/kW13. Maintenance of the equipment may also be costly, as shown in the electricity production price of 0.072 US$/kWh13. The minimum temperature required for the water reservoir to sustain an electricity geothermal power plant is approximately 150C°86. According to the temperature of the reservoir, three different technologies may apply: dry steam, flash steam or binary cycle. Unfortunately, sometimes the heat coming from Earth’s core near the surface do not encounter a water reservoir and ends up heating the rock. When this happens, a technology called enhanced geothermal system (EGS) must be used. EGS is a process in which fluids are controlled-pumped underground to reactivate pre-existing fractures and restore permeability88. This allows to expand geothermal sites and geothermal potentials. Nevertheless, efficiency may be a problem, as the geothermal-to-electricity process manages to convert on world average only 12% of steam power into electricity89. The good news is that geothermal power plants require small acreages86, as most of the work is done underground. The geothermal-to-electricity process cannot be confused with geothermal heat pumps (GHP), or ground source heat pumps (GSHP), as these are used only to heat up buildings or water, but the temperature of the fluid does not allow for electricity production. A GHP or GSHP system can be installed basically anywhere in the world, as temperature requirements are much lower.\n\n• Oceanic: there are four major types of processes today that can convert the energy accumulated by the ocean into electricity, three of them converting kinetic energy from tides, waves and currents, and the other converting ocean thermal energy (OTEC) from the ocean temperature differences90. The first three technologies use the motion of the water (waves, tides or currents) to spin turbines and produce electricity through buoys, floaters, and other submergible or floating devices. The OTEC technology uses a different approach, taking advantage of the difference in temperature between the surface of the ocean, exposed to sunrays, and the cold-water temperatures at over 1,000 m deep. The difference of only 20°C can yield a positive result90. OTEC can be implemented using two different processes: a closed cycle that uses a working fluid such as ammonia, and an open cycle that vaporizes surface water in a vacuum. The choice between these processes will be according to location, sizes, water temperature at the surface, and other factors. In Burman and Walker90 work, prepared for the US Department of Energy, they sustain that the major challenges of this technology are due to its nature, the ocean. First, the environmental impact can be a concern, as by developing such structure on water there is the need to prioritize the ocean biodiversity and ecosystem and be sure to impact the least. Consequently, this brings us to the second challenge, obtaining site permits. Permits are released not only based on the environmental study, but also based on transportation routes, national security issues, and many other factors. Last, this technology faces the dilemma of being far from any electrical grid. The cost to transport the electricity produced and injected into a national grid, may be more expensive than the technology itself. On the other hand, what is interesting about this technology is its efficiency rate that stands between 70% and 90% due to the water density57. Unfortunately, this technology has not been implemented much, therefore it’s hard to estimate a correct value for electricity production and initial investment cost. There are some infrastructures around the world such as Sihwa tidal power station (South Korea), La Rance tidal power station (France), Annapolis Royal generating station (Canada), Jiangxia tidal power station (China), Kislaya Guba tidal power station (Russia), with massive differences between each other in terms of their investment and production costs91. Salinity gradient technology is also considered to be an oceanic energy source, as it takes advantage of the difference in salinity at river mouths. This study will not consider salinity gradient due to its small practical use.\n\nWe finally arrived at the last piece of our SURESC model, the source selection. We have explored the different and most common renewable energy sources exploited on our planet, now we need to select what best could fit our upstream SURESC model. Table 2 resumes all major traits of these energy sources, and some considerations must be done. If the goal of the SURESC model is to diminish time to achieve price parity between green and brown energies by selecting one technology where to address resources to, even if in different situations different sources are superior (Norway, Brazil and Colombia for hydropower), we need to select a widely distributed energy source with high expansion capabilities. As stated, hydropower is geographically restricted, and most of its potentials are well known or well exploited92. Shayegh et al.42 show that hydropower learning curve is stagnant, thus investing resources into it would potentially mean to sustain the hydropower industry for a very long period of time. Consequently, we can exclude hydropower form our SURESC model. Next to be dismissed will be geothermal, which apart from being available only in regions where the core heats the crust, its efficiency is very low and its CAPEX very high. Iceland is doing a good job with this technology but has unique naturalistic traits that allows for a feasible usage of geothermal. Oceanic energy instead, is available globally but unavailable to all landlocked countries, risking an energy dependence from coastal neighbors. Moreover, this technology is at early stages (not mature), where CAPEX and LCOE haven’t reached a stabilized value. For it has to be dismissed too. On another level, as mentioned previously, biomass is a very controversial argument among the energy sector, as its implementation may threaten biodiversity82, thus will be dismissed too. We are now left with three mature renewable technologies, PV, CSP and wind. Not accounting for offshore wind farming due to its high CAPEX and high LCOE, onshore wind energy has also its issues, as winds tend to be stronger at higher altitudes and therefore turbines must rise very high from the ground78, creating an arguable ugly visual impact, strong logistics constrains, environmental issues (killing birds, mainly raptors) and creating aerospace security concerns. Nevertheless, it has the lowest LCOE among all renewable energies, possess an acceptable efficiency and can be delivered widely. But “solar energy dwarfs all other renewable and fossil-based energy resources combined” [17, p.467], compensating for its low efficiency rate provided by both PV and CSP, and can potentially produce sufficient energy to supply long-term growth. Consequently, I believe that solar energy would be preferred over wind energy on a global scale. We are now left with the last two: photovoltaic and concentrated solar power. This is a hard choice, as both are very similar, and more studies comparing these two technologies should be done. At status quo, I am obliged to choose PV over CSP for only one reason: costs. This seems unfair, as CSP has not seen the same technological evolution as PV, and with time, it could become a strong PV competitor, but today is too expensive both in CAPEX and LCOE and must be discarded. Finally, we have the last piece of our puzzle, solar PV, which will be the choice for our upstream SURESC model.\n\n\nConclusion\n\nThe main trait of the SURESC model is to limit the number of technologies receiving resources, allocating more resources to less technologies and speed-up technological price parity with the competition. In this paper I have proposed a possible implementation of the SURESC Model, but to extend our analyses on hydrogen, the International Renewable Energy Agency (IRENA) has produce a report prepared for the 2nd Hydrogen Energy Ministerial Meeting in Japan64, which updates hydrogen’s role in the renewable energy sector. Their findings strongly suggest that hydrogen should have a central role in the decarbonization of power production and hydrogen produced from renewable sources could become competitive soon. Furthermore, IRENA suggests that hydrogen can be used as a downstream energy provider for vehicles and heat power, in symbiosis with fuel cells. Even though there are some initiatives in this direction93,94, I don’t believe this will be a market changer, and I strongly discourage the pursue of this strategy for three main reasons:\n\n1. Hydrogen is a very flammable element and must be handled with care. To diminish risks associated to human safety, the environment and to things, hydrogen should be produced and embedded into ammonia in a confined and secured space. Ammonia is safer to handle and doesn’t ignite so easily.\n\n2. Electric powered vehicles are already on the marker. Tesla, as a pioneer, is gaining daily market shares in the automotive industry, which encouraged all major automotive makers to follow Tesla’s example. Volvo, Toyota, FIAT, Renault, BMW, Porche, Mercedes-Benz and others, all have hybrid or electric motors options associated to their models. Countries all over the world are implementing strong incentives for owners to buy electric cars. Creating a new hydrogen market didn’t worked out in the past, and just won’t be competitive anymore.\n\n3. Creating a new distribution network for hydrogen-fueled vehicles would cost much more than to adjust the current electrical backbones to provide electrical energy dispensers. The same principle can be applied for home use of hydrogen as a fuel.\n\nEven if many studies suggest that hydrogen could potentially substitute natural gas in existing middle stream infrastructures69–73, but implying that such conversions require a case-by-case analyses rather than a general assumption, many others point to ammonia as a preferred energy carrier over hydrogen55,59,67 for existing infrastructures.\n\nAs a final observation, we need to underline that the two key elements to reduce the price of ammonia are the costs of electrolyzers (used in hydrogen production) and the LCOE derived from solar PV13. Electrolyzers are scaling up quickly, form MW to GW, but their prices are decreasing slowly, and If no breakthrough comes along, projections show a reduction on half of today’s price (840 $/kW) by 205013. This trend is too slow, and incentives towards decreasing costs of electrolyzers at a faster pace should be taken into serious consideration. Diverting part of the resources used today in other technologies could incentive a faster price reduction. PVs’ LCOE depends on the scale of the market and technological advancements (R&D), but even with todays’ technology, PV could potentially provide a competitive LCOE if PV farming grew in numbers. As a real-life example, Saudi Arabia intends to start producing green ammonia form a hybrid wind-PV system as an alternative fuel for their power plants’ feedstock13. The delivery price with today’s technology is forecasted to be on average at 5 $/kg of ammonia, and according to Nagashima95, parity with fossil fuels would be achieved in the country with a price of 3.5 $/kg (-42%). This is very encouraging, as Saudi Arabia is the 3rd largest world oil producer, where its oil extraction price is very low, making it a good fit for top benchmark price parity between green ammonia and fossil fuels. Therefore, in other countries this parity should be achievable with a smaller coefficient.\n\nBased on the analyses above, Figure 11 indicates what a SURESC model could possibly be like.\n\n\nRecommendations\n\nThe SURESC model per se will speed-up the energy transformation process but it may not be enough, as it requires governments coordination with coordinated legislations39 creating non-convex economies with convenience equilibria through R&D and taxes/subsidies. Even though standard economic framework suggests that markets and not policymakers and energy geeks should decide winners and losers, in order to speed-up the energy shift process, governments should incentive a technological restrictive resources allocation policy to achieve a roadmap designed to implement the SURESC model. Furthermore, investments in new oil and gas explorations and the development of new certified reservoirs should be heavily discouraged. In 2019, new investments made on the oil and gas upstream only summed up at an astonishing 505B$, compared to 166B$ of subsidies globally allocated to the renewable energy upstream industry, and keeps rising at an average of 4% on a year base36. If that money would have been invested on a clear road map, SURESC could play an important role and the energy shift could be a reality in a relatively very short period of time. The issue is not to mitigate new emissions, but to diminish the existing ones and contemporarily quench new energy needs, as we are already producing more CO2 than the earth can possibly absorb. Perhaps, a possibility would be to pair the SURESC model to the ineffective carbon credits96 formalized by the Kyoto protocols of 1997, and relaunch them as a new green strategy. This opens the opportunity to new research topics.\n\nAs a preliminary study, this research is intended to provide a high-level analysis on the renewable industry, consequently not digging enough into each technology, and further studies are required as it presents few limitations and new research opportunities:\n\n1. A more in-depth study on each SURESC’s stream is required to check that figures and numbers align.\n\n2. This research has considered only tested technologies and dismissed those in a conception phase, which in the future could grant a better overall efficiency and become a technological breakthrough;\n\n3. Even if there is plenty of literature on solar PV applications, the environmental impact of producing and installing solar panels on such a vast scale needs to be addressed, so those of a large-scale electrolysis for hydrogen production. Other issues related to this industry such as rare earth exploitation needs further studies and discussions;\n\n4. The renewable industry is very dynamic, where prices change on a monthly base, therefore there is a need to monitor the evolution and constantly update numbers;\n\n5. The geopolitical implications of such an energy shift are not properly approached, issues like an energy free market or energy dependences require a better understanding and further studies;\n\n6. More studies on the consequences (both to the environment and to humans) for hydrogen, ammonia and NO2 leaks into the atmosphere should be done;\n\n7. There is the need to quantify SURESC in terms of costs, and size it respectively.\n\n\nData availability\n\nAll data underlying the results are available as part of the article and no additional source data are required.",
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(N.D.): Energy and the Hydrogen Economy. US Department of Energy, office of Energy Efficiency and Renewable Energy. Accessed April 2020. Reference Source\n\nChristopher K, Dimitrios R: A review on exergy comparison of hydrogen production methods from renewable energy sources. Energy Environmental Science. 2012; 5(5): 6640–6651. Publisher Full Text\n\nIRENA: Hydrogen: A renewable energy perspective. International Renewable Energy Agency, Abu Dhabi. 2019. Reference Source\n\nUS Department of Energy (N.D.): Hydrogen Storage – Basics. US Department of Energy, office of Energy Efficiency and Renewable Energy. Accessed April 2020. Reference Source\n\nNayak-Luke R, Bañares-Alcántara R, Wilkinson I: “Green” ammonia: impact of renewable energy intermittency on plant sizing and levelized cost of ammonia. Ind Eng Chem Res. 2018; 57(43): 14607–14616. Publisher Full Text\n\nNowotny J, Sorrell CC, Sheppard LR, et al.: Solar-hydrogen: environmentally safe fuel for the future. Int J Hydrogen Energy. 2005; 30(5): 521–544. Publisher Full Text\n\nPanfilov M: Underground and pipeline hydrogen storage. In: Compendium of Hydrogen Energy. Elsevier. 2016; 91–115. Publisher Full Text\n\nDNV GL: Hydrogen infrastructure Assessment. Verkenning waterstofinfrastructuur. 2017.\n\nFasihi M, Efimova O, Breyer C: Techno-economic assessment of CO2 direct air capture plants. J Clean Prod. 2019; 224: 957–980. Publisher Full Text\n\nGutknecht V, Snæbjörnsdóttir SÓ, Sigfússon B, et al.: Creating a carbon dioxide removal solution by combining rapid mineralization of CO2 with direct air capture. Energy Procedia. 2018; 146: 129–134. Publisher Full Text\n\nSutherland BR: Pricing CO2 Direct Air Capture. Joule. 2019; 3(7): 1571–1573. Publisher Full Text\n\nVan Cappellen L, Croezen H, Rooijers F: Feasibility study into blue hydrogen. Technical, economic & sustainability analysis. CE Delft. 2018. Reference Source\n\nOliveira AC: The energy shift: towards a renewable future. 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Accessed January 2020. Reference Source\n\nGroom M, Gray E, Townsend P: Biofuels and biodiversity: principles for creating better policies for biofuel production. Conserv Biol. 2008; 22(3): 602–609. PubMed Abstract | Publisher Full Text\n\nIsmail M, Rossi A, Geiger N: A Compilation of Bioenergy Sustainability Initiatives: Update. Rome: Food and Agriculture Organization of the UN (FAO). 2011.\n\nIEA Bioenergy: Basic Principles of Biomass Combustion. 2019; Accessed January 2020. Reference Source\n\nBiomass Energy Resource Center: Biomass Energy: Efficiency, Scale and Sustainability. 2014; Accessed January 2020. Reference Source\n\nUS Department of Energy (N.D.): Geothermal FAQs. Accessed January 2020. Reference Source\n\nUnwin J: What is Geothermal Energy? Power Technology, Verdict Media. 2019. Reference Source\n\nTester JW, Anderson BJ, Batchelor AS, et al.: The future of geothermal energy. Massachusetts Institute of Technology. 2006; 358. Reference Source\n\nZarrouk SJ, Moon H: Efficiency of geothermal power plants: A worldwide review. Geothermics. 2014; 51: 142–153. Publisher Full Text\n\nBurman K, Walker A: Ocean Energy Technology Overview. Federal Energy Management Program. NREL, Pub. No. DOE/GO-102009-2823. 2009. Reference Source\n\nUnwin J: Potential vs. expense: is tidal energy worth the cost? Power Technology, Verdict Media. 2019. Reference Source\n\nBartle A: Hydropower potential and development activities. Energy policy. 2002; 30(14): 1231–1239. Publisher Full Text\n\nIEA: The Future of Hydrogen – Seizing Today’s Opportunities. 2019; Accessed January 2020. Reference Source\n\nToyota: As Easy as a Conventional Car. 2020; Accessed January 2020. Reference Source\n\nNagashima M: Japan's Hydrogen Strategy and its Economic and Geopolitical Implications. 2018; 12–75. Reference Source\n\nCames M, Harthan R, Füssler J, et al.: How Additional is the Clean Development Mechanism? Oko-Institut, CLlMA.B.3/SERl2013/0026r. 2016. Reference Source"
}
|
[
{
"id": "76545",
"date": "18 Jan 2021",
"name": "Giacomo Falchetta",
"expertise": [
"Reviewer Expertise Michel Noussan: energy technologies",
"energy policy",
"Giacomo Falchetta: energy economics",
"energy modelling"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe aim of the paper may be of interest, given the importance of the subject in the current debate on the energy transition. Unfortunately, the quality of this paper is not suitable for an international publication. The author presents a theoretical “model” (I would rather call it framework, by the way) but without any description of the calculation process (which we suspect was not carried out, i.e. the framework has not been tested against real world data), and its conclusions do not seem to be reproducible. The selection of the ‘most suitable technology’ at page 18 seems not to be grounded by a scientific analysis but just based on a qualitative discussion, which is at odds with introducing what the author calls ‘a model’. Also, there is poor documentation on some key parameters/values considered. In particular, most of the figures for ammonia do not seem to be reliable. The efficiency of 72% is wrong, and the cited source (50) is not dealing with ammonia at all. Considering the ammonia supply chain, a total efficiency of 72% seems rather hard to reach (especially compared to the lower figures for hydrogen proposed by the author), as hydrogen must still be produced via electrolysis, and at the end electricity needs to be generated from ammonia to be supplied to the users, just like for the hydrogen supply chain. In addition, the energy consumption of the process needs to be considered.\nIn general, any proposed model needs to be reproducible, clearly describe the input data and the calculation procedures, to support a sound presentation of the results. Moreover, any result needs to include a description of the possible errors and approximations, by presenting a sensitivity analysis that highlights the possible variations. This is particularly true for complex energy systems, whose parameters show significant variations over time and in different world regions. All these aspects are missing in this manuscript, and thus I think that this research paper is not suitable for publication in its present form.\nAnother general comment to the framework: how about comparative advantage in generation and production + trade between countries? The introduced framework may be okay in a one-nation world with even distribution of RE potential. But if country A has significant comparative advantage for producing PV modules and generating electricity with PV and country B has a similar comparative advantage for wind turbines, then cumulative investment requirements are lower if country A targets investments in PV and country B targets investments in wind and they trade the produced electricity, rather than if both invest massively in PV (this is simply Ricardo’s comparative advantage).\nThere are other issues in the manuscript. Although it is nice to see a paper written in an ‘entertaining’ language, sometimes the tone of the papers does not look suitable for a scientific publication. Moreover, there are several instances where important references are not cited:\nSection ‘Geopolitics of the black gold’ à at least cite an IPCC report when illustrating the link between energy consumption and climate change. Discussion on ‘The Dutch Disease’ à cite and critically discuss academic literature on the resource curse please\nPage 4: “I propose that there is a direct positive relation…” à this is the core assumption of the paper and it should be better defended with some evidence, e.g. from the literature! I understand you later introduce a conceptual framework to back this assumption up, but the model is not validated or tested on real world data, so you could sketch a framework for any arbitrary assumption you wish to make. At least say ‘I hypothetise that’. Page 4: “non-convex economies” : define what they are perhaps citing some literature, it is not obvious\nSection ‘And green we go…’, line ‘(with exception of hydropower)’ à and biomass; also e.g. CSP necessitates significant amounts of water.\nSome charts are provided without numbers in axes (e.g. Figure 2), and the sources are not always properly referred to. In particular in Figure 2 the author should either specify it is a sketch or put values of the axes. Also, even if it is a sketch, put a source. In current form, it is not acceptable from a scientific perspective. Also, I question the linearity of these \"curves\"! At least specify immediately that it is a sketched graph that neglects the declining returns (second derivative negative) to learning-by-doing.\n\nMoreover, a fixed cost for fossil generation of 50 €/MWh appears rather approximated: there is in fact a range of costs depending on multiple variables, including a variation across fossil sources, including natural gas and coal (the latter being usually cheaper). Also, below Figure 2: “Solar PV has a learning quotient of 23%, intercepting fossil fuel line (price parity) with a future cumulative quantity (power deployed) at over 1000 TWh” à future when and where?! In some cases, limited examples are given that are not representing the complexity of the situation. In the section “Dangers of unbalancing the energy geopolitics”. There are also countries that are actually decreasing their carbon footprint. The example of the US is important, but additional figures from other countries may help to have a broader perspective. While it depends on producer vs. consumer perspective, it is still a false statement for the EU (see https://ec.europa.eu/eurostat/statistics-explained/images/3/35/CO2_emissions_%E2%80%94_production_and_consumption_perspective%2C_EU-28%2C_2008-2015_%28index_2008_%3D_100%29.png) Section “Energy Streams”: this section reports a limited perspective. It is true that energy cannot be created or destroyed, as stated by the first principle of thermodynamics. However, the second principle states also that the quality of energy always decreases, due to the increase of entropy, as in real world energy conversions are non-reversible. Without considering those aspects, this discussion is misleading.\nSection “Downstream”: the author states “We shall therefore not account for the transportation sector in this research as it will shape and adapt by itself according to the external environment and clients’ needs”. This sentence is very hard to justify, since the EV market is currently heavily pushed by environmental policies and public incentives. The author also states that transport “will be the strongest growing energy demand sector in the future”. Thus, overlooking it seems not a satisfactory choice. The authors should also discuss the possible limitations on shifting towards electricity for specific applications, such as buildings heating. While heat pumps are promising, they are not directly applicable in all contexts, and they may require a significant improvement of power networks’ installed capacity, especially in some specific time frames.\nThere are other minor typos/errors. “concentrated solar PV” is a typo, as concentrated solar power is a different technology than photovoltaic (PV). Cumulative power deployed (describing Figure 2) cannot be expressed in TWh, which is a unit for energy and not for power.\nOther typos/language issues:\nPage 3: “Not least, the impact to the environment for such amounts of fossil-fuel consumptions is well documented8–11 and accounts” à “Not least, the impact on the environment for such amounts of fossil-fuel consumption is well documented8–11 and is responsible for…”\n\nPage 4: “The randomization nature of the world’s natural resources distribution” à randomization is improper; I would say uneven distribution\n\nPage 4: “lacking 11 TWh of power generation that has been supplied by carbon fuels” à typo, should be 101 TWh\n\nPage 4: “The literature seam to point” à seems to point\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "6290",
"date": "21 Jan 2021",
"name": "Emiliano Finocchi",
"role": "Author Response",
"response": "Denigrating other people work is not a constructive way of doing a peer review. Contents could be discussed without the need for an offensive use of the language. This review seams to be written from a biased source and questions the integrity of the reviewer itself. When the reviewer refers to my paper as written in a “entertaining language”, I would like to underline that this paper is intended not only for the academics, but for practitioners too. Many definitions are written on purpose to help the non-academic reader. Down to content: First, this is a Theory-Building Research (for more information on theory-building please consult: Lynham, Susan. (2002). The General Method of Theory-Building Research in Applied Disciplines. Advances in Developing Human Resources), and not an empirical study, where theories are built on other researchers’ work following a rigorous scientific reasoning. The theoretical model (not a framework) I present should be tested with empirical data on a second study (including a sensitivity analyses), opening an opportunity rather than a flaw. Real data can support or not support the model, in either case, it can’t question methodology. To build the model, I have started from Shayegh et al work (Shayegh S, Sanchez DL, Caldeira K: Evaluating relative benefits of different types of R&D for clean energy technologies) and mathematically calculated my way through. Calculations can be found from page 5 to page 8. The figures (not sketches) are generic, based on previous studies, and having a scale attached to the axes would not change the result. Figure 2 in particular, is drawn from Shayegh et al work. Doubting this figure, means to doubt a published work and should not be mentioned in this review. Moreover, it’s well written that the starting point which Figure 2 was drawn, is driven by Shayegh et al work. In my second version I will make this clearer. In fact, when the reviewer states on Figure 2 that “I question the linearity of these \"curves” “he is questioning the linearity of Shayegh et al work, not mine. It is clear that the reviewer did not spent time to read Shayegh et al work at all. When the reviewer comments “Figure 2: “Solar PV has a learning quotient of 23%, intercepting fossil fuel line (price parity) with a future cumulative quantity (power deployed) at over 1000 TWh” à future when and where?!” misses the entire point of what I am trying to support. When and where are not the questions I am answering. “How fast or how slow compared to”, would be the correct question. The reviewer is asking questions I myself did not ask in the paper. Moreover, the reviewer states that the model is not replicable, but it doesn’t explain why (it doesn’t help much). When the reviewer states that “The selection of the ‘most suitable technology’ at page 18 seems not to be grounded by a scientific analysis but just based on a qualitative discussion” I rather question if the reviewer acknowledges that a qualitative analysis is indeed a scientific analysis. When the reviewer refers to ammonia as “The efficiency of 72% is wrong” I may understand his doubts, as there is an error on that reference. The correct reference 50 is “Nayak-Luke, R., Bañares-Alcántara, R., & Wilkinson, I. (2018). “Green” ammonia: impact of renewable energy intermittency on plant sizing and levelized cost of ammonia. Industrial & Engineering Chemistry Research, 57(43), 14607-14616”. Nayak-Luke et al work states green ammonia is achievable at 72%. This is a published work. If we shall question every published work without another publishable work that dismisses the previous one, why are we so busy to publish? Based on Nayak-Luke work, the reviewer is wrong. I will correct all references in my second version. When the reviewer states “Section ‘Geopolitics of the black gold’ à at least cite an IPCC report” what it really means? What is “at least” for him? Are my sources not enough? Why? “At least” is not a constructive comment if it’s not backed up. The reviewer’s comment on the Dutch Disease is not clear. I really did not understand, as it was a dismissible reference, not part of the main reasoning. He could have simply advised to remove the comment. I don’t believe there is the need to remove it, I will keep it in my next version. The reviewer’s comment on non-convex economies is understandable. I will explain more on the subject in my second version of the study. In terms of competitivity (Riccardo’s comparative advantage), the study argues that if countries cooperate and basket all resources for a common technology, that technology will achieve competitiveness at a faster pace. Rather than building wind turbines in your country, use the resources to build solar PV in other countries in a cooperative context. This implies building power generation in a country and power usage in others. If the reviewer had focused on the paper, he would understand that the framework within which the model is built, does not consider political implications. I will make it explicit in the second version that the model foresees the collaboration of nations rather than competition among them. The entire aim of the paper is to push for cooperation and collaboration, and not to spike competitiveness. Riccardo’s paper assumes winners and losers, in a competitive environment, which in my paper, I assume that in a global warming scenario, we all win, or we all lose. When the reviewer states that “the second principle states also that the quality of energy always decreases, due to the increase of entropy, as in real world energy conversions are non-reversible. Without considering those aspects, this discussion is misleading.” I don’t see where is misleading. Maybe the reviewer could share with us how this is misleading. Section “downstream”, as suggested by the reviewer, opens to another (or many), new studies. Nevertheless, the reviewer is correct, and I shall explicitly define the boundaries of the study. I will correct this aspect in the second version. “Other type of language errors” section of the review will be amended as suggested in the second version of the paper. Thank you"
}
]
}
] | 1
|
https://f1000research.com/articles/9-1391
|
https://f1000research.com/articles/10-444/v1
|
04 Jun 21
|
{
"type": "Research Article",
"title": "Characterization of CTX-M-15-Klebsiella pneumoniae from inpatients and outpatients of a teaching hospital",
"authors": [
"Muzaheed Muzaheed",
"Naveed Sattar Shaikh",
"Saeed Sattar Shaikh",
"Sadananda Acharya",
"Shajiya Sarwar Moosa",
"Mohammad Habeeb Shaikh",
"Faisal M. Alzahrani",
"Amer Ibrahim Alomar",
"Muzaheed Muzaheed",
"Naveed Sattar Shaikh",
"Sadananda Acharya",
"Shajiya Sarwar Moosa",
"Mohammad Habeeb Shaikh",
"Faisal M. Alzahrani",
"Amer Ibrahim Alomar"
],
"abstract": "Background The presence of Extended-spectrum β-lactamase (ESBL) positive bacteria in hospital setting is an aggravating influential factor for hospitalized patients, and its consequences may be hazardous. Therefore, there is a need for rapid detection methods for newly emerging drug-resistant bacteria. This study was aimed at the molecular characterization of ESBL-positive Klebsiella pneumoniae isolates recovered from clinical samples.\n\nMethods A total of 513 K. pneumoniae isolates were obtained from various clinical samples during June 2019 to May 2020. The collected isolates were investigated for antimicrobial susceptibility (antibiogram), and PCR and DNA sequencing were performed to analyse the ESBL genes.\n\nResults Among the 513 isolates, as many as 359 (69.9%) were ESBL producers and 87.5% were multi-drug resistant, while none had resistance to imipenem. PCR scored 3% blaTEM, 3% blaSHV, and 60% blaCTX-M-15 genes for the tested isolates.\n\nConclusion The study showed that CTX-M-15 was the major prevalent ESBL type among the isolates. Additionally, all the isolates were susceptible to carbapenems. Screening and detection of ESBL tests are necessary among all isolates from the enterobacteriaceae family in routine microbiology laboratory to prevent associated nosocomial infections. A larger study is essential to understand molecular epidemiology of ESBL producing organisms to minimize morbidities due to these multidrug resistant organisms.",
"keywords": [
"K. Pneumoniae",
"ESBL",
"TEM",
"SHV",
"CTX-M-15"
],
"content": "Introduction\n\nThe emergence of Extended-spectrum β-lactamase (ESBLs) producing organisms has imposed a great threat on majority of the antibiotic classes, particularly cephalosporins.1 The situation worsens when the patient infected with ESBL-producing organism is administered an antibiotic to which the organism is resistant.1 Clinical practitioners globally have been facing problems related to plasmid mediated ESBL producing Klebsiella pneumoniae (K. pneumoinae). These plasmids contain genes encoding resistance to antibiotics such as aminoglycosides, sulfonamides, tetracycline, chloramphenicol, and quinolones.2 Cephalosporins are β-lactam antibiotics that are widely used in clinical practice and in the treatment of bacterial infections.3 In addition, K. pneumoniae is reported in nosocomial infections and community acquired infections.4\n\nA study conducted by Maltezou et al.5 revealed that the incidence rate of ESBL producing K. pneumoniae infection was 16.71% for Northern Europe, 24.41% for Southern Europe, 58.71% for Eastern Europe, 28.2% for the Asia Pacific region, 51.9% for South America, and 12.3% for North America.5\n\nCTX-M-type β-lactamase, has become more predominant than conventional SHV and TEM-type ESBL, which have covered an extensive range of clinically significant bacteria and over a wide environmental area.6 Moreover, strains that yield ESBL often reveal resistance to antibiotics belonging to other classes (i.e. aminoglycosides, quinolones, and sulfonamides); making its management more complicated.7\n\nConsequently, this class of bacteria makes a need to ensure the reporting of ESBL producers in clinical isolates and detection of newly emerging drug resistant isolates. The changing trends of drug resistant ESBL-producing K. pneumoniae need time to watch for management, confinement and isolation of patients in hospitals before discharge. It is also necessary to monitor the prevalence and types of ESBLs and define the appropriate therapeutic options accordingly. Hence, the purpose of the current study was to observe the current trends of ESBL producing K. pneumoniae drug resistant patterns and to identify the occurrence of ESBL genes in Sindh region of Pakistan.\n\n\nMethods\n\nA total of 1458 non-duplicate clinical samples were collected between June 2019 and May 2020 from outpatient and inpatient wards of People's University of Medical and Health Sciences, Nawabshah, Pakistan through its diagnostics and research laboratory. The samples were not specifically collected for this research, they were used after the completion of routine laboratory investigations upon the permission of the concerned laboratory's authority. The isolation of bacteria was carried out by conventional bacteriological techniques and identification was confirmed by API 20E identification kit (BioMerieux, France).8 As many as 513 K. pneumoniae isolates from various clinical samples and sites (Figure 1A) were obtained and included in the present study.\n\nK. pneumoniae isoaltes obtained from various clinical samples showed high prevalence as blood borne infections (A); genotypic distribution showed blaCTX-M-15 to be highly prevalent (B); age group wise analysis showed elderly group of 50 years old and above showed high incidences (C); ESBL positivitiy to be 70% among all isolates tested (D), with their antibiotic susceptibility profile (E).\n\nPatients referred by their primary physicians for screening tests (such as blood complete count and erythrocyte sedimentation rate (ESR)) were recruited in the study. The clinical samples including blood, sputum, urine, cerebrospinal fluid, tracheal secretions, and pus samples were collected by standard techniques (Figure 1A). The clinical samples, which yielded the K. pneumoniae were selected for further assessment, while others were excluded. The demographic data was retrieved from clinical survey that included age, gender, specimen type, town, and susceptibility patterns (Table 2).\n\nAntimicrobial susceptibility testing (AST) was performed by Kirby Bauer method on Mueller-Hinton agar plates (Beckton Dickinson, Sparks, MD, USA) according to Clinical Laboratory Standards Institute (CLSI).8 Disks (Beckton Dickinson) comprising of the following antibiotics were used: cefixime 30 μg, amoxicillin 30 μg, ceftazidime 30 μg, cefotaxime 30 μg, Ofloxacin 10 μg, imipenem 10 μg, amikacin 30 μg, gentamicin 10 μg, ciprofloxacin 5 μg and chloramphenicol 30 μg.\n\nDouble disk diffusion methods were used to detect ESBL using four antibiotic disks: cefotaxime 30 μg, cefotaxime with clavulanic acid 10 μg, ceftazidime 30 μg, and ceftazidime with clavulanic acid 10 μg. A more than 5 mm increase in zone of inhibition width for whichever antimicrobial agent tested in combination with clavulanic acid against its zone of inhibition when tested alone was labelled as ESBL positive.9 The inoculum and incubation conditions were the same as recommended for standard disk diffusion. K. pneumoniae ATCC 700603 (American type culture collection, ATCC, Manassas, USA) was used as quality control strain.\n\nBacterial genomic DNA was seperated by boiling the young bacterial colony in 50μl distilled water in a hot bath set at 98°C. This DNA template was used for all PCR reactions. Amplification of blaTEM, blaSHV and blaCTX-M-15 ESBL genes was done on GeneAmp PCR System 9700 (Applied Biosystems, Foster City, CA, USA). The primers used are given in Table 1. The PCR yields were run on 1% agarose gels and observed in UV light. Purified PCR products of CTX-M genes were sequenced on an Applied Biosystems 3730 DNA analyzer (Applied Biosystems, Foster City, CA, USA).\n\n* Ref: Muzaheed et al., 2008 (32).\n\nThe data were analyzed by Statistical Package of Social Sciences (SPSS) version 21.0. Continuous and categorical variables were analyzed by t-test and Chi-square testing, respectively (these tests can also be carried out on the open source software R). Variance of resistance levels of various antimicrobials in ESBL producing isolates versus non-ESBL producing isolates were calculated by the Fisher exact test. The data was analyzed at 95% Confidence interval (p ≤ 0.05 indicates a significant difference).\n\n\nResults\n\nDuring the study period, a total of 513 (35.18%) K. pneumoniae were isolated. From those 513 positive cultures, 411 (80.1%) belonged to males and 102 (19.8%) to females (p = 0.0001). The demographic characteristics of patients including age, gender, rural or urban, and clinical interventions are summarized in Table 2. The results show that the majority of patients were in the older age group (50 and above) and lived in urban areas. The categories of patient's ages have been shown in Figure 1C. The mean age of the total study subjects was 48.5 ± 8.9 years.\n\nOut of 513 isolates 359 (69.9%) were ESBL producing K. pneumoniae (Figure 1D). The incidences of ESBL was higher in males as compared to females. The frequency of ESBL producing K. pneumoniae from different samples (n = 359) has been shown in Table 3 and Figure 1A. The means ± SD age of patients with ESBL positive and negative was 47 ± 17.5 years and 47.5 ± 12.8 years, respectively (p = 0.093).\n\nThe results show that 64% of K. pneumoniae in our sample were resistant to Amoxicillin and Cefixime. In addition, an important drop of 30–40% was perceived in the susceptibility for all Cephalosporins. However, K. pneumoniae presented a dissimilar sensitivity rate to Chloramphenicol, Ofloxacin, Gentamicin and Amikacin with 94%, 98%, 97%, and 97%, respectively and depicted in Table 4.\n\nRegarding the PCR and DNA sequencing of ESBL genotypes, it was found that all of the ESBL-positive K. pneumoniae isolates had one or more ESBL genes that were tested in the present study and presented in Table 5. Overall, 83.56% (300/359) of K. pneumoniae isolates were positive for one or more ESBL genes. The PCR assay and DNA sequencing results indicated the following frequencies of ESBL genotypes: 85% blaCTX-M-15 gene, 26% blaSHV gene, and 28% blaTEM gene.\n\n* Overall Total CTX-M-15 is 255 [85]; SHV = 78 [26] and TEM = 84 [28].\n\n\nDiscussion\n\nESBL's are the major causes of β-lactam antibiotic resistance, particularly in K. pneumoniae, which is amongst the most common gram-negative bacteria belonging to Enterobacteriaceae families.10 A study from Ziauddin University Karachi, Pakistan has showed that ESBL producing K. pneumoniae frequency is 84.16% amongst reported cases.11 Similarly, Saleem et al. (Aga Khan University, Karachi, Pakistan) have reported a frequency of 80% of ESBL producing K. pneumoniae.12 These findings were higher as compared to the results presented in the current study, which showed that the frequency of ESBL producing K. pneumonia is 69.6% with a higher incidence in male than in female patients. In this repect, the frequency of EBSL producing K. pneumoniae varies from one institution/hospital to another. Several factors could govern this variation such as; the use of antibiotics, drug dose, infection control measures, treating physicians, and the duration of drug therapy - all of these elements may cause a difference in results. The frequency of ESBL producing K. pneumoniae in previous research conducted at Aga Khan University Karachi, Pakistan was 30.1% and 47.8%, which is low compared to the present study, as well as, previous studies conducted by Mansouri et al.10 and Ejaz et al.13 A Pakistani study found a frequency of ESBLs producing K. pneumoniae of 70%,14 which is in agreement with our study.\n\nCarbapenems are often the final influential therapy of choice to treat infections resulting from MDR Enterobacteriaceae. Based on our study and other studies, 100% sensitivity was seen with Imipenem, which have been found to be the most effective antibiotics on the isolates that produce ESBLs. This is an important result of the present study because many infections can be treated with Carbapenems.12,15\n\nblaCTX−M is a predominant genotype in this area of the subcontinent. A further study from Pakistan has reported that 72% of ESBL producing strains had the blaCTXM−15 gene, which was higher than the prevalence of blaCTX-M gene reported in the present study.16 Limited studies from different regions have also shown a higher prevalence of the blaCTX-M genotype amongst strains including 84.7% (Chile), whereas a very high prevalence of 98.8% was reported in China and, significantly, a low prevalence of 13.6% in Tanzania.17–19\n\nIn conclusion, the findings of the current study emphasizes the urgent need for screening and surveillance of ESBL producing K. pneumoniae in routine microbiology laboratories for early detection, prompt intervention, and successful clinical management before exacerbation of the infection magnitude. In this regard, the current findings may be a valuable contribution to the medical literature providing physicians with an updated prevelance status of ESBL producing K. pneumoniae. Finally, the limited sample size along with the limited time frame are two common limitations, which could affect the outcomes of the study.",
"appendix": "Acknowledgement\n\nThe authors greatly acknowledges the assistance received from Dr. Omar Soliman Mohamed Elmasry, Imam Abdulrahman Bin Faisal University, Dammam, through various stages of this study. The authors are very thankful to the Diagnostic and Research Laboratory, People's University of Medical and Health Sciences (PUMHS) Nawabshah, Sindh, Pakistan, for their contribution to this research.\n\n\nEthical approval\n\nPrior to the study we contacted the institutional review board representative (PUMHS, IRB) for discussion. The IRB representative confirmed that since patients are not directly involved and the samples are not collected specifically for this research there is no need for IRB approval. Patient data consent was not required as we didn't retrieve any personal information, such as medical record numbers, national ID, and names, from patients. The data was completely anonymous and thus does not violate the privacy or confidentiality of any of the patients.\n\n\nReferences\n\nAli Abdel Rahim KA, Ali Mohamed AM: Prevalence of Extended Spectrum β-lactamase-Producing Klebsiella pneumoniae in Clinical Isolates. Jundishapur J Microbiol. 2014; 7(11): e17114-e. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDallenne C, Da Costa A, Decre D, et al.: Development of a set of multiplex PCR assays for the detection of genes encoding important beta-lactamases in Enterobacteriaceae. J Antimicrob Chemother. 2010; 65(3): 490–5. PubMed Abstract | Publisher Full Text\n\nPeer Maroof Ahmad MAT, Bashir AF, Ahmed K: Extended Spectrum-β-Lactamase producing Klebsiella pneumoniae at a tertiary care setup in Kashmir, India: Comparative phenotypic detection and antimicrobial susceptibility pattern. Rev Infect. 2010; 1(2): 124–33.\n\nMunoz-Price LS, Poirel L, Bonomo RA, et al.: Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis. 2013; 13(9): 785–96. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaltezou HC: Metallo-beta-lactamases in Gram-negative bacteria: introducing the era of pan-resistance? Int J Antimicrob Agents. 2009; 33(5): 405 e1-7. PubMed Abstract | Publisher Full Text\n\nPishtiwan AH, Khadija KM: Prevalence of blatem, blashv, and blactx-M Genes among ESBL-Producing Klebsiella pneumoniae and Escherichia coli Isolated from Thalassemia Patients in Erbil, Iraq. Mediterr J Hematol Infect Dis. 2019; 11(1): e2019041-e. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMahon CR, Lehman DC, Manuselis G: Textbook of Diagnostic Microbiology - E-Book: Elsevier Health Sciences. 2014.\n\nMatuschek E, Brown DF, Kahlmeter G: Development of the EUCAST disk diffusion antimicrobial susceptibility testing method and its implementation in routine microbiology laboratories. Clin Microbiol Infect. 2014; 20(4): O255–66. PubMed Abstract | Publisher Full Text\n\nMuzaheed DY, Adams-Haduch JM, Shivannavar CT, et al.: Faecal carriage of CTX-M-15-producing Klebsiella pneumoniae in patients with acute gastroenteritis. Indian J Med Res. 2009; 129(5): 599–602. PubMed Abstract\n\nMansouri S, Kalantar Neyestanaki D, Shokoohi M, et al.: Characterization of ampc, CTX-M and mbls types of β-lactamases in clinical isolates of Klebsiella pneumoniae and Escherichia coli producing Extended Spectrum β-lactamases in Kerman, Iran. Jundishapur J Microbiol. 2014; 7(2): e8756-e. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAfridi FI, Farooqi BJ, Hussain A: Frequency of extended spectrum beta lactamase producing enterobacteriaceae among urinary pathogen isolates. J Coll Physicians Surg Pak. 2011; 21(12): 741–4. PubMed Abstract\n\nSaleem AF, Qamar FN, Shahzad H, et al.: Trends in antibiotic susceptibility and incidence of late-onset Klebsiella pneumoniae neonatal sepsis over a six-year period in a neonatal intensive care unit in Karachi, Pakistan. Int J Infect Dis. 2013; 17(11): e961–5. PubMed Abstract | Publisher Full Text\n\nEjaz H, Ul-Haq I, Mahmood S, et al.: Detection of extended-spectrum β-lactamases in Klebsiella pneumoniae: comparison of phenotypic characterization methods. Pak J Med Sci. 2013; 29(3): 768–72. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBari F, Shah H, Wazir R: Frequency and detection of extended spectrum betalactamase in Escherichia coli and Klebsiella pneumoniae: A study at lady reading hospital peshawar. J Postgrad Med Inst. 2015; 29(4).\n\nSourav chakraborty KM, Sarker PK, Zahangir Alam MD, et al.: Prevalence, antibiotic susceptibility profiles and ESBL production in Klebsiella pneumoniae and Klebsiella oxytoca among hospitalized patients. Period biol. 2016; 118(1): 53–8. Publisher Full Text\n\nEjaz H, Ul-Haq I, Mahmood S, et al.: Detection of extended-spectrum beta-lactamases in Klebsiella pneumoniae: comparison of phenotypic characterization methods. Pak J Med Sci. 2013; 29(3): 768–72. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPavez M, Troncoso C, Osses I, et al.: High prevalence of CTX-M-1 group in ESBL-producing enterobacteriaceae infection in intensive care units in southern Chile. Braz J Infect Dis. 2019; 23(2): 102–10. PubMed Abstract | Publisher Full Text\n\nQuan J, Zhao D, Liu L, et al.: High prevalence of ESBL-producing Escherichia coli and Klebsiella pneumoniae in community-onset bloodstream infections in China. J Antimicrob Chemother. 2017; 72(1): 273–80. PubMed Abstract | Publisher Full Text\n\nSonda T, Kumburu H, van Zwetselaar M , et al.: Prevalence and risk factors for CTX-M gram-negative bacteria in hospitalized patients at a tertiary care hospital in Kilimanjaro, Tanzania. Eur J Clin Microbiol Infect Dis. 2018; 37(5): 897–906. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "86850",
"date": "05 Jul 2021",
"name": "SUPRIT DESHPANDE",
"expertise": [
"Reviewer Expertise HIV molecular virology",
"immunology and antibody discovery"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 “Characterization of CTX-M-15-Klebsiella pneumoniae from inpatients and outpatients of a teaching hospital” by Muzaheed et al., the authors studied and surveyed the prevalence of ESBL producing genes in Klebsiella pneumoniae infections. The authors have screened K. pneumoniae from 1458 clinical samples from the individuals enrolled under a different study. Increase in number of cases due to bacterial drug resistance has become a severe cause of global concern. Here, authors have screened the K. pneumoniae isolates and with the help of genotyping they tried to identify the distribution of different class of ESBL genes and their prevalence.\nThis paper imparts more of a kind “molecular epidemiological surveillance” of ESBL producing genes in one of the predominant nosocomial pathogen K. pneumoniae, whereas the title of the paper is about characterization of one of the ESBL producing genes (CTX-M). Author needs to re-think about the title of this paper as the existing title seems not suitable for the kind of study actually done and reported through this manuscript\n\nSince the samples were not specifically collected for this study, then the inclusion and exclusion criteria would have been not as per this current study? This needs to be clarified. Also, it would be better to shift the entire sentence about sample collection from isolation and identification paragraph to the paragraph on participants inclusion and exclusion criteria.\n\nUnder methods, the second paragraph on sample collection, inclusion and exclusion criteria needs to be shifted first and the present first paragraph on isolation and identification needs to be shifted second.\n\nDouble parentheses for ESR in inclusion and exclusion criteria paragraph in methods section need to be removed.\n\nAuthor mentioned Kirby bar method, it needs to be mentioned as Kirby Bar Disk diffusion method.\n\nUnder methods section in the paragraph on ESBL screening and confirmation by phenotypic methods, in the last but one line the standard disc diffusion where “method” is missing needs to be written.\n\nThere is no mention about ESBL positive K. pneumoniae in the Figure 1A description/legend, whereas the same has been described in the running text.\n\nFigure 1B is not described in the running text. Also in figure there is confusion with the numbering corresponds to the genes, for instance in TEM, SHV and CTX-M there should be three numbers (one number for each gene) but only two numbers are given along with the percentage. Please check and confirm.\n\nClinical relevance of demographic characteristics with the results obtained in this study is not described clearly by the authors in discussion section. This needs to be elaborated.\n\nAs per the study it’s not only Carbapenems but also quinolones (Ciprofloxacin) also that showed their effectiveness with 100% sensitivity. Authors has missed to point it out and describe about it in the running text.\n\nThe highest percent of ESBL was found in blood specimens, is there any scientific reason for this? If yes, it needs to be described in the discussion part.\n\nWhat is the denominator for 411 males and 102 females clinical specimens from whom K. pneumoniae were isolated? If the sample sizes for male and female donors were different then before coming to the conclusion saying that in males it was higher than in females it needs to be proved statistically. Authors needs to clarify this.\n\nAs per the Fig 1E, the authors have tested different classes of antibiotics, here what was the rationale behind choosing these specific antibiotics? The results illustrates that the more percent resistance was mainly observed in the antibiotics belongs to class of cephalosporins, is there any clinical relevance for this kind of observation, this needs to be discussed in the discussion section with relevant references if available.\n\nAuthors mentioned in the method that the genomic DNA was separated upon boiling the bacterial colony at 98 degrees Celsius and the same DNA was used for PCR amplification of ESBL genes. The ESBL genes are mainly encoded by plasmid DNA. Here, in this study the authors used which DNA (bacterial genomic DNA or plasmid DNA) for PCR amplification to understand the genetic diversity of ESBL genes?\n\nAuthors mentioned the amplicons were sequenced to identify the genetic diversity of different ESBL producing genes, I am not sure about the journal’s policy and whether these need to be submitted to the GenBank?\n\nRelevant references needs to be quoted for conventional bacteriological techniques in methods.\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": "6888",
"date": "23 Jul 2021",
"name": "Saeed Sattar Shaikh",
"role": "Author Response",
"response": "We thank you for your valuable comments and suggestions. We have revised our manuscript accordingly. Please, find below our responses to reviewer comments. This paper imparts more of a kind “molecular epidemiological surveillance” of ESBL producing genes in one of the predominant nosocomial pathogen K. pneumoniae, whereas the title of the paper is about characterization of one of the ESBL producing genes (CTX-M). Author needs to re-think about the title of this paper as the existing title seems not suitable for the kind of study actually done and reported through this manuscript Author’s Response: Thank you for your suggestions we have modified title as suggested. Since the samples were not specifically collected for this study, then the inclusion and exclusion criteria would have been not as per this current study? This needs to be clarified. Also, it would be better to shift the entire sentence about sample collection from isolation and identification paragraph to the paragraph on participants inclusion and exclusion criteria. Author’s Response: The inclusion and exclusion criteria were set based on our focused organism that is Klebsiella pneumoniae. Also, we have shifted the entire sentence about sample collection from isolation and identification paragraph to the paragraph on participants inclusion and exclusion criteria. Under methods, the second paragraph on sample collection, inclusion and exclusion criteria needs to be shifted first and the present first paragraph on isolation and identification needs to be shifted second. Author’s Response: Updated shifted as suggested. Double parentheses for ESR in inclusion and exclusion criteria paragraph in methods section need to be removed. Author’s Response: Thank you, removed. Author mentioned Kirby bar method, it needs to be mentioned as Kirby Bar Disk diffusion method. Author’s Response: Thank you, updated as suggested. Under methods section in the paragraph on ESBL screening and confirmation by phenotypic methods, in the last but one line the standard disc diffusion where “method” is missing needs to be written. Author’s Response: Thank you, updated as suggested. There is no mention about ESBL positive K. pneumoniae in the Figure 1A description/legend, whereas the same has been described in the running text. Author’s Response: Thank you, updated figure legend as suggested. Figure 1B is not described in the running text. Also in figure there is confusion with the numbering corresponds to the genes, for instance in TEM, SHV and CTX-M there should be three numbers (one number for each gene) but only two numbers are given along with the percentage. Please check and confirm. Author’s Response: figure 1B is now mentioned in running text. The names of the genes have been written as per the standard procedures followed in previous literatures. Clinical relevance of demographic characteristics with the results obtained in this study is not described clearly by the authors in discussion section. This needs to be elaborated. Author’s Response: The aim and objectives of the study were to perform molecular epidemiology of the isolates regardless of their clinical sources and clinical presentations. This was beyond the scope of clinical correlations. However, existing data were being used for further study and analysis where additional publication is being tried. As per the study it’s not only Carbapenems but also quinolones (Ciprofloxacin) also that showed their effectiveness with 100% sensitivity. Authors has missed to point it out and describe about it in the running text. Author’s Response: Carbapenems are often the final influential therapy of choice to treat infections resulting from MDR Enterobacteriaceae that is why the authors have only concentrated on it. The highest percent of ESBL was found in blood specimens, is there any scientific reason for this? If yes, it needs to be described in the discussion part. Author’s Response: Because the clinical samples were mostly from blood. What is the denominator for 411 males and 102 females clinical specimens from whom K. pneumoniae were isolated? If the sample sizes for male and female donors were different then before coming to the conclusion saying that in males it was higher than in females it needs to be proved statistically. Authors needs to clarify this. Author’s Response: The dominator is 513, which were positive K. pneumoniae Out of which 411 were males and 102 females. As per the Fig 1E, the authors have tested different classes of antibiotics, here what was the rationale behind choosing these specific antibiotics? The results illustrates that the more percent resistance was mainly observed in the antibiotics belongs to class of cephalosporins, is there any clinical relevance for this kind of observation, this needs to be discussed in the discussion section with relevant references if available. Author’s Response: The antibiotics were selected according to CLSI guidelines, Physician’s desk reference, Medical Letters and Peer-reviewed literature. Authors mentioned in the method that the genomic DNA was separated upon boiling the bacterial colony at 98 degrees Celsius and the same DNA was used for PCR amplification of ESBL genes. The ESBL genes are mainly encoded by plasmid DNA. Here, in this study the authors used which DNA (bacterial genomic DNA or plasmid DNA) for PCR amplification to understand the genetic diversity of ESBL genes? Author’s Response: Bacterial genomic DNA was used for PCR amplification. Whereas Trans-conjugation experiments were performed to identify conjugal resistance transfer. Which will be reported in next possible publication. Authors mentioned the amplicons were sequenced to identify the genetic diversity of different ESBL producing genes, I am not sure about the journal’s policy and whether these need to be submitted to the GenBank? Author’s Response: As per our Institutional policy, we have to deposit all research data to our institution. Hence it takes much administrative procedures before the institution deposits it to GenBank. Relevant references needs to be quoted for conventional bacteriological techniques in methods. Author’s Response: Thank you, reference added as suggested."
}
]
},
{
"id": "88330",
"date": "05 Jul 2021",
"name": "Abbas Farahani",
"expertise": [
"Reviewer Expertise Microbiology"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSummary:\n\nThis research article seeks to isolate and characterize ESBL-producing K. pneumoniae from inpatients and outpatients. The ESBL genotype and molecular relatedness of strains identified here were done using standard and acceptable methods and procedures. K. pneumoniae isolates were identified in 35.18% (n=513) of all samples. More than half (69.9%) of all isolates were ESBL producers and all of the ESBL-positive K. pneumoniae isolates had one or more ESBL genes. Their study showed that CTX-M-15 was the major prevalent ESBL type among the isolates.\n\nComments:\n\nTeaching hospital needs description of the hospital, number of beds, number of admission and other information about the hospital is required.\n\nThe authors claimed that to have used the CLSI guideline, while reference number 8 is related to the European Committee on Antimicrobial Susceptibility Testing (EUCAST)?\n\nWhere did you source your antibiotics from?\n\nThe concentration of each reaction in PCR must be added.\n\nPlease provide information about quantifying and qualify DNA samples.\n\nPlease add company and country for SPSS software.\n\nThe sequenced products of the isolates need to be deposited in a database (i.e. Genbank) and accession numbers need to be given.\n\nProvide the accession numbers of the sequenced products in the article.\n\nIn Table 2; mean ± SD is 47 ± 17.5 while in text is 48.5 ± 8.9 years? Please explain.\n\nIn the title of the article the authors have mentioned that isolates collected from inpatients and outpatients of a teaching hospital, but in the main text is no mention of them and the number of isolates in each group is not mentioned? Please explain.\n\nFinally, I recommend merging both Results and Discussion sections for better clarity and impact, and move to Rapid Communication submission.\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? Yes",
"responses": [
{
"c_id": "6887",
"date": "23 Jul 2021",
"name": "Saeed Sattar Shaikh",
"role": "Author Response",
"response": "We thank the reviewer for taking time and reviewing our article. We have revised our manuscript to address the comments. Please, find below our responses to reviewer comments. Teaching hospital needs description of the hospital, number of beds, number of admission and other information about the hospital is required. Author’s Response: Details of hospital updated. The authors claimed that to have used the CLSI guideline, while reference number 8 is related to the European Committee on Antimicrobial Susceptibility Testing (EUCAST)? Author’s Response: Replaced with new reference. Where did you source your antibiotics from? Author’s Response: Updated the details of antibiotics. The concentration of each reaction in PCR must be added. Author’s Response: PCR reaction mixture details are added. Please provide information about quantifying and qualify DNA samples. Author’s Response: The information and data were not mentioned because, for PCR reaction purified DNA was not required and crude DNA was sufficient for detection. Please add company and country for SPSS software. Author’s Response: Updated the details of SPSS software. The sequenced products of the isolates need to be deposited in a database (i.e. Genbank) and accession numbers need to be given. Author’s Response: As per our Institutional policy, we have to deposit all research data to our institution. Hence it takes much administrative procedures before the institution deposits it to GenBank. Provide the accession numbers of the sequenced products in the article. Author’s Response: As per our Institutional policy, we have to deposit all research data to our institution. Hence it takes much administrative procedures before the institution deposits it to GenBank. In Table 2; mean ± SD is 47 ± 17.5 while in text is 48.5 ± 8.9 years? Please explain. Author’s Response: The correct one is 48.5 ± 8.9 years; and is now corrected. In the title of the article the authors have mentioned that isolates collected from inpatients and outpatients of a teaching hospital, but in the main text is no mention of them and the number of isolates in each group is not mentioned? Please explain. Author’s Response: Authors trying to indicate; Inpatient and outpatients as all patients attending the hospitals. We have updated the title of the article to avoid confusion. Finally, I recommend merging both Results and Discussion sections for better clarity and impact and move to Rapid Communication submission. Author’s Response: We do not have any problem in merging results and discussion if journal format allows us."
}
]
}
] | 1
|
https://f1000research.com/articles/10-444
|
https://f1000research.com/articles/8-1708/v1
|
01 Oct 19
|
{
"type": "Research Article",
"title": "Drug Utilization Evaluation of Vancomycin among Patients in Jafar Ibn Auf Pediatric Hospital, 2018",
"authors": [
"Tagwa A. M. Salih",
"Bashir A. Yousef",
"Mohamed A. M. Salih",
"Khalid S. Eltom",
"Tagwa A. M. Salih",
"Mohamed A. M. Salih",
"Khalid S. Eltom"
],
"abstract": "Background: Vancomycin is an antibiotic of growing importance in the treatment of hospital-acquired infections; with a particular emphasis on its value in the fight against Methicillin-resistant Staphylococcus aureus. Increasing reports of Vancomycin resistance have raised concerns about the effectiveness of this drug. Drug utilization evaluation has an important role in controlling rational use of antibiotics to prevent the emergence of resistance. Methods: We conducted a retrospective 6-months study at Jafar Ibn Auf pediatric hospital. Data including patient's demographics, diagnosis, Dosage regimen, and treatment duration were reviewed. The concordance of practice with the Hospital Infection Control Practices Advisory Committee (HICPAC) guidelines and principles of antibiotic therapy was assessed. Results: 127 medical records were reviewed in this study. Sepsis (29%) and Pneumonia (19.6%) were the most common indications. Culture test was requested in 20.5% of patients. Monitoring of serum creatinine was carried in 81.1% of patients. Based on HICPAC guidelines vancomycin was administered appropriately in 67.7% percent of cases. Considering the infusion rate, most of patients with specific order were received vancomycin in 1 hour. Conclusions: The results showed that vancomycin was used empirically without subsequent adjustment of the antimicrobial agent according to culture and sensitivity data and lack of paying enough attention to the infusion rate and serum creatinine monitoring.",
"keywords": [
"Vancomycin",
"Drug utilization evaluation",
"Pediatrics"
],
"content": "Introduction\n\nThe majority of admitted inpatients are given antimicrobials as therapy or prophylaxis during their hospitalization. It has been shown that at least 50% of antimicrobial prescriptions are unnecessary. Antimicrobial over prescription increases the costs of health care, increases super-infection due to antimicrobial-resistant bacteria, and may increase the likelihood of an unwanted side-effects1.\n\nOne critical challenge that health care faces is resistance to vancomycin, which is antibiotic that has a definite indications and a crucial role in treating infections in patients allergic to beta-lactam antibacterial medications or in bacterial infections that are resistant to other antibiotics2. Vancomycin acts by inhibiting the earlier stage of development of the bacterial cell wall compared to beta-lactams, it blocks cell wall phospholipid synthesis by inhibiting transglycosylase enzymes3,4. Vancomycin has a narrow antibacterial spectrum against Methicillin-Resistant Staphylococcus aureus (MRSA), penicillin-resistant Enterococcus and Streptococcus pneumonia infections, thus is saved for these serious public health concerns5–7.\n\nMRSA has become one of the predominant health care issues, and its resistance to vancomycin is growing. Cases of MRSA have increased in the US from 35.9% in 1992 to 64.4% in 2003, mainly due to inappropriate prescribing of broad spectrum antibiotics8. Additionally, 10 to 30% of nosocomial infections in US were caused by vancomycin-resistant enterococci (VRE)9. The increase in VRE has led to the development of recommendations for the use of vancomycin by the Hospital Infection Control Practices Advisory Committee (HICPAC)10, a part of the Centers for Disease Control and Prevention (CDC), published in 1995. They indicate what constitutes appropriate and inappropriate usage of vancomycin, and advises physicians to use the guidelines to decrease the emergence of vancomycin-resistant strains11.\n\nDrug utilization evaluation (DUE) studies have an important role in controlling rational use of antibiotics to prevent resistance9. Since we did not have any data regarding how rationally vancomycin is being prescribed in Jafar Ibn Auf Pediatric Hospital, we conducted this DUE study to determine the rate of rational use of vancomycin according to the standard guidelines.\n\n\nMethods\n\nWe performed a retrospective cross-sectional record-based study of vancomycin use in Jafar Ibn Auf Pediatric Hospital, Khartoum, Sudan. From January 2018 to June 2018\n\nMedical records of all patients hospitalized during the study period were reviewed.\n\nInclusion criteria included: any pediatric patients receiving vancomycin during their hospitalization.\n\nExclusion criteria included: patients who received vancomycin orally because the infusion rate is one of the variables that should be measured and/or patients with incomplete data.\n\nMedical records were reviewed, and the following data was extracted using a check list (see extended data12): dose of vancomycin; duration of infusion; duration of treatment with vancomycin; serum creatinine monitoring; culture and sensitivity test results; concurrent antimicrobials and nephrotoxic drugs; and adverse drug reactions.\n\nThe study was carried out by reviewing all medical records of patients who were admitted and received vancomycin during the study period. A data collection form was used to gather patients’ information. Patients were grouped according to their age into: neonates (1–28 days), infants (1–24 month) and children (2–14 years). Appropriate or inappropriate use of vancomycin was classified according to the guidelines issued by HICPAC. The reasons for appropriate use include: the treatment of β-lactams-resistant gram-positive infections, treatment of patients allergic to β-lactams with gram-positive infections, discontinuation of vancomycin therapy when microbial cultures are negative, and empiric therapy in patients with risk factors; such as patients with co-morbidities and intensive care unit patient’s or confirmed gram-positive infections by culture. Cases in which the use was empiric in patients with risk factors has been justified by hospital epidemiology – due to a high prevalence of methicillin-resistant Staphylococcus aureus (MRSA).\n\nStatistical analysis SPSS version 20.0 was used to analyze the data. Continuous variables were analyzed using Student’s t-test. Chi-squire test was used to compare qualitative variables. P values less than 0.05 were considered to be statistically significant.\n\nEthical clearance (FPEC-07-2018) was obtained from the Ethical Committee of the Faculty of Pharmacy, University of Khartoum. Additional approval for checking the medical records was obtained from Jafar Ibn Auf Pediatric Hospital.\n\n\nResults\n\nDuring the study period, 127 patients (61 females and 66 males) received vancomycin (Underlying data12). As shown in Table 1, about a quarter of patients were hospitalized in a period of 11 to 15 days. Culture tests were performed in 20.5% of patients, with blood being the most common sample taken for microbiology study. Moreover, about 38.6% of patients received vancomycin for 4 to 7 days. (Table 1)\n\nAccording to clinical indication, vancomycin was used to treat sepsis and pneumonia in 29% and 19.7% of patients respectively (Table 2). However, around 55% of patients had received vancomycin without specific instructions from physicians to the nurses regarding the duration of infusion, while 26.8% and 18.1% of patients were receiving vancomycin with specific instructions stated from the physician in the medical records to give vancomycin for duration of 1 hour or 30 min, respectively (Table 2).\n\nResults for the monitoring of serum creatinine are presented in Table 3. Appropriate dose (dosing and frequency) was observed in 81% of the patients (including renal dose adjustment), the need for dose adjustment was essential in 21 patients, but only 11 cases were adjusted. Recorded adverse drug reactions and drug-drug interactions are shown in Table 3. Only 5% of patients developed nephrotoxicity, and furosemide was the most common prescribed drug recorded to have a potential drug-drug interaction.\n\nNSAID – nonsteroidal anti-inflammatory drugs\n\nAccording to the HICPAC guidelines, vancomycin use was considered appropriate in 86 participants (67.8%) (Table 4). Of these, 27.6% of cases (35) were empiric therapy in patients with risk factors; such as patients with co-morbidities and intensive care unit patients. 22.8 % (29) was for the treatment of β-lactams-resistant gram-positive infections treatment, 12.6% (16) for confirmed gram positive infections by culture, 2.4% (3) for treatment of patients allergic to β-lactams with gram-positive infections and 2.4% (3) for discontinuation of vancomycin therapy when microbial cultures are negative. Moreover, there was a significant difference in the appropriateness of vancomycin use in the three groups based on age (neonates, infants and children), with P value= 0.015 (Table 4).\n\n\nDiscussion\n\nVancomycin is an antibiotic used to treat serious infections in patients hypersensitive to β-lactam antibiotics, or those caused by bacteria resistant to β-lactams such as MRSA13. In this study, sepsis (29%) and pneumonia (19.6%) were the most common indications for vancomycin use; a similar finding has been reported in Oman14. On the other hand, an Iranian study showed that vancomycin was mostly used to treat febrile neutropenia (87.9%) and sepsis (74.5%)15, which was similar to results reported in Hong Kong16 . Considering the duration of vancomycin therapy, the maximum duration (40 days) was prescribed in one patient suffering from pneumonia; the minimum period of administration was one day. Most infections, including gram-positive bacteria, can be treated for less than 15 days with vancomycin, but the duration of treatment with vancomycin for endocarditis and osteomyelitis can last for up to an 8-week period17.\n\nOur study demonstrated that most patients received vancomycin empirically without following culture and sensitivity testing. The rate of requesting culture and sensitivity tests was low (20.5%), similar to Salehifar et al. In which culture and sensitivity test was performed in 30.1% of cases18.\n\nAccording to the HICPAC guidelines, 67.7% of the vancomycin prescriptions were appropriate; the reasons for its appropriate use included the treatment of β-lactams-resistant gram-positive infections, treatment of patients allergic to β-lactams with gram-positive infections, and discontinuation of vancomycin therapy when microbial cultures have been negative. Empiric therapy is also in patients with risk factors and confirmed gram-positive infections by culture. The rate of adherence to HICPAC recommendations was lower in our study compared to other trials, including Alfandari et al.19 and Melo et al.20 studies, in which the rate of appropriate use was 71% and 95% respectively. However, in Askarian et al’s study out of 200 vancomycin prescriptions, only 12 (6%) were considered appropriate21; which was very low compared to our results.\n\nGiven the importance of infusion rate, and the occurrence of “red man syndrome” by vancomycin22 (a hypersensitivity reaction characterized by flushing, erythema and pruritus, particularly of the upper body), the guidelines recommend that the time of infusion should be ≥ 30 minutes per 500 mg dose of vancomycin to avoid this infusion-related anaphylaxis–like reaction23,24. The results showed that in more than half of the patients (55%) there were no specific instructions regarding the duration of infusion. An anaphylactic reaction occurred in two patients.\n\nNephrotoxicity is one of the most common adverse drug reactions, so daily monitoring of serum creatinine and estimated creatinine clearance, in addition to ensuring the proper vancomycin dose can be effective while preventing renal toxicity25,26. Multiple risk factors influencing the occurrence of nephrotoxicity include; treatment duration beyond one week, pre-existing renal insufficiency, concurrent administration of nephrotoxic drugs, sepsis and critical illnesses, as well as infusion rate27,28. In this study, nephrotoxicity occurred in 4.7% of patients, although serum creatinine testing was performed in 81% of patients.\n\nConcerning serum creatinine monitoring, guidelines recommend that it should be monitored at least twice weekly, and weekly for long term therapy29. In this study, in 60.6% of patients; serum creatinine was monitored once (75% of them before initiating vancomycin therapy and 25% during treatment with vancomycin therapy), while only 20% of patients were monitored twice weekly. 19% of cases had no serum creatinine monitoring. In Oliveira and Ribeiro’s study, serum creatinine was monitored to 93.4% patients which was higher compared to our results30.\n\nRegarding dosing of vancomycin; in neonates, 15mg/kg is the suggested starting dose, then 10 mg/kg every 12 hours up to the first week after birth, followed by 10 mg/kg every 8 hours up to the age of one month ;for children >1 month 15 mg/kg every 8 hours (maximum daily dose 2 g) is recommended31. Appropriate dosing was observed in 81% of the patients, which was higher than an Iranian study in which 52% of the participants were given an appropriate dose18. Since 80% to 90% of vancomycin is excreted unchanged in the urine, dose adjustment is required in renal insufficient/failure patients24. In this study, the need for dose adjustment was essential in 21 patients, but only 11 of cases were adjusted.\n\nRegarding drug-drug interactions, the most common interactive drugs used were furosemide (12.6%), amikacin (2.4%) and non-steroidal anti-inflammatory drugs (NSAID) (4.7%). Two patients were receiving vancomycin, furosemide and amikacin concomitantly. All these medications have been reported to increase the risk of vancomycin-induced nephrotoxicity27. Specially, the combination of aminoglycosides with vancomycin has shown to increase renal injury by 20% to 30%28,29.\n\nRegarding the appropriate use of vancomycin, a significant variation in the appropriateness of vancomycin use was observed in the three groups based on age (Neonate, Infant, child), P value = 0.015. The most appropriate use was in neonates 85.7%. Dehghan et al. also showed a significant difference in the appropriateness of vancomycin use in three groups based on age (neonates, infants, and children) with P value of 0.017, however, the most appropriate use was observed in infants (68.1%)32. The recorded irrational use of vancomycin in this study indicates deficiencies in utilization practices at the level of this hospital and perhaps the entire region. Such practices require further restrictive measures on vancomycin prescribing.\n\nOne of the major limitations was the poor documentation in the medical records used. Thus, information such as therapeutic monitoring of serum vancomycin concentrations was not available; therefore, we exclude it from the variables to be measured and we recommend that it is essential to document serum concentration levels when using vancomycin.\n\n\nConclusion\n\nOur findings confirmed that more than 30% of patients received vancomycin without fulfilling the HICPAC criteria. Insufficient attention to monitor the rate of infusion of vancomycin and serum creatinine, in addition to low rate/lack of requesting culture and sensitivity testing are collectively indicated the reasons for inconsistence to HICPAC guidelines.\n\n\nData availability\n\nFigshare: Drug utilization evaluation of vancomycin among patients in Jafar Ibn Auf Pediatric Hospital: a retrospective chart review, https://doi.org/10.6084/m9.figshare.8397350.v112\n\nVancomycin Data.xlsx (Extracted data from medical records)\n\nFigshare: Drug utilization evaluation of vancomycin among patients in Jafar Ibn Auf Pediatric Hospital: a retrospective chart review, https://doi.org/10.6084/m9.figshare.8397350.v112\n\nCheck-list.doc (Checklist used for data extraction from medical records)\n\nData are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication)",
"appendix": "Grant information\n\nThe author(s) declared that no grants were involved in supporting this work.\n\n\nAcknowledgments\n\nThe authors would like to acknowledge all members of Jafar Ibn Auf Pediatric Hospital for their contributions.\n\n\nReferences\n\nRehm SJ, Sekeres JK, Neuner E: Guidelines for Antimicrobial Usage. Pharm D Professional Communications Inc. Cleveland Clinic, 2012–2013.\n\nAngaran DM: Quality assurance to quality improvement: measuring and monitoring pharmaceutical care. AM J Hosp Pharm. 1991; 48(9): 1901–1907. PubMed Abstract | Publisher Full Text\n\nNightingale J, Chaffe BW, Colvin CL, et al.: Retrospective evaluation of vancomycin use in a university hospital. Am J Hosp Pharm. 1987; 44(8): 1807–1809. PubMed Abstract | Publisher Full Text\n\nKaiser AB: Antimicrobial prophylaxis in surgery. N Engl J Med. 1986; 315(18): 1129–1138. PubMed Abstract | Publisher Full Text\n\nMandell, Douglas, Bennett: Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: Churchill Livingston; 2015; 377–400. Reference Source\n\nSvetitsky S, Leibovici L, Paul M: Comparative efficacy and safety of vancomycin versus teicoplanin: systematic review and meta-analysis. Antimicrob Agents Chemother. 2009; 53(10): 4069–4079. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLiu C, Bayer A, Cosgrove SE, et al.: Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011; 52(3): e18–55. PubMed Abstract | Publisher Full Text\n\nKlevens RM, Edwards JR, Tenover FC, et al.: Changes in the epidemiology of methicillin-resistant Staphylococcus aureus in intensive care units in US hospitals, 1992-2003. Clin Infect Dis. 2006; 42(3): 389–391. PubMed Abstract | Publisher Full Text\n\nCenter of Disease Control and Prevention guideline for Antibiotic Resistance Threats in the United States 2013. Reference Source\n\nCenters of Disease Control and Prevention for management of Multidrug-Resistant Organisms in Healthcare Settings 2007.\n\nRecommendations for preventing the spread of vancomycin resistance. Recommendations of the Hospital Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep. 1995; 44(RR-12): 1–13. PubMed Abstract\n\nYousef B; Salih T, Salih M, et al.: Drug utilization evaluation of vancomycin among patients in Jafar Ibn Auf Pediatric Hospital: a retrospective chart review. figshare. Dataset. 2019. http://www.doi.org/10.6084/m9.figshare.8397350.v1\n\nTarar WL, Farooq M, Amin F, et al.: Drug Utilization Evaluation of Vancomycin in Teaching Hospitals of Lahore. J Pharm Sci Res. 2012; 4(2): 1728–33. Reference Source\n\nAl Za’abi M, Shafiq S, Al Riyami D, et al.: Utilization Pattern of Vancomycin in a University Teaching Hospital in Oman: Comparison with International Guidelines. Trop J Pharm Res. 2013; 12(1): 117–121. Publisher Full Text\n\nVazin A, Japoni A, Shahbazi S, et al.: Vancomycin utilization evaluation at hematology-oncology ward of a teaching hospital in iran. Iran J Pharm Res. 2012; 11(1): 163–170. PubMed Abstract | Free Full Text\n\nYou JH, Lyon DJ, Lee BS, et al.: Vancomycin utilization at a teaching hospital in Hong Kong. Am J Health Syst Pharm. 2001; 58(22): 2167–9. PubMed Abstract | Publisher Full Text\n\nEna J, Dick RW, Jones RN, et al.: The epidemiology of intravenous vancomycin usage in a university hospital. A 10-year study. JAMA. 1993; 269(5): 598–602. PubMed Abstract | Publisher Full Text\n\nSalehifar E, Babamahmoodi F, Alikhani A, et al.: Drug Utilization Evaluation of Vancomycin in a Referral Infectious Center in Mazandaran Province. J Pharm Care. 2014; 2(2): 55–59. Reference Source\n\nAlfandari S, Levent T, Descamps D: Evaluation of glycopeptide use in nine French hospitals. Med Mal Infect. 2010; 40(4): 232–7. PubMed Abstract | Publisher Full Text\n\nMelo DO, Sasaki M, Grinbaum RS: Vancomycin use in a hospital with high prevalence of methicillin-resistant Staphylococcus aureus: comparison with Hospital Infection Control Practices Advisory Committe Guidelines (HICPAC). Braz J Infect Dis. 2007; 11(1): 53–6. PubMed Abstract | Publisher Full Text\n\nAskarian M, Assadian O, Safaee G: Vancomycin use in a large teaching hospital in Shiraz, Islamic Republic of Iran, 2003. East Mediterr Health J. 2007; 13(5): 1195–201. PubMed Abstract | Publisher Full Text\n\nPolk RE, Healy DP, Schwartz LB, et al.: Vancomycin and the red-man syndrome: pharmacodynamics of histamine release. J Infect Dis. 1988; 157(3): 502–7. PubMed Abstract | Publisher Full Text\n\nFrymoyer A, Hersh AL, Benet LZ, et al.: Current recommended dosing of vancomycin for children with invasive methicillin-resistant Staphylococcus aureus infections is inadequate. Pediatr Infect Dis J. 2009; 28(5): 398–402. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRossi S: Adelaide: Australian Medicines Handbook 2013. Reference Source\n\nGreen K, Schulman G, Haas DW, et al.: Vancomycin prescribing practices in hospitalized chronic hemodialysis patients. Am J Kidney Dis. 2000; 35(1): 64–68. PubMed Abstract | Publisher Full Text\n\nCappelletty D, Jablonski A, Jung R: Risk factors for acute kidney injury in adult patients receiving vancomycin. Clin Drug Investig. 2014; 34(3): 189–93. PubMed Abstract | Publisher Full Text\n\nCarreno JJ, Kenney RM, Lomaestro B: Vancomycin-associated renal dysfunction: where are we now? Pharmacotherapy. 2014; 34(12): 1259–1268. PubMed Abstract | Publisher Full Text\n\nRybak MJ, Albrecht LM, Boike SC, et al.: Nephrotoxicity of vancomycin, alone and with an aminoglycoside. J Antimicrob Chemother. 1990; 25(4): 679–687. PubMed Abstract | Publisher Full Text\n\nAlberta Health Services: vancomycin Monitoring and Dosing Guidelines. 2011.\n\nMelo DO, Ribeiro E: Vancomycin use in a Brazilian teaching hospital: comparison with the Hospital Infection Controlpractices Advisory Committee Guidelines (HICPAC). Braz J Infect Dis. 2009; 13(3): 161–4. PubMed Abstract | Publisher Full Text\n\nBroome L, So TY: An evaluation of initial vancomycin dosing in infants, children, and adolescents. Int J Pediatr. 2011; 2011: 470364. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDehghan F, Khorami N, Taslimi Taleghani N, et al.: Drug Utilization Evaluation of Vancomycin in Pediatric Department. Novel Biomed. 2018; 6(1): 9–14. Reference Source"
}
|
[
{
"id": "59899",
"date": "15 Apr 2020",
"name": "Ghulam Jilany Khan",
"expertise": [
"Reviewer Expertise Antimicrobials",
"Tumor Metastasis",
"Non Small Cell Lung Cancer",
"Diabetes",
"Basic and Clinical Pharmacology/Oncology",
"MDR Nanocareer Drug Deliver System"
],
"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\nVancomycin is an important antimicrobial drug particularly against MRSA however its growing development of resistance against the microbes has made it an important drug for further studies and a higher level of understanding for its utility and mode of usage. In present study, the authors conducted a retrospective study at Jafar Ibn Auf Hospital which is one of the good health care facility for infectious and other diseases. The results concluded that 86 patents (67.8%) were receiving the Vancomycin therapy appropriately against Sepsis (29%) and Pneumonia (19.6%) as most common indication.\nThe authors have reported that the therapy was given to a pneumonia patient for 40 days and alternatively it was recommended for another patient for one day only, here I would suggest the authors to update the record for this duration of one day as well and whether it was discontinued for some medical reason OR due to treatment success OR due to something else. As per my understanding Vancomycin therapy should not be given for that much limited duration.\n\nThe authors have reported that in most of the cases vancomycin therapy was given as an imperial treatment, and culture sensitivity testing rate is very low, The authors should explain (in discussion) why they have this much low rate of culture sensitivity testing?\n\nI highly recommend the acceptance of this manuscript for publication as it will provide the basis for antimicrobial regimen design against certain diseases.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? No\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7411",
"date": "12 Nov 2021",
"name": "Bashir Yousef",
"role": "Author Response",
"response": "1- The authors have reported that the therapy was given to a pneumonia patient for 40 days and alternatively it was recommended for another patient for one day only, here I would suggest the authors to update the record for this duration of one day as well and whether it was discontinued for some medical reason OR due to treatment success OR due to something else. As per my understanding Vancomycin therapy should not be given for that much limited duration. Reply: The authors would like to thank the reviewer for this important comment. This patient was suffered from many diseases that made him stay for 40 days in the hospital. As a response: We have added the explanation in the discussion section Considering the duration of vancomycin therapy, the maximum duration (40 days) was prescribed in one patient suffering from pneumonia due to he suffered from other diseases. 2- The authors have reported that in most of the cases vancomycin therapy was given as an imperial treatment, and culture sensitivity testing rate is very low, The authors should explain (in discussion) why they have this much low rate of culture sensitivity testing? Reply: The authors appreciate this important suggestion and we agree about the importance of explanations of the low rate of culture. The main reason for this is high cost of the culture, and many patients couldn’t afford to do it. As a response: we added the explanation in the discussion part The main reason for the low rate of requesting culture is that most patients had no health insurance to cover the cost of culture. 3- I highly recommend the acceptance of this manuscript for publication as it will provide the basis for antimicrobial regimen design against certain diseases Reply: We appreciate your words about the importance of this study."
}
]
},
{
"id": "98730",
"date": "09 Nov 2021",
"name": "Khalid O. Alfarouk",
"expertise": [
"Reviewer Expertise Pharmacology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nDear Editor,\nThank you very much for the current work titled: Drug Utilization Evaluation of Vancomycin among Patients in Jafar Ibn Auf Pediatric Hospital, 2018.\nThe authors performed a drug utilization study to determine the rational use of vancomycin according to the standard guidelines at Jafar Ibn Auf Hospital. The topic is crucial and describes how vancomycin is prescribed, which provides the basis for utilizing an antimicrobial regimen against diseases.\n\nHowever, before betting the house, some points should addressed in this manuscript:\nWas the study reported according to the STROBE statement for writing a cross-sectional study?\n\nRegarding the exclusion criteria for the participants. Are there any other exclusion criteria in addition to who received vancomycin orally and/or patients with incomplete data?\n\nThe authors should represent both the number and frequency % for each variable in the tables for the table.\nSincerely,\nKhalid\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": "7412",
"date": "09 Nov 2021",
"name": "Bashir Yousef",
"role": "Author Response",
"response": "1- Was the study reported according to the STROBE statement for writing a cross-sectional study? Reply: Authors appreciate the reviewer for this valuable comment. We want to inform you that the study was conducted according to the STROBE statement. 2- Regarding the exclusion criteria for the participants. Are there any other exclusion criteria in addition to who received vancomycin orally and/or patients with incomplete data? Reply: The authors would like to thanks the reviewer for this important question about the exclusion criteria for the participants. As we mentioned in this study, the only exclusion criteria were patients who received vancomycin orally and/or patients with incomplete data. 3- The authors should represent both the number and frequency % for each variable in the tables for the table. Reply: We thanks the reviewer for this suggestion that further simplify the tables. As a response: All Tables in the manuscript were modified by adding the number of the participants and frequency % for each response or answer."
}
]
}
] | 1
|
https://f1000research.com/articles/8-1708
|
https://f1000research.com/articles/10-932/v1
|
16 Sep 21
|
{
"type": "Research Article",
"title": "COVID-19 impact: Customised economic stimulus package recommender system using machine learning techniques",
"authors": [
"Rathimala Kannan",
"Ivan Zhi Wei Wang",
"Hway Boon Ong",
"Kannan Ramakrishnan",
"Andry Alamsyah",
"Ivan Zhi Wei Wang",
"Hway Boon Ong",
"Kannan Ramakrishnan",
"Andry Alamsyah"
],
"abstract": "Background: The Malaysian government reacted to the pandemic’s economic effect with the Prihatin Rakyat Economic Stimulus Package (ESP) to cushion the novel coronavirus 2019 (COVID-19) impact on households. The ESP consists of cash assistance, utility discount, moratorium, Employee Provident Fund (EPF) cash withdrawals, credit guarantee scheme and wage subsidies. A survey carried out by the Department of Statistics Malaysia (DOSM) shows that households prefer different types of financial assistance. These preferences forge the need to effectively customise ESPs to manage the economic burden among low-income households. In this study, a recommender system for such ESPs was designed by leveraging data analytics and machine learning techniques. Methods: This study used a dataset from DOSM titled “Effects of COVID-19 on the Economy and Individual - Round 2,” collected from April 10 to April 24, 2020. Cross-Industry Standard Process for Data Mining was followed to develop machine learning models to classify ESP receivers according to their preferred subsidies types. Four machine learning techniques—Decision Tree, Gradient Boosted Tree, Random Forest and Naïve Bayes—were used to build the predictive models for each moratorium, utility discount and EPF and Private Remuneration Scheme (PRS) cash withdrawals subsidies. The best predictive model was selected based on F-score metrics. Results: Among the four machine learning techniques, Gradient Boosted Tree outperformed the rest. This technique predicted the following: moratorium preferences with 93.8% sensitivity, 82.1% precision and 87.6% F-score; utilities discount with 86% sensitivity, 82.1% precision and 84% F-score; and EPF and PRS with 83.6% sensitivity, 81.2% precision and 82.4% F-score. Households that prefer moratorium subsidies did not favour other financial aids except for cash assistance. Conclusion: Findings present machine learning models that can predict individual household preferences from ESP. These models can be used to design customised ESPs that can effectively manage the financial burden of low-income households.",
"keywords": [
"COVID-19",
"low-income households",
"economic stimulus package",
"customisation",
"data analytics",
"machine learning",
"Gradient Boosted Tree"
],
"content": "Introduction\n\nThe novel coronavirus 2019 (COVID-19) pandemic has created devastation in people’s lives worldwide, both socially and economically (Shah et al., 2020). As a result, governments have adopted various strategies aimed at reducing the pandemic’s impact, particularly the financial strain. The Malaysian government has introduced a series of economic stimulus packages to support various segments of its citizens. One such support is the Prihatin Rakyat Economic Stimulus Package (ESP) to cushion the impact of COVID-19 on low-income households after the first movement control in the country. The ESP consists of cash assistance, utility discount, moratorium, Employee Provident Fund and Private Remuneration Scheme (EPF and PRS) cash withdrawals and Credit Guarantee Scheme and Wage subsidies (Flanders et al., 2020). Following the implementation of ESP, the Department of Statistics Malaysia (DOSM) carried out a special survey from April 10 to April 24,2020 to better understand the implications of COVID-19 on the economy and households. The study included questions on social and economic factors and subsidy preferences.\n\nA typical low-income household often bears considerable debt and has limited savings. When movement control was implemented, households that lost their income sources faced difficulties in accessing necessities, such as food and housing (Flanders et al., 2020). Even though the government offered ESP to help residents cope financially, the demands and desires of citizens in the event of a pandemic are unknown. For example, several households are reluctant to withdraw from EPF and PRS due to its reduction on their savings for old age. A personalised ESP can be built to reduce residents’ financial burden in this crisis if we can foresee their requirements and preferences for various subsidies, such as cash allowance, utility discount, moratorium or EPF and PRS withdrawals. Using data analytics and machine learning approaches, this study attempted to analyse survey data and construct predictive models for customised economic stimulus packages. The following research questions were put forward.\n\n1. Can we develop a general profile of households who prefer moratorium subsidies?\n\n2. Can we develop a general profile of households who prefer utility discount subsidies?\n\n3. Can we develop a general profile of households who prefer EPF and PRS withdrawals?\n\nThis study contributes to the literature by using four machine learning techniques on socioeconomic survey data and predicting household subsidy preferences. A comparison of the feature selection methods, such as Gini index, Gain–Ratio and various partitioning ratios of the training and test data sets were carried out. The outcomes of this study can help the government deliver better and improved stimulus packages in the future based on individual preferences.\n\n\nMethods\n\nFor planning and execution, this study used the Cross-Industry Standard Process-Data Mining (CRISP-DM), which is the industry-independent de-facto standard for implementing data mining initiatives (Schröer et al., 2021). This process has six phases, namely, business understanding, data understanding, data preparation, modelling, evaluation and deployment. Figure 1 depicts the activities carried out in each phase, as further explained below.\n\nThis phase identifies the problems to solve using the machine learning perspective and approach. All three research questions were selected as the problems, and the purpose was to propose predictive models for the moratorium, utility discount and EPF and PRS subsidies in the Prihatin Rakyat ESPs.\n\nData gathering, evaluating, characterising and assuring its quality are part of this phase. DOSM performed a special survey (Round 2) to investigate the consequences of the COVID-19 epidemic on household economics and status (“Department of Statistics Malaysia Official Portal,” 2020; Malaysia, 2020). The dataset includes 36 questions and 41,386 respondents. However, the data obtained from DOSM were not complete due to missing questions. The missing questions were Q3, Q6, Q19, and Q27 – Q31. In terms of the total respondents, the data were complete and had a total of 41,386 participants, all of them were aged 15 and older. 96.8% of the respondents have received benefits from Prihatin Rakyat ESPs. The raw data were based on responses from respondents, which included qualitative personal opinions on economy, employment, lifestyle, and education. The original dataset was in Malay language, and is translated into English for this study and given below as Table 1.\n\nThere were 28 questions available for further analysis in this study, eliminating the missing ones. Question 32 and 33 were excluded from the survey because they focused on the primary food and non-food products purchased during the time of movement control orders. Given that the dataset was cluttered with missing values and errors, a considerable effort was spent on its cleaning before applying descriptive analytics techniques. Q34, Q35 and Q36 had missing values of 2071, 2243 and 2310 respectively and were replaced by the most frequent values. By cleaning the data, the raw data is transformed into structured data. Without losing any information, all lengthy responses were reduced to short and detailed responses. If the original answer for respondent’s dwelling state was \"Wilayah Persekutuan Kuala Lumpur,\" it was converted to \"KL.\" Questions with answers were labelled \"Yes,\" whereas those without answers are labelled \"No.\" One question, for example, inquired about respondents' willingness to eat out as part of the new norm's lifestyle adjustments. Those who agreed said they \"will not eat out.\" Those who opposed to the shift in lifestyle left the question unanswered. As a result, these questions were changed to a \"Yes\" or \"No\" format.\n\nVarious machine learning techniques were used in this phase to meet the study objectives. To create prediction models, we used four machine learning techniques: Decision Tree, Random Forest, Gradient Boosted Tree and Naïve Bayes. These four machine learning techniques were chosen from a literature review (Mostafa et al., 2021; Sangavi et al., 2020) and used to determine the optimal model by adjusting their parameters. Feature selection methods, such as Gini index, Gain–Ratio and various partitioning ratios of the training and test data sets were also compared (Trivedi, 2020).\n\nIn this phase, the best predictive model for each subsidy was selected based on the standard performance evaluation metrics: Sensitivity, Precision, F-Score and Accuracy (Moscato et al., 2021). The formulas used to calculate each of the metrics are given below.\n\n\n\nTP = True Positive, TN = True Negative, FP = False Positive, FN = False Negative\n\nThe completeness of a prediction model was measured by sensitivity, also known as recall and total positive rate (TPR). This metric determined the proportion of positive predictions by a model that corresponds to true positive values (Moscato et al., 2021). The formula is given below.\n\n\n\nPrecision in data analytics refers to a model’s ability to correctly forecast outcomes. In other words, precision is a true positive divided by a combination of true and false positives.\n\n\n\nF-Score, also known as F1 Score, is a balance of both precision and sensitivity. Hence, this study used F-Score to evaluate the machine learning models.\n\n\n\nIn the final phase a deployment strategy for the model was created and documented. The best predictive model as determined for each of the subsidies was to be recommended for further deployment. The entire CRISP-DM phases were carried out using the Konstanz Information Miner (KNIME 4.3.2), a free and open-source data analytics software.\n\nThis study was carried out from November 23, 2020 to October 06, 2021 and has obtained ethics approval (EA1322021) by Technology Transfer Office, secretariat of research ethics committee, Multimedia university.\n\n\nResults\n\nThe outcomes of this study were organised as descriptive analytics, model optimisation and findings. Descriptive analytics helps to understand the characteristics of each respondent and the relationship between variables. Table 2 provides the descriptive information on the respondents.\n\nFigure 2 shows the various types of subsidies offered in the ESP. Among the 41,386 respondents, 72.2% were eligible to receive subsidies, 21.9% were newly applied, 3.2% were not eligible and 2.7% had appealed. Figure 2 also shows the most beneficial forms of support. The most popular type of subsidy was cash allowance, followed by moratorium, utility discounts and EPF and PRS cash withdrawals. The least preferred type was the credit guarantee plan and wage subsidies.\n\nFollowing the descriptive analytics, the four machine learning techniques were applied to develop prediction models for each moratorium, utility discount and EPF withdrawals subsidies. Decision Tree, Gradient Boosted Tree, Random Forest and Naïve Bayes are subjected to parameter tuning to determine the best model and parameter values.\n\nTable 3 to Table 6 show how the optimal model was obtained from each machine learning technique. Partitioning ratio indicates the training and test data. Gain ratio, Gini index and information gain were used to measure the quality of each predictor in classifying the target variable. The results show that the Gradient Boosted Tree and Naïve Bayes techniques performed well when 60% of the data were used to train the machine learning models and the other 40% was used for testing. Random Forest and Decision Tree techniques generated the best models when the training data were 80% and the test data were 20%. F-Score was used as the evaluation measure to select the optimal models. After identifying the optimal models, the best was selected among the four machine learning techniques. Table 7 shows the results. Gradient Boosted Tree outperformed the rest of the techniques in predicting the moratorium preference with 93.8% sensitivity, 82.1% precision and 87.6% F-score.\n\nA similar process was carried out to develop machine learning models for utility discounts and EPF and PRS subsidies. The results show that for both subsidies, Gradient Boosted Tree was the best machine learning technique. Table 8 and Table 9 show that this technique can predict utility discount with 86% sensitivity, 82.1% precision and 84% F-score, as well as EPF and PRS with 83.6% sensitivity, 81.2% precision and 82.4% F-score, respectively.\n\n\nDiscussion\n\nIn this study, Gradient Boosted Tree was found as the best machine learning model for predicting moratorium subsidies. However, this model cannot explain the relationship between the predictors and the target, and thus decision tree rules were derived to understand the overall profile of households who prefer a moratorium. Rule support refers to the number of respondents to whom this condition applies. Rule confidence indicates the probability of having a moratorium as the preferred subsidy. Table 10 shows the basic characteristics of families that choose moratorium subsidies with a rule support of 400 and above.\n\nThe first rule shows that households who prefer to have a cash allowance and their race is either Malay or Native Sabah/Sarawak or others, while those aged between 25 to 64 prefer moratorium. Table 11 explains the first rule indicating the general profile of households who prefer moratorium subsidies. Similarly, Table 12 and Table 13 show the general profile of households preferring utility discounts and EPF and PRS cash withdrawals.\n\nThe results imply that households that prefer moratorium subsidies did not favour other financial aids except cash assistance. By contrast, households that prefer for utility discounts, EPF and PRS withdrawals also chose moratorium subsidies and cash assistance. All households preferred cash assistance, which had the highest score among financial aids, followed by moratorium subsidies. Utility discounts, EPF and PRS withdrawals can be implemented according to the household income group preferences.\n\nWage subsidy and credit guarantee scheme were the least preferred financial assistance. First, the Prihatin wage subsidy is only for eligible Social Security Organisation (SOCSO) subscribers. Hawkers, small businesses and their employees might not subscribe to SOCSO and thus, ineligible to apply for financial aid. Second, the credit guarantee scheme was not preferred due to economic uncertainty from COVID-19. Economic uncertainty adversely affects household income, resulting in their inability to repay the loan instalments.\n\nThe following are some of the limitations of this study's findings: The data used are survey responses and cannot be considered to represent the views of all Malaysians. According to DOSM, it should not be used to analyse the impact of COVID-19 in Malaysia and should not be considered official statistics. It can, however, be utilised to assist in the reflection process (“Department of Statistics Malaysia Official Portal,” 2020; Malaysia, 2020).\n\n\nConclusions\n\nThis study used data analytics and machine learning approaches to derive insights from the “Effects of COVID-19 on the Economy and Individual - Round 2” survey dataset. The CRISP-DM approach was applied to develop prediction models for households’ preferred subsidies, such as moratoriums, utility discounts and EPF and PRS using four machine learning algorithms, namely, Decision Tree, Random Forest, Naïve Bayes and Gradient Boosted Tree. For all three subsidies, the best predictive model was obtained by Gradient Boosted Tree. The findings can be used to design customised ESPs that effectively manage the economic burden of low-income households.\n\n\nData availability\n\nData used in this study were obtained from a survey dataset “Effects of COVID-19 on the Economy and Individual - Round 2,” available from the Department of Statistics, Malaysia (DOSM). A report published by the DOSM based on the survey can be viewed on the DOSM website. Access to this data requires application, as stated on the DOSM website. A guide for how to apply for dataset access is available on the Data Request page or requests for more information can be emailed to data@dosm.gov.my.",
"appendix": "Acknowledgements\n\nThe authors thank the Department of Statistics Malaysia for allowing us to use “Effects of COVID-19 on the Economy and Individual - Round 2” survey data to carry out this study. The authors also acknowledge Multimedia University for supporting this research.\n\n\nReferences\n\nDepartment of Statistics Malaysia Official Portal: 2020; Retrieved June 27, 2021. Reference Source\n\nFlanders S, Nungsari M, Chuah HY: The COVID-19 Hardship Survey: An Evaluation of the Prihatin Rakyat Economic Stimulus Package. 2020; 1–44. Reference Source\n\nMalaysia D of S: Technical Note _Special Survey Covid19_Individuals. 2020.\n\nMoscato V, Picariello A, Sperlí G: A benchmark of machine learning approaches for credit score prediction. Expert Syst Appl. 2021; 165: 113986. Publisher Full Text\n\nMostafa MM, El-Masry AA, Chen Y, et al.: Impact of Classification Algorithms on Census Dataset. International Journal of Recent Technology and Engineering. 2021; 97(2019): 526–534.\n\nSangavi N, Jeevitha R, Kathirvel P, et al.: Impact of Classification Algorithms on Census Dataset. International Journal of Recent Technology and Engineering. 2020; 8(5): 2666–2670. Publisher Full Text\n\nSchröer C, Kruse F, Gómez JM: A Systematic Literature Review on Applying CRISP-DM Process Model. Procedia Computer Science. 2021; 181: 526–534. Publisher Full Text\n\nShah AUM, Safri SNA, Thevadas R, et al.: COVID-19 outbreak in Malaysia: Actions taken by the Malaysian government. Int J Infect Dis. 2020; 97: 108–116. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrivedi SK: A study on credit scoring modeling with different feature selection and machine learning approaches. Technology in Society. 2020; 63: 101413. Publisher Full Text"
}
|
[
{
"id": "95430",
"date": "06 Oct 2021",
"name": "Setia Pramana",
"expertise": [
"Reviewer Expertise Machine Learning",
"Data mining",
"statistics",
"official statistics",
"bioinformatics",
"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\nResearch questions and the discussion and conclusion are not inline. The authors mentioned three research questions, but they are not discussed throughout the manuscript. Instead, the authors focus on comparing different methods for predicting household subsidy preferences. Please address the research question on the results and discussion as well.\n\nPlease explain the question used in the study and why some questions are missing. Is it due to not being the focus of the study, or for other reasons?\n\nPlease elaborate more on the discussion of the results of the study. What would be the impact of utilizing best methods for result of the stimulus, especially for the citizen? Would it be that big a difference if we use the other classification methods?\n\nPlease explain the advantages and disadvantages of the methods being compared in the study.\n\nThe result shows that the decision tree, gradient boost, and random forest, does not differ much, how will it affect the stimulus package?\n\nIf the data changes would the results change? The authors may divide the data into testing, training and validation data set. Several times as discussed by this paper: Lessman et al. (20151).\n\nPlease use a flowchart to explain the modelling and analysis process.\n\nWhy discuss on different ratio partitioning, in this case it is better use simulation dataset to see the impact of the ratio into the 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? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7428",
"date": "12 Nov 2021",
"name": "Rathimala Kannan",
"role": "Author Response",
"response": "1. Research questions and the discussion and conclusion are not inline. The authors mentioned three research questions, but they are not discussed throughout the manuscript. Instead, the authors focus on comparing different methods for predicting household subsidy preferences. Please address the research question on the results and discussion as well. Though we have answered all three research questions in the discussion section, we noticed it is not presented well. Thank you for your comment. Now we have answered each question separately in the discussion section. 2. Please explain the question used in the study and why some questions are missing. Is it due to not being the focus of the study, or for other reasons? As mentioned in the previous answer, now we have revised the discussion section which clearly addresses all three research questions. 3. Please elaborate more on the discussion of the results of the study. What would be the impact of utilizing best methods for result of the stimulus, especially for the citizen? Would it be that big a difference if we use the other classification methods? The aim of this study is to identify the households that prefer to have a specific subsidy which is expected to lessen their financial burden during this pandemic. Therefore, we focus on the classification model which can predict more accurately the household’s choice. It is possible to test with other classification methods, and they might have better accuracy. However, we focus also the model interpretability, thus we use mostly on decision tree algorithm family plus naïve bayes algorithm. Machine learning models are always a trade-off between accuracy and interpretability (Hastie, Tibshirani, James, & Witten, 2021). Hastie, T., Tibshirani, R., James, G., & Witten, D. (2021). An Introduction to Statistical Learning (2nd Edition). Springer Texts, 102, 618. (chapter 2.1.3 page 24) 4. Please explain the advantages and disadvantages of the methods being compared in the study. Different approaches, such as information-based learning, similarity-based learning, error-based learning, and probability-based learning, can be used to create classifiers. This research used information based learning (a decision tree algorithm family) as the best model for explaining decision logic .(Kelleher, Namee, & D’Arcy, 2015) Kelleher, J. D., Namee, B. Mac, & D’Arcy, A. (2015). Fundamentals of Machine Learning for Predictive Data Anayltics: Algorithms, Worked Examples, and Case Studies (Ist). The MIT Press. 5. The result shows that the decision tree, gradient boost, and random forest, does not differ much, how will it affect the stimulus package? The aim here is to predict household’s preference as much possible correctly. Thus we chose the model that performs the best compared to the rest. 6. If the data changes would the results change? The authors may divide the data into testing, training and validation data set. Several times as discussed by this paper: Lessman et al. (20151). – Yes. We can divide the dataset in to 3 sets. We conducted K-fold cross validation method to evaluate the performance of a classifier and presented the results in the following table. When the data is partitioned with k= 5, and K=10, the findings reveal little difference in classifier performance, and the Gradient boosting tree performs best. When the data set is small, k-fold cross validation produces a superior model; but, when the data set is large, it produces no change. A current study backs up this conclusion (Marcot & Hanea, 2021). Marcot, B. G., & Hanea, A. M. (2021). What is an optimal value of k in k-fold cross-validation in discrete Bayesian network analysis? Computational Statistics, 36(3), 2009–2031. https://doi.org/10.1007/s00180-020-00999-9 Machine Learning Technique Partitioning Ratio Target Variable: Moratorium Precision Sensitivity F-score Accuracy Decision Tree 80:20 (Gini Index) No 0.779 0.727 0.752 0.802 Yes 0.816 0.854 0.834 K=5-fold cross validation (Gini Index) No 0.770 0.702 0.735 0.789 Yes 0.801 0.851 0.826 K=10-fold cross validation (Gini Index) No 0.772 0.697 0.733 0.789 Yes 0.799 0.854 0.826 Gradient Boosted Tree 60:40 No 0.891 0.711 0.791 0.844 Yes 0.821 0.938 0.876 K=5-fold cross validation No 0.889 0.705 0.786 0.841 Yes 0.818 0.938 0.874 K=10-fold cross validation No 0.889 0.705 0.787 0.841 Yes 0.818 0.938 0.874 Random Forest 80:20 (Gini Index) No 0.825 0.769 0.796 0.837 Yes 0.844 0.885 0.864 K=5-fold cross validation (Gini Index) No 0.821 0.761 0.790 0.832 Yes 0.839 0.882 0.860 K=10-fold cross validation (Gini Index) No 0.826 0.757 0.790 0.833 Yes 0.837 0.887 0.862 Naïve Bayes 60:40 No 0.64 0.453 0.53 0.667 Yes 0.679 0.819 0.742 K=5-fold cross validation No 0.634 0.446 0.524 0.664 Yes 0.676 0.818 0.740 K=10-fold cross validation No 0.634 0.446 0.524 0.664 Yes 0.676 0.818 0.740 7. Please use a flowchart to explain the modelling and analysis process. A flowchart has been provided. Thank you for your comment. 8. Why discuss on different ratio partitioning, in this case it is better use simulation dataset to see the impact of the ratio into the results. Data partitioning ratio is considered as one of the parameters and the aim was to identify the best ratio that can provide better classification model. We also used k-fold cross validation method as explained earlier."
}
]
},
{
"id": "95431",
"date": "15 Oct 2021",
"name": "Shahrinaz Ismail",
"expertise": [
"Reviewer Expertise Data analytics with knowledge management"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nSince this is a full research paper, it is recommended that a Literature Review section be included. It is believed that there are some previous research that have performed the 4 ML techniques covered by this research, hence the need to also mention those and how they differ in results as compared to the results found in here.\nSome additional elaboration is required for technical parts of this paper, especially in clarifying the relation between the formula and the techniques used. Do all the formulas need to be performed for each of the 4 techniques?\nIf there is a step taken before the evaluation that uses the formulas, please include them at least as summary. If this part is covered in the published paper (part 1), perhaps that should be mentioned. If this paper only covers the result on which technique is the best, then perhaps the title should reflect that. At the moment, the title does not reflect the research questions.\nResearch questions are usually asked with the word \"how\" instead of \"can\". It would be more sound to rephrase them to \"how\".\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7429",
"date": "12 Nov 2021",
"name": "Rathimala Kannan",
"role": "Author Response",
"response": "Since this is a full research paper, it is recommended that a Literature Review section be included. It is believed that there are some previous research that have performed the 4 ML techniques covered by this research, hence the need to also mention those and how they differ in results as compared to the results found in here. We have added brief literature review in the modelling section. Due to the limitation of total words to be within 2500 words, a separate section is not added. Some additional elaboration is required for technical parts of this paper, especially in clarifying the relation between the formula and the techniques used. Do all the formulas need to be performed for each of the 4 techniques? We employed standard performance indicators to evaluate the classification models. If there is a step taken before the evaluation that uses the formulas, please include them at least as summary. If this part is covered in the published paper (part 1), perhaps that should be mentioned. If this paper only covers the result on which technique is the best, then perhaps the title should reflect that. At the moment, the title does not reflect the research questions. We have revised the discussion section which summarizes the process and the results. Research questions are usually asked with the word \"how\" instead of \"can\". It would be more sound to rephrase them to \"how\". The research questions are rephrased to start with \"how\"."
}
]
},
{
"id": "97108",
"date": "25 Oct 2021",
"name": "Sreeja N.K",
"expertise": [
"Reviewer Expertise Supervised Learning",
"Swarm 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 have compared few classifiers on Effects of COVID-19 on the Economy and Individual - Round 2 data set to predict individual household preferences from ESP.\n\nI would recommend the authors to use k-fold cross validation method to evaluate the performance of a classifier instead of a random 60-40 or 80-20 split. This would guarantee that all k subsets are used as a test set once.\n\nThe authors can also perform some statistical tests to validate the results obtained from experiments.\n\nIn Page 4, (section Evaluation), TPR is the True positive rate and not as mentioned by the authors.\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": [
{
"c_id": "7430",
"date": "12 Nov 2021",
"name": "Rathimala Kannan",
"role": "Author Response",
"response": "I would recommend the authors to use k-fold cross validation method to evaluate the performance of a classifier instead of a random 60-40 or 80-20 split. This would guarantee that all k subsets are used as a test set once. Thank you for your comments. As we are aimed to tune the parameters to get the optimal model from each machine learning techniques, separate tables were provided with the various parameter values. Also the data size was 40k. We conducted K-fold cross validation method to evaluate the performance of a classifier. When the data is partitioned with k= 5, and K=10, the findings reveal little difference in F-score values, and the Gradient boosting tree performs best. When the data set is small, k-fold cross validation produces a superior model; but, when the data set is large, it produces no change. A current study backs up this conclusion (Marcot & Hanea, 2021). Marcot, B. G., & Hanea, A. M. (2021). What is an optimal value of k in k-fold cross-validation in discrete Bayesian network analysis? Computational Statistics, 36(3), 2009–2031. https://doi.org/10.1007/s00180-020-00999-9 Machine Learning Technique Partitioning Ratio Target Variable: Moratorium Precision Sensitivity F-score Accuracy Decision Tree 80:20 (Gini Index) No 0.779 0.727 0.752 0.802 Yes 0.816 0.854 0.834 K=5-fold cross validation (Gini Index) No 0.770 0.702 0.735 0.789 Yes 0.801 0.851 0.826 K=10-fold cross validation (Gini Index) No 0.772 0.697 0.733 0.789 Yes 0.799 0.854 0.826 Gradient Boosted Tree 60:40 No 0.891 0.711 0.791 0.844 Yes 0.821 0.938 0.876 K=5-fold cross validation No 0.889 0.705 0.786 0.841 Yes 0.818 0.938 0.874 K=10-fold cross validation No 0.889 0.705 0.787 0.841 Yes 0.818 0.938 0.874 Random Forest 80:20 (Gini Index) No 0.825 0.769 0.796 0.837 Yes 0.844 0.885 0.864 K=5-fold cross validation (Gini Index) No 0.821 0.761 0.790 0.832 Yes 0.839 0.882 0.860 K=10-fold cross validation (Gini Index) No 0.826 0.757 0.790 0.833 Yes 0.837 0.887 0.862 Naïve Bayes 60:40 No 0.64 0.453 0.53 0.667 Yes 0.679 0.819 0.742 K=5-fold cross validation No 0.634 0.446 0.524 0.664 Yes 0.676 0.818 0.740 K=10-fold cross validation No 0.634 0.446 0.524 0.664 Yes 0.676 0.818 0.740 In Page 4, (section Evaluation), TPR is the True positive rate and not as mentioned by the authors. Thank you for spotting this typo error. We have corrected it."
}
]
}
] | 1
|
https://f1000research.com/articles/10-932
|
https://f1000research.com/articles/10-399/v1
|
18 May 21
|
{
"type": "Research Article",
"title": "Scientific research and innovation response to the COVID-19 pandemic in Peru",
"authors": [
"Jeel Moya-Salazar",
"Lucia Gomez-Saenz",
"Betsy Cañari",
"Hans Contreras-Pulache",
"Lucia Gomez-Saenz",
"Betsy Cañari"
],
"abstract": "Background: COVID-19 has shaken countries at all levels, putting public health at risk. Global efforts have allocated funding for the development of research for the development of vaccines, digital tools, epidemiologic, social, and economic studies. Although these efforts have been developed worldwide, not all countries have prioritized the same topics, and may have a different impact on solving problems and containing the spread of COVID-19. Methods: A descriptive study was conducted with secondary data of \"Special Projects COVID-19” in order to analyze the prioritization of proposals and projects to Peruvian needs in the face of pandemic. Two calls were made by the Peruvian research council (CONCyTec); the first with five areas and second with seven. The global amounts financed by each call were 342,857 USD (1,200,000 soles) and 700,000 USD (1,750,000 soles), respectively. Results: A total of 1,101 research projects were presented, 600 (54.5%) in the first call. In this call, 176 (29.3%) projects were from the technological development and innovation and 29 were winners (with a global budget of 1,711,907.25 USD /6,077,270.75 soles). In the second call, 120 (23.9%) projects were from the area of Social and economic research and 21 were winners (global budget of 1,284,002.25 USD/558,208.55 soles) (p=0.043). The largest proportion of winning projects in both calls was 12 (41.4%) in Technological developments and innovation, then five (17.2%) each in telehealth and mobile health, and epidemiological and social studies. Across both calls, 214 (55.8%) and 160 (51.9%) projects were of private organizations and universities, respectively. Conclusions: This research shows ~2% of rapid response \"Special Projects COVID-19” were financed by the CONCyTec call with over a million dollars of funds. Although the main topics were technological innovation, detection systems, and vaccines, these priorities have not had a global impact on the epidemiological development of the pandemic in Peru.",
"keywords": [
"COVID-19",
"research",
"funding",
"SARS-CoV-2",
"Peru"
],
"content": "Introduction\n\nCOVID-19 is an emerging infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belong to the coronaviridae family and is usually associated with mild-and-upper respiratory tract infections. SARS-CoV-2 is highly infectious, with an estimated mortality rate of between 2-4%, and high incidence of complications in the respiratory system (~29%), mainly in populations with risk factors and chronic diseases, (such as obesity, diabetes mellitus, hypertension, etc.).1,2 This led almost all countries to opt for compulsory social isolation through quarantines, which led to the development and establishment of virtualization for educational, labor, and social purposes.3,4\n\nThe COVID-19 crisis in Latin America afflicts communities with complex epidemiological profiles and social problems such as Venezuelan migration and corruption.5 For these reasons, it is considered that the impact generated by this disease not only has repercussions on health but also is aggravating the economic and socio-political crises, forcing countries to take actions to reduce their progress even at the cost of their political-economic stability.5 In their eagerness to face the pandemic, countries adopted preparedness and risk controls, where it established the creation of strategies that allow a correct and timely approach to patients, so they seek to provide diagnostic methods, mechanical ventilators, personal protective equipment (PPE), and health professionals.6,7\n\nAll current technology is being deployed to face the health emergency due to COVID-19. Therefore governments, understanding the importance of science and technology, are providing funds for scientific and technological research and innovation to promote the development of rapid-response projects generally in infrastructure, equipment, diagnosis, and therapy of COVID-19.5\n\nIn Peru, there is the National Council of Science, Technology and Technological Innovation (CONCyTec), which has the mission of formulating policies, and promoting and managing actions to create and disseminate knowledge and develop the social and economic aspects of the country, is providing financing facilities for innovative projects in the face of the COVID-19 pandemic \"Special Projects\" (CPSP) in the cultural, social, and health context. The impact of these government-funded projects should have a decisive impact on the course of the pandemic, providing solutions and generating knowledge as a means to understand, confront and control SARS-CoV-2, just as other countries are doing.8–11\n\nThe objective of this research was to analyze the proposals and projects under the development of CPSP in the prioritization axis and as a proportional response to the needs in the face of COVID-19. Likewise, the prioritized thematic areas and the economic scope in the face of the COVID-19 pandemic in Peru were analyzed.\n\n\nMethods\n\nA descriptive cross-sectional study was designed with secondary data analysis of CPSP in the two calls launched by the government in search and recruitment of projects in science and technology during April - July 2020. The search parameters were all the projects presented and selected in both stages of the contest, following the admission and selection criteria of the CPSP: relevance, feasibility, and sustainability and impact of the proposals. There were no project limits in both calls. We searched the CPSP project database between November 10 and November 30, 2020. The underlying data used in this study is available on the CPSP site: https://fondecyt.gob.pe/convocatorias/innovacion-y-transferencia-tecnologica/proyectos-especiales-respuesta-al-covid-19.\n\nDue to the lockdown by COVID-19, the Peruvian government through CONCyTec launched the first open call CPSP with an opening date of March 31, 2020, having two end dates: the first cutoff date, which is April 27, and the second cutoff date, which ended on April 30, 2020, to search for projects in five thematic areas assigned in the call:\n\n\n\n1. Development and/or validation of detection systems\n\n2. Telehealth and mobile health\n\n3. Technological developments and innovation\n\n4. Treatment\n\n5. Epidemiological and social studies.\n\nThe call was divided into stages and had a maximum funding of 42,857.20 USD (150,000 soles), 80,000 USD (200,000 soles), 120,000 USD (300,000.00 soles), and 140,000 USD (350,000 soles) for each subject respectively, and 342,857 USD (1,200,000 soles) overall. 600 research projects were presented that included the participation of national and private universities, national institutes, and the private sector (Figure 1). 51 projects were shortlisted in this call at the end of April according to CPSP criteria. From this list the winners were then selected. (Full list of project applicants and winners are available at: https://fondecyt.gob.pe/convocatorias/innovacion-y-transferencia-tecnologica/proyectos-especiales-respuesta-al-covid-19)\n\nDevelopment of calls for research projects according to the trend line of cases (R, red line), mortality rate (black and white bars) and period of time of the study.\n\nBetween May 27, and June 17, 2020, the second open call for \"Special Projects: Modality-Emerging Needs to COVID-19 2020-02”. (Data available at: https://fondecyt.gob.pe/convocatorias/innovacion-y-transferencia-tecnologica/proyectos-especiales-modalidad-necesidades-emergentes-covid-19) This call-maintained distribution in seven thematic areas:\n\n\n\n1. Treatment and transmission of SARS-Cov-2\n\n2. Vaccines, antigens, and antivirals\n\n3. Diagnosis\n\n4. Surveillance and digital health\n\n5. Sanitary devices\n\n6. Epidemiology and prevention\n\n7. Social and economic research\n\nThe call had a maximum funding of 85,714.28 USD (300,000 soles), 100,000 USD (350,000 soles), 85,714.28 USD (300,000.00 soles), 42,857.20 USD (150,000 soles), 57,142.85 USD (200,000 soles), 85,714.28 USD (300,000 soles), and 42,857.20 USD (150,000 soles), for each area, respectively. The total financing was 500,000 USD (1,750,000 soles) for all projects. The call followed the same contest criteria as the first, except that they had different general themes. As of July 11, 2020, 501 research projects were submitted, of which 125 were preselected according to CPSP criteria (Figure 1).\n\nFrom the websites of both calls, free access data was collected on the projects presented in the five and seven categories in the first and second calls, respectively. The variables included for the study were: General topic, requesting entity, and approved budget. The data was included and coded in a data matrix in MS-Excel 2013 v15.0 for Chrome (Google, CA, US), where it was subcategorized by the areas, calls, and project status as listed on the CPSP site. To avoid errors in data collection, two independent researchers participated in this process and two quality evaluations were carried out on the matrix obtained. As official data was used, no biases were identified.\n\nThe data analysis initially included a descriptive evaluation in both calls, presenting the findings of the category and continuous variables in frequencies. To show differences between calls and subject areas, we used non-paired Student's T-test and Tchi-Square considering a value of p <0.05 as significant. The statistical analyzer was SPSS v21.0 (IBM, Armonk, US) for Windows.\n\n\nResults\n\nA total of 1,101 research projects were presented, 600 (54.5%) in the first call. For this call, 176 (29.3%) projects were from the technological development and innovation area, 164 (27.3%) from the telehealth and mobile health area, 95 (15.8%) were from the epidemiology and social studies area, 84 (14%) from the treatment area, and 81 (13.5%) in the area for development and/or validation of detection systems. In the second call, 501 projects were presented, of which 120 (23.9%) were from the area of social and economic research, 105 (20.9%) from epidemiology and prevention, 101 (20.1%) from sanitary accessories, 59 (11.7%) from surveillance and digital health, 54 (10.7%) from treatment and transmission of SARS-CoV-2, 47 (9.3%) from diagnosis, and 15 (2.9%) from vaccines, antigens, and antivirals (Table 1).\n\nProjects according to themes of the Special Projects: Response to COVID-19 contest. Data in n (%).\n\nThe organizations that participated in both calls are detailed in Table 2. In the first call, 214 (55.8%) organizations were private entities, 137 (35.7%) organizations were universities, 15 (3.9%) were public entities, and 17 (4.4%) were from the Ministry of Health of Peru (MINSA). In the second call, 51.9% (160 organizations) of organizations were universities, followed by 39.9% (123 organizations) private entities, 2.5% (eight organizations) public entities, and 5.5% (17 organizations) MINSA institutions. We found differences between the types (national, private, etc.) of participating institutions in both calls (p = 0.033).\n\nTotal of participating entities according to themes of the Special Projects: Response to COVID-19 contest for both calls. Data in n (%).\n\nTotal winning projects for both calls was 50 (8.3%) projects with a global budget of 2,995,909.51 USD (10,635,478.75 soles). According to the selection of projects, 29 winners were obtained in the first call, with 12 (41.4%) in technological developments and innovation, and five (17.2%) in each telehealth and mobile health, and epidemiological and social studies (Figure 2). For these projects, a global budget of ~1.7 million dollars (6,077,270.75 soles) was distributed as 35.6% (610,092.45 USD/2,165,828.20 soles) allocated for projects in technological development and innovation, and 16.4% (280,956.21 USD/997,394.55 soles) for projects to epidemiological and social. For the second call, there were a total of 21 winners, six (28.6%) in Epidemiology and prevention and five (23.8%) in Sanitary accessories, with a global assigned budget of 1,284,002.25 USD (4,558,208.55 soles) (Table 3). We found differences in funding amounts between calls (p = 0.043) and between the areas within each call (p = 0.010).\n\nBudget approved for each theme for the winning projects of the Special Projects: Response to COVID-19 contest for first (A) and second (B) calls.\n\nThe main universities responsible for the winning projects were Universidad Peruana Cayetano Heredia (UPCH) (n = 10, 20%), the Pontifica Universidad Católica del Perú (PUCP) (n = 7, 14%), and the Universidad Nacional Mayor de San Marcos (n = 3, 6%). Other institutions with winning projects were the National Health Institute of Peru (n = 4, 8%) and Farmacológicos Veterinarios S.A.C. (n = 2, 4%) corresponding to the Ministry of Health and the private sector, respectively.\n\n\nDiscussion\n\nIn this study, we determined that Peru has allocated more than 2.9 million dollars for research on COVID-19 in order to obtain the necessary tools to face the inclemency of the pandemic. Of the 50 award-winning projects, those prioritized were those of technological development and innovation, telehealth and mobile health, and epidemiological and social studies, proposed mainly by private institutions.\n\nAlthough Peruvian institutions have shown interest in promoting the efforts to meet the needs of the COVID-19 pandemic and the extensive measures to reduce contagion and mortality rates, the results have shown the opposite. Peru has been the first country to foresee prevention activities against COVID-19, these strategies have shown promise and have involved high costs due to prolonged quarantine, social immobility, and SARS-CoV-2 detection tests.5 However, during the last six months it has become the opposite. Peru’s double problem is that it is the first country with the largest number of deaths per 100,000 inhabitants and, due to its political complexity, its potential future economic recession (GDP -15.5%) is the largest in the United States.12,13\n\nThis situation also seems to affect Peruvian science and technology. Efforts to promote technological innovation and research projects in the sciences and humanities are being intransigent, due to the low impact they have achieved. The onsets of the pandemic brought concern about the supply of diagnostic tests throughout the world, and, in Peru with funding from CONCyTec, funds were directed to the development of molecular detection and diagnostic tests (and also in-house systems of oxygen supply). Contrary to expectations, more than six projects14 are still waiting to complete the validation and approval stages of the government patent bodies (Instituto Nacional de Defensa de la Competencia y de la Protección de la Propiedad Intelectual - INDECOPI) that are not adequately planned and are being “built” together with the progress of the pandemic.\n\nAlthough Peru does not have an industry specifically designed for mass production of vaccines or diagnostic tests, the government has prioritized the development of these projects (Table 2 and 3). Most of the government funds for R+D+i have been directed to the development of Peruvian vaccines against SARS-CoV-2.15 Also, in this context, the most formulated public policies have impeded their advance, despite their inclusion on the list of vaccine candidates by the World Health Organization.16\n\nIn Peru, CONCYTEC presented two calls, accepted 50 projects, and provided USD 2,995,909.51 (10,635,478.75 soles) in financing (Table 3). The purposes of these projects have been based on the health realities of other countries with high rates of mortality and contagion, although they differ through the San Carlos III Institute with a budget of € 24 million with the goal of financing projects that increase knowledge of the management of the disease to optimize the response to the pandemic.10 This initiative has financed a total of 132 projects, prioritizing the proposals for rapid diagnosis techniques of the virus, biologic-molecular clinic, prognosis, complications of COVID-19, vaccine development, epidemiological surveillance, socio-economic impact and artificial intelligence, and the massive analysis of integrated data oriented to epidemiological control. On the other hand, the Spanish BBVA Foundation has funded research on biomedicine (Biomed-COVID-19), big data and artificial intelligence (Data-IA-COVID-19), ecology and veterinary medicine (Eco-Vet-COVID-19), economics and social sciences (Socioecon-COVID-19), humanities (Human-COVID-19) with € 250,000, € 150,000, € 100,000, € 100,000, and € 75,000, respectively.17\n\nIn Latin America, several countries have intensified their support and interest in research and scientific innovation on COVID-19, such as the calls from Argentina (PISAC-COVID 19), Mexico (CONACYT), Chile (ANID), Costa Rica (UCREA), and Ecuador (United States Embassy - Opportunity Funds for the year 2020). Also, the National Agency for Research and Development of Chile made a call that embraced the diagnosis, treatment, prevention, control, or aspects from the technological, social, cultural, economic, and humanistic field of COVID-19, whereof a total of 1,055 projects, 63 (5.9%) were approved and the budget for each project was 11,608.41 USD (731,304 USD in total).9,18,19\n\nIn the case of the United States, the National Institutes of Health (NIH) and Johns Hopkins University have made international efforts to develop scientific and technological projects. Until August 2020, the NIH approved a total of 653 projects, one of them with the largest budget of all the projects analyzed: characterizing SARS-COV-2-Specific Immunity in Convalescent Individual with a total of 138,462 987 USD. Johns Hopkins University granted funding for August 2020, to a total of 77 projects, where two projects reached the highest budget with USD 22 million for both: Phased Large Awards in Comparative Effectiveness Research (PLACER) and NEW Making a Difference Request for Proposals - Fall 2020. This university has also been developing global technological development events, such as the Johns Hopkins Healthcare Design Competition 2020 and MedHacks 2020, with budgets of more than 30,000 USD8.\n\nThis study had limitations: 1. We did not have access to the comprehensive review of the winning projects, to know their objectives and deadlines; 2. We were unable to follow up on the projects, to find out how many projects met their objectives and how many gave up. Despite these limitations, this study presents for the first time the analysis of rapid response projects against COVID-19 in Peru.\n\n\nConclusions\n\nIn conclusion, in Peru around 8% of CPSP against COVID-19 were financed after being submitted to the CONCyTec call with more than 2.9 million US dollars of funds allocated. Although the main topics were technological innovation, mobile health, and epidemiological and social studies, these priorities have not had an impact on the epidemiologic development of the pandemic in the country. It is necessary to improve public policies that limit the rapid application of these projects as part of the strategies to face the pandemic, and the social and economic consequences that it is leaving.",
"appendix": "Acknowledgements\n\nWe appreciate the support of Valeria and Javier Sevillano-Jimenez on data collection.\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\nReferences\n\nHelmy YA, Fawzy M, Elaswad A, et al.: The COVID-19 pandemic: a comprehensive review of taxonomy, genetics, epidemiology, diagnosis, treatment, and control. J Clin Med. 2020; 9(4): E1225–E1225. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMiller IF, Becker AD, Grenfell BT, et al.: Disease and healthcare burden of COVID-19 in the United States. Nat Med. 2020; 26: 1212–1217. PubMed Abstract | Publisher Full Text\n\nGray DM, Joseph JJ, Olayiwola JN: Strategies for Digital Care of Vulnerable Patients in a COVID-19 World—Keeping in Touch. JAMA Health Forum. 2020; 1(6): e200734–e200734.\n\nUnited Nations: Policy Brief: Education during COVID-19 and beyond.New York: UN. 2020.\n\nPan-American Health Organization: Response to COVID-19 in the Americas.Washington D.C.: PAHO; 2020.\n\nAllam M, Cai S, Ganesh S, et al.: COVID-19 Diagnostics, Tools, and Prevention. Diagnostics. 2020; 10(6): 409. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSorbello M, El-Boghdadly K, Schumacher J, et al.: Personal protective equipment, airway management, and systematic reviews. Br J Anaesth. 2020; 125(4): e360–e361. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJohn Hopkins Biomedical Engineering: 2020 Johns Hopkins Healthcare Design Competition. Accessed Jan 10, 2021 Reference Source\n\nAgencia Nacional de Investigación y Desarrollo: Concurso para la Asignación Rápida de Recursos para Proyectos de Investigación sobre el Coronavirus (covid-19) año 2020. Accessed Jan 10, 2021 Reference Source\n\nInstituto de Salud Carlos III: Solicitud urgente de expresiones de interés para la financiación extraordinaria de proyectos de investigación sobre el SARS-CoV-2 y la enfermedad COVID-19. Accessed Jan 12, 2021 Reference Source\n\nJaniaud P, Axfors C, van’t Hooft J, et al.: The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days [version 2; peer review: 2 approved]. F1000Res. 2020; 9: 1193. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuigley J: Peru Now World’s Deadliest Covid Hot Spot: Latam Virus Wrap. Accessed Jan 22, 2021 Reference Source\n\nEconomic Commission for Latin America and the Caribbean: Special Report COVID-19 No 5.ECLAC; Santiago de Chile. 2020.\n\nPrensa Latina: Producción de pruebas moleculares de Covid-19 frenada en Perú. Accessed Jan 30, 2021 Reference Source\n\nRodriguez ME: Latin American scientists join the coronavirus vaccine race. Nature. 2020; 582(7813): 470–582. PubMed Abstract | Publisher Full Text\n\nWHO: Draft landscape of COVID-19 candidate vaccines.Geneva:WHO.2020.\n\nBBVA Foundation: The BBVA Foundation supports 20 COVID-19 research projects with €2.7 million. Accessed Jan 10, 2021 Reference Source\n\nAgencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación: Acciones sobre COVID-19. Accessed Jan 20, 2021 Reference Source\n\nAgencia Nacional de Investigación e Innovación: Desafío: test serológicos covid-19. Accessed Jan 11, 2021 Reference Source"
}
|
[
{
"id": "85661",
"date": "23 Jul 2021",
"name": "Rodrigo Ernesto Salazar Gamarra",
"expertise": [
"Reviewer Expertise Public healthcare & Healthcare innovation"
],
"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\nFrom a public health perspective, it is important to understand how the priorities of government instances and stakeholders work together to allow the community to work for its society. In that sense, the objective of the present research has a high-importance relevance to analyze this situation for the Peruvian population.\n\nThis research touches on funding assignments for the scientific community called CONCYTEC. This is the principal grant opportunity for Peruvian scientists to execute their projects and it is important to do a discussion around how it impacted this pandemic time. Results showed that there is still important work around public policies improvement.\nI agree with the indexing of this article.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? 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": "94812",
"date": "01 Oct 2021",
"name": "Mario Coccia",
"expertise": [
"Reviewer Expertise COVID-19 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\nScientific research and innovation response to the COVID-19 pandemic in Peru\nThe topics of this paper are interesting but the structure and content have to be revised by authors before being considered for indexing.\nThe abstract needs to show briefly, health, research, and social policy implications.\n\nThe introduction needs to better clarify the research questions of this study. Moreover, authors need to better describe the different sources of transmission dynamics of COVID-19 (e.g., mobility, environment, etc.) and risk factors in society, and restriction policies that affect the socioeconomic system of Peru (see suggested readings that have to be all read and used in the text).\n\nThe methods of this study are not clear. The section of Materials and methods needs to be restructured with the following three sections: Sample and data, and research settings, Measures of variables, and data analysis procedure.\n\nResults. Figure 1 needs to show the measure of the variable on the y-axis. The legend has to be in English.\n\nDiscussion can show, if possible, the implications of these calls in terms of scientific output (publications or patents) to assess the effects on basic and applied research. Suggested papers, including some of mine, are important to reinforce the theoretical framework and support a better discussion and best practices of the scientific and technological change to face the COVID-19 pandemic crisis.\n\nThe conclusion has not to be a summary but authors have to focus on manifold limitations of this study and provide suggestions of health and social policy and strategies of prevention.\n\nOverall the paper is interesting but the theoretical framework is weak, and some results create confusion… structure of the paper has to be improved; study design, discussion, and presentation of results have to be clarified using suggested comments.\nIf the paper is improved, by using all comments, maybe it can be considered.\nSuggested readings of relevant and new papers that have to be read and all inserted in the text and references.\nAlves, I., Analide, C., Vaz, F.\n\n2022. The Relationship Between Financial Execution in R&D and Scientific Production Lecture Notes in Networks and Systems, 332, pp. 171-1811\nCoccia M. 2022. Preparedness of countries to face covid-19 pandemic crisis: Strategic positioning and underlying structural factors to support strategies of prevention of pandemic threats, Environmental Research, n. 111678 2.\nDurán, R.L.2021. COVID-19 and heterogeneous vulnerabilities in the Peruvian labor market: implications for social inequalities and for gender gaps, Economia Politica 3\nCoccia M. 2021. Effects of the spread of COVID-19 on public health of polluted cities: results of the first wave for explaining the dejà vu in the second wave of COVID-19 pandemic and epidemics of future vital agents. Environmental Science and Pollution Research. 4\nPortocarrero Merino, E., Veramendi Villavicencios, N.G., Enrique Suero Rojas, E., Mendoza Loli, J.S. 2021. Development and validation of scale resilient coverage and future expectations in university of huanuco in times of COVID-19 | [Desarrollo y validación de escala afrontamiento resiliente y expectativas de futuro en universitarios de huanuco en tiempos de COVID-19], Universidad y Sociedad, 13(4), pp. 132-142 5\nCoccia M. 2021. Pandemic Prevention: Lessons from COVID-19. Encyclopedia 2021, 1, 433–444. MDPI, Basel, Switzerland, Encyclopedia of COVID-19 ISSN 2673-8392, journal, (https://www.mdpi.com/journal/encyclopedia) 6\nKinnunen, J., Georgescu, I., Hosseini, Z., Androniceanu, A.-M.\n\n2021, Dynamic indexing and clustering of government strategies to mitigate Covid-19,\n\nEntrepreneurial Business and Economics Review, 9(2), pp. 7-20 7\nCoccia M. 2021. High health expenditures and low exposure of population to air pollution as critical factors that can reduce fatality rate in COVID-19 pandemic crisis: a global analysis. Environmental Research, vol. 199, Article number 111339, 8\nBarreto, I.B., Sánchez, R.M.S., Marchan, H.A.S. 2021, Economic and social consequences of human immobility due to COVID-19: Peru case study | [Consecuencias económicas y sociales de la inamovilidad humana bajo Covid – 19 caso de estudio Perú],\n\nLecturas de Economia, (94), pp. 285-303 9\nTang, X., Wu, C., Li, X., Song, Y., Yao, X., Wu, X., Duan, Y., (...), Lu, J. 2020. On the origin and continuing evolution of SARS-CoV-2 , (2020) National Science Review, 7 (6), pp. 1012-1023.10\n\nIs the work clearly and accurately presented and does it cite the current literature? No\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nPartly\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": [
{
"c_id": "7401",
"date": "12 Nov 2021",
"name": "Jeel Moya-Salazar",
"role": "Author Response",
"response": "Dear Dr. Coccia, We have received and reviewed your comments, and we welcome your suggestions so that we can improve our research. All changes have been made in the abstract, introduction, methodology, discussion, and conclusions as indicated. We have reviewed the studies you suggested and included some of them as part of the research. Figure 1 that had some Spanish terms has been adjusted. We hope this new version of the study in Peru will improve your background in research and development. We have learned a lot from the research we have read during the corrections. Sincerely,"
}
]
}
] | 1
|
https://f1000research.com/articles/10-399
|
https://f1000research.com/articles/10-654/v1
|
26 Jul 21
|
{
"type": "Software Tool Article",
"title": "RNfuzzyApp: an R shiny RNA-seq data analysis app for visualisation, differential expression analysis, time-series clustering and enrichment analysis",
"authors": [
"Margaux Haering",
"Bianca H Habermann",
"Margaux Haering"
],
"abstract": "RNA sequencing (RNA-seq) is a widely adopted affordable method for large scale gene expression profiling. However, user-friendly and versatile tools for wet-lab biologists to analyse RNA-seq data beyond standard analyses such as differential expression, are rare. Especially, the analysis of time-series data is difficult for wet-lab biologists lacking advanced computational training. Furthermore, most meta-analysis tools are tailored for model organisms and not easily adaptable to other species. With RNfuzzyApp, we provide a user-friendly, web-based R shiny app for differential expression analysis, as well as time-series analysis of RNA-seq data. RNfuzzyApp offers several methods for normalization and differential expression analysis of RNA-seq data, providing easy-to-use toolboxes, interactive plots and downloadable results. For time-series analysis, RNfuzzyApp presents the first web-based, fully automated pipeline for soft clustering with the Mfuzz R package, including methods to aid in cluster number selection, cluster overlap analysis, Mfuzz loop computations, as well as cluster enrichments. RNfuzzyApp is an intuitive, easy to use and interactive R shiny app for RNA-seq differential expression and time-series analysis, offering a rich selection of interactive plots, providing a quick overview of raw data and generating rapid analysis results. Furthermore, its orthology assignment, enrichment analysis, as well as ID conversion functions are accessible to non-model organisms.",
"keywords": [
"RNA-seq",
"data normalization",
"data visualization",
"differential expression analysis",
"time-series analysis",
"soft clustering",
"Mfuzz",
"R shiny"
],
"content": "Introduction\n\nThe development of next generation sequencing (NGS) methods has boosted the rapid generation of large datasets and RNA sequencing (RNA-seq) has become the standard for performing robust transcriptional profiling and thus quantifying gene expression in various contexts. Next to the comparison of two conditions, the generation of time-series RNA-seq data has become amenable and popular, allowing to monitor the gene expression dynamics over a process such as development, ageing or cancerogenesis. While web-based, user-friendly R shiny apps have become available recently for differential expression analysis and data visualization of RNA-seq data,1–7 the analysis of time-series data within R remains largely command-line based and therefore challenging for bench scientists without programming knowledge.\n\nWe here present RNfuzzyApp, a user-friendly, web-based R shiny app with an intuitive user interface for the full workflows of differential expression analysis, as well as time-series analysis of RNA-seq data. RNfuzzyApp provides an interface for easy and fast data normalization and differential analysis using several methods, a variety of interactive plots for a quick overview of data and results, and an easy-to-use interface for the complete pipeline of time-series expression analysis using the fuzzy clustering algorithm Mfuzz.8 In addition, RNfuzzyApp offers ID conversion, orthology assignment and enrichment analysis using gprofiler2.9 We show the usability of RNfuzzyApp on two examples: an RNA-seq dataset of the ageing limb muscle of mouse, as well as developmental time-series RNA-seq data of the Drosophila melanogaster leg.\n\n\nMethods\n\nRNfuzzyApp was built in R (V.4.0.4) using the Shiny framework. The app currently depends on the following R packages: shiny, shinydashboard, shinycssloaders, shinythemes, shinyWidgets, shinyBS, rmarkdown, plotly, dplyr, RColorBrewer, utils, tidyr, devtools, cluster, DESeq2,10 edgeR,11 TCC,12 including baySeq,13 heatmaply,14 gprofiler2,9 Mfuzz,8 as well as the package e1071. As a basic feature and to allow users to upload any identifier for analysis, ID conversion is included, using the gprofiler2 package.\n\nRNfuzzyApp can be launched locally from any computer with R (version 4.0.4 or higher) installed and will run in any web-browser. As RNfuzzyApp auto-installs all required R-packages, there exist no additional software requirements. Installation instructions are also available. All interfaces and plots of RNfuzzyApp are highly interactive, allowing users to visualize data in real-time as well as to interact efficiently with the data and plots.\n\nThe general workflow of RNfuzzyApp is shown in Figure 1. It can be divided into two independent parts: 1) a complete workflow for differential expression analysis of RNA-seq data (Figure 1a); and 2) a complete workflow for the clustering of RNA-seq using the soft clustering algorithm Mfuzz (Figure 1b).\n\n(a) RNA-seq differential expression analysis workflow with the three main parts: data upload and visualization, data normalization and differential expression analysis, as well as enrichment analysis and orthology assignment. The types of analyses are shown, as well as the various possible R programs provided for data analysis. (b) Mfuzz workflow for clustering of time-series RNA-seq data. The workflow includes the selection of cluster numbers, checking the overlap of Mfuzz clusters, loop calculations of Mfuzz, Mfuzz plot generation, as well as enrichment analysis of Mfuzz clusters.\n\nThe differential expression analysis workflow of RNfuzzyApp can be divided in three main parts: the upload and visualization of the raw data; the normalization of the data and the differential expression analysis; and finally, enrichment analysis of results and orthology assignment (Figure 1a). In each part, several options exist for visualizing the data and thus getting a first-hand impression of the quality of the data, as well as the filters that are applied.\n\nData upload and visualization of raw gene expression data\n\nFigure 2 shows the RNfuzzyApp start interface, featuring data upload, filtering, as well as raw data visualization possibilities. As a first step, raw read counts need to be uploaded to the app, in the form of a csv count matrix. Data can be filtered for raw read counts (Figure 2c), the resulting summary of the data are interactively updated in the Summary box of the interface (Figure 2d). Groups can be assigned directly in the interface (Figure 2e). Three tables are available for download: the actual table, containing only the genes that pass the filtering threshold; the original input table; as well as a table containing all genes filtered out due to low read counts (Figure 2f). Raw data can also be visualized (see top of the menu, Figure 2): the count distribution of raw read counts can be visualized (Figure 3a). Moreover, raw read counts can be used for hierarchical clustering, as well as a PCA analysis.\n\n(a) The RNfuzzyApp menu box is highlighted in red. This box is shown consistently over all interfaces and links to Data visualization, DE analysis, Data normalization and analysis, different visualization possibilities (MA plot, Volcano plot, Heatmap and PCA), Time series clustering (using the pipeline for Mfuzz soft clustering), Enrichment analysis, Orthology assignment, as well as ID-conversion. The main interface shown here belongs to Data visualization (highlighted in dark red). (b) Data upload box, for upload of user-provided data. (c) Data filter box, in which the user can choose to filter out genes with low read counts. (d) Group assignment box, in which the user has to assign the groups (e.g. wild-type and mutant, or different time-points) to the data. (e) Data summary box. The data shown in this box are updated and in case of filtering and are renewed on the fly. (f) Data table box. Three tables are provided: the actual table, including genes that were not discarded due to filtering; the input table, containing all data uploaded; finally the filtered table, containing genes that were removed due to filtering.\n\nWe used data from the Tabula muris senis project for demonstration purposes. (a) Count distribution plot of mice from 3 months, 12 months and 27 months. Only replicates from male mice were chosen. Data are grouped by condition. The title of the plot, as well as the X-axis label can be chosen by the user. Raw read counts were chosen for visualization. (b) Hierarchical clustering of normalized read counts. Spearman correlation was used for clustering. (c) PCA plot of normalized read counts. The PCA plot can be visualized in 2D or 3D. DESeq2 was used for normalization of data.\n\nData normalization and differential expression analysis\n\nRNfuzzyApp offers several packages for data normalization, as well as for differential expression analysis. Normalization can be done using DESeq2; TMM (trimmed mean of M values), RLE (relative log expression) or upperquantile offered by edgeR; finally the TCC package providing TMM or DESeq2 normalization. As for raw read counts, the count distribution, a heatmap for clustering samples (Figure 3b), as well as PCA analysis with a 2D as well as 3D PCA plot (Figure 3c) is available for visualising normalized data. Differential expression analysis can be done using DESeq2, edgeR and bayseq. Pairwise comparisons can be visualized with MA and Volcano plots. The plots are interactive and the user can obtain detailed information about a gene hovering over the dots of the plots.\n\nClustering of expression data using heatmaply\n\nWe wanted to provide a simple way of clustering gene expression data from a limited number of samples, e.g. from a short time-series. To this end, RNfuzzyApp offers a heatmap, generated by heatmaply. Figure 4a shows the heatmap of a time-course of 3 time points from the Tabula muris senis project,15 where the gene expression levels of the replicates per time point are clustered using hierarchical clustering. The user can choose the distance matrix and agglomeration method, as well as the FDR cut-off of genes to include in the clustering. Clustering is done using hclust and cutree to generate the coloured dendrogram on the heatmap. The genes contained in the different clusters indicated by the colours in the dendrogram are downloadable as a table for further analysis.\n\n(a) Heatmap of gene expression levels of the Tabula muris senis limb muscle data. Only significant genes were selected for plotting, with an FDR cutoff of 0.01, resulting in 624 DEGs. These DEGs could be clustered in 5 independent clusters, indicated by different colours in the dendrogram. (b) Enrichment analysis results for cluster 4 and cluster 5 of the limb muscle heat map. In cluster 4, processes related to energy and amino acid metabolism are enriched. Genes belonging to this process have a higher expression level in young versus old mice, suggesting more active metabolism in young muscle cells. In cluster 5, processes related to translation are enriched, whereby associated genes have higher expression levels in young muscle versus old muscle. The minus log10 of the p-value of the enriched process is plotted.\n\nEnrichment analysis and orthology assignment.\n\nFor enrichment analysis of Gene Ontology (GO-) terms,16 pathways (Wikipathways,17 Reactome18 and KEGG19), Human Protein Atlas,20 CORUM data on protein complexes,21 and TRANSFAC,22 the gprofiler2 package is included in RNfuzzyApp. Results are displayed as an image of overall enrichment, as well as a results table. The table together with a bar plot of the enriched term names sorted according to p-value are downloadable by the user (Figure 4b, bar plot of enrichments generated from downloaded table).\n\nFuzzy clustering of time-series expression data is a highly useful technique for analysing temporal data. The Mfuzz package from R was developed for soft clustering of temporal gene expression data.8 Starting from a count matrix, genes are clustered according to their expression profiles over time. As Mfuzz is a soft clustering algorithm, a gene can in theory be part of more than one cluster. Mfuzz, however, is not straightforward to use for non-experts. First, a number of clusters must be chosen prior to clustering. Second, repeated Mfuzz runs will result in slightly different cluster memberships of genes. A user is therefore well advised to repeat Mfuzz clustering several times to test the robustness of the clustering. The decision, which cluster number is suited for the data then often includes analysis of cluster overlaps, as well as enrichment analyses of clusters and comparative analysis between several chosen numbers of clusters. Several packages exist to help decide on cluster numbers and the entire workflow for a successful Mfuzz clustering can be programmed in R. However, for untrained bench scientists, this is not easily done. We therefore included the complete workflow of Mfuzz soft clustering of time-series expression data in RNfuzzyApp (Figure 1b): first, for choosing the right cluster number, we implemented the inertia (using the hclust and dist packages) and elbow (using the e1071 package) methods. Inertia performs hierarchical clustering and plots the dendrogram, indicating the distance steps (height) against the number of clusters. Ideally, a cluster number is chosen when the drop in height gets minimal (Figure 5a). The elbow method looks at the total of the within-clusters sums of squares (WCSS) as a function of the number of clusters. The “elbow” shape is formed when WCSS is minimal. These two methods should converge to help choose the right number of clusters. After Mfuzz clustering has been performed, the overlap of clusters can be checked. To do so, the overlap.plot function from Mfuzz is used and results can be visualized (see Figure 5b). After choosing a suitable number of clusters, Mfuzz is run ten times in a loop to test the robustness of clustering results (Figure 1b). Membership lists of the ten Mfuzz clustering runs can be downloaded and checked for robustness. Plots are generated using the mfuzz.plot function and are also downloadable (Figure 6a). Should core clusters be unstable, this entire process can be repeated. Finally, enrichment can be done on Mfuzz cluster gene lists, using gprofiler2 (Figure 6b).\n\n(a) Pre-clustering of data to select the cluster number for Mfuzz time-series clustering. The plot shows the intertia drops of the dendrogram. At 12 clusters, the inertia drop was minimal, suggesting that additional clusters would not provide better modelling of the data. (b) Control plot of Mfuzz cluster overlap. A PCA plot is performed with the selected 12 clusters, showing here that no overlap between clusters exists. Data from the developing Drosophila leg was chosen for demonstration purposes.\n\n(a) Mfuzz clusters of Drosophila leg developmental RNA-seq data. Some similar patterns emerged, with expression profiles peaks early (30 h), mid-phase (50 h) or late (72 h APF (after puparium formation)). (b) Mfuzz clusters have been enriched using gprofiler2. In the parameters box, settings have to be chosen, such as the cluster number submitted for enrichment, the number of results to show, the organism, as well as the databases used for enrichment analysis. The plot on the right-hand side shows the enrichment of cluster 9. (c) Enrichment of the top 10 processes from cluster 10 and cluster 12. In cluster 10, processes related to RNA metabolism, as well as splicing are enriched, associated genes show a decrease in expression over time. In cluster 12, processes related to mitochondrial energy metabolism are enriched, with associated genes showing an increase in expression over time.\n\n\nData preparation\n\nTabula muris senis15 limb muscle raw read data (data accessible at NCBI GEO database,23 accession GSE132040) were taken as is and read into RNfuzzyApp for data processing and differential expression analysis. Raw read data from developing leg muscle24 (data accessible at NCBI GEO database, accession GSE143430) were first averaged over replicates before reading them into RNfuzzyApp, as Mfuzz does not accept replicates (available as Habermann, Bianca; Haering, Margaux (2021), extended Datatables).\n\n\nResults\n\nWe used data from the ageing limb muscle from the Tabula muris senis project (GSE GSE13204015). We selected three time-points: 3 months, 12 months and 27 months. We only used samples from male mice. After data upload, we filtered for lowly expressed genes with less than 50 read counts. We then visualized raw read counts of all samples (Figure 3a). After normalization using DESeq2, we compared samples using hierarchical clustering (Figure 3b), which showed that replicates cluster together. We also performed PCA analysis and could confirm that samples from the same time-point cluster together (Figure 3c). We next subjected samples to differential expression analysis using DESeq2, comparing all time-points against each other (see Extended data: Tables 1a-c). We found 177 genes differentially regulated between 12 and 3 months, 873 genes differentially regulated between ages 27 and 3 months and 31 genes differentially expressed between ages 12 and 27 months when using an FDR of 0.01 and a log2FC of |0.5|. Enrichment analysis of the lists of differentially expressed genes revealed terms related to translation in young versus adult mice, metabolic and extracellular organisational processes between young and aged mice, as well as between adult and aged mice (Extended data: Tables 1d-f).\n\nWe next used hierarchical clustering of genes to identify gene groups changing over time. After finding appropriate points to cut the dendrogram from hierarchical clustering using heatmaply, we found five different clusters with differing expression levels of genes (Figure 4a): two clusters with high expression levels in aged mice and low in young mice, one with high expression levels in adult mice, and two with high expression levels in young mice and low expression levels in aged mice. We subjected all clusters to enrichment analysis (Extended data: Tables 2a-e). For example, cluster 4 and 5, which both show high expression levels in young and low ones in aged mice, had terms related to translation as well as metabolism (energy, amino acids) highly enriched, suggesting more active translation, as well as metabolism in young muscle cells (Figure 4b).\n\nWe used RNA-seq data from a developmental time course of Drosophila leg for soft clustering using the Mfuzz pipeline included in RNfuzzyApp. We used normalized read counts from GEO25 gene expression dataset GSE14343024 and uploaded it to RNfuzzyApp. In brief, leg samples had been collected at three stages during pupal development (30, 50 and 72 h APF) and had been subjected to RNA-sequencing. We wanted to analyse the wild-type expression profiles of genes during these three developmental stages and to identify potentially enriched terms and pathways.\n\nWe first checked with the inertia method the ideal number of clusters (Figure 5a). We chose 12 clusters, as we found no significant change with cluster numbers higher than that. We next tested the overlap of clusters using the overlap.plot function of Mfuzz and found good separation of the 12 clusters (Figure 5b). We ran Mfuzz for clustering gene expression profiles and repeated this step 10 times. One of the resulting Mfuzz plots is shown in Figure 6a. We found expression profiles with high expression at 30 h gradually decreasing at 50 h and 70 h (clusters 9 and 10), high expression at 30 h and 50 h, which dereased at 70 h (clusters 1 and 4), expression peaks at 50 h (clusters 3 and 5), low expression levels at 50 h (clusters 2 and 7), low expression levels at 30 h, gradually increasing at 50 h and 70 h (clusters 8 and 12), as well as expression peaks at 70 h (cluster 6). We used all genes of each cluster for enrichment analysis using gprofiler2 within RNfuzzyApp (Figure 6b, Extended data: Table 3a-l). We found terms relevant for muscle development enriched in cluster 10 (high expression at 30 h, which gradually decreased at 50 h and 70 h), relating to mRNA metabolic processes and specifically, RNA splicing. RNA splicing has been shown to be essential for muscle cell type specification26,25 (Figure 6c). Cluster 12, which contained genes with increasing expression levels from 30 h to 70 h was enriched for terms related to mitochondrial function and energy production (Figure 6c). These results are in accordance with earlier observations of increasing electron transport chain components in flight muscle development.27,26\n\n\nConclusions\n\nWe introduced RNfuzzyApp, an intuitive R shiny app for the complete and interactive workflows of RNA-seq, as well as time-course RNA-seq data analysis. RNfuzzyApp includes several algorithms for data normalization and differential expression analysis and offers the possibility for intuitive and interactive data visualization. All data tables and plots are downloadable by the user. While several R shiny apps exist for differential expression analysis, to the best of our knowledge, this is the first web-based, user-friendly R shiny interface for the complete workflow of time-series analysis using the soft clustering app Mfuzz, making RNfuzzyApp the first accessible tool for time-series analysis for wet-lab biologists. We demonstrated the usability of RNfuzzyApp with two examples of RNA-seq data, one from a mouse ageing study of the Tabula muris senis project, and one from the developing leg in Drosophila melanogaster.\n\nWe chose to offer several packages for normalization, as well as differential expression analysis. This allows the user to exploit several possible combinations of tools for differential expression analysis. Our choice for enrichment analysis in this version of RNfuzzyApp fell on gprofiler2. There are many software tools available for enrichment analysis. Gprofiler2, however, is available also for non-standard model organisms. Therefore, our app can be used for organisms other than human, mouse, Drosophila, C. elegans or yeast. Moreover, gprofiler2 allows in addition ID conversion, as well as ortholog assignment and both these functions were made available in RNfuzzyApp. In future releases of RNfuzzyApp, we consider including more enrichment tools, providing a broader spectrum of data to include, such as EnrichR.28\n\nTo conclude, RNFuzzyApp is an intuitive and easy to use R shiny app that was designed for experimental biologists to enable them to perform RNA-seq and time-series RNA-seq analysis without the need of coding to get a fast overview of their data, results and figures.\n\n\nData availability\n\nGene Expression Omnibus (GEO): Tabula Muris Senis: Bulk sequencing. Accession number GSE132040; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE132040.15\n\nGene Expression Omnibus (GEO): Muscle-type specific transcriptomic expression patterns in Drosophila. Accession number GSE143430; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE143430.24\n\nDryad: Extended data tables to Haering and Habermann, F1000Res, RNfuzzyApp: an R shiny RNA-seq data analysis app for visualisation, differential expression analysis, time-series clustering and enrichment analysis. https://doi.org/10.5061/dryad.8pk0p2nnd.\n\nThis project contains the following extended data:\n\n• Table 1a: Haering_etal_extendedDatatable_1a_Tabulamurissenis_3vs12m_DEA.txt: results of differential expression analysis (DEA) of Tabula muris senis project (GSE132040), limb muscle, 3 vs 12 months.\n\n• Table 1b: Haering_etal_extendedDatatable_1b_Tabulamurissenis_3vs27m_DEA.txt: results of DEA of Tabula muris senis project (GSE132040), limb muscle, 3 vs 27 months.\n\n• Table 1c: Haering_etal_extendedDatatable_1c_Tabulamurissenis_12vs27m_DEA.txt: results of DEA of Tabula muris senis project (GSE132040), limb muscle, 12 vs 27 months.\n\n• Table 1d: Haering_etal_extendedDatatable_1d_Tabulamurissenis_3vs12m_gpofiler.txt: gprofiler results of Tabula muris senis project (GSE132040), DEA, limb muscle, 3 vs 12 months.\n\n• Table 1e: Haering_etal_extendedDatatable_1e_Tabulamurissenis_3vs27m_gpofiler.txt: gprofiler results of Tabula muris senis project (GSE132040), DEA, limb muscle, 3 vs 12 months.\n\n• Table 1f: Haering_etal_extendedDatatable_1f_Tabulamurissenis_12vs27m_gpofiler.txt: gprofiler results of Tabula muris senis project (GSE132040), DEA, limb muscle, 3 vs 12 months.\n\n• Table 2a: Haering_etal_extendedDatatable_2a_Tabulamurissenis_cluster1_gpofiler.txt: gprofiler results of hierachical clustering of Tabula muris senis project (GSE132040), limb muscle, cluster 1.\n\n• Table 2b: Haering_etal_extendedDatatable_2b_Tabulamurissenis_cluster2_gpofiler.txt: gprofiler results of hierachical clustering of Tabula muris senis project (GSE132040), limb muscle, cluster 2.\n\n• Table 2c: Haering_etal_extendedDatatable_2c_Tabulamurissenis_cluster3_gpofiler.txt: gprofiler results of hierachical clustering of Tabula muris senis project (GSE132040), limb muscle, cluster 3.\n\n• Table 2d: Haering_etal_extendedDatatable_2d_Tabulamurissenis_cluster4_gpofiler.txt: gprofiler results of hierachical clustering of Tabula muris senis project (GSE132040), limb muscle, cluster 4.\n\n• Table 2e: Haering_etal_extendedDatatable_2e_Tabulamurissenis_cluster5_gpofiler.txt: gprofiler results of hierachical clustering of Tabula muris senis project (GSE132040), limb muscle, cluster 5.\n\n• Table 3a: Haering_etal_extendedDatatable_3a_DmLeg_cluster1_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 1.\n\n• Table 3b: Haering_etal_extendedDatatable_3b_DmLeg_cluster2_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 2.\n\n• Table 3c: Haering_etal_extendedDatatable_3c_DmLeg_cluster3_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 3.\n\n• Table 3d: Haering_etal_extendedDatatable_3d_DmLeg_cluster4_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 4.\n\n• Table 3e: Haering_etal_extendedDatatable_3e_DmLeg_cluster5_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 5.\n\n• Table 3f: Haering_etal_extendedDatatable_3f_DmLeg_cluster6_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 6.\n\n• Table 3g: Haering_etal_extendedDatatable_3g_DmLeg_cluster7_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 7.\n\n• Table 3h: Haering_etal_extendedDatatable_3h_DmLeg_cluster8_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 8.\n\n• Table 3i: Haering_etal_extendedDatatable_3i_DmLeg_cluster9_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 9.\n\n• Table 3j: Haering_etal_extendedDatatable_3j_DmLeg_cluster10_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 10.\n\n• Table 3k: Haering_etal_extendedDatatable_3k_DmLeg_cluster11_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 11.\n\n• Table 3l: Haering_etal_extendedDatatable_3l_DmLeg_cluster12_gpofiler.txt: gprofiler resuts of mfuzz clustering of Drosophila leg dataset (GSE143430), cluster 12.\n\n• Table 4: Haering_etal_extendedData_DmdevLeg_GSE143430_mean.txt: mean normalized read counts from GSE143430 to be uplaoded for Mfuzz clustering.\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\nSoftware available from: https://gitlab.com/habermann_lab/rna-seq-analysis-app.\n\nZenodo: 10.5281/zenodo.5084275 (https://zenodo.org/record/5084275#.YO_e_y0iuik).\n\nSource code available from: https://gitlab.com/habermann_lab/rna-seq-analysis-app.\n\nArchived source code as at time of publication: Zenodo: RNfuzzyApp: an R shiny RNA-seq data analysis app for visualisation, differential expression analysis, time-series clustering and enrichment analysis. https://doi.org/10.5281/zenodo.5084275.29\n\nLicense: GNU public license 3.\n\n\nAuthor contributions\n\nMA and BHH conceived this project. MA was solely responsible for code implementation, software development and testing. MA and BHH performed data analyses. MA and BHH wrote this manuscript.",
"appendix": "Acknowledgements\n\nWe want to thank Fanny Chazal, Cedric Maurange for critical input and acting as test user of RNfuzzyApp and Fabio Marchiano for helpful discussions. We thank the CNRS, Aix-Marseille University, as well as the IBDM for supporting this work.\n\n\nReferences\n\nSu W, Sun J, Shimizu K, et al.: TCC-GUI: a Shiny-based application for differential expression analysis of RNA-Seq count data. BMC Res Notes. 2019; 12: 133–6. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGuo W, et al.: 3D RNA-seq: a powerful and flexible tool for rapid and accurate differential expression and alternative splicing analysis of RNA-seq data for biologists. RNA Biol. 2020: 1–14. PubMed Abstract | Publisher Full Text\n\nZhang C, et al.: iSeq: Web-Based RNA-seq Data Analysis and Visualization. Methods Mol Biol. 2018; 1754: 167–81. PubMed Abstract | Publisher Full Text\n\nGao B, et al.: Quickomics: exploring omics data in an intuitive, interactive and informative manner. 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}
|
[
{
"id": "90442",
"date": "11 Aug 2021",
"name": "Oliver Hahn",
"expertise": [
"Reviewer Expertise Bioinformatics",
"Systems Biology",
"Epigenetics"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nRNA-sequencing (RNA-seq) is a widely used technology across a range of biomedical fields. While the method itself - that is, the data generation step - is relatively easy to execute by wet lab researchers or can be outsourced into genomic core facilities, the analysis of the resulting data remains a challenge without substantial coding experience. This is particularly the case for experimental designs involving more than two conditions (i.e. treatment vs. control) as it is the case for time course data or dose-response paradigms. In this study, the authors present a new, graphical user interface (GUI) software package, RNAfuzzy App, with the aim to provide a single environment for standard quality control, normalization, differential expression, clustering and functional enrichment operations.\nThe authors re-analyzed two time course datasets from mouse and fruitfly to demonstrate the basic steps and workflows that can be executed with RNAfuzzy App. The package is distributed as a single R shiny app, that the authors design with the intent for easy installation and setup. The demonstrated workflows encompass known steps in RNA-seq analysis including filtering, quality control (via PCA/hierarchical clustering), normalization with several state-of-the-art methods and differential expression involving the accepted software packages Deseq2 and edgeR. The authors highlight the implementation of a soft-clustering workflow involving iterative runs of the Mfuzz algorithm (for analysis of time course trajectories), as well as diagnostic plots that are aiding the user towards correct selection of adjustable workflow parameters. Finally, the authors use the clustering results as input for a functional enrichment workflow, that includes reference data from a range of pathway and transcription factor databases.\nThe authors have pursued the development of a highly relevant software package that provides a very comprehensive set of functions and tools. Current RNA-seq data is generated at impressive scale yet remains frequently under-analyzed due to limited coding experience of the experimenters that generate the data. The implementation of elaborative clustering methods and diagnostic plots to aide the user in deciding for the right settings is particularly commendable. Similarly relevant is the implemented functional enrichment workflow, that is well-suited within this package, instead of just finishing the analysis with a set of gene lists that needs to be interpreted elsewhere. The workflows are based on accepted practices and are in agreement with the field’s ‘standard’ analyses. This is important and commendable as several other tools provide misleading workflows that experimental biologists are unaware of.\nHowever, the software package is currently challenging to install, several functions throw error messages or cause a crash of the app altogether. There is - at least as far as I can tell - very limited documentation (none regarding installation) on how to prepare input data or operate individual workflows. I provide specific details below. I consider myself proficient in bioinformatics in general and RNA-seq data analysis in R in particular, and I struggled and ultimately failed to operate this app.\nWhile I do acknowledge that the authors are not primarily responsible for the individual challenges the user may face - there are always unforeseeable issues - it needs to be noted that a significant emphasis of the manuscript is on the ‘user-friendly’ (mentioned at least six times in the manuscript) features of RNfuzzy. It also makes the software, which is the heart of this manuscript, difficult to review. There is no link to an already-running ‘reviewer web version’ or a built-in function that loads a tutorial dataset (like the ones used in the manuscript). I have tried to load both the published datasets and a bulk RNA-seq dataset of my own but could not progress beyond loading and quality control due to frequent errors or crashes. That was probably due to some mis-formatting of the input data but without clear guidance on how to prepare the count matrix, or at least an already-formatted dataset, I do not see how untrained experimental biologists will be able to efficiently interact with this app.\nIf the authors can improve on these aspects and after I have been able to verify the functionality of the software (at least with data provided by the authors or within a ‘reviewer version’), I would support the indexing of the manuscript.\n\nIn addition, there are multiple points regarding the analysis and statistical methods that would be required to be addressed as well.\nPlease find my detailed comments below:\n\nMajor concerns:\nCurrently there is no guidance on how to install and launch the app (at least to my knowledge). The authors state on page 3 that ‘Installation instructions are also available.' This is not correct - the adjacent github provides no instructions on how to install the app or how to launch it. Most users do not know how to start a shiny app in their own desktop environment. In addition, when launched, the app throws an error message as the devtools package is not properly loaded and so the ‘install_github’ function is missing. Only when opening R, loading devtools and then launching the app, the setup (including auto-install) is working.\n\nThere is very limited information on how to prepare the input count matrix. The authors state that a csv matrix is required but there is no information on how genes or sample names should be provided. I assume as row- and column-names, respectively, but that is not clear. Also, should the genes receive an extra header (i.e. a column name that says ‘genes’ or something like that)? Should genes be provided as symbols, ensmebl ids…?\nNeither the github or the app provide much information herein. E.g. the ‘input file description’ within the app states:\n\nHow are all sample IDs provided in just one column? How should other covariates be supplied here? I could not find information on how to use covariates in the provided analysis workflows, neither in the manuscript nor within the app.\nIf the input data is not provided correctly, I assume that many analyses will not work or just crash. So this input step is critical. To prevent failures here, the authors could provide a) a detailed description on the input format and/or b) the option to load a template/tutorial dataset.\n\nWhile I was able to load a count matrix into app and run e.g. the hierarchical clustering, all other functions caused errors (e.g. Count distribution, PCA) or a complete crash (normalization, differential expression using DESeq2). I assume this to be due to some problems with the input data, but I cannot verify that as no example/tutorial dataset was provided.\nMinor concerns:\nThe authors allow the filtering of low count genes. Could the authors provide references on the legitimacy of this? Packages like Deseq2 require an unaltered count matrix to properly build up e.g. independent filtering, dispersion estimation, etc. and are therefore warranting against any prior filtering or data manipulations.\n\nIs the PCA plot calculated on the whole count matrix, or only the filtered one? Is the data somewhat transformed (rlog, varianceStabilizing transformation?) before running the PCA? The PCA function is currently running very slowly and may benefit from some sort of feature selection (e.g. top 10,000 expressed genes).\n\nWhy do the authors limit their time course analysis to just three timepoints of the published tabula muris datasets? The dataset contains up to 10 timepoints and it may be more convincing to demonstrate the usefulness of RNfuzzy on as many datapoints as possible.\n\nThe enrichment analysis is currently only allowing ‘Only annotated genes’ or ‘All known genes’ as statistical domain scope (i.e. the ‘background set’). It is common within the RNA-seq field to rather use a set of ‘expressed genes’ to compensate for biases in e.g. tissue-specific expression. DEGs from neuronal tissue will inevitably be enriched for neuronal functions when the whole genome is used as background. To prevent wet lab researches to be deceived by such results, a user-provided expressed set (e.g. normalized counts of 1+ ) or one that is directly loaded from the input matrix, would be beneficial.\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": "7392",
"date": "12 Nov 2021",
"name": "Bianca H Habermann",
"role": "Author Response",
"response": "We thank Dr. Hahn for their very critical and helpful comments. Indeed, we failed to provide a thorough user manual to help inexperienced users with the installation procedure, as well as the workflow itself. As Dr. Hahn correctly points out - this software should be user-friendly and not challenge the user with problems, already at the installation step. We hope that with the help of Dr. Hahn’s comments, we could significantly improve the user-friendliness of RNfuzzyApp and would like to thank him here for his valuable input. In general, we do not provide a running web-server. Our idea was to provide an app that can be locally installed, also because of limitations in server availability on our side. However, we have now tried to significantly improve the installation instructions, as well as corrected several issues of RNfuzzyApp during the installation procedure, which arose due to the fact that many of us make daily use of some of the tools required during automatic installation of RNfuzzyApp. We also realized, when installing it on a ‘brand-new’ machine that has not seen many of the required packages before that quite a few of them need to be installed in addition. We have now added all required packages to the install procedure and thoroughly tested it. We therefore hope that the software installs smoothly. However, it should be noted that depending on the users’ environment, still some errors could occur due to missing pre-installed packages that should normally be present within the R environment. The best advice is to read the error messages during installation within R, which should list the packages that still need installing. Our responses to the major and minor concerns of Dr. Hahn: Major concerns: 1. Currently there is no guidance on how to install and launch the app (at least to my knowledge). The authors state on page 3 that ‘Installation instructions are also available.' This is not correct - the adjacent github provides no instructions on how to install the app or how to launch it. Most users do not know how to start a shiny app in their own desktop environment. In addition, when launched, the app throws an error message as the devtools package is not properly loaded and so the ‘install_github’ function is missing. Only when opening R, loading devtools and then launching the app, the setup (including auto-install) is working. Our response: We now provide detailed installation instructions in the user manual that can be found in RNfuzzyApp git repository, including how to install shiny itself (should it be missing), how to call the App and what other errors might occur, e.g. when a Mac is used. We have also tried to remove any error coming from missing packages, so installation should now work in most R environments. 2. There is very limited information on how to prepare the input count matrix. The authors state that a csv matrix is required but there is no information on how genes or sample names should be provided. I assume as row- and column-names, respectively, but that is not clear. Also, should the genes receive an extra header (i.e. a column name that says ‘genes’ or something like that)? Should genes be provided as symbols, ensembl ids…? Neither the github or the app provide much information herein. E.g. the ‘input file description’ within the app states: How are all sample IDs provided in just one column? How should other covariates be supplied here? I could not find information on how to use covariates in the provided analysis workflows, neither in the manuscript nor within the app. If the input data is not provided correctly, I assume that many analyses will not work or just crash. So this input step is critical. To prevent failures here, the authors could provide a) a detailed description on the input format and/or b) the option to load a template/tutorial dataset Our response: a) We now provide all sample data with the App, in a folder called test_files that can be found at the RNfuzzyApp gitlab site and is downloaded when the software is downloaded. b) Covariates was a misleading term, in fact, we only allow read counts (from any type of experiment). We have removed it from the Input File Description. c) The genes can be provided as any valid identifier, e.g. Symbols, ENSEMBL IDs etc. 3. While I was able to load a count matrix into app and run e.g. the hierarchical clustering, all other functions caused errors (e.g. Count distribution, PCA) or a complete crash (normalization, differential expression using DESeq2). I assume this to be due to some problems with the input data, but I cannot verify that as no example/tutorial dataset was provided. Our response: While we cannot tell why RNfuzzyApp crashed, we have now tried the app on several of our machines and were not able to get it crashing during normalization or differential expression analysis. We hope that with the provided input sample data, this error will be solved. We also now show in detail in the user manual how to load the data, normalize it, perform differential expression analysis and visualize the results. It should be noted at this point that, when uploading samples from three different conditions or time-points, normalization and initial differential expression analysis will be done over all samples. In order to compare only two conditions, and hence profit from the MA and Volcano plot visualizations, we have now introduced the ‘Filter data’ menu, where the user can choose which conditions (or time-points) to compare. We have also simplified the sample assignment. The app now automatically recognizes replicates from a given condition, provided that the header of the columns of the respective data are formatted correctly (condition1_rep1, condition1_rep2, …). Minor concerns: 1. The authors allow the filtering of low count genes. Could the authors provide references on the legitimacy of this? Packages like Deseq2 require an unaltered count matrix to properly build up e.g. independent filtering, dispersion estimation, etc. and are therefore warranting against any prior filtering or data manipulations. Our response: In fact, in the DESeq2 vignette, filtering is suggested (see the DESeq2 vignette, which states (http://bioconductor.org/packages/release/bioc/vignettes/DESeq2/inst/doc/DESeq2.html#pre-filtering): ’Pre-filtering While it is not necessary to pre-filter low count genes before running the DESeq2 functions, there are two reasons which make pre-filtering useful: by removing rows in which there are very few reads, we reduce the memory size of the dds data object, and we increase the speed of the transformation and testing functions within DESeq2. Here we perform a minimal pre-filtering to keep only rows that have at least 10 reads total. Note that more strict filtering to increase power is automatically applied via independent filtering on the mean of normalized counts within the results function.’ However, the user can choose whether they want to do low read count filtering or not. 2. Is the PCA plot calculated on the whole count matrix, or only the filtered one? Is the data somewhat transformed (rlog, varianceStabilizing transformation?) before running the PCA? The PCA function is currently running very slowly and may benefit from some sort of feature selection (e.g. top 10,000 expressed genes). Our response: a) PCA analysis of raw read counts is done using all the genes. b) PCA analysis of normalized data can be done once differential expression analysis has been performed. In this case, the top genes, as well as the FDR-cutoff can be chosen by the user. In both cases, the data are log transformed using the log1p() function. 3. Why do the authors limit their time course analysis to just three timepoints of the published tabula muris datasets? The dataset contains up to 10 timepoints and it may be more convincing to demonstrate the usefulness of RNfuzzy on as many datapoints as possible. Our response: We have limited our analysis here on only very few time-points for easier understanding of the tool and also to provide small test data files. Indeed, Mfuzz clustering will especially be useful to analyse larger time-series. However, this will inevitably lead to large test data files, as well as large figures. As an example, for our dataset on flight muscle development published in (doi: 10.7554/eLife.34058), we have created 40 clusters from 8 time-points using Mfuzz. Using only three time-points makes the demonstration of the software simply easier. We would also like to note that many researchers will only have two conditions to compare using the differential expression analysis function, which is equally useful in RNfuzzyApp. 4. The enrichment analysis is currently only allowing ‘Only annotated genes’ or ‘All known genes’ as statistical domain scope (i.e. the ‘background set’). It is common within the RNA-seq field to rather use a set of ‘expressed genes’ to compensate for biases in e.g. tissue-specific expression. DEGs from neuronal tissue will inevitably be enriched for neuronal functions when the whole genome is used as background. To prevent wet lab researchers from being deceived by such results, a user-provided expressed set (e.g. normalized counts of 1+ ) or one that is directly loaded from the input matrix, would be beneficial. Our response: While we agree in principle with the idea of taking only the expressed genes as a background list, we would prefer to currently not make this possibility available. We would like to note that many enrichment tools do not provide this functionality and either annotated genes or all known genes from the organism’s genome are used as background lists. I do also think that when comparing DEGs from two conditions of a neuronal tissue (e.g. WT and knock-out), or two time-points from the same tissue, not only neuronal-specific terms will appear, so I do not think that the user will be deceived by the results. In our example of the mouse muscle of mice from 3, 12 and 27 months, for instance, muscle terms are not strongly enriched between the different time-points."
}
]
},
{
"id": "90440",
"date": "16 Aug 2021",
"name": "Rhonda Bacher",
"expertise": [
"Reviewer Expertise genomics",
"RNA-seq",
"single-cell RNA-seq",
"time-series RNA-seq",
"package development",
"R shiny"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis manuscript presents an R shiny application called RNfuzzyApp. The app is designed for ease-of-use for visualizing and analyzing RNA-seq datasets. The app is very nicely designed and has the potential to be very useful to scientists. However, a number of clarifications are needed.\nWhat is orthology assignment mean? This should be defined more clearly in the manuscript\n\nIt is not clear how to install or run the app. This took me a few tries to figure out. I finally just downloaded the folder from gitlab and then did: > library(shiny)\n\n> runApp(\"~/Downloads/rna-seq-analysis-app-master-App/App/\"). Instructions should be put on the main page of the Gitlab landing page if that is where users will be initially directed.\n\nA simple example csv the users/reviewers can download to test the app would be useful. This would also help users understand the format that the app is expecting. I tried to upload the csv from the GEO and this message appeared: “Maximum upload size exceeded”.\n\nImprove error handling, I tried uploading data with genes on the rows and the app crashed saying it had duplicate row names. The app also crashed or would freeze when trying to upload a dataset that was a 5.5MB csv (8 samples). Are there limitations to the upload size?\nI highly suggest finding someone to try the app who was not involved in the development to ‘try to break it’ to identify issues like these.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": [
{
"c_id": "7393",
"date": "12 Nov 2021",
"name": "Bianca H Habermann",
"role": "Author Response",
"response": "We would like to thank Dr. Bacher for reviewing our paper and their very useful comments, which helped us to improve our App, as well as the paper. We have tried to address all points. Indeed, they were greatly overlapping with the comments from Dr. Hahn and show that our user instructions were really done very poorly. We have tried to improve them greatly by creating a very detailed user menu that is available from our gitlab account. Concerns raised: 1. What is orthology assignment mean? This should be defined more clearly in the manuscript Our response: Orthology assignment means that we can find the orthologs of another species using the gprofiler package. We have now tried to clarify in the text what we mean and provide a detailed user manual on how to use this function. 2. It is not clear how to install or run the app. This took me a few tries to figure out. I finally just downloaded the folder from gitlab and then did: > library(shiny) > runApp(\"~/Downloads/rna-seq-analysis-app-master-App/App/\"). Instructions should be put on the main page of the Gitlab landing page if that is where users will be initially directed. Our response: We now provide on the gitlab readme page the instructions on how to install the app. We also tried to remove any installation error that we encountered on machines with a very ‘basic’ R environment. We also provide a detailed user manual, which again includes installation instructions and detailed instructions on how to use the app. The user manual is available from the RNfuzzyApp gitlab page. 3. A simple example csv the users/reviewers can download to test the app would be useful. This would also help users understand the format that the app is expecting. I tried to upload the csv from the GEO and this message appeared: “Maximum upload size exceeded”. Our response: We now provide test files for both functions of RNfuzzyApp , differential expression analysis, as well as Mfuzz clustering, on our gitlab account (in App/test_files). The “maximum upload size exceeded error” could be due to size limits within R shiny, which we have tried to circumvent. The size limit of R shiny can be changed with the following command: options(shiny.maxRequestSize = n*1024^2). We have changed this to 100MB, which should be sufficient for most datasets. In case of larger datasets, this would have to be set individually by the user. 4. Improve error handling, I tried uploading data with genes on the rows and the app crashed saying it had duplicate row names. The app also crashed or would freeze when trying to upload a dataset that was a 5.5MB csv (8 samples). Are there limitations to the upload size? Our response: See our response above: it seems that R shiny has a rather low size limit for data upload, which can be changed with the command: options(shiny.maxRequestSize = n*1024^2). We have set it to 100MB, which should suffice for most datasets. 5. I highly suggest finding someone to try the app who was not involved in the development to ‘try to break it’ to identify issues like these. Our response: We have tried this now and hopefully have found all obvious bugs of RNfuzzyApp."
}
]
},
{
"id": "90441",
"date": "25 Aug 2021",
"name": "Anita Grigoriadis",
"expertise": [
"Reviewer Expertise cancer bioinformatics"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an excellent paper presenting an R-shiny to analyze RNA-seq data for non-computational scientists. It provides clear instruction on how to proceed, gives several options to analyze the data, and even includes a mfuzz clustering method, to work with time-series data. I can foresee that it will be used frequently.\nHaering and Habermann have clearly stated why the software is developed. RNAseq analyses has become a standard analytical approach. This software will give non-computational scientists to explore RNAseq data on several levels.\nThe description of the software is sound and can be reproduced by others.\nThe graphical display and the results provide detailed information, so that the analysis and the data can be interpreted accurately.\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/10-654
|
https://f1000research.com/articles/10-358/v1
|
07 May 21
|
{
"type": "Research Article",
"title": "Identification of potential inhibitors of SARS-CoV-2 S protein–ACE2 interaction by in silico drug repurposing",
"authors": [
"Fabiola E Tristán-Flores",
"Diana Casique-Aguirre",
"Raquel Pliego-Arreaga",
"Juan A Cervantes-Montelongo",
"Ponciano García-Gutierrez",
"Gerardo Acosta-García",
"Guillermo A Silva-Martínez",
"Fabiola E Tristán-Flores",
"Diana Casique-Aguirre",
"Raquel Pliego-Arreaga",
"Juan A Cervantes-Montelongo",
"Ponciano García-Gutierrez",
"Gerardo Acosta-García"
],
"abstract": "Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new coronavirus discovered that appeared in Wuhan, China, in December 2019, causes COVID-19 disease which have resulted in cases similar to SARS-atypical pneumonia. As of March 1, 2021, Mexico had reached 2.11 million cases of COVID-19 and 189 thousand deaths; around 116 million cases and 2.57 million deaths are reported worldwide with new cases and increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represents an alternative strategy to block the binding of SARS-CoV-2 protein S and forestall virus adhesion, internalization and replication in the host cell. Methods: Rigid molecular docking was performed using receptor binding domain of the S1 subunit of S protein (RBDS1)-ACE2 (PDB ID: 6VW1) interaction site and 1,283 drugs FDA approved and prescribed by the Mexican Public Health System. The results were analyzed by docking score, frequency of the drug in receptor site and the types of interactions at the binding site residues. Results: About 40 drugs were identified as a potential inhibitor of RBDS1-ACE2 interaction. Within the top-ranked drugs, we identified ipratropium, formoterol and fexofenadine, which stands out as they are used as therapies to treat chronic obstructive pulmonary disease, asthma and virtually any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.",
"keywords": [
"COVID-19",
"SARS-CoV-2",
"ACE2",
"Molecular Docking",
"Drug Repurposing"
],
"content": "Introduction\n\nEmerging viruses can be defined as those whose incidence has increased in the last twenty years or whose presence has a high probability of increasing in the near future. Diseases caused by emerging viruses are one of the biggest public health threats globally. Some of the viruses that fall within this catalog are the avian influenza virus subtype H5N1, severe acute respiratory syndrome (SARS), Ebola, Zika, and MERS-CoV, to name a few1. Coronaviruses (CoVs) are classified into four genera, α-CoV, β-CoV, γ-CoV, and δ-CoV2. α and β infect mammals, γ birds and δ birds and mammals, respectively2. These viruses are of public health importance because they cause enteric, renal, and neurological respiratory diseases that range from asymptomatic to fatal3,4.\n\nSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared in Wuhan, China, in December 2019, causing cases of SARS-like atypical pneumonia5,6, with a clinical picture of fever, general malaise, dry cough, shortness of breath and was called the coronavirus disease 2019 (COVID-19)7. It can be asymptomatic, develop mild-to-severe symptoms, or cause death in elderly individuals or in patients with chronic diseases, such as hypertension, diabetes, and obesity8. On January 31st 2020, the World Health Organization (WHO) declared COVID-19 a public health emergency of international concern and, on March 12th, it was declared a global pandemic9. In Mexico, local transmission (phase 2 of transmission) was declared on March 24th 2020, which resulted in the suspension of non-essential activities in the country, generating economic losses in addition to public health problems and deaths associated with the disease. As of March 1st 2021, Mexico had reached 2.1 million cases of COVID-19 and 189 thousand deaths; around 63.6 million cases and 1.47 million deaths have been reported worldwide.\n\nTo date, there is no specific commercial treatment to control the infection10–12. Measures such as early detection, blocking the route of transmission through social isolation, isolation of suspected cases, disinfection of objects, as well as frequent hand washing with soap, in addition to the use of biosafety equipment such as surgical masks for health personnel, which has been effective in reducing the transmission of COVID-19.\n\nCoronaviruses, such as SARS-CoV-2, are positive-stranded RNA viruses enveloped on a membrane. The coronaviral genome is composed of approximately 30,000 nucleotides containing the envelope (E), membrane (M), spike (S), nucleocapsid (N) and ORFs, that encode non-structural proteins, including enzymes that appear during their in-host reproductive cycle-genes13.\n\nThis virus measures 70 to 100 nm and belongs to the genus β-CoV14 and it has been proposed that any of the aforementioned proteins that make up CoVs may be targets for the development of vaccines or drugs4. Protein S plays an essential role on COVID-19 infection as it mediates the internalization on host cell and for the spread of the virus in the infected host15,16. This starts when the receptor binding domain of the S1 subunit (RBDS1) of S protein binds to the peptidase domain of angiotensin-converting enzyme 2 receptor (ACE2)17 and it is know that disrupting the binding of S protein to ACE2 prevents the attaching an the later internalization of the virus to the host cell18.\n\nThis protein interaction has recently been crystallized and deposited in the Protein Data Bank database19, allowing us to use it as a model of study to test different strategies to counter SARS-CoV-2 infection, like blocking S glycoprotein-ACE2 interaction through the discovery of sites of potential pharmaceutical interest.\n\nIn 2019, Research and Development (R&D) spending in the pharmaceutical industry totaled 186 billion U.S. dollars globally and its projected to reach 233 billion U.S. dollars to 2026. Unfortunately, drug development takes large time and financial resources that not all countries possess, especially developing countries, like Mexico.\n\nIn this sense, drug repurposing or repositioning allow us to integrate all evidence, pharmacodynamics/kinetics, bioavailability, among other important parameters, from an existing and approved drug in order to manage emerging diseases, like COVID-19. All this translates into a considerable decrease in research time and investment of resources in R&D.\n\nDifferent approaches have been taken in order to disrupt SARS-CoV-2 protein S-ACE2 interaction, as an example, many works has focus on finding potential biding sites on protein S structure, however, new variant strains has been detected worldwide, like B117 in UK, P1351 in South Africa, P1 and P2 in Brazil. All variant strains display the N501Y mutation, which is located on the RBD of the S protein, making the interaction more effective. In this sense, targeting RBD may be a transitory approach, therefore, an alternative strategy would be aiming at the ACE2 receptor. Some authors have pointed out some concerns about using drugs that targeting the renin–angiotensin signaling (RAS) pathway20–22, but Jia and collaborators23 highlight current efforts of exploiting ACE2 as therapeutic target, like the use of pseudo-ligands to dominate the binding site for SARS-CoV-2 as an example. Therefore, inhibition of the SARS-CoV-2 protein S-ACE2 interaction trough aiming ACE2 receptor it is a plausible strategy. In this study, we screened a library consisting of 1300 FDA-approved drugs and acquired by Ministry of Health of Mexico in order to identify potential inhibitors of SARS-CoV-2–ACE2 interaction.\n\n\nMethods\n\nIn order to run the docking simulation, we selected the X-ray crystal structure of SARS-CoV-2 RBDS1 in a complex with the ACE2 (PDB ID: 6VW1) which makes it have a more compact conformation in comparison with the SARS-CoV-2 RBD alone19. Chains B, E, F, and oligosaccharides and crystallographic water molecules were removed from the system; hydrogen atoms were added, and the receptor structure was protonated at pH 7.0 and 300 K using the Protonate 3D tool. Partial charges were assigned using the Amber10:EHT forcefield. Later, the protein structure was subjected to energy minimization using the same forcefield. Site Finder MOE was employed to analyze potential binding sites near to the receptor binding ridge on ACE2 and docking simulation were carried out. The docking parameters were set to take each ligand conformation as unique molecule, using the Alpha Triangle algorithm as placement method (at least 100 different orientations or poses on potential binding site) and further evaluation keeping the thirty best poses accordingly the London scoring function for binding affinity with a second refinement as a Rigid Receptor using Affinity dG algorithm keeping the ten best poses. The results were analyzed by docking score, frequency of the chemical compound as a stable conformation and the types of interactions at the binding site residues.\n\nData repositories such DrugBank, ZINC and PubChem were used to download the dataset from an updated list of reference medicine and The National Compendium of Health Supplies of Mexico (June 2020 update). The structures (sdf) dataset comprises 1,283 unique drugs, which the later were converted into Molecular Database format (mdb) using the Conformation Import MOE, feature available in MOE 2020.09 software (Molecular Operating Environment, Chemical Computing Group, Montreal, Canada) in MOE with an imposed limit of 3 kcal/mol strain energy and a maximum of 250 conformations per molecule and hydrogen atoms were added. Minimum energy configuration was calculated using the Amber10:EHT forcefield.\n\n\nResults\n\nThe structural analysis for the SARS-CoV-2 RBDS1 of the spike protein in a complex with the ACE2 (PDB ID: 6VW1; Figure 1A) revealing a potential site for ligand binding inside ACE2 structure (Table 1). The identified receptor site (Figure 1B) is proximal to the binding site of RBDS1 with a size of 86, therefore it can be used for simulating rigid molecular docking since receptor atoms are in an exposed region of the structure, which could be in favor of drug binding.\n\nA) Crystallographic structure (PDB ID: 6VW1) of RBDS1 (red) and ACE2 receptor (blue); B) Molecular surface of the selected binding site in ACE2.\n\nAn average of 78 conformations were generated for each ligand by Conformation Import MOE, generating 100,450 ligand conformations of the FDA approved and prescript drugs by the Mexican Public Health System.\n\nThe docking results were sorted and analyzed based on their S score, binding frequency which the drug binds to the receptor site and type of interactions, preferably, hydrogen bond, of the ligand with the selected site.\n\nWe selected 38 drugs (Table 2) that presents the best docking score between −10.04 and −4.04. Subsequently, we shortlisted nine drugs based on their risk of teratogenicity, route of administration, interaction with other drugs, side effects and by their background as pharmacological therapy for the treatment of respiratory diseases.\n\nFexofenadine showed interactions of hydrogen bond with Lys 74, Ala 99, Ser 105, Ser 106, Trp 203 and Asp 509 (Figure 2A) with a docking score of −7.89. Pitavastatin displays hydrogen bond interaction with Gln 102, Tyr 196, Asp 206 and pi-H stacking with Leu 73 (Figure 2B) and a docking score of −8.40. Arformoterol showed hydrogen bond interactions with Tyr 202 and Asp 206 (Figure 2C) with a docking score of −6.85. Formoterol presented hydrogen bond interactions with Gln 98, Asn 194, ionic interaction with Glu 208 and pi-H interaction with Leu 85 (Figure 2D) and presents a docking score of −6.15. Ipratropium exhibited hydrogen bond interaction with Gln 98, Gln 208 and pi-H stacking with Asp 206 (Figure 2E) and a docking score of −5.38. Pargeverine shows hydrogen bond interactions with Gln 98, Gly 205, Glu 208 and ionic interaction with Glu 208 (Figure 2F) and presents a docking score of −4.53. Cholecalciferol presented hydrogen bond interaction with Gln 102 (Figure 2G) and had a docking score of −5.81. Lopinavir displays hydrogen bond interaction with Gln 102, Tyr 196 (Figure 2H) and a docking score of −8.62. Cefixime showed hydrogen bond interaction with Gln 98, Tyr 202, Glu 208, Arg 219, Lys 562 and ionic interaction with Arg 219, Lys 562 (Figure 2I) and a docking score of −9.02.\n\nThe blue arrows indicate the structural hydrogen bridge bonds and the green arrows are the hydrogen bridge bonds with the side chain. A) Fexofenadine, B) pitavastatine, C) aformoterol, D) formoterol, E) ipatropium, F) pargeverine, G) cholecalciferol, H) lopinavir and I) cefixime.\n\nSome pharmacokinetics characteristics of the shortlisted potential inhibitors of the RBDS1–ACE2 interaction are summarized in Table 3 and schematic representations of the interaction maps of these drugs with the selected binding site are shown in Figure 2.\n\n\nDiscussion\n\nIt has been established that S protein of SARS-CoV-2 virus plays a major role during viral infection. The S protein mediates receptor recognition, cell attachment and fusion of viral membrane with host cell membrane24–29. The S protein binds to ACE2 receptor through the RBDS1, mediating viral attachment to host cell30. ACE2 expression it is distributed mainly in lung, intestine, heart and kidney, also alveolar epithelial type II cells had higher expression levels21. The RBD region is a critical therapeutic target (vaccines and drugs) due to its indispensable function; however, it is suggested that mutations in this region may render pharmacological or immunological therapies ineffective31,32.\n\nIn order to block this event, we propose an in silico approach to identify potential inhibitors of the SARS-CoV-2–ACE2 interaction aiming at the ACE2 receptor, blocking the virus accessibility to the membrane-bound ACE2. Here, we screened a drug library consisting of 1300 drugs, FDA approved and prescribed by the Mexican Public Health System, for potential SARS-CoV-2−ACE2 inhibitors, using a rigid receptor docking approach. Utilization of an FDA-approved drug library is an effective and ideal tool for drug repurposing in antiviral research33,34, such as zika virus35, human rhinovirus36 and hepatitis B virus37. We identify 38 potentially inhibitor drugs of SARS-CoV-2−ACE2 interaction and these are listed on Table 2. Several of those drugs were previously reported to be used for the treatment of respiratory diseases.\n\nWithin this list of potential inhibitors of the SARS-CoV-2−ACE2 interaction, is fexofenadine, a third-generation antihistame whose therapeutic indication is the treatment of symptoms of stationary allergies through the selective blockade of H1 receptors38. In silico evidence39,40 suggest that it may interact with the SARS-CoV-2 main protease enzyme MPro, a key enzyme in viral replication41, acting as a potential inhibitor. Cefixime is a third-generation antibiotic derived from cephalosporin whose use is indicated for the treatment of infections in the upper and lower respiratory tract, otorhinolaryngological42 and urinary tract43, inhibiting the synthesis of the bacterial wall by binding to specific binding proteins for penicillin and is currently used as a secondary therapy to prevent opportunistic infections during the development of COVID-1944. Pitavastatin is a statin indicated for lowering blood cholesterol levels by inhibiting HMG-CoA reductase, preventing cholesterol synthesis45, and it has also been observed that statin treatments can interfere with viral infectivity through inhibition of glycoprotein processing46 also, they modulates the inflammatory process at cellular level47, which is a remarkable characteristic of the SARS-CoV-2 infection. Additionally, in silico findings suggest that could be an efficient inhibitor of SARS-CoV-2 MPro48 and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp)49 thru active site binding. Lopinavir is a protease inhibitor indicated as first barrier therapy, in conjunction with Ritonavir, to treat infection caused by the HIV virus by inhibiting the HIV-1 protease50 in addition, studies in cell cultures have shown its effectiveness as an inhibitor of the replication of the MERS-CoV virus51 and SARS-CoV-152, while in severe cases of SARS-CoV-2 infection, the results of clinical trials indicate that it is not useful53. Formoterol and aformoterol, anenantiomer of formoterol, are long-lasting selective β agonists indicated for the treatment of chronic obstructive pulmonary disease (COPD) and bronchospasms54, in the same way there is evidence of the use of these drugs as a partial inhibitor of viral replication in primary epithelial cells cultures55 and in silico data suggest their binding to the papain-like protease PLpro, a coronavirus enzyme essential for viral spread56. Ipratropium is a bronchodilator anticholinergic indicated for the treatment of asthma, shortness of breath, cough and tightness in the chest in patients with COPD57,58. Inhalation therapy with ipratropium is currently in use to dilate bronchioles in COVID-19 patients to increase oxygen saturation levels (from <80% to 94%)59. Pargeverine is an antispasmodic opioid alkaloid whose therapeutic indication is aimed at the treatment of painful spasms60, also, acts as anticholinergic and has a moderate and non-selective blockade of muscarinic cholinergic fibers61. Since cholinergic activity contribute to airway narrowing, this might be a potential agent to open airway obstruction. Cholecalciferol, is a form of vitamin D (vitamin D3) that can be synthesized naturally in the skin and acts as a hormonal precursor, being converted into calcitriol, and therapeutically is used as a vitamin supplement to treat deficiencies of this vitamin62. In addition, it has been observed that vitamin D supplementation is favorable to reduce viral infections such as influenza63,64 or more aggressive cases such as HIV65 and it has recently been suggested that it also presents favorable effects before and during the infection caused by SARS-CoV-266.\n\nLikewise, it is important to take into account that ACE2 plays an important biological role since regulates cardiovascular functions and innate immune system and, therefore cautions must be taken. Another point to take into account is the delivery method of the drug, since the primary target must be smooth muscle, like the one surrounding the bronchioles, and lung epithelial cells in the airway and airspace compartments, hence, inhalable delivery would be the acceptable choice to deliver the drug in a selectively and localized manner.\n\nGiven these characteristics, the results obtained through our in silico approach, we consider that the aforementioned drugs are outlined as possible inhibitors of the RBDS1-ACE2 interaction. These drugs are well tolerated, commonly used and affordable, hence, most of the drugs on this list can be tested in vitro, and even in vivo and, consequently, in clinical trials for the development of adjuvant therapies to treat COVID-19.\n\n\nConclusion\n\nIn the absence of approved therapies for treatment or prevention, drug repurposing has provided fast and valuable insight into the treatment of COVID-19. Targeting ACE2 receptor as a COVID-19 therapy it is a conceivable approach since it is essential for the viral internalization. However, this approach requires an integrative evaluation of the pros and cons by a clinical context since ACE2 is a multifunctional protein. Jia and collaborators23 present an extensive review for this underexplored approach to treat COVID-19, pointing that it is imperative to determine, by clinicians, the stage of the disease and comorbidities that could prove consequential for an ACE2-targeting regimen. Several drugs are currently investigated by clinical trials or are already in use to treat COVID-19 patients, like lopinavir or ipratropium. In this in silico study using structure-bases virtual screening, we identified potential inhibitors of SARS-CoV-2–ACE2 by their interaction with ACE2 receptor. We identify the uridine trisodium salt, methotrexate sodium, raltritedex, folotyn, CDP-choline(1-), cefuroxime, fexofenadine, fludarabine phosphate, cefixime, aloin, domperidone, tamsulosin, cromoglycic acid, macitentan, tafluprost -taflutan, thiopental(1-), metoprolol, irinotecan, pitavastatin(1-), amlodipine, verapamil, tolterodine, lopinavir, glimepiride, arformoterol, formoterol, ipratropium, pargeverine, pyrilamine, biperiden, orlistat, glyburide, ribociclib, ibesartan, cholecalciferol, gravignost, disopyramide phosphate and primaquine. Based on desired characteristics like pharmacokinetics, route of administration or by their background as pharmacological therapy, we propose a shortlist of drugs suitable for testing their potential RBDS1–ACE2 inhibitory activity: fexofenadine, cefixime, pitavastatine, lopinavir, arformoterol, formoterol, ipratropium, pargeverine and cholecalciferol. Our identification of potential inhibitors of the SARS-CoV-2–ACE2 interaction among commonly use drugs highlights their potential use for treating COVID-19. Further in vitro, in vivo or clinical trial are needed to validate their potential use as inhibitors of SARS-CoV-2–ACE2 interaction.\n\n\nData availability\n\nProtein Data Bank: Crystal structure of SARS-CoV-2 receptor binding domain (RBDS1) of the spike protein in a complex with the ACE2 receptor. https://identifiers.org/pdb:6vw1\n\nMinistry of Health of Mexico: Drug list used by the Ministry of Health of Mexico (June 2020 version). http://www.csg.gob.mx/Compendio/CNIS/cnis.html.\n\nPubChem: Ligands.https://pubchem.ncbi.nlm.nih.gov.\n\nDrugbank: Ligands. https://go.drugbank.com.\n\nZINC database: Ligands. http://zinc.docking.org/.\n\nFigshare: Identification of potential inhibitors of SARS-CoV-2 S protein–ACE2 interaction by in silico drug repurposing, https://doi.org/10.6084/m9.figshare.1446633367\n\nThis project contains the underlying data file:\n\n- Table_E1_DrugsAccessionNumber.xlsx (Accession numbers of drugs used for docking simulations)\n\nData is available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0)",
"appendix": "Author contributions\n\n\n\nFET-F and DC-A performed most of the bioinformatics work, shared first authorship, equal contribution to this work; FET-F wrote the initial manuscript draft; JAC-M and RP-A generated the ligand data base and assisted bioinformatic analysis; GA-G revising critically the initial manuscript draft and provision facility resources; P.G.-G, DC-A and GAS-M contributed intellectually to the project conceptualization and participate in the initial manuscript draft; DC-A and G.A.S.-M designed and supervised the project. G.A.S.-M conceptualize, acquire the financial support for the project leading to this publication, supervised the bioinformatic work and wrote the final version of the manuscript; all authors read and approved the final manuscript version.\n\n\nAcknowledgements\n\nThe authors would like to thank Ruy E. Pineda-Silva for the supporting work in data acquisition; Martha C. 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}
|
[
{
"id": "85900",
"date": "18 Jun 2021",
"name": "Fernando Yepes-Calderon",
"expertise": [
"Reviewer Expertise Medical devices development",
"Medical Imaging",
"Methods development"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nAuthors use molecular docking tools to test existing medicine in their efficacy to impede the S protein-ACE2 binding and thus, disabling the entry point of Cov2 to human cells. The authors use a solid justification to support this project. Since medicine creation is an expensive and long-lasting task, verifying if some active molecules in already FDA-approved medicine might block the binding between the S-protein and the ACE2 is an excellent alternate path.\nThe document is generally well organized and pleasant to read. I suggest adding some corrections to the abstract as follows.\nBackground A new coronavirus outbreak, firstly reported in Wuhan, China, in December 2019, causes COVID-19, which symptoms are similar to SARS-atypical pneumonia. Worldwide, around 116 million cases and 2.57 million deaths are reported, with new cases increasing mortality every day. To date, there is no specific commercial treatment to control the infection.\nRepurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represent an alternative strategy to block the binding of CoV2's protein S and forestall virus adhesion, internalization, and replication in the host cell.\nMethods We performed rigid molecular docking using the receptor-binding domain at the S1 subunit of the S protein (RBDS1)-ACE2 (PDB ID:6VW1) interaction site and 1,283 FDA-approved drugs. The docking score, frequency of the drug in the receptor site, and interactions at the binding site residues were used as analyzing criteria.\nResults This research yielded 40 drugs labeled as potential inhibitors of RBD S1-ACE2 interaction. Among the inhibitors, compounds such as ipratropium, formoterol, and fexofenadine can be found. Specialists employ these drugs to treat chronic obstructive pulmonary diseases, asthma, and almost any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19.\nThe proposed modifications focus on keeping the communications global. The CoV2 numbers in Mexico are absent in this suggested abstract since the authors provide worldwide numbers. I also shortened some sentences and fixed some wrongly used singulars.\nCorrect the hyphenation in the whole document. If the authors are using a latex template, use the command \\hyphenation{co-rrect, se-pa-ra-tion, sche-me}. Events: Janu-ary and associ-ated (intro, paragraph 2), lig-and (methods, paragraph 2).\n\nIntroduction, page 3, paragraph 2. Current events suggest that Covid19 is not only lethal in the elder or patients with chronic diseases. I might suggest deleting this statement.\n\nIntroduction, page 3, paragraph 2. something is missing in this paragraph. Also, the statement may be misleading; the actual spread and high contamination levels are proof of non-efficiency. If isolation and the other measurements were effective, what would be the sense for the proposal?\n\nIn subsection \"Database preparation,\" you have information already provided in the first subsection of the methods.\n\nDiscussion, page 7, paragraph 1. In \"ACE2 expression it is\" the authors might have two nouns in the same sentence.\nRegarding the methodology, the authors used a standard: importing the macromolecule, edit or delete water molecules, add hydrogens, add charges, and the ligand. Did the authors have any particular issue during the process? In case affirmative, add it to assert reproducibility.\nThe list of potential inhibitors is highly appreciated. The authors presented the interactions of the selected drugs nicely.\nI suggest the authors reinforcing their discussion with arguments derived from the mutation capacity of the retrovirus that might render current vaccination not entirely compelling. Therefore, the presented alternatives could set as plausible options for treatment.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7363",
"date": "11 Nov 2021",
"name": "Guillermo A Silva-Martinez",
"role": "Author Response",
"response": "We thank you for the detailed revision of our paper and for suggesting improvements. Also, we want to apologize for the long delay on our response, we were waiting for a second reviewer report to edit our manuscript. Authors use molecular docking tools to test existing medicine in their efficacy to impede the S protein-ACE2 binding and thus, disabling the entry point of Cov2 to human cells. The authors use a solid justification to support this project. Since medicine creation is an expensive and long-lasting task, verifying if some active molecules in already FDA-approved medicine might block the binding between the S-protein and the ACE2 is an excellent alternate path. The document is generally well organized and pleasant to read. I suggest adding some corrections to the abstract as follows. Response: We thank the reviewer for the detailed revision of our paper and for suggesting improvements. We are pleased that you found the structure of the writing to be pleasant. Background A new coronavirus outbreak, firstly reported in Wuhan, China, in December 2019, causes COVID-19, which symptoms are similar to SARS-atypical pneumonia. Worldwide, around 116 million cases and 2.57 million deaths are reported, with new cases increasing mortality every day. To date, there is no specific commercial treatment to control the infection. Repurpose drugs targeting the angiotensin-converting enzyme 2 (ACE2) receptor represent an alternative strategy to block the binding of CoV2's protein S and forestall virus adhesion, internalization, and replication in the host cell. Methods We performed rigid molecular docking using the receptor-binding domain at the S1 subunit of the S protein (RBDS1)-ACE2 (PDB ID:6VW1) interaction site and 1,283 FDA-approved drugs. The docking score, frequency of the drug in the receptor site, and interactions at the binding site residues were used as analyzing criteria. Results This research yielded 40 drugs labeled as potential inhibitors of RBD S1-ACE2 interaction. Among the inhibitors, compounds such as ipratropium, formoterol, and fexofenadine can be found. Specialists employ these drugs to treat chronic obstructive pulmonary diseases, asthma, and almost any respiratory infection. Conclusions: Our results will serve as the basis for in vitro and in vivo studies to evaluate the potential use of those drugs to generate affordable and convenient therapies to treat COVID-19. Response: Taking into account your contribution, in the manuscript the abstract has been improved and better organized. The proposed modifications focus on keeping the communications global. The CoV2 numbers in Mexico are absent in this suggested abstract since the authors provide worldwide numbers. I also shortened some sentences and fixed some wrongly used singulars. Correct the hyphenation in the whole document. If the authors are using a latex template, use the command \\hyphenation{co-rrect, se-pa-ra-tion, sche-me}. Events: Janu-ary and associ-ated (intro, paragraph 2), lig-and (methods, paragraph 2). Response: We thank the reviewer for this observation. The hyphenation has been corrected in the whole manuscript. Introduction, page 3, paragraph 2. Current events suggest that Covid19 is not only lethal in the elder or patients with chronic diseases. I might suggest deleting this statement. Response: We agree with the reviewer's observation, however it’s important to remark that adult individuals (over 40 years) and patients with comorbidities are prone to death by COVID 19 disease. This paragraph was restructured. Introduction, page 3, paragraph 2. something is missing in this paragraph. Also, the statement may be misleading; the actual spread and high contamination levels are proof of non-efficiency. If isolation and the other measurements were effective, what would be the sense for the proposal? Response: We thank the reviewer for this comment. This paragraph was rewritten. In subsection \"Database preparation,\" you have information already provided in the first subsection of the methods. Response: We thank to reviewer for this comment. Changes were made in this section. Discussion, page 7, paragraph 1. In \"ACE2 expression it is\" the authors might have two nouns in the same sentence. Response: We thank the reviewer for this comment. Changes were made in this section. Regarding the methodology, the authors used a standard: importing the macromolecule, edit or delete water molecules, add hydrogens, add charges, and the ligand. Did the authors have any particular issue during the process? In case affirmative, add it to assert reproducibility. Response: We do not have any issue during the structure preparation; therefore, reproducibility can be achieved without any problem. The list of potential inhibitors is highly appreciated. The authors presented the interactions of the selected drugs nicely. Response: We appreciate that the reviewer finds our data well-presented. I suggest the authors reinforcing their discussion with arguments derived from the mutation capacity of the retrovirus that might render current vaccination not entirely compelling. Therefore, the presented alternatives could set as plausible options for treatment. Response: We thank the reviewer for suggesting improvements to our discussion section. Reinforced of the discussion section were made in the manuscript taking reviewers suggestion."
}
]
},
{
"id": "93444",
"date": "21 Sep 2021",
"name": "Yogendra Nayak",
"expertise": [
"Reviewer Expertise Pharmacy and 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\nI am pleased to write the review for this manuscript. In this manuscript, authors have used computational tools to predict the activity of a suitable drug to treat/ prevent COVID-19. The specific target can prevent the entry of SARS-CoV-2 in human body. Thus keeping the receptor for virus entry ACE2, the available drugs are screened for their binding efficacy, which indirectly correlates the biological activity. Though the computational predictions are widely accepted, this manuscript has few limitations in its current form. Hence, I would suggest minor changes or amendments might be necessary before acceptance. Followings are a few of them:\nAbstract:\nAs the pandemic is dynamically changing the numbers, giving a country specific might not hold good. I suggest to add the data related to the world-wide data can be put. An important observation is the number of drugs from US-FDA can be written the same number as it was mentioned later in the manuscript (1,283 may not be correct).\n\nIntroduction:\nI feel many places few more additional support from the literature is required. Which can be strengthened by citing references.\n\nMethods:\nMolecule selection for docking appears incorrect. It is protein selection for ligand docking. Moreover, authors have optimised the protein structure, which should have been more appropriate. The resolution of 6VW1 is missing. The rationale for taking 6VW1 appears missing in methodology. Database preparation appears incorrect. It can be dataset/ or ligand preparation. When DrugBank/ZINC15 was accessed is missing (month of accession). Which version of ZINC library was used is missing. Most importantly, the reason why ligands conformation was generated is missing.\nResults:\nTable 3, the details regarding generation of data appears missing. I feel the detailed legends can be given.\n\nThe current gold standard for molecular activity prediction is MD simulation, this can be tried by authors.\nDiscussion:\nIn the methodology the number of drugs selected were 1283, but here it changed to 1300. This looks inconsistent.\n\nIn the methodology, authors have mentioned that they have generated some conformers. Which conformation of drugs were active?\n\nOverall, I feel the discussion part appears very weak and lacks substantial evidence for how these drugs could be used in COVID-19.\nConclusions:\nThe conclusion can be made simple by reducing the number of sentences. Most of the journals will not accept citations (references) in conclusions. Hence, the authors can give a thought to modify the conclusion by keeping their views only on objectives/ aims.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Partly\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": [
{
"c_id": "7364",
"date": "11 Nov 2021",
"name": "Guillermo A Silva-Martinez",
"role": "Author Response",
"response": "We thank the reviewer for the detailed revision of our paper and for suggesting improvements. Abstract: As the pandemic is dynamically changing the numbers, giving a country specific might not hold good. I suggest to add the data related to the world-wide data can be put. An important observation is the number of drugs from US-FDA can be written the same number as it was mentioned later in the manuscript (1,283 may not be correct). Response: We thank the reviewer for this suggestion to improve the impact of our abstract. US-FDA approved drug number was corrected. Introduction: I feel many places few more additional support from the literature is required. Which can be strengthened by citing references. Response: We agree with the reviewer's observation, however, we believe that the introduction provides the necessary information to be in context to the overall objective of our work. Methods: Molecule selection for docking appears incorrect. It is protein selection for ligand docking. Moreover, authors have optimized the protein structure, which should have been more appropriate. The resolution of 6VW1 is missing. The rationale for taking 6VW1 appears missing in methodology. Database preparation appears incorrect. It can be dataset/ or ligand preparation. When DrugBank/ZINC15 was accessed is missing (month of accession). Which version of ZINC library was used is missing. Most importantly, the reason why ligands conformation was generated is missing. Response: We thank the reviewer for the comments and for suggesting improvements. Changes on the subsections mentioned above were made. Resolution of 6VW1, the rationale of using that structure and accession date to databases were added to the manuscript. In the “Protein selection for ligand docking”, it is now clearly specified that rigid molecular docking is carrying out. In this type of docking, protein orientation is fixed and only ligands are allowed to vary their orientation, therefore each conformer allow to simulate this variation. We assumed that no further explanation was needed. Results: Table 3, the details regarding generation of data appears missing. I feel the detailed legends can be given. Response: We shortlisted nine drugs based on their risk of teratogenicity, route of administration, interaction with other drugs, side effects and by their background as pharmacological therapy for the treatment of respiratory diseases. It is described in the Results section, subsection Virtual Screening and Molecular docking, paragraph 3. The current gold standard for molecular activity prediction is MD simulation, this can be tried by authors. Response: We agree with the reviewer comment. Unfortunately, we do not have the computational infrastructure or access to supercomputer cluster to run MD. We are trying to run MD on our workstations, but those simulations will take time. However, we feel that our work is a valid approximation for COVID19 drug repurposing. Discussion: In the methodology the number of drugs selected where 1283, but here it changed to 1300. this looks in consistency. Response: We thank reviewer comment. See response above. In the methodology, authors have mentioned that they have generated some conformers. Which conformation of drugs were active? Response: In order to generate active conformers for docking simulation, we impose a 3 kcal/mol limit on strain energy, which means that conformation elucidates under these criteria can occur under physiological conditions and maintain their activity. Methodology section was restructured to be more clear. Overall, I feel the discussion part appears very weak and lacks substantial evidence for how these drugs could be used in COVID-19. Response: We thank the reviewer for this comment. We feel that most of the relevant evidence -to date of manuscript submission- regarding COVID19 and the potential inhibitors, were discussed. Conclusions: The conclusion can be made simple by reducing the number of sentences. Most of the journals will not accept citations (references) in conclusions. Hence, the authors can give a thought to modify the conclusion by keeping their views only on objectives/ aims. Response: We thank the reviewer for this observation. This section was restructured."
}
]
}
] | 1
|
https://f1000research.com/articles/10-358
|
https://f1000research.com/articles/10-810/v1
|
16 Aug 21
|
{
"type": "Method Article",
"title": "Conceptual design of smart multi-farm produce dehydrator using a low-cost programmable logic controller and raspberry pi",
"authors": [
"Sunkanmi Oluwaleye",
"Victoria Oguntosin",
"Francis Idachaba",
"Sunkanmi Oluwaleye",
"Francis Idachaba"
],
"abstract": "Background: Acceptable food processing techniques require the removal of water contents from the crop or food sample without destroying the nutritional qualities of the food sample. This poses a strict requirement on the dehydrator or oven that will be used in the dehydrating techniques to have the ability to control both temperature and humidity of its drying chamber. Methods: This work centres on how an autonomous multi-farm produce dehydrator that can also serve as an oven can be designed with a raspberry pi and a low-cost programmable logic controller (PLC). The dehydrator gives the users the flexibility to control both the drying chamber’s temperature and humidity from its web interface via a mobile device or the dehydrator’s HMI. Heat energy from the Liquid Petroleum Gas (LPG) is used so that the dehydrator can be readily available for commercial or industrial use. The small electricity required to power the electronics devices is obtained from the hybrid power solution with an electric energy source from either the mains electricity supply or solar.. The design was tested by creating an operation profile from the proposed web application for the dehydrator. The operation trend was analysed from the web application’s Trendlines page. Results: The report showed that both the temperature and humidity of the dehydrator could be controlled, and access to historical operation data will give insight to the user on how to create a better operation profile. Conclusion: The setup described in this work, when implemented was able to produce a dehydrator/oven whose temperature and humidity can be perfectly controlled and its generated heat is evenly distributed in its drying chamber to ensure efficient and effective drying techniques use in crop preservation and food processing.",
"keywords": [
"Dehydrator",
"Low-Cost PLC",
"Multi-Farm Produce",
"Raspberry Pi"
],
"content": "Introduction\n\nOver the years, the need for postharvest food preservation has been on the high increase, especially in Africa, where farmers depend on the natural climate for the cultivation of their crops. For this reason, the harvest of crops has been seasonal, leading to a surplus of farm produce at one time, hence, postharvest wastage, and scarcity at another time.1 Furthermore, things have become worse with the recent inconsistency in the climate, which has negatively affected the farmers’ productivity.2\n\nTherefore, it has become very critical to optimise the farmers’ harvest using postharvest preservation technique with dehydrators that are built for African farmers and food processors.3 An ideal dehydrator removes the water content from food crops using heat and airflow in a controlled environment while not compromising the nutrient quality of the crops.4 Several studies have been done on the development of crop dehydrators.5-8 The use of electricity was used in the design and fabrication of portable dehydrator in Nadu’s study,5 where the dehydrator chamber’s temperature and airflow were controlled with the use of heating coils and an air blower, respectively. Also, the use of renewable heat energy from the sun was used as described by R. O Lamidi,6 where the harvested heat energy was distributed into the drying chamber with the help of an air blower. This approach was extended to the design of a hybrid dehydrator where liquid petroleum gas (LPG) was used to generate the required heat energy when solar energy was not available.\n\nThis work aims to design an autonomous multi-farm produce dehydrator that can also be used as an oven. Unlike the other works cited above, the dehydrator will be used for industrial purposes; the user can create his or her operation profile for a dehydrating process via the dehydrator’s web interface. The operation profile is stored by the device and can be used for future drying operations. As shown in Figure 1, a user can monitor the drying process or download previous operation data using the local web interface of the dehydrator or from its small human-machine interface (HMI).\n\nThe work will focus on the conceptual design of the dehydrator from the mechanical structure to the electrical components, including the software development. A low-cost programmable logic controller (PLC) and Raspberry Pi will be used to create industrial-grade electronic hardware for the dehydrator; the user will be able to create an operation profile for a particular type of crop by setting the target temperature, target humidity, maximum fan speed, minimum fan speed, and duration for the operation. The proportional–integral–derivative (PID) control program running on the PLC will use a feedback control loop mechanism to ensure the drying operation is carried out as specified in the configured profile.9 The raspberry pi functions as a computer to handle remote connectivity and local resource management such as data storage and hosting of the web application responsible for the system operation. Finally, the user will be able to download the previous operation data from the system for further analysis.\n\nOver the years, the drying of crops has been advancing using continuously improved techniques to attain the goal of safely removing desired moisture content from crops without compromising their nutritional qualities.7,10 Drying methods can be broadly categorised as natural drying and artificial drying.4 Natural drying makes use of direct heat from the sun for drying; the sample is spread on the horizontal plane that is opened to direct sunshine without any shade and heat energy from the sun is used in the drying process. This is regarded as passive solar drying.11 The problem with this approach is that the drying process is dependent on environmental conditions, which posed a serious limitation on the sample drying rate. Unfortunately, during the harvest period of most crops in both tropical and subtropical zones, the environmental conditions are usually not favourable because of the rainfall. Hence, the need for an artificial drying method becomes paramount. Artificial drying techniques can be categorised as: hot air convection drying, freeze and vacuum drying, drum drying, and spray drying.\n\nHot air convection drying is the most commonly used artificial drying technique because of its relatively low cost of production and flexibility. It can be set up mechanically without the use of electricity, complex structure, and electronic control, making it suitable for farmers in a very remote area who need to dry for personal storage or small-scale business demand. In this scenario, the source of heat energy can either be biomass, geothermal, waste heat, oil, natural gas, or solar.11-13 Sometimes these sources are combined as a hybrid heat source.14,15 The problem with this approach is that the drying process compromises the nutritional quality of the product because the drying conditions (temperature, humidity, and air velocity) cannot be adequately controlled. To solve this problem, C. Pacco8 demonstrated how temperature control could be simulated in a dehydrator using LabView software version 2016; this can be implemented in hot air convection drying where the heat energy source, air velocity, and humidity can be controlled. Automated hot air convection drying can broadly be categorised as static or discontinuous drying, and continuous drying. Static or discontinuous drying is used for small or medium-scale food drying where complex structure and control techniques can be afforded.16 This comes in the form of batch tray drying, where the sample has to be dried batch by batch. The samples are stacked stationarily in the drying chamber. The major problem with this approach is that the samples closer to the heat source are dried faster, causing non-uniform drying of the whole drying samples. Because of the cost-effectiveness of this drying approach, the goal of this work is to use this static drying and, at the same time, evenly distribute the heat across the drying chamber in an efficient and uniform manner.\n\nContinuous drying with hot air convection requires a more complex structure and more robust industrial control to meet the need of large-scale industrial food drying. Uniform drying is easily achieved in the continuous dryer because the mass drying sample is in a continuous circulation within the drying chamber until the drying time is reached. Examples of this type of dryers are rotatory, tunnel, belt, fluidised bed, and impingement dryers.17\n\nFreeze and vacuum drying are techniques of drying that do not involve heat.18 Because heat is not involved, the product dried usually retains their nutritional qualities. The downside to this approach is cost, especially for the small and medium scale crops and food processors. The drum dryer is used for drying paste or slurry roll over a heated drum19 and the drying time is determined by the drum’s rotational speed. It is very popular with the pharmaceutical industries. Spray dryers are advanced application-specific dryers. Through the spray drying process, dried powders are produced from the liquid slurry or paste,20 which procudes products such as powdered milk.\n\nThe goal of this work is to optimise a tray-type hot air convection dryer. As demonstrated by M. S. Badahman and Y. S. Susiapan,21 a NodeMCU ESP8266 main microcontroller was used to build a smart oven that estimated the drying/cooking time of a particular food product by processing the weight of the food obtained by integrating loadcell into the system. A thermocouple was used as a temperature sensor; it senses the temperature of the oven’s drying chamber, and based on the temperature value, the microcontroller either turns on or off the electric heater that generates the required heat energy for the oven. Because a NodeMCU ESP8266 was used, it can be easily integrated into the cloud for remote monitoring. The limitation of this approach was that no provision was made for heat distribution and hot air velocity control. This means that the approach will not be suitable for a bigger oven that requires uniform drying. In this work, the dryer’s drying chamber humidity with be controlled by varying the speed of the extractor fan that moves out the moist air from the system. Also, a Proportional, Integral, and Derivative (PID) temperature control will be used to ensure that the samples are dried with even temperature control for better quality.\n\nIn S. Istiqphara and N. Adliani’s study,22 an adaptive dryer was developed for drying medicinal plants using the heat energy generated from the solar collector. The main controller used was a microcontroller connected to a DHT11 temperature sensor that captured the temperature of the drying chamber. The temperature of the drying chamber is regulated using two extractor fans. These fans come on to remove the excess heat in the drying chamber to maintain a constant temperature. A fuzzy logic PID controller is used to control when the fans come on and how long they have to stay on. The internet of things (IoT) was implemented by using a raspberry pi minicomputer that was connected to the microcontroller and the remote server over the internet. With this, end-users can connect to the dehydrator with their laptops or mobile devices to monitor the drying operation. However, the humidity of the drying product is not considered in this work which will limit the use of the dehydrator to drying products that are not affected by the moisture content of the drying air. In this work, the user will control the system humidity and the temperature simultaneously to ensure effective and qualitative drying, as shown by S. Misha et al.23 Furthermore, S. Istiqphara and N. Adliani’s22 system may not be commercially feasible when a high production rate of dried samples is required.\n\nIn a nutshell, several works have been done to improve dehydrator/oven operation performance by coming up with different techniques to control the drying temperature and humidity, as stated above. However, none of these designs have single-handedly control of both the temperature and humidity of the drying chamber simultaneously. In this work, the designed dehydrator will ensure the even distribution of heat within the drying chamber and, at the same, regulates both the temperature and the humidity of the drying chamber. Furthermore, the dehydrator will be user friendly, such that the user can create different operation profiles for different types of crops or any drying sample, and also set the desired duration for the operation.\n\n\nMethods\n\nThis paper focuses on a conceptual design of a dehydrator for drying multi-farm produce, the product has not been physically fabricated and tested. The mechanical or structural design has been carried out but not yet fabricated while the control or instrumentation design was done and tested on a physical PLC with sensors connected and on a raspberry pi board 3B+. The materials required to build this dehydrator can be categorised as mechanical or structural materials, and electrical or instrumentation materials. The structural parts include the drying chamber, heat exchanger, control box chamber, burner chamber, and the gas cylinder with its accessories. The heat energy generated for the drying operation is liquefied petroleum gas (LPG) because it is readily available and suitable for continuous industrial operation. The mechanical structure was designed using Autodesk Inventor Professional 2020 version 2020.1.1. The alternative open-source version that can be used is FreeCAD. The electrical/instrumentation parts consist of the gas controller, sensors, mini-PLC, raspberry pi, fans, HMI screen, AC/DC converter module, solar panel, solar charge controller, and the battery pack. The electrical/instrumentation parts will be described in greater detail later in this section. All these components are mechanically or electrically connected, as the case may be at the end of the component integration. The electrical components are powered from the 12Vdc source that can be autonomously backed up by the battery pack that is charged with AC/DC converter or the solar charge controller.\n\nThe inner parts of the drying chamber are made of stainless steel to conform to the food safety standard.24 The mechanical specifications of the dehydrator are shown in Table 1. The outer parts are made of iron steel plate to save cost. The space of 50mm between the inner plate and the outer plate of the drying chamber is loaded with insulation material such as fibreglass to prevent heat energy loss in the drying chamber as demonstrated by Brandon Tinianov.25 The heat exchanger is installed inside the drying chamber, with its base protruding below the drying chamber into the burner chamber. The burner chamber houses the gas burner and the igniter. The gas supplied point on the burner is connected to the gas cylinder, whose opening is proportionally controlled by an electronic valve.\n\nThe control box is positioned on the top of the drying chamber; the box houses all the electrical components except the temperature sensors that are connected to the heat exchanger and the proportional electronic valve. At the centre of the control box is the cylindrical exhaust pipe that runs from the drying chamber to the top of the control box, where the exhaust fan is sitting. The exhaust cylinder is insulated to avoid damaging the electronics component with excessive heat and preventing heat loss from the system. The final structure of the dehydrator and the components of the dehydrator are shown in Figures 2 and 3.\n\nThe components selected for this work are based on industrial-grade standards as recommended by the International Society of Automation (ISA)26 and not from an experimental perspective. This is because this product is designed to be used in an industrial environment where an experimental board like Arduino would not be suitable as it is not protected against harsh, dirty, and electrically noisy environments. Furthermore, industrial actuators and electrical transducers cannot be easily integrated with Arduino without an extra interface board. Hence, using a PLC is a better choice because it is designed to operate in an industrial environment having inputs and outputs ports that can easily interface with industrial-grade sensors and actuators. The electronical component architecture is shown in Figure 4. The PLC handles the hardware interface (connections to all sensors and actuators) and control. At the same time, the raspberry pi plays the role of a computer, providing the web server that hosts the dehydrator web app, data storage, and supervises the PLC's operation. The user can interact with the system via its web interface over its Wi-Fi hotspot using a mobile device or PC. Alternatively, the web interface is also made available on the system HMI screen. The 12Vdc power source is provided from either the solar panel or the connected mains power, depending on which source is available.\n\nThe mini-PLC is a low-cost version of the industrial programmable logic controller (PLC). PLCs are widely used in the industry because of its high processing speed and easy connection interface with industrial field devices such as sensors and actuators.27,28 The mini-PLC has a limited but sufficient number of inputs and outputs required for the work required in this design. The role of this PLC is to interface with all other hardware in the system.\n\nThe PLC basic structure is shown in Figure 5. The programming device, in most cases, is the personal computer (PC) on which the PLC programming software is running. In this project, GX Works2 Station version 1 was used, developed by Mitsubishi Corporation. From this software, the user can write the new software to the PLC and read the software that is already running on the PLC to the PC. The processor keeps cycling the code at a very fast speed at the same time, reading from the input register or bits and writing to the output register and bits as programmed in the running code.\n\nThe available input and output ports for the mini-PLC is given in Table 2. The acceptable wiring connection for the digital input and output port are described in Figure 6. The digital output is a dry contact relay type, and any voltage can be connected to the common pin of the digital output port. The Y output pin associated with the common pin is electrically linked when the output bit is activated within the PLC code. For the input pin X, the associated bit in the PLC code is activated if the input pin is grounded, as shown in Figure 6. The complete wiring diagram of the PLC is shown in Figure 7. The PLC is powered from a 12Vdc source, and the digital inputs signals trigger from the door switch, igniter alarm, gas leakage sensor, and reset button which are wired to the digital input pins of the PLC while the analogue input signals from the PT100 sensors and temperature and humidity sensors are wired to the analogue input pins of the PLC. The digital output actuators and analogue output actuator are connected to the PLC digital output pins and analogue output pin, respectively.\n\nThe role of raspberry pi is to function as a computer,26 and it will be constantly connected to the PLC using a Modbus RS485 communication protocol to get all operational data that will be stored on its MongoDB database. Furthermore, all user configurations will be set and stored on the raspberry pi. The settings can be done from the mini-HMI screen or the web interface built on the raspberry pi.25,28 Finally, the raspberry pi is the central control unit of the system; it decides when operation starts and ends and sets the operation parameter used by the PLC.\n\nThe list of the sensors used, and their function is given below:\n\n➢ PT100 temperature sensors: three-wire type, used to obtain the temperature of the heat exchanger),\n\n➢ Temperature and humidity sensor; with 4-20mA transmitter, used to obtain the temperature and the humidity of the drying chamber.\n\n➢ Voltage sensor for the battery: The battery voltage sensor is a DC voltage transmitter that can measure up to 100VDC and transmit a 0-4mA output signal to the PLC. This is used to measure the battery voltage. The system intelligently uses this value to implement a battery low voltage disconnection process that prevents the battery from being over drained.\n\n➢ Gas leakage sensor: This digital signal is triggered when there is gas leakage to ensure both the user and system's safety.\n\n➢ Door switch: The system knows the status of the door with this input signal.\n\n➢ Igniter alarm switch: The is helps the system to detect fault from the gas igniter controller.\n\nAll the sensors will be wired to the PLC, as shown in Figure 7.\n\nThe role of this device is to automatically ignite the gas burner in the burner chamber. It starts the ignition process based on the signal received from the PLC. It will afterwards send feedback to the PLC to confirm if the ignition process was successful or not.\n\nThis part comprises the 12V 100AH battery pack, the solar panel, the solar charge controller, and the AC/DC converter module. This part aims to supply the 12Vdc source required to power all the components in the system. The AC/DC converter can connect to a 230V AC source from the mains and gives 12Vdc output that can power the system and, at the same time, charge the battery pack. Also, if the mains power supply is not available, the solar panel can harvest solar power through the solar charge controller, which outputs 12Vdc that can power the system and charge the battery pack. The system power requirement is given in Table 3.\n\nThe estimated time (Tb) for the battery to power the farm load at 45% depth of discharge (DoD) can be calculated as shown in equation 1:\n\nBc is the battery capacity, Vs is the system voltage, and Lp is the total power consumed by the system. Inputting the specific values of Bc, Vs, Lp and DoD gives the estimated time for battery power, Tb as shown in equation 2:\n\nHence, this means that the system can run on the connected battery for six hours and 32 minutes. This is based on the electrical parameters of this battery size as this has not been fabricated and tested.\n\nA 150W 12V solar panel is used; the open-circuit voltage and short-circuit current of the solar panel are 18V and 9.4A, respectively. Two of these solar panels can be connected in parallel to charge the battery effective if the user wants to depend more on solar power. 30A 20V PWM solar charge controller is used to save cost; the MPPT version of this controller would have been better if the user will be comfortable with the price. A 230Vac input and 12Vdc out battery charger is used to charge the battery when the system is connected to the mains power.\n\nThe software development for this work will be categorised into two sections which are the PLC software program and the raspberry pi software program. Figure 8 shows the software architecture for this system. The web app that serves the users via the available web interfaces (the HMI screen and over the Wi-Fi connection) connects to the local server on the raspberry. JavaScript programming language was used to build both the frontend and the backend software. The backend software stores and retrieves data from the MongoDB server using mongoose API endpoints, and the backend software also communicates with the PLC using RS485 RTU protocol. The software on the PLC retrieves data from the raspberry pi via its Modbus assigned data registers and bits; these data determine the operation parameter such as target temperature, humidity, operation duration and alarm set points. Also, the PLC ladder logic software reads data from the connected sensors set the corresponding actuators accordingly. The details of the PLC software are further explained in the section below.\n\nThe ladder logic or ladder diagram (LD) is a programming language used for programming PLC in the automation industry. It is popular among automation engineers because it evolved from electrical relay circuits, making it easier to learn for anyone with basic knowledge of relay controls and electrical circuits. The primary functions of the PLC are carried out in the ladder logic program, as shown by the flow chart described in Figure 9. The PLC (a slave in the Modbus network) starts by reading the sensor data from the connected digital and analogue input sensors. These data are moved to the assigned Modbus data registers and bits to be read by the raspberry pi (the master in the Modbus network). The PLC also read Modbus data from the raspberry pi to get the command for the next action and obtain desired operation parameter from the user. The PLC executes dehydration operation based on the set operation parameter if the bit assigned for the command (‘start drying’) is true. The PLC keeps track of the operation time as desired by the user and detect if an alarm is activated.\n\nThe PLC has 12 bits ADC (Analogue to Digital Converter), and its analogue input values are read from data register D8030 to D8045; each register corresponds to the analogue input port AD0 to AD15. The calibration of this analogue input value is dependent on the characteristics of the sensor and the input type on the PLC. The analogue input type can be 0-10V, 4-20mA, k-type thermocouple, PT100, and others, depending on the application and the type of sensor that is selected. This PLC uses PT100 and 4-20mA input types. Table 4 indicates the individual sensors that are connected to the analogue input ports.\n\nThe calibration of both sensors used for drying chamber temperature and humidity is done by using the formula given below in equations 3 and 4:\n\nxt and xh are the analogue values read from the data register for the connected temperature and humidity sensor, respectively. Similarly, yt and yh are the final temperature and humidity. Figure 10 shows how the dehydrator or oven temperature reading is obtained from the ladder logic program.\n\nPID (Proportional Integral Derivative) control blocks are available in PLC. A PID controller is a control feedback mechanism used to regulate a plant’s process variable such as temperature, speed of an electric motor, pressure, flow rate, and other process variables.29 The general model for a PID controller is given by equation 4:\n\nwhere Cpid is the control signal for the system (PID output), e(t) is the error between the desired setpoint and the system output, de(t) is the derivation of error e(t), and Ki,Kp, and kd are integral gain, proportional gain and derivative gain, respectively.\n\nTunning of the PID means modifying the values of Ki,Kp, and kd accordingly. The role of the PID controller in this work is to regulate the dehydrator/oven temperature, humidity and fans’ speed.\n\nTo regulate the temperature, humidity, and the fan’s speed in this work, the command below is used to perform PID control that changes the output value according to the amount of change in the input. Setting the entries of Figure 11 based on the details of Table 5 activate a single input single output (SISO) PID function.\n\nAfter setting the target value S1, the measured value S2, and the parameters S3~S3+6 in the execution program, the operation result (MV) is saved to the output value D. every sampling time S3.\n\nThe two programming tools used to develop the raspberry pi software are Node.js linux binaries (ARM) version 14.17.3 and Linux Bash Shell Script. The shell script is used to automate the hardware configuration of raspberry pi on boot up, such as modem connection, activation of Nginx server, Wi-Fi hotspot setup, Virtual Private Internet Service activation and main program loading. The Node.js programming package is used to develop the main application, whose features are listed below:\n\n➢ Frontend web interface: This provides a user-friendly interface for the dehydrator. The users can access the interface from the HMI screen or via their mobile devices or PCs over the dehydrator’s Wi-Fi connection using available web browsers. The user can view the current operating parameters of the dehydrator, download historical operation data, create an operation profile, and start/stop the operation process.\n\n➢ Database Management: The application uses the MongoDB database, which is accessed using mongoose API endpoints. The current operation parameters are stored in the database only when an operation is active to conserve memory space. A newly created or edited operation profile by the user is also stored in the database.\n\n➢ PLC operation control: The application connects to the PLC as a Modbus master to read data and set the PLC operation parameters.\n\nNode.js is a JavaScript runtime built on Chrome’s V8 JavaScript engine. V8 compiles JavaScript directly to native machine code using just-in-time compilation.30 This approach makes it possible to write JavaScript language on the webserver side of our application and control the microcontroller hardware. Figure 12 shows the details of the Node.js App structure. The software development takes advantage of Node.js’s heavy support for libraries contributed by its community. Node package manager (NPM) helps to manage the node application’s dependencies on libraries used. The details of the major NPM packages in the application are listed below:\n\n➢ Express.js: A node.js web application framework, this handles all HTTP request required by the application.\n\n➢ Mongoose.js: This provides useful API endpoints to interact with the database from the node.js application. It is used to store created operation profile by the user, operation data read from the PLC and the activated alarms during the operation. It is also used to retrieve this stored data as required.\n\n➢ Modbus-serial.js: It is used to implement RS485 Modbus RTU on the application. As a master on the Modbus network, the application can read and write data to the PLC that is acting as a slave on the Modbus network.\n\n➢ Axios.js: This is used from the frontend to handle API request.\n\n\nResults\n\nAs this is a conceptual design, an operation test was performed to simulate how the system would perform in an enclosed chamber. A workbench test was carried out on how the temperature PID control will perform by creating an operation profile. In addition, the logs for this operation was downloaded and analysed to test the performance of the setup. The basic functionality of the frontend section was tested with both PC and Mobile phone.\n\nThe operation profile named ResearchTest was created from the configuration page. Clicking on the configuration tab on the left side of the web page opens the user to the configuration page shown in Figure 13(a). The user can edit or delete existing operation profiles and create a new operation profile from this page. The target temperature was set to 50°C; the target humidity was set to 35%; the maximum and minimum fan speed was set to 2000rpm and 600rmp respective. Also, in the configuration, duration time was activated, and the desired duration time for the operation was set to 40 minutes. The newly created operation was selected on the dashboard page shown in Figure 13(b), and the start button was clicked for the operation to commence.\n\nThe user can view real-time operating parameters such as the drying chamber temperature and humidity, and fan speed on the dashboard page. Furthermore, other operation details such as set time for the operation and operation timer are shown on the dashboard page. The user can navigate to other pages by clicking on different tabs on the web page's left side.\n\nThe trendlines page can view the operation trends, which can be viewed by clicking on the Trendlines tab on the left side of the webpage. The trend chart for this test operation is shown in Figure 14. This shows the temperature and the humidity chart; as shown in the chart, the drying chamber temperature recorded was between 48.5°C to 51°C, around 50°C set as the target temperature. The raw data for this operation was downloaded from the dehydrator web interface and further analysed, as shown in Figure 15. The temperature was around 50°C, as shown on the trend charts. The data is also available in Excel format.31\n\nThe chart shows temperature in °C as a function of time for the Operational Test on PID Temperature Control.\n\nFurthermore, the data operation data was downloaded from the download page; navigation to this page was done by clicking on the Data Export tab. The data was downloaded in excel format and was further processed in excel to produce Figure 15, which shows how the PID controller forces the drying chamber temperature around 50°C, the set temperature.\n\n\nDiscussion\n\nBased on the charts above, during the ResearchTest operation, the heater raised the system temperature to the target temperature and stayed around it. The PID control is not as perfect as expected because the process temperature toggled between 48.7°C to 51.8°C. This is because the test was carried out in open space and not in the closed drying chamber that the oven will provide after fabrication. The temperature PID control performance can be improved on the final implementation by tuning the PID controller parameters to reduce the ripple. Furthermore, the frontend section of the web application was tested to ensure that it was in sync with the backend section that interacts with the system hardware and manages the database. The dehydrator has been designed but has not been fabricated. So only an operational test could be performed to simulate how the system would perform in an enclosed chamber. Future work would involve creating a physical prototype of the design carried out in this work and validating the operational test.\n\n\nConclusion\n\nThe setup discussed in this work showed a design for a dehydrator or oven with full control over the drying chamber temperature and humidity. Gas is used as a source of heat energy because it is readily available and suitable for continuous industrial operation. Also, the setup gives the user the flexibility to create different operating profiles for different crops to make the dehydrator suitable for drying any type of crops or food samples. The user access to the historical operation data will provide insight into creating a better operation profile for a particular crop of interest.\n\nFurthermore, the hybrid power solution provided gives the user the opportunity to use the dehydrator in remote places that are not connected to the national grid or places that experience unstable power supply.\n\n\nData availability\n\nZenodo. ResearchTest Data. https://doi.org/10.5281/zenodo.5105996.31\n\nThis project contains the following underlying data:\n\n- ResearchTest data.xlsx. (Temperature in °C as a function of time for the Operational Test on PID Temperature Control)\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\nSoftware available from: https://zenodo.org/record/5126962.32\n\nSource code available from: https://github.com/vickkiee/Dehydrator_Software.\n\nArchived source code at time of publication: Dehydrator Software, https://doi.org/10.5281/zenodo.5126962.\n\nLicense: Creative Commons Attribution 4.0 International (CC-BY 4.0).",
"appendix": "References\n\nPino-Hernández E, Pereira RN, Ballesteros LF, et al.: Effects of Moderate Electric Fields on the Post-harvest Preservation of Chestnuts. Food Bioprocess Technol. 2021. Publisher Full Text\n\nShantaram M: Impact of climate change on agriculture. Biomed . 2020; 40(4): 412–413. Publisher Full Text\n\nBradford KJ, et al.: The dry chain: Reducing postharvest losses and improving food safety in humid climates. Trends Food Sci. Technol . 2018; 71(November 2017): 84–93. Publisher Full Text\n\nGunathilake DMCC, Senanayaka DP, Adiletta G, et al.: Drying of Agricultural Crops. January 2019; 2018.\n\nNadu T: Design and fabrication of portable food dehydrator. Int. J. Food Sci. Nutr. 2020;5(4):49–52.\n\nLamidi RO, Jiang L, Pathare PB, et al.: Recent advances in sustainable drying of agricultural produce: A review. Appl. Energy. 2019; 233–234(September 2018): 367–385. Publisher Full Text\n\nRahman MS: Dried food properties: Challenges ahead. Dry. Technol. 2005; 23(4): 695–715. Publisher Full Text\n\nPacco C, Honorato: Temperature simulation and control for lab-scale convection dehydrators. Procedia Comput. Sci . 2021; 180: 922–934. Publisher Full Text\n\nSamin RE, Jie LM, Zawawi MA: PID implementation of heating tank in mini automation plant using programmable logic controller (PLC). InECCE 2011 - Int. Conf. Electr. Control Comput. Eng . 2011: 515–519. Publisher Full Text\n\nRodrigues L, et al.: Impact of Spray Drying Parameters on Lactose-Free Milk Powder Properties and Composition. J. Agric. Stud. 2020; 8(3): 32. Publisher Full Text\n\nSharma A, Chen CR, Vu Lan N: Solar-energy drying systems: A review. Renew. Sustain. Energy Rev. 2009; 13(6–7): 1185–1210. Publisher Full Text\n\nCacua K, Olmos-Villalba L, Herrera B, et al.: Experimental evaluation of a diesel-biogas dual fuel engine operated on micro-trigeneration system for power, drying and cooling. Appl. Therm. Eng. 2016; 100: 762–767. Publisher Full Text\n\nSumotarto U: Design of a geothermal energy dryer for beans and grains drying in Kamojang geothermal field, Indonesia. Trans. - Geotherm. Resour. Counc. 2006; 30(I): 235–239.\n\nOkoroigwe FCOEC, Ndu EC: Comparative evaluation of the performance of an improved solar-biomass hybrid dryer.2017. Publisher Full Text\n\nOkoroigwe EC, Ndu EC, Okoroigwe FC: Comparative evaluation of the performance of an improved solar-biomass hybrid dryer. J. Energy South. Africa . 2015; 26(4): 38–51. Publisher Full Text\n\nSadaf Anchal L, Dubey A, Kumar P: Development of Static Flat-bed Batch Dryer for Small Scale Grain Drying. Curr. J. Appl. Sci. Technol. 2020; 38(6): 1–7. Publisher Full Text\n\nKerr WL: Food drying and evaporation processing operations. Elsevier Inc; 2019.\n\nTang XC, Nail SL, Pikal MJ: Freeze-Drying Process Design by Manometric Temperature Measurement: Design of a Smart Freeze-Dryer.2005; 22(4). PubMed Abstract | Publisher Full Text\n\nMujumdar AS: Drying Research - Current State and Future Trends.2002; 10: 225–246. Publisher Full Text\n\nPiñón-Balderrama CI, Leyva-Porras C, Terán-Figueroa Y, et al.: Encapsulation of active ingredients in food industry by spray-drying and nano spray-drying technologies. Processes . 2020; 8(8). Publisher Full Text\n\nBadahman MS, Susiapan YS: Smart Oven with Temperature Control.2020; 3(2): 1–12.\n\nIstiqphara S, Adliani N: IJEScA Based on Smart Fuzzy and Internet of. pp. 1–7.\n\nMisha S, Mat S, Ruslan MH, et al.: The effect of drying air temperature and humidity on the drying kinetic of kenaf core. Appl. Mech. Mater. 2013; 315(May 2014): 710–714. Publisher Full Text\n\nHedberg Y, Mazinanian N, Wallinder IO: Compliance tests of stainless steel as a food contact material using the CoE test guideline.2014; 1(2013): 1–9.\n\nBrandon Tinianov DM, Nakagawa M: Prediction of the thermal conductivity of fiberglass insulation using propagation constant: A technique overview. J. Acoust. Soc. Am. 117(4): 2555–2555. Publisher Full Text\n\nA.-50. 00. 0.-1975 (R2012): Compatibility of Analog Signals for Electronic Industrial Process Instruments.” International Society of Automation.Reference Source\n\nLevenson RM, Nelson ZE, Adegbege AA: Programmable Logic Controller for Embedded Implementation of Input-Constrained Systems. IFAC-PapersOnLine . 2017; 50(1): 14412–14417. Publisher Full Text\n\nVadi S, Bayindir R, Toplar Y, et al.: Induction motor control system with a Programmable Logic Controller (PLC) and Profibus communication for industrial plants — An experimental setup. ISA Trans. 2021; no. xxxx. PubMed Abstract | Publisher Full Text\n\nPriyanka EB, Maheswari C, Thangavel S: Online Monitoring and Control of Flow rate in Oil Pipelines Transportation System by using PLC based Fuzzy-PID Controller. Flow Meas. Instrum. 2018; 62(January 2017): 144–151. Publisher Full Text\n\nTilkov S, Vinoski S: Node.js: Using JavaScript to build high-performance network programs. IEEE Internet Comput. 2010; 14(6): 80–83. Publisher Full Text\n\nOluwaleye S, Oguntosin V: ResearchTest Data (Version 1) [Data set]. Zenodo. 2021. Publisher Full Text\n\nOguntosin V: vickkiee/Dehydrator_Software: dehydrator_software (Version 1). Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "95419",
"date": "18 Oct 2021",
"name": "Henry Inegbedion",
"expertise": [
"Reviewer Expertise Economics",
"Finance",
"Operations Research",
"Marketing and Agricultural Science"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors investigated the “conceptual design of smart multi-farm produce dehydrator using a low-cost programmable logic controller and raspberry”. The research problem is very important. This is a clear case example of applied research as the authors seek to provide a solution to the age-long dilemma that has been confronting farmers in Sub-Saharan Africa since its inception. The results of the study promise to contribute to the stabilization of the farm products, which are often very cheap during harvest seasons because the farmers are often willing to part with the products due to the high degree of perishability.\nNevertheless, I am persuaded that the paper has a gap, which the authors should bridge in order to enhance the quality of the paper. I suggest that they indicate the financial feasibility of the equipment. The authors should indicate the capacity of the dehydrator in terms of a specific farm produce. Based on this capacity, estimates of the expected benefits of the specific farm produce in post-harvest seasons should be forecasted. Taking cognizance of the cost of producing and/or purchasing the multi-farm produce dehydrator vis-à-vis the expected returns from the post-harvest sales of the preserved farm produce, the financial benefit of the equipment should be indicated.\nThe above is important because the value of the dehydrator to a farmer is a function of its capacity to enhance their economic fortunes. While the government may, in addition, be interested in using the equipment to enhance food security, the possibility of using the equipment to generate revenue will stimulate their interest and thus attract their attention faster. The financial feasibility of the equipment will enhance the value of this article.\nLastly, the authors should indicate whether this proposed equipment is the first of its kind. If not, they should indicate what is unique about this very one.\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? Yes",
"responses": [
{
"c_id": "7397",
"date": "11 Nov 2021",
"name": "victoria Oguntosin",
"role": "Author Response",
"response": "We thank you for your time in reviewing the article. To emphasize the uniqueness of this dehydrator, none of these designs in the reviewed literature have control of both the temperature and humidity of the drying chamber simultaneously. In this work, the designed dehydrator will ensure the even distribution of heat within the drying chamber and, at the same, regulate both the temperature and the humidity of the drying chamber. Furthermore, the dehydrator will be user-friendly, such that the user can create different operation profiles for different types of crops or any drying sample, and also set the desired duration for the operation. The above has been explained in the article. Also, the paper has been updated with a section on the financial feasibility of the dehydrator. This section has the bill of quantities of materials used in the development of the dehydrator and discusses the capacity of the equipment. The pricing strategy of the equipment was also discussed for low-income farmers since the device is intended to be used in low-income countries."
}
]
},
{
"id": "95420",
"date": "01 Nov 2021",
"name": "Marly Grajales Amorocho",
"expertise": [
"Reviewer Expertise Biology",
"agriculture",
"biotechnology."
],
"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\nWe do not know if the focus of the article is in our area, since it is on agricultural engineering, on the design of the dehydrator and in our case it would be more appropriate to evaluate the purpose or the function of the equipment, However, we give our review:\nThe article reports the design of a new equipment for drying agricultural products which can be used anywhere in the world, mainly in those regions where climatic conditions such as high rainfall and low solar radiation prevent moisture removal to a safe level for storage. In addition, the design of the equipment is thought to be easy to operate since it has an automated electronic system that will control the conditions necessary for the dehydration process to occur if the products lose their natural properties. The design is novel, inexpensive and facilitates a continuous and permanent, automated process.\nThe conceptual design conforms to the proposed parameters, however they conclude as if it had been used and so far there is no evidence that it works. It has a very good application in agriculture but it is more an engineering design. However, we suggest rewriting the conclusion that is formulated as a justification.\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/10-810
|
https://f1000research.com/articles/10-1071/v1
|
22 Oct 21
|
{
"type": "Case Report",
"title": "Case Report: The resiliency journey of a Vietnamese female sexual abuse survivor: an exploration in life history",
"authors": [
"Thien-Vu Giang",
"Duy-Hung Le",
"Thanh-Huan Nguyen",
"Van-Son Huynh",
"Diem-My Nguyen-Thi",
"Duy-Hung Le",
"Thanh-Huan Nguyen",
"Van-Son Huynh",
"Diem-My Nguyen-Thi"
],
"abstract": "Currently, the studies on sexual abuse trauma, and resilience in Confucian survivors are still limited. The purpose of this study is to explore the resilience of Confucian women after sexual abuse trauma to provide evidence to support in counseling and psychotherapy practices. The article describes the resiliency story of a Vietnamese Confucian female survivor who was abused by her brother from the age of 8 to 16. The life history approach used in qualitative narrative research was applied in this study. The researcher identified two factors that strongly influence the survivor’s resilience: (1) the effectiveness of passive education in the general education curriculum is oriented to both competence and quality development; and (2) an authentic understanding of the core Confucian philosophical doctrine: the neutrality and the self-nurture. Based on the findings, we propose a 7-stage flow diagram of a Confucian women's resilience following sexual abuse. These findings provide important evidence-based practice for counselors and clinicians in supporting and intervening for sexually abused Confucian women and contribute to the impact of studies on religious and spiritual factors affecting the resilience of sexual abuse survivors.",
"keywords": [
"Child sexual abuse",
"sexual abuse trauma",
"resilience",
"Confucian female survivor",
"life history",
"narrative research."
],
"content": "Introduction\n\nChild sexual abuse (CSA) is a crime that happens across countries, races, religions, classes, and cultures and has lifelong effects. CSA includes any interaction between a child and an adult (or another child) in which the child is used for the sexual stimulation of the perpetrator or an observer (Bolen & Gergely, 2014). CSA leaves serious consequences on the victim's mental health, which can have long-term effects without appropriate support and intervention strategies. There have been a lot of previous studies done to understand, support, and heal the sexual abuse trauma (SAT) experienced by survivors. These studies can be divided into three groups: (1) studies on the current situation surrounding CSA (Blakemore et al., 2017; Murray et al., 2014; Stoltenborgh et al., 2011); (2) studies on CSA prevention (Barron & Topping, 2013; Rudolph & Zimmer-Gembeck, 2018; Rudolph et al., 2018); and (3) studies on support, intervention and healing the SAT (Adams et al., 2018; Sanjeevi et al., 2018). This research is the result of the efforts of various countries, communities, and societies working together to protect children's rights.\n\nWhen studying the survivors' life experiences, it is essential to learn about the development of their social relationships after the abuse. Some of the negative long-term effects that CSA has on a child is the consequences and precariousness of the victim's communication abilities, interaction, and social connections when they become adults (O'Leary et al., 2010), go to work (Colarusso, 2010), get married (Fergusson et al., 2013) and even after having children (Mrazek & Kempe, 2014). It is also important when studying the essence of relationships to consider the cultural, religious, and social factors that influence the survivor’s life. This is a research direction that has garnered focus and is carried out in many countries in order to provide the most effective and appropriate solutions for survivors through consideration of religion and spirituality as a means of healing.\n\nOn the other hand, studies on the direction of mental health support and interventions for abused children always mention that a counselor, a clinician, or a social worker will be the one to conduct support and intervention for the victim (Dietz et al., 2012; Furniss, 2013). The issue of self-resilience, as well as the discovery of the link between the victim’s internal resources and SAT, is an area that relatively few researchers have addressed. Clinical studies on resilience in people who have been sexually abused are still highly subjective. Therefore, there is a lot of debate about in-depth research in this field to provide evidence that will develop mental health support and intervention through diverse perspectives for children who have been sexually abused.\n\nIn Vietnam, research on CSA has been limited to presenting the situation (Linh, 2021; Tran, 2020), proposing solutions (Nguyen, 2018), practicing some manipulations of counseling, psychotherapy (Nguyen et al., 2016), and providing social support for victims (Dinh Vinh, 2020), there has been no longitudinal study addressing the long-term effects of CSA, or in-depth research on the psychological development, the essence of psychological phenomena in adults who were abused as children. Therefore, conducting a longitudinal study to understand the psychological transformation of CSA survivors in adulthood is urgent and a prerequisite for providing practical clinical evidence focusing on the post-intervention period in the group of survivors.\n\nThis article presents the resiliency journey of an adult female survivor of CSA that occurred from the age of eight as a typical case of trauma recovery involving religious and educational factors. The study’s findings demonstrate women’s ability to overcome adversity, as well as their emotional resilience, within a modern understanding of Confucian philosophical doctrine and of education as a preventive factor.\n\nPrevious global studies all show that victims of CSA suffer long-term effects of psychiatric, psychological, and physical symptoms. CSA has been correlated with higher levels of depression, guilt, shame, self-blame, eating disorders, somatic concerns, anxiety, dissociative patterns, repression, denial, sexual problems, and relationship problems (Bentovim et al., 2018). In some cases, survivors experienced sexual dysfunction when they came into adolescence. A study done on the prevalence and predictors of sexual dysfunction in the US revealed that victims of CSA experience sexual problems more than the general population. They found that male victims of CSA were more likely to experience erectile dysfunction, premature ejaculation, and low sexual desire, and they found that women were more likely to have arousal disorders (Laumann, Piel, & Rosen, 1999). These mental health issues are explored by psychologists and clinicians through empirical evidence. Also drawing on these long-term effects of CSA, many intervention strategies have been implemented, corresponding to different problems and different individuals. Therefore, it is important to point out that each victim’s responses and experiences in CSA will not be the same. Although it is often viewed as a traumatic experience, there is no single symptom among all survivors, and clinicians need to focus on the individual needs.\n\nIn addition to psychotherapy and medical interventions, religion and spirituality are commonly regarded as important coping strategies by victims of CSA. Religion may contribute to greater resilience, attribution of meaning, and guidance as well as providing a social support network (Durà-Vilà et al., 2013). Although the spiritual impact of abuse can be devastating, some studies also document that spirituality can be a source of resiliency for many children and that those who can cope spiritually, also do a better job of coping emotionally and physically (Crisp, 2007). Religious and spiritual activities that are often performed by victims/survivors to recover from the SAT are: increasing the spiritual knowledge (e.g., religious education, Bible study), practicing spiritually (e.g., ritual, virtuous actions), consolidating the spiritual relationships (e.g., church involvement, holy matrimony), and experiencing spirituality and religion (e.g., meditation, prayer; see Pargament, 2013). Each of these activities is designed to sustain and strengthen the individual’s relationship with the Gods, Saints, Buddha or other supernatural forces. Therefore, religion and spirituality are confirmed as being supportive factor in recovering from sexual abuse. However, when reviewing studies on the application of religion and spirituality as a form of mental support to sexual abuse survivors, there were only studies on Catholicism (Durà-Vilà et al., 2013), Christianity (Yan, 2001), Islam (Bhutto & Rind, 2019), and Buddhism (Sasson, 2014). The impact of other religions and belief systems has rarely been studied and deployed only at the level of common sense and indigenous knowledge.\n\nThe long-term effects of CSA analyzed above were confirmed to exist in Vietnamese adult survivors (Tran, 2020). Intervention strategies from psychologists, clinicians as well as support from social organizations have contributed to a positive effect in helping this group of survivors recover. At the same time, the application of spiritual and religious support strategies with the group of survivors was also carried out, focusing on Buddhism and Christianity – the two religions with the largest number of followers in Vietnam (Phan, 2010). However, a study on the psychological trauma of children and adolescents living in incomplete families by Nguyen (2019) reported that Confucianism and Confucian educational ideology in the family were the factors that aggravated the trauma of children being abused by their family members and were even a cause of suicide in children and adolescents. When studying the psychological trauma of sexually abused children, Nguyen et al. (2016) also found that Confucian philosophical ideas of gender and the prejudice that stems from within the family is the main reason female victims are not protected and have no voice in the family.\n\nConfucianism has had a profound impact on the culture and spiritual life of Vietnamese people (Vuong et al., 2018). The doctrine of Confucianism is divided into two parts: Lower (studying the social relationships) and upper (studying the operation of the universe and human beings). This doctrine is preached through forms of education, family activities, and social relationships (Vuong et al., 2018). In particular, over the past 1000 years, Confucian philosophy has become an educational viewpoint, a cultural feature, and an educational tradition of many Vietnamese families (Smith, 2021). From these analyzes, combined with practical evidence on SAT in Vietnam, it can be seen that the Confucian perspective is associated with the long-term effects of CSA as well as the resilience of this group of victims. Research on the resiliency process in survivors living in Confucian families, as well as the relationship between Confucianism and CSA, is urgently needed to serve as practical evidence to contribute to the case study or to consider as a model case in clinical psychotherapy and counseling.\n\n\nMethodology\n\nThis study is part of a longitudinal research project on mental support and intervention measures for female sexual abuse victims since 2016 in Vietnam (Nguyen et al., 2016). The purpose of the present study is to understand the lived experiences of a Confucian woman who had been sexually abused as a child by her brother and to understand her resiliency process throughout her childhood, adolescence, and adulthood.\n\nWith this goal, the researchers posed two research questions to explore:\n\n1. How did she survive in the family that caused her trauma?\n\n2. How did she recover from the SAT?\n\nThe five researchers involved in this study with different tasks are presented in Table 1 (see Table 1).\n\nThe participant is currently a student studying at the research team's university. There was no prior relationship between the research team and the participants. When the recruitment information for research volunteers was announced to the classes through the lecturers, the participant actively contacted the research team with the desire to better understand her trauma and help disseminate the project’s values to other survivors. Before participating, the participant was given full information about this project, including the objectives, vision and ethical issues in personal information security and scientific publication.\n\nAs Creswell and Poth (2016) noted, qualitative research strategies are particularly appropriate to address the experience and perspectives of the participant. The method of investigating those realities and experiences is referred to as narrative research, a qualitative research method designed to capture the detailed stories or life experiences of an individual. With narrative research, we can learn about the survival and resiliency process of CSA victims throughout their psychological development. Through time-lapse narrative interviews, the researchers documented the participant’s key milestones, thereby identifying key events and drivers that create, or promote the resilience.\n\nThe wider longitudinal research study, of which this study is a part, was conducted through 25 in-depth interviews between two researchers and the participant, each lasting between 45 to 60 minutes. The interview location was a psychological counseling office belonging to a key university in the south of Vietnam, which guaranteed a comfortable space and the confidentiality of the interviewee information.\n\nThis study belongs to the research project ‘Counseling for sexually abused children with artist playtherapy’ (Nguyen et al., 2016), which is funded by the Ministry of Education and Training of Vietnam, project number B2020.SPS.19 and supervised by the Department of Science and Technology Ethics committee of the Ho Chi Minh City University of Education (under the Ministry of Education and Training of Vietnam). This project aims to design and test the psychological interventions and support for sexually abused children. The data extraction used to conduct this study was approved by the Department of Science and Technology Ethics committee of the Ho Chi Minh City University of Education (Permit number: 1815/QD-BGDDT) and conducted in accordance with the Declaration of Helsinki. The participant was fully informed about the study process of the project, as well as the study conducted in this article prior to the interview.\n\nConsent for participation in the research project was given by the participant in the interview recording and signed consent form. The name and personal information of the participant in this study were anonymized. The data used for publication was approved by the participant. The written informed consent from the participant is confirmed by her signature and the research team, under the supervision and guarantee of the Department of Science and Technology Ethics committee of the Ho Chi Minh City University of Education. Written informed consent for publication of the participant’s case details was obtained from the participant.\n\nOnce participants contacted the researchers to take part in the larger research project, a single participant from the group was purposively sampled for this case study based on the following criteria: 1. The participant must have experience of SAT. 2. Must be currently undergoing recovery. 3. Must follow the Confucian religion.\n\nThe criteria were assessed during the recruitment process through classroom discussions, where the participants voluntarily shared their experiences. CSA is a traumatic experience and not every survivor can overcome it and recover. Therefore, the researchers requested a private and confidential meeting with the selected participant to double-check that the participant was indeed willing to share the story. Screening criteria were discussed again privately with the participant, and further information on the research project was given. After the participant agreed to take part, the contact details were shared with the fifth researcher who contacted the participant officially. Confidentiality of the participant information was maintained through all stages of the recruitment and research phases.\n\nIn this section, the participant's information is presented in the form of biographical summaries, as well as key events in her life history. The participant was a Confucian woman (anonymous name L), who was 20 years old at the time the study took place, studying at university. L has a history of being sexually abused by her biological brother (older than L 12 years old) between the ages of 8 and 16 years old. The types of abuse changed over time. For the first three years L was completely unaware that she was being abused. The brother would occasionally use erotic statements when talking with L and show L pictures of adult women wearing underwear or nude. L thought this was just normal communication and was amused when her brother introduced her to the development of the female body as an adult. From 12 to 15 years old, when L entered puberty with many drastic changes in the body, the brother approached L more, often sending messages via social media such as Facebook to confide in L. He often told L about his broken relationships to gain her trust and understanding. At first, her brother sometimes used some sensitive words when referring to the private area, but he gradually increased his erotic language, as well as sending L pictures and clips of sex as a way to educate her. From the age of 14, L started to feel uncomfortable when her brother kept texting her and sending her explicit pictures. L once told her parents, but they responded with silence and distrust. L was disappointed and lived a closed life. By the time L was 15, CSA cases were exposed and widely published in Vietnam, creating opportunities for many victims to speak up and ask for help from society. At this point, with the support of her homeroom teacher, L realized that she had been abused for a long time. L decided to speak up and protest to her brother. L asked her brother to stop the abuse, or else she would report it to the police. This only deterred her brother for the first three months, however. After that, he became even more aggressive in stroking L, touching her sexually, making her feel very uncomfortable and “dirty”. When L was 16 years old, the abuse reached its climax. She was lured by her brother to drink alcohol and perform sexual acts, and was eventually raped by her brother. L fell into despair and depression and shared that she once attempted suicide but was discovered by her father, so it was not successful. By this time, the parents believed that what L shared was true and took action to intervene with her brother. Although they did not report to the police, L's parents took L to live with her aunt in another city and she continued to attend high school. L had managed to cut off the source of her abuse from here. However, the period that followed was the most challenging as she tried her best to balance her emotions, resilience, and reintegration into daily life. Details of her resilience and how she coped with the SAT are presented in the findings and key events sections which follow.\n\nGiven the scope of the current article, data collection was based on L’s SAT-related events since the age of 8. This life-history method, according to Goodson (2001), generates not only deeper knowledge about the individual but also about the social reality and family relationship that she has to act out and operate within. Data collected from the accounts reported by L are collectively known as ‘socially read biography’, which provides insight into her resilience process, and the socio-cultural context, and offers a significant source of information and knowledge about Confucian female CSA survivors. From the perspective of social transformation, the employment of the life history method in this study is in line with the social approach to narrative research which enables the survivor to express her voice and attitudes towards the CSA.\n\nFurther, in line with the life-history method, data were collected by in-depth, unstructured interviews (Goodson, 2001). Because CSA is a sensitive topic to discuss as well as to research, the interviews were face-to-face with just two people present in addition to the interviewee. During the first two sessions, the researchers established a relationship with L through open and friendly exchanges to create a safe, positive and comfortable atmosphere for L. When L felt ready to share her story, the researcher conducted 25 interviews. Parallel to each interview, the researcher observed in detail L's views, feelings, and behaviors, especially unconscious behaviors and body language expressions when retelling her story. L was interviewed with open-ended questions and was encouraged to answer and share her experiences as a victim and survivor of CSA. Interview questions focused on exploring life experiences, the resiliency process following SAT, and the impact of religion and education on the participant’s resiliency ability. Specifically:\n\n(1) How do you understand your resiliency ability after these bad things happen to you?\n\n(2) For you, how did Confucianism and your belief in Confucianism affect your resilience? (see all questions in Giang, 2021)\n\nThe 25 interviews were conducted in Vietnamese for convenience and so that the participant felt most comfortable when sharing her experience. All the details in L's story quoted in this article were translated from Vietnamese into English by the author, who is fluent in both languages. Interview data was recorded (under the restricted conditions with the consent of the participant) and the research team confirmed not to use these for any personal interest. These recordings, after being processed, were stored in a secure data system set up by the Computer Science Center of the university where the participants are studying. During the interview process, the researcher systematized the events that occurred in the participant's story in chronological order, noting important events as well as keywords and sentences serving the data analysis. As data collection was underpinned by the method of life history, deliberate strategies were employed for data analysis of the participant’s narratives (Goodson, 2001). In other words, the stories told by L during the interview were interpreted to highlight the foci of the study.\n\nThe data analysis was based on transcriptions of in-depth life history interviews with detailed observations of the participant's behaviors, emotions, and perspectives. The story told by L was considered and analyzed in the broader context of mental health and social life in Vietnam rather than examined in isolation. The analysis process was interpreted independently by three researchers (the 1st, 2nd and 3rd authors). After that, the three results are discussed in a group and supervised by the 4th researcher to ensure reliability and semantic consistency. After the group discussion, the result was returned to a participant for comment and approved to be used in the findings section.\n\n\nFindings\n\nThe main findings are presented in this section and they are illustrated with quotations extracted from the transcripts (Giang, 2021). After briefly describing L’s experiences, we propose a resiliency journey that involves learning Confucian philosophies and preventive education programs at school.\n\nL described various types of sexual abuse trauma (SAT), involving violence, harassment (in person and online), coercion, intimidation, and mental/physical stress. The acts of sexual abuse mainly took place at L's family home, during periods of parental absence, or when L used online social networks. During the period of abuse before developing more resilience, L experienced a range of emotions and thoughts. The emotions and thoughts verbalized during L’s interview were summarized in Table 2 by the research team (see Table 2).\n\nIt can be seen that the feelings, thoughts, and responses (behavior), as well as the psychological trauma and forms of abuse, experienced by L during the period of abuse, are similar to those found in other victims of SAT. However, when considering the long-term effects, there is a significant difference between L and other published cases. The next findings section presents L’s recovery process of struggle and resilience from the age of 16, when completely separated from the perpetrator and she is no longer being abused.\n\nSince moving to her aunt's house, L has not seen her brother. She also blocked him on Facebook and other social networking sites in order to completely cut contact. She only keeps in touch with her parents. However, the days following this transition were a challenging time for her. During one interview L recounted the first day of entering a new school:\n\nIn my religion, if a woman is not a virgin before marriage, it is a sin to my family and my future husband. I'm embarrassed. (Session 3, March 14th, 2020)\n\nIn the first three months following the move, it was difficult for L to adjust to the new learning environment and make new friends. Her trust in society seemed to be falling apart. L withdraws and limits communication with friends:\n\nMy 16-year-old [self] was in a crisis! I couldn't trust anyone and myself! I do not want anyone to know this ugly thing! (Session 3, March 14th, 2020)\n\nNot only that, but L’s trust in her parents also broke down:\n\nWhy did not they denounce him? Why are they defending him before the law? Instead, they moved me to live somewhere else. Is the role and face of the eldest son in the family so important? Parents are willing to let their daughters suffer because they do not want to hurt their sons! It is not fair! (Session 6, April 25th, 2020)\n\nIt can be seen that L suffered fierce internal struggle and torment related to her role in the family, her outlook on life, and the way she interacts and integrates socially. L commented:\n\nI know I have been abused. That is a crime. I am a victim of this incident and I must move on … That is what I learned and [was] advised from my 9th grade homeroom teacher. However, I cannot forgive my family (including father, mother, and brother). I want to be recognized in my family! (Session 4, March 28th, 2020)\n\nIn addition, L suffered a period of depression as a result of feeling trapped and unsupported:\n\nEvery night, feelings of emptiness and despair rise within me. Even in my dreams, I see myself being rejected by my parents. If my father had not stopped me that day, I would be dead by now. Death might be better in this case. It took me a long time to get over that emptiness and despair. (Session 5, April 11th, 2020)\n\nL recalled the day she was most desperate, the day she attempted suicide, her father was able to intervene and tell L:\n\nWhen he dissuaded me from committing suicide, my father told me a philosophy of life. What makes me reflect and overcome the trauma later: [a] good person needs to learn all the time to know and correct himself. If you want to correct yourself, you must first keep your heart and mind for success, and then bring happiness to yourself and society. For the time being, please temporarily live away from family to observe and study the root of the problem, including your wishes. From there, train your own will, purify your soul from the pollution of CSA. Finally, correct your mistakes to be happy. (Session 7, May 9th, 2020)\n\nL’s father's words were from the Confucian philosophies. The training of will and knowledge is the way to help people overcome suffering. Her father’s teachings act as a resource to help L continue to live and explore this life. Her parents do not hate L but show their love skilfully. The parent separate L from the place that causes her suffering. Even so, they still protect L's brother to a certain extent. As for her brother, L cut off contact. Since then, L has always showed resistance and kept her distance from her brother, so he could not do anything to her:\n\nWhen describing how she overcame the fear, humiliation, torment, and pain caused by the SAT, L reports that she never forgets her father’ statement [a] and considers it as her life philosophy, helping herself to be motivated to learn and overcome her dark past. L said:\n\nEverything that happens in the world has a cause. The fact that I was taken advantage of by my brother, as well as the way my parents treated me, was for a reason. Recalling at the age of 17, a year after that terrible day, I’m a different person! I was able to make friends and continue my education. (Session 8. May 23rd, 2020)\n\nIt is not easy for a survivor to make it through the SAT and related past experiences on their own. The case of L is different. L recovered significantly in just one year. So, what happened during that period? L recalled and recounted that:\n\nI met my old homeroom teacher again. I told her about moving to another place. She was glad that I was no longer abused. She asked me what I plan to do and how to live in the future. This made me think a lot. I recall a lesson in secondary school. It was a famous short story from Vietnam in 1986, about the awakening of a son just because he was so focused on searching for faraway things that he forgot about the small and simple happy things next to him. I realized I was missing out on my friends in class. They always ask and encourage me. Why did I leave them and live a closed life? Am I being too selfish and indulging my feelings? I have to change! (Session 9, June 8th, 2020)\n\nThe influence of educational factors, mostly passive education (integrated across subjects, taught throughout lessons and different blocks in the educational program) had created a solid psychological foundation for L. Thanks to her father’s advice, combined with her reflection on life, L realized her resources and understood how to recover from the SAT.\n\nL did not deny that CSA was a traumatic event, and faced it step by step:\n\nIt was very painful. There are times when I want to give up. Those memories still appear, in waves, not as many and fast as before. Gradually, I realized that I had lived with the SAT for almost 10 years and that I was still alive. I acknowledge the existence of this pain in my life. I never forget, and I do not allow myself to forget. The perpetrator will have to pay the penalty. I learned this in Civic Education. I know more about the legal and social support of CSA. I will fight to free myself! (Session 17, September 14th, 2020)\n\nThus, one year after the end of the abuse, although the pain and trauma still affect her, L has learned to adapt and change herself to overcome that pain. L continued to reflect on her father’s words, her former homeroom teacher's questions, and what she learned in the educational program she went through. This was her coping strategy: The last year of high school, when the pressure of studying and exams hit, was also the time when L was enlightened with many philosophies to overcome the painful past and work towards a good future. L stated:\n\nI did not expect the pressure of college entrance exams to be the driving force pushing myself to overcome my SAT. (Session 11, July 7th, 2020)\n\nL has determined her academic goals and future, thereby overcoming the darkness of her past. For L, the memory of being abused becomes a driving force that makes her constantly learn and strive to improve herself, protect herself, and help those around her to change their perception of the CSA. The following quotes from L clearly describes how she overcame darkness and became enlightened:\n\nThe noble moral values of the Vietnamese people, as well as the practical value of life skills, give me the courage to overcome these bad things. (Session 12, July 21st, 2020)\n\nMy father's statement and my family's Confucian upbringing are the things that have influenced me to this day … Whoever you are, you will have these relationships and you have the things you need to do to achieve balance, or so-called neutrality. By the time my parents found out I was raped, my father taught me about the cycle of life. It is a lesson about self-nurture (lessons of being and relationships) in the lower part of Confucian philosophy. It took me three years to think, reflect, and learn about this lesson. (Session 12, July 21st, 2020)\n\nWhen we properly understand Confucianism and behave correctly with the core views on human life, social relationships, and neutrality, it will help us to have a better and broader understanding of the problems, thereby creating internal strength to overcome the SAT. (Session 12, July 21st, 2020)\n\nBy studying Confucian philosophy, L strengthened her beliefs in herself. This philosophical contemplation created a tremendous change in her resilience. With this, L has accepted her past and overcome the darkness of her life. She was enlightened and had gained valuable religious experiences. Besides, there is also the participation of education as passive, long-term support. All form a solid and enlightening spiritual resource, leading L to find her rights and her ego. Following high school, L's life was able to develop as she entered university. This was also the time when L realized her dreams and sublimated negative emotions into positive, meaningful experiences. L recounted how she felt on the first day she entered the university lecturing hall:\n\nIt was a great day at 18 when I was no longer a schoolgirl, but a student. This is the first step for me to achieve my goal of regaining equality for women in Confucian families with antiquated, outdated views. I want parents to properly understand the spirit of Confucianism and give equal love to both sons and daughters. At the same time, I want female survivors like me to be brave, to fight against prejudice to gain happiness. (Session 20, October 5th, 2020)\n\nAt this stage, when reiterating the issue of CSA as well as her SAT, L was able to share very comfortably. With L, those experiences are valuable life experiences and a driving force for her development. L never forgot, nor let it affect her negatively. L commented:\n\nIt is part of my life. I cannot deny it. The Confucian philosophy, especially the neutrality and unconditioned lifestyle, has guided me to the right, to the fight for the equal rights and safety of women and girls.\n\nInitially, I joined a non-governmental organization for the protection of children’s rights. During my studies, I will participate more in projects to protect children, as well as provide psychological support to victims of sexual abuse. I will help them overcome the SAT themselves. (Session 15, August 30th, 2020)\n\nL's academic and life goals went quite smoothly, she achieved what she set out to do and became an advocate and volunteer to provide mental support for sexually abused children in remote areas – an area that is still heavily prejudiced in Vietnam. The researcher met L again in the next interview session, where L shared that:\n\nStep into the university, I shine and spread positive existential values! I hope my story will be an inspiration or a living testimony to other survivors … (Session 23, October 26th, 2020)\n\nNow my brother has been held accountable for his behavior. He contracted STDs and lost the ability to have children. This is retribution, a proper punishment of Heaven for him. Truly to the Confucian philosophy of ‘What you sow, you reap what you reap!’... I am not happy, not sad, and not despise him … (Session 24, November 3rd, 2020)\n\nAfter a long time, I have continuously struggled and provided knowledge about CSA, corrected Confucian ideology and gender equality, my parents have changed their minds. They acknowledged the truth about my brother and expressed their regret for treating me unequally in the past. Everything happens for a reason! My father used to say so! (Session 24, November 3rd, 2020)\n\nIn the last conversation between the researcher and L, L shared a message that she wants to send to female survivors who are stuck, repressed, and resigned in Confucian prejudiced families:\n\nIf I use a symbol to describe my life, I will be a lotus. The lotus is the Vietnamese national flower, symbolizing purity, being close to the mud without the foul smell of mud. I used to live in the mud, in the painful darkness of the SAT. I was miserable, ugly, and despised myself. But I was enlightened, I shined and showed my beauty – a beautiful lotus rose in the dirty mud! I want to send a message to the other survivors: ‘Live like a lotus, beautiful and radiant in your way!’ (Session 25, November 10th, 2020)\n\n\nDiscussion\n\nL’s story provides insight into the journey of resilience of a Vietnamese Confucian female CSA survivor. L experienced the long-term effects of CSA that previous studies have reported: depression, suicide, low self-image, low self-esteem, social isolation, etc. (Hailes et al., 2019). She overcame the SAT to find spiritual balance, reintegrate into daily life and grow. Based on the findings, we propose a 7-stage diagram of the psychological progression of a Confucian woman's resilience after sexual abuse. In this section, we focus our analysis and discussion on the findings from L's story to explore the stages of SAT resiliency.\n\nIn L’s story, we discovered two factors influencing her resilience: the passive effect of the educational program, and Confucianism. These two factors create mental and spiritual resources that helped L to cope and gradually overcome the SAT.\n\nPrevious studies have confirmed that religion can be a support or impediment to the resilience of sexual abuse victims (Durà-Vilà et al., 2013; Murray-Swank & Pargament, 2005). Our findings correspond with this view. Confucianism was both a barrier and spiritual support to the survivors. In L's case, during the period of abuse, Confucian philosophy was a constraint on her equal rights. She did not have a voice and couldn’t denounce her abuser. Previous studies on mental trauma and the mental health of Vietnamese children and adolescents also provides good evidence for this outdated prejudice (Nguyen et al., 2016; Nguyen, 2018). Vu argues that only once the outdated stereotypes of Confucianism have been phased out of Vietnamese families and society, can women truly have freedom (Vu, 2009). We argue, however, that L's story demonstrates how when the neutrality in Confucian philosophical doctrine is properly understood, it can form a great spiritual resource to help overcome the SAT. The idea of neutrality was particularly significant for L: 'Whoever you are, you will have these relationships and you have the things you need to achieve balance' (Session 12, July 21st, 2020). When survivors maintain a neutral attitude toward the perpetrator and CSA-related issues by being non-judgmental, non-retaliatory, and accepting that the trauma that has happened in their life; they will be strengthened in will and inner strength. When a survivor’s will and inner strength is strong enough that they can live independently they can transform the SAT into value. This is also a philosophy within the lower part of Confucianism. In Confucianism, there is no need for formalities, religious rituals, prayers, or participation in religious activities to balance emotions, or talk and repent with God. It is paramount that you read, understand, and reflect on the teachings of Confucianism. To properly understand the authentic perception and successfully apply Confucian philosophy to life, one must learn the lower part first, then the upper part (O'Harrow, 2021). In the lower part, you have to learn from self-nurture (get to know yourself, isolate things to observe, find out the roots, train your will, get rid of sins, correct your mistakes, and find happiness), behave in accordance with the norms of the family and the country (appropriate social behavior) and with the world (contribute to society, find happiness in yourself and those around you). L had studied the Confucian doctrine from the beginning to enlighten and better understand the philosophy, as a foundation to overcoming SAT.\n\nIn terms of the impact of education, Tho (2016) states that Vietnamese education is heavily influenced by Confucianism. Confucianism attaches great importance to learning and considers it to be the foundation of human development in society. According to Yao and Yao (2000), in Confucianism, the five minimum moral qualities of a person are Benevolence (loving others), Propriety (showing respect and order in words and deeds), Righteousness (behaving morally), Wisdom (showing understanding and good judgement), and Trustworthiness (being reliable and honest). These are still the leading educational maxims in Vietnam, especially in moral education (self-nurture) and students’ comprehensive personality development. The five basic qualities of Confucianism, and other valuable aspects derived from Vietnamese traditions are considered indispensable content in moral education and are integrated into all school subjects. Thus, with foundations in Confucian doctrine, the Vietnamese curriculum equips students with solid spiritual roots and moral values as resources for them to cope effectively with adversity. In L’s story, it is impossible not to consider her participation in the preventive educational program on life skills, especially the CSA prevention skills that have been promoted in Vietnam since the 2015-2016 academic year (Nguyen, 2018). CSA prevention skills that have been deployed in educational activities for Vietnamese students include: safe and unsafe touches, privacy protection, supportive relationships, safe social media usage, safe dating, and refusal skills (Nguyen, 2018; Linh, 2021; Tran, 2020). These are also the skills that L had learned since the 9th grade. Along with the skills education, the subject of Civic Education and Literature equipped L with core beliefs and values. In Civic Education, L was taught the five moral values (of Confucianism), but also equipped with legal knowledge on women’s and children’s rights. This knowledge system has similarities with Confucian doctrine when it comes to moral cultivation, law enforcement and social stabilization. Because of her interest in Confucianism, L instilled these values. In Literature, L was taught to love herself in the past, present and future. The life values that this subject brings to L are love, tolerance and forgiveness. L forgives her past, her brother’s crime, and resolves to live a fulfilling life. The comprehensive prevention skills, and education on moral values underpinning human potential, particularly the five basic qualities of Confucianism, have supported the formation of positive mental resources and supported abused victims to overcome SAT through the concept of neutrality.\n\nThe findings show that L's resiliency journey had stages, with the learning and improvement of life values learned in school and an authentic understanding of Confucian philosophy through different timelines. Her story started with curiosity around sex; to guilt and self-loathing; then acceptance and seeking out resources; finally, contemplation, enlightenment, and overcoming pain. In terms of long-term effects, L experienced torment, loss of faith in herself and her family, social isolation, depression, and even attempted suicide. This SAT experience, as well as expressions of long-term effects, is quite similar to that of survivors in other cultures (Hailes et al., 2019). According to Durà-Vilà et al. (2013), the psychological process that abused victims, specifically Catholic nuns go through to achieve recovery includes 8 stages: (1) Shock and distress; (2) Self-doubt; (3) Anger and mistrust; (4) Withdrawal and mediation; (5) Secrecy or disclosure; (6) Community acceptance; (7) Spiritual integration; (8) Posttraumatic growth. The nuns’ understanding of their abuse in the light of their religious beliefs enabled the trauma to be transformed into a potential catalyst for growth. Therefore, considering religious and spiritual aspects when supporting religious people with SAT may allow religious narratives that incorporate the trauma to unfold. It is important for the believers to have an authentic perception of the religious philosophy and how to apply these philosophies in daily life.\n\nThroughout her story, L discusses self-nurture and neutrality - two core principles of Confucian philosophy that any believer must understand and live by. These are also two factors that motivated L to learn about her trauma and overcome it. Initially, she could not accept the fact, but her interest in the authentic perception in Confucian philosophy prompted her to search for explanations. L learned how to analyse problems neutrally and applied this to her SAT. She was successful in transforming her crisis into a motivation for learning and was able to practice self-nurture with the core philosophical values of Confucianism. Some contents of the current Vietnamese educational program still maintain the Confucian philosophy, taking the cultivation of qualities as the main focus in the development of student's personality. This is an inheritance of Confucian philosophy in education and has created a powerful inner resource to help L overcome her SAT. L was able to turn SAT into a resource for her self-development, so that she could serve the community and help prevent future cases like hers.\n\nFrom L’s story, we have proposed a model of SAT resiliency detailed in seven stages (see Figure 1).\n\n\nConclusion\n\nL’s narrative highlights the importance of early prevention of CSA through educational programs, as well as using religious-spiritual factors as a resource rather than a perpetuation of the problem. The passive effect of the educational curriculum and the authentic perception of Confucian doctrine are the two factors helped L overcame the SAT. It is the core values of Confucianism - nurture and the neutrality - that have changed L's perception of CSA and SAT in a positive light. L's resiliency journey went through seven stages with different psychological developments, starting with suffering and depression, through the process of contemplation and understanding of the Confucian philosophy of life to move on to dedication and happiness. This resiliency journey reflects the Confucian point of view of education and human development: Self-nurture. Clinicians or mental health counselors working with religious trauma victims, especially Confucian victims, should be mindful of the importance of considering their spiritual beliefs and their acknowledgment of the Confucian philosophy. It is necessary and highly feasible to help this group of clients understand the authentic perception of Confucianism, as well as elicit hidden values passively created from the educational program.\n\nHowever, this study has some limitations. Although in the case presented here, L’s religious beliefs seems to have had a positive impact on her well-being, it would be naıve to think that this is always the case. Confucian beliefs can be a source of meaning and resilience but also have the potential to be damaging and present barriers to women’s equality. Clinicians and mental health counselors need to be alert to maladaptive cognitions and coping reactions in traumatized religious patients. With these findings, we have only approached it from the perspective of a typical case in Vietnam, and more descriptive studies as well as large-scale interviews are needed to fully understand Confucian CSA. In addition, as part of our long-term study on CSA, these results are of great significance in preparing an experimental model according to the stages of SAT resilience in a Confucian woman. This is the basis for us to continue studying this research question using an ethnographic approach on CSA and SAT in Confucian survivors. Accordingly, the study supports the notion that greater attention needs to be paid to religiosity in the lives of adults who have been sexually abused as children.\n\n\nData availability\n\nFigshare: The resiliency journey of a Vietnamese female sexual abuse survivor: An exploration in life history. https://doi.org/10.6084/m9.figshare.15390255.v3 (Giang, 2021).\n\nThis project contains the following underlying data:\n\n‐ Anonymised transcripts (in English)\n\nThis project contains the following extended data:\n\n‐ Interview guide (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).",
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Publisher Full Text\n\nTran MH: Mo hinh phoi hop lien nganh trong Giao duc Phong, Chong xam hai Tinh duc the em [Model of interdisciplinary cooperation in child sexual abuse prevention education]. People’s Police Academy;2020.\n\nVu K: Về giá trị đương đại của Nho giáo Việt Nam [On contemporary values of Vietnamese Confucianism]. Philosophy. 2009; 8(219): 37–40.\n\nVuong QH, Bui QK, La VP, et al.: Cultural additivity: behavioural insights from the interaction of Confucianism, Buddhism and Taoism in folktales. Palgrave Communications. 2018; 4(1): 1–15. Publisher Full Text\n\nYao X, Yao HC: An introduction to Confucianism. Cambridge University Press;2000. Publisher Full Text\n\nYan KSW: How childhood sexual abuse impacts a fundamental Christian woman's perception of God: An integration of self psychology and Christianity. California School of Professional Psychology-San Diego;2001."
}
|
[
{
"id": "97618",
"date": "28 Oct 2021",
"name": "Anthony F. Santoro",
"expertise": [
"Reviewer Expertise Early life adversity",
"clinical psychology",
"neurocognitive functioning",
"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\nThis case report presents data from a series of interviews with a Vietnamese Confucian woman with a history of child sexual abuse (CSA). This manuscript has several strengths, including its emphasis on the importance of socio-cultural and religious factors in the context of the long-term effects of CSA, as well as its appreciation of religion/spirituality as a potential source of support and coping resource for individuals who experienced CSA. Considering that much of the related research has focused on Judeo-Christian samples, research is warranted exploring associations between religious/spiritual beliefs and CSA among people from other faith systems (e.g., Confucian faiths). The presented participant’s understanding of her process of healing from CSA through her identity as a Vietnamese Confucian woman makes for an interesting read. That said, although this case’s story is inspiring, it is unclear how the findings are relevant to the field’s understanding of disease processes, diagnosis, or treatment. Of note, the case presented is not of a patient and does not focus on the case’s treatment. The case report does not include information regarding any physical examinations, diagnostic tests, treatment, or related outcomes, and additional details related to family and personal background are needed for the reader to contextualize findings. The manuscript would benefit from more clearly stating: (1) the rationale for presenting this participant’s story as a case report; (2) how this case report is relevant to the field’s understanding of disease processes, diagnoses, or treatment; and (3) the importance of findings and how other practitioners might find this case useful. The manuscript also makes a few statements that seem beyond what can be supported by the data and level of evidence, making this reviewer have reservations about recommending this manuscript for approval in its present form. Detailed comments and suggestions are listed below:\nThis reviewer recommends greater care in referring to evidence-based practice. For instance, the manuscript writes, “findings provide important evidence-based practice for counselors and clinicians” (Giang et al., 2021, p. 3). This statement is beyond the scope of a case report and not supported by the data presented. Please see Bolton (2001)1 and Reid et al. (2017)2 for related definitions.\n\nThe manuscript’s emphasis on the pervasiveness of CSA across nationalities and cultures seems to contrast with specifying CSA as a “crime” (Giang et al., 2021, p. 2), considering laws and legal considerations vary regionally and across jurisdictions. Considering the manuscript’s focus on CSA as a traumatic experience, and not the criminality of CSA, the provided definition should reflect this focus.\n\nThe introduction would benefit from additional details, with supporting citations, on the long-term mental health consequences of CSA.\n\nThe manuscript would benefit from providing a definition of sexual abuse trauma (SAT) and explaining how this differs from CSA. These terms are used interchangeably throughout the manuscript, and this can be confusing to the reader. This reviewer recommends using one term consistently throughout the manuscript to benefit the reader. Considering the manuscript’s focus’ on CSA, it might be clearer to the reader if the manuscript focused solely on CSA.\n\nThe manuscript would benefit from clarifying what is meant by “the current situation surrounding CSA” (Giang et al., 2021, p. 3). Does this refer to the experiences of CSA? The contexts in which CSA occurs? The immediate, as opposed to long-term, consequences of CSA?\n\nThe manuscript’s consideration of socio-cultural and religious contexts regarding the effects of CSA is much appreciated and a strength of the manuscript. The introduction may benefit from briefly discussing and referencing previous studies that have found differences across specific socio-cultural or religious groups regarding the impact of CSA and other early life trauma. Please see: Arredondo and Caparrós (2019)3; McCormick et al. (2017)4; Santoro et al. (2016)5.\n\nThe manuscript would benefit from describing what is meant by “self-resilience” (Giang et al., 2021, p. 3) and explaining how this differs from general resilience.\n\nThe manuscript would benefit from clarifying what is meant by, “Clinical studies on resilience in people who have been sexually abused are still highly subjective” (Giang et al., 2021, p. 3). This statement appears to overlook the empirical studies that have examined resilience among persons who experience sexual abuse (e.g., Wilcox, Richards, & O’Keeffe, 20046; Williams & Nelson-Gardell, 20127).\n\nThe phrase “manipulations of counseling” (Giang et al., 2021, p. 3) is unclear and comes across as strong language. Using “manipulations” suggests negative connotations. Perhaps this sentence can be re-written to improve clarity and use more tempered language.\n\nThe manuscript states, “there has been no longitudinal study addressing the long-term effects of CSA” (Giang et al., 2021, p. 3). This statement is not factual; please see Wilson and Widom (2008)8; Fergusson, McLeod, and Horwood (2013)9.\n\nThe introduction emphasizes the importance of longitudinal studies examining the long-term effects of CSA. Although this assertion seems appropriate, it is unclear how this strengthens the rationale for the current case study.\n\nThe manuscript would benefit from avoiding generalizing presented findings to all women. This case is unlikely to represent the larger population of Vietnamese Confucian women; the manuscript would benefit from removing statements about the larger population.\n\nThe first paragraph in the section named “The long-term effects of sexual abuse and mental support” (Giang et al., 2021, p. 4) would benefit from including additional supporting citations.\n\nThe manuscript’s mention of both the potential positive and negative influence of religion/spirituality in the context of CSA is important. However, the introduction focuses on the positive aspects of religion/spirituality, with limited attention to potential negative influences. The manuscript would benefit from also briefly mentioning how CSA may negatively impact a person’s religiosity/spirituality and may result in religious/spiritual struggles. Please see Burg, Mayers, and Miller (2011)10.\n\nIt is unclear what the term “incomplete families” (Giang et al., 2021, p. 4) means. Clarification is needed. Likewise, this reviewer recommends considering using more sensitive language.\n\nThe following sentence in the introduction requires supporting citations: “it can be seen that the Confucian perspective is associated with the long-term effects of CSA as well as the resilience of this group of victims” (Giang et al., 2021, p. 4).\n\nThis reviewer appreciates the manuscript’s inclusion of the reflexivity section.\n\nTo remain respectful of the participant’s confidentiality and better protect anonymity, the details identifying the participant’s attended university should be removed. Simply stating that the participant is a university student is sufficient.\n\nPlease clarify the term “time-lapse narrative interviews” (Giang et al., 2021, p. 5).\n\nHow was the second inclusion criterion, “2. Must be currently undergoing recovery” (Giang et al., 2021, p. 5), determined?\n\nAdditional details regarding the case’s background would be beneficial, specifically, details related to the family structure and dynamics, social and school functioning, any significant medical history, personality attributes, etc. Further information about the level of adult supervision and the frequency in which she was left alone with her brother would be helpful. Additional details about how she disclosed the abuse to her parents and how her parents reacted to this disclosure seem appropriate. Further information describing the progression and frequency of the abuse are needed. Additional details about the circumstances that prompted disclosing the abuse to her teacher, how she disclosed the abuse to her teacher, and how her teacher reacted to this disclosure seem important. How soon after the sexual assault was her suicide attempt?\n\nAdditional methodological details are needed. How often did interviews occur? How long did interviews last? How were the data analyzed? What were the steps taken to process and analyze the data? Was a set of thematic codes developed and applied to interviews? How were disputes between the three researchers who analyzed the interview data resolved?\n\nThe participant’s father’s words to her seem like he is blaming her for the abuse. In tandem with being sent to live with her aunt, it reads like she was punished for the abuse. Did the participant report such feelings? If so, how were they resolved?\n\nFrom the presented quotes, it seems like the participant’s source of support came from her interpersonal relationships (e.g., her teacher, making new friends) and academic engagement (e.g., focusing on entrance exams). More clarity is needed regarding how her religious beliefs and personal spirituality supported her coping.\n\nThe participant alludes to experiencing intrusive thoughts (e.g., memories entering her mind). Did she experience other symptoms of post-traumatic stress? Did these symptoms impact her social or academic functioning?\n\nThe manuscript notes, “all form a solid and enlightening spiritual resource, leading L to find her rights and her ego” (Giang et al., 2021, p. 10). The term “ego” has theoretical connotations linked to psychodynamic theory and should be avoided here. Replacing the term “ego” with another word (e.g., confidence, self-esteem, self-worth) is recommended.\n\nAddition clarification is needed regarding how her understanding of Confucian philosophies evolved through processing her trauma.\n\nIt seems like the participant’s beliefs were reinforced by external events, such as her brother contracting a sexually transmitted infection and losing his ability to have children – essentially being punished. How did her healing journey reinforce her religious beliefs?\n\nThe description of the core tenets of Confucian philosophies in the discussion is informative, and this should be presented earlier in the manuscript.\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? 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? No",
"responses": [
{
"c_id": "7400",
"date": "11 Nov 2021",
"name": "VŨ GIANG",
"role": "Author Response",
"response": "On behalf of the authors, I would like to thank you for your precious review. Based on your suggestions, we have adjusted the article to better fit a reported case, as well as further clarify the view of the findings of this article in support of Clinicians have a new approach to intervene for CSA victims. Specifically: 1. This reviewer recommends greater care in referring to evidence-based practice. For instance, the manuscript writes, “findings provide important evidence-based practice for counselors and clinicians” (Giang et al., 2021, p. 3). This statement is beyond the scope of a case report and not supported by the data presented. Response: I have corrected the statement into the scope of a case report. The findings can be referenced as a new approach in counseling for CSA survivors with different religion. 2. The manuscript’s emphasis on the pervasiveness of CSA across nationalities and cultures seems to contrast with specifying CSA as a “crime” (Giang et al., 2021, p. 2), considering laws and legal considerations vary regionally and across jurisdictions. Considering the manuscript’s focus on CSA as a traumatic experience, and not the criminality of CSA, the provided definition should reflect this focus. Response: I have corrected the manuscript to focus on the CSA as a traumatic experience. 3. The introduction would benefit from additional details, with supporting citations, on the long-term mental health consequences of CSA. Response: I have supported more citations on the term mental health consequences of CSA. 4. The manuscript would benefit from providing a definition of sexual abuse trauma (SAT) and explaining how this differs from CSA. These terms are used interchangeably throughout the manuscript, and this can be confusing to the reader. This reviewer recommends using one term consistently throughout the manuscript to benefit the reader. Considering the manuscript’s focus’ on CSA, it might be clearer to the reader if the manuscript focused solely on CSA. Response: I have edited the manuscript to focus only on the CSA. 5. The manuscript would benefit from clarifying what is meant by “the current situation surrounding CSA” (Giang et al., 2021, p. 3). Does this refer to the experiences of CSA? The contexts in which CSA occurs? The immediate, as opposed to long-term, consequences of CSA? Response: I have edited this meaning into ‘studies on the CSA’s traumatic experience and causes’. 6. The manuscript’s consideration of socio-cultural and religious contexts regarding the effects of CSA is much appreciated and a strength of the manuscript. The introduction may benefit from briefly discussing and referencing previous studies that have found differences across specific socio-cultural or religious groups regarding the impact of CSA and other early life trauma. Response: I have added and reviewed more studies in the impact of socio-culture or religion to CSA. 7. The manuscript would benefit from describing what is meant by “self-resilience” (Giang et al., 2021, p. 3) and explaining how this differs from general resilience. Response: I have corrected the mistaken word ‘self-resilience’ into ‘resilience’ with the clear definition. 8. The manuscript would benefit from clarifying what is meant by, “Clinical studies on resilience in people who have been sexually abused are still highly subjective” (Giang et al., 2021, p. 3). This statement appears to overlook the empirical studies that have examined resilience among persons who experience sexual abuse. Response: I have corrected the idea with the new citation from the studies of resilience in CSA survivors. 9. The phrase “manipulations of counseling” (Giang et al., 2021, p. 3) is unclear and comes across as strong language. Using “manipulations” suggests negative connotations. Perhaps this sentence can be re-written to improve clarity and use more tempered language. Response: I have corrected the idea into ‘practicing counseling, psychotherapy’. 10. The manuscript states, “there has been no longitudinal study addressing the long-term effects of CSA” (Giang et al., 2021, p. 3). This statement is not factual. Response: I meant the Vietnamese studies. I have corrected the statement according to the Vietnamese context. 11. The introduction emphasizes the importance of longitudinal studies examining the long-term effects of CSA. Although this assertion seems appropriate, it is unclear how this strengthens the rationale for the current case study. Response: We have limited the scope of study into conducting a case study to understand the psychological transformation of Vietnamese CSA survivors for providing practical clinical evidence focusing on the post-intervention. 12. The manuscript would benefit from avoiding generalizing presented findings to all women. This case is unlikely to represent the larger population of Vietnamese Confucian women; the manuscript would benefit from removing statements about the larger population. Response: I have removed the statements about the larger population, especially ‘women’ into ‘woman’. 13. The first paragraph in the section named “The long-term effects of sexual abuse and mental support” (Giang et al., 2021, p. 4) would benefit from including additional supporting citations. Response: I have included more citations from previous studies in long-term effects of CSA. 14. The manuscript’s mention of both the potential positive and negative influence of religion/spirituality in the context of CSA is important. However, the introduction focuses on the positive aspects of religion/spirituality, with limited attention to potential negative influences. The manuscript would benefit from also briefly mentioning how CSA may negatively impact a person’s religiosity/spirituality and may result in religious/spiritual struggles. Response: I have briefly mentioned the negative impact of religiosity/spirituality to the CSA trauma of survivors. 15. It is unclear what the term “incomplete families” (Giang et al., 2021, p. 4) means. Clarification is needed. Likewise, this reviewer recommends considering using more sensitive language. Response: I have adjusted the term ‘incomplete families’ into ‘broken families’. 16. The following sentence in the introduction requires supporting citations: “it can be seen that the Confucian perspective is associated with the long-term effects of CSA as well as the resilience of this group of victims” (Giang et al., 2021, p. 4). Response: I have added the supporting citation to this sentence in the manuscript. 17. To remain respectful of the participant’s confidentiality and better protect anonymity, the details identifying the participant’s attended university should be removed. Simply stating that the participant is a university student is sufficient. Response: I have re-stated that the participant is a university student. 18. Please clarify the term “time-lapse narrative interviews” (Giang et al., 2021, p. 5). Response: I have clarified the three key elements of narrative theorizing when processing the time-lapse narrative interviews. 19. How was the second inclusion criterion, “2. Must be currently undergoing recovery” (Giang et al., 2021, p. 5), determined? Response: I have added the information, ‘2. Must be currently undergoing recovery (Self-assessed and double-checked by the researchers)’. 20. Additional details regarding the case’s background would be beneficial, specifically, details related to the family structure and dynamics, social and school functioning, any significant medical history, personality attributes, etc. Further information about the level of adult supervision and the frequency in which she was left alone with her brother would be helpful. Additional details about how she disclosed the abuse to her parents and how her parents reacted to this disclosure seem appropriate. Further information describing the progression and frequency of the abuse are needed. Additional details about the circumstances that prompted disclosing the abuse to her teacher, how she disclosed the abuse to her teacher, and how her teacher reacted to this disclosure seem important. How soon after the sexual assault was her suicide attempt? Response: I have corrected and adjusted the additional information of the participant which included: the participant’s background (family structure and dynamics, social and school functioning, any significant medical history, personality attributes) and further information (the level of adult supervision and the frequency, her parents’ disclosure, the progression and frequency of the abuse, the circumstances that prompted disclosing the abuse to her teacher, the time she attempt to suicide after the sexual assault). 21. Additional methodological details are needed. How often did interviews occur? How long did interviews last? How were the data analyzed? What were the steps taken to process and analyze the data? Was a set of thematic codes developed and applied to interviews? How were disputes between the three researchers who analyzed the interview data resolved? Response: I have added more additional methodological details based on your suggestions in the manuscript in the Data collection and analysis section. 22. The participant’s father’s words to her seem like he is blaming her for the abuse. In tandem with being sent to live with her aunt, it reads like she was punished for the abuse. Did the participant report such feelings? If so, how were they resolved? Response: I have adjusted the sentence to be more clear. Her father had no intention of blaming her. He wanted her to think hard about suicide, is it the best solution? This is a view in Confucian philosophy of neutrality. 23. From the presented quotes, it seems like the participant’s source of support came from her interpersonal relationships (e.g., her teacher, making new friends) and academic engagement (e.g., focusing on entrance exams). More clarity is needed regarding how her religious beliefs and personal spirituality supported her coping. Response: I have adjusted the sentence to be more clear. The influence of Confucian philosophical educational factors, mostly passive education (integrated across subjects, taught throughout lessons and different blocks in the educational program) had created a solid psychological foundation for the participant to explore clearer the Confucian philosophy. Thanks to her father’s advice, her interpersonal relationships (her teacher and new friends), combined with her reflection on life, she realized her resources and understood how to recover from the CSA: Self-nurture, the lessons of being and relationship. 24. The participant alludes to experiencing intrusive thoughts (e.g., memories entering her mind). Did she experience other symptoms of post-traumatic stress? Did these symptoms impact her social or academic functioning? Response: I have adjusted the sentence to be more clear, ‘The appearance of intrusive memories and panic attacks sometimes recurred during the first year. L took care of herself by learning to adapt and change herself to overcome that pain. This was a great effort in her self-nurture journey because at this time, psychotherapy services in Vietnam were not popular.’ 25. The manuscript notes, “all form a solid and enlightening spiritual resource, leading L to find her rights and her ego” (Giang et al., 2021, p. 10). The term “ego” has theoretical connotations linked to psychodynamic theory and should be avoided here. Replacing the term “ego” with another word (e.g., confidence, self-esteem, self-worth) is recommended. Response: Thank you for your recommendation. I have replaced the term ‘ego’ with ‘self-esteem’. 26. Addition clarification is needed regarding how her understanding of Confucian philosophies evolved through processing her trauma. Response: I have adjusted the sentences in the Findings section to clarify the impact of Confucian philosophy evolved through the CSA trauma’s resilience. You can read it again in the manuscript. 27. It seems like the participant’s beliefs were reinforced by external events, such as her brother contracting a sexually transmitted infection and losing his ability to have children – essentially being punished. How did her healing journey reinforce her religious beliefs? Response: I have added a paragraph to clarify this issue in the end of the Findings section. It concerns the nature of Confucian philosophy and the processes of human development and self-learning after attaining the self-nurture. 28. The description of the core tenets of Confucian philosophies in the discussion is informative, and this should be presented earlier in the manuscript. Response: Thanks for your comment. I have adapted and used important information on Confucian philosophy in the section ‘The long-term effects of sexual abuse and mental support’."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1071
|
https://f1000research.com/articles/9-364/v1
|
14 May 20
|
{
"type": "Brief Report",
"title": "Health technology assessment capacity at national level in sub-Saharan Africa: an initial survey of stakeholders",
"authors": [
"Samantha A. Hollingworth",
"Francis Ruiz",
"Mohamed Gad",
"Kalipso Chalkidou",
"Francis Ruiz",
"Mohamed Gad",
"Kalipso Chalkidou"
],
"abstract": "Background: Health technology assessment (HTA) is an effective tool to support priority setting (PS) in health. Stakeholder groups need to understand HTA appropriate to their role and to interpret and critique the evidence produced. We aimed to rapidly assess current health system priorities and policy areas of demand for HTA in Sub-Saharan Africa, and identify key gaps in data and skills to inform targeted capacity building. Methods: We revised an existing survey, delivered it to 357 participants, then analysed responses and explored key themes. Results: There were 51 respondents (14%) across 14 countries. HTA was considered an important and valuable PS tool with a key role in the design of health benefits packages, clinical guideline development, and service improvement. Medicines were identified as a technology type that would especially benefit from the application of HTA. Using HTA to address safety issues (e.g. low-quality medicines) and value for money concerns was particularly highlighted. The perceived availability and accessibility of suitable local data to support HTA varied widely but was mostly considered inadequate and limited. Respondents also noted a need for training support in research methodology and data gathering. Conclusions: While important in raising awareness of HTA as a tool for PS, this study had a low response rate, and that respondents were self-selected. A more refined survey will be developed to support engagement strategies and capacity building.",
"keywords": [
"Health technology assessment",
"Sub-Saharan Africa",
"survey",
"capacity building"
],
"content": "Introduction\n\nMany countries have committed to universal health coverage (UHC) in the context of the sustainable development goals1 for affordable access to essential medicines and other health technologies. Many countries in sub-Saharan Africa (SSA) have established national health insurance systems (or are planning to)2 but they require governments to set health priorities within fiscal limits3.\n\nHealth technology assessment (HTA) provides a structured approach to synthesising evidence of clinical and cost effectiveness to inform priority-setting activities. Institutionalised HTA systems involve active participation from a range of stakeholders4 including (government) decision makers, clinicians, academics, consumers, development partners, and HTA knowledge brokers5. The International Decision Support Initiative (iDSI) is a global network of health, policy and economic expertise, which seeks to support countries make better decisions about efficient spending on healthcare. iDSI has been working in SSA since 2013 to develop local capacity and support implementation of robust HTA processes6,7. There is growing interest across the continent but the current HTA landscape is fragmented and undocumented. We aimed to assess the current health system priorities and policy areas that need HTA, the demand for HTA, and the supply of HTA efforts to identify gaps in data and skills.\n\n\nMethods\n\nWe used an existing framework to examine the need, demand, and supply of HTA in an anonymous survey comprising 12 questions8. We used an online survey tool with purposive sampling; participants were contacted by email from the membership lists of the iDSI network and the African Health Economics and Policy Association (AfHEA). The survey was opened in June 2018. There were no inclusion or exclusion criteria regarding the participants. We analysed scale and ranking questions as the mean, and thematically analysed responses to open questions using an inductive approach9.\n\nThis survey was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008. All participants acknowledged written consent by starting the survey (as noted in the survey information section). No survey respondents can be identified in this paper as data has been aggregated. We do not have access to respondent’s details – data is fully anonymized. Respondents could leave the survey at any time. We used a scientific society distribution list to send emails to participants but we did not have access to the list.\n\n\nResults\n\nOf the 357 recipients, 14% responded with 30 fully completing the survey. Half were from a research institute or university, or from within the Ministry of Health (27%). Respondents were from 14 countries but many were from Ghana (40%). The individual-level results are available as Underlying data9.\n\nIn relation to the importance of particular attributes of HTA, respondents highlighted (mean rating out of 10): allocative efficiency (8.9), improving the quality of health care (8.8), transparency in decision making (8.4), budget control (8.0), and equity (7.9). They ranked the six main policy areas for which HTA was considered as urgently needed: 1) informing the design of the basic health benefits package (HBP); 2) producing clinical guidelines or disease management pathways; 3) informing the design of health service delivery; 4) coverage or reimbursement of individual health technologies; 5) provider payment or pay for performance schemes; and 6) registration of health technologies. A key consideration in HBP design was identifying services and technologies that should be covered but in a way that is financially sustainable.\n\nMedicines were considered the most important technology type that would benefit from HTA approaches, followed by vaccines, public health programs, medical devices and diagnostics, service delivery initiatives or incentives, screening or referral programs, and other (e.g. surgical) interventions. Medicines were prioritised because of their relatively large budget impact and their use for many high-burden diseases. Improving the availability and management of vaccines would help to reduce the burden from communicable diseases.\n\nRespondents emphasised three key decision problem areas that could be informed by HTA: health system financing; burden of disease considerations; and health service provision. Challenges in financing included inefficient financing structures (funding schemes and management); lack of funds; sustainability of national insurance; and the costs of medicines. In terms of burden of disease, respondents concerns included antibiotic resistance, and the impact of a growing dual burden of disease (communicable and non-communicable).\n\nThe respondents identified a need for research in: 1) health system financing (financing schemes, medicine pricing, and the design of sustainable essential benefits packages); 2) health service provision taking into account equity, efficiency, quality; 3) burden of disease (antibiotic medicine resistance, non-communicable disease, childhood immunisation); and 4) health policy research.\n\nThe respondents provided information on who they considered to be the key users of HTA information and the types of HTA evidence most useful for decision making. The users were identified as: ministries of health; other government departments; public health insurance bodies; providers and health professionals; universities and research institutes; donor organisations; and pharmaceutical companies. The evidence considered most useful was: safety; economic issues; information on technology effectiveness; and accounting for social/ethical concerns. The safety concerns were explicitly linked to the availability and use of generic medicines where quality could not be guaranteed. The economics issues related to the tension between growing claims on, but limited availability of, health resources.\n\nAll respondents were associated with organisations that generated or facilitated health services research. Research institutes highlighted their ability to provide expertise and skills for HTA research but some respondents noted a lack of human capacity for HTA. Political support was regarded as essential but could be impeded by politicised decision-making, internal politics in the leadership of the HTA process, cultural barriers in data and information sharing, and lack of funding for HTA activities.\n\nThe availability and accessibility of local data varied; generally, medicine prices were available but the costs of health services were neither easily known nor available. There are often data on the burden of disease but its application may be limited due to incomplete or unreliable documentation10. The organisations which either generate or supply evidence mostly included government agencies, university and affiliated research institutes and donors plus development partners.\n\nRespondents were asked to consider issues related to the wider ‘HTA infrastructure’ including the availability of existing process and methods manuals, or processes for involving the public in decision making. Respondents focused on the role of the public and civil society, and three themes emerged: 1) the extent of public involvement in consultation processes; 2) the role of advocacy; and 3) the absence of any public role in priority-setting decisions. Many respondents stressed the importance of consulting the public, but noted that in practice there was no involvement. Some respondents posited that such groups adopt an advocacy role by holding decision makers accountable, and creating pressure through media campaigns and other means to highlight dysfunctions in the health system.\n\nFour main areas of training needs for HTA generators and users were identified: 1) research methods in HTA and data gathering (and economic evaluations); 2) identifying and implementing evidence and using it to inform policy; 3) conducting economic evaluations; and 4) developing capacity and building awareness. Some respondents noted that both HTA generators and health policy-makers and practitioners need training in HTA to facilitate the reliable and efficient interpretation and use of research results, translation into policy, and advocacy.\n\n\nDiscussion\n\nHTA was considered an important and valuable priority-setting tool with a key role in HBP design, clinical guideline development, and service improvement. Medicines and vaccines were the health technologies that would most benefit from HTA. The perceived availability and accessibility of suitable local data varied but was broadly considered inadequate and limited. There was a strong need for training support in research methodology and data gathering for HTA evidence.\n\nThis is, as far as the authors are aware, the first systematic survey of the HTA landscape in SSA. It is a preliminary survey; we will refine in future iterations. It appears that some questions were not entirely understood; this may have contributed to the low response rate. Despite this, we elicited in-depth responses from many respondents. They responded as individuals and so their views may not reflect those of particular agencies or governments.\n\nOur results largely align with the WHO Global Survey on Health Technology Assessment by National Authorities11 with regards to capacity needs, especially in the African region. The main barriers were a lack of qualified human resources, funding, and information11. The interest in HTA as a priority-setting tool in the context of UHC is evident in the Asian region where HTA is more established than in SSA but there are ongoing challenges in the inconsistent use of HTA as means of updating benefits packages, concerns over transparency, and barriers related to data sharing12.\n\nThe interest in using HTA to support priority-setting decisions for medicines and vaccines is welcome as these represent a high proportion of healthcare expenditure. Access to such technologies, particularly in the poorest countries, has been facilitated by international development partners but as the national income of aid-recipient countries increases, so do co-financing obligations. At some point countries will ‘graduate’ from aid – they will need mechanisms to effectively manage healthcare resources. Ghana has begun its journey to reduce reliance on donor assistance for health7,13.\n\nAlthough HTA remains relatively under-developed in SSA, there is growing political commitment and policy interest14,15. Priority setting is inevitable: the question is not whether, but rather how, to set them. The HTA challenges outlined here could be mitigated by building HTA systems through pooling resources across countries and harmonising policies in health (e.g. medicines regulatory harmonisation, upstream of HTA16,17). The benefits of such harmonisation can be further enhanced through coordinated action on HTA policies which will help secure innovation uptake subsequent to regulation, at value-based prices reflecting local conditions.\n\n\nData availability\n\nUQ eSpace: iDSI HTA survey SSA Data sharing. https://doi.org/10.14264/uql.2020.1789.\n\nFile ‘iDSI_HTA_survey_SSA_Data_sharing.csv’ contains individual-level responses from each survey respondent.\n\nData are available under the terms of the UQ Terms & Conditions: Permitted Re-Use with Acknowledgement.",
"appendix": "Acknowledgements\n\nWe would like to thank Alex Winch, Jessica Fraser, Suyai Ehlers & Y Ling Chi from Imperial College London and Grace Njeri and Tommy Wilkinson from AfHEA.\n\nA preliminary version of this work was presented at two events.\n\n1. Conference: Hollingworth SA, Fraser J, Gad M, Ruiz F & Chalkidou K (2019) Health technology Assessment: survey in Sub Saharan Africa. African Health Economics and Policy Association 5th Biennial Conference 11–14 March 2019; Accra, Ghana.\n\n2. Invited Global Meeting (Ref 6): Hollingworth SA, Gad M, Ruiz F & Chalkidou K (2018) Health Technology Assessment: state of play in Sub-Saharan Africa. iDSI + HTAi Setting Prioprities Fairly Sustainable Policies for Effective Resource Allocation. 26 September 2018; Accra, Ghana.\n\nThis work was produced as part of the International Decision Support Initiative (www.idsihealth.org), a global initiative to support countries to get the most from every dollar they spend on health.\n\n\nReferences\n\nWorld Health Organization: SDG 3: Ensure healthy lives and promote wellbeing for all at all ages. 2019. (Accessed 11 November 2019). Reference Source\n\nKusi A, Hansen KS, Asante FA, et al.: Does the National Health Insurance Scheme provide financial protection to households in Ghana? BMC Health Serv Res. 2015; 15: 331. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGlassman A, Chalkidou K, Giedion U, et al.: Priority-setting institutions in health: recommendations from a center for global development working group. Glob Heart. 2012; 7(1): 13–34. PubMed Abstract | Publisher Full Text\n\nLi R, Ruiz F, Culyer AJ, et al.: Evidence-informed capacity building for setting health priorities in low- and middle-income countries: A framework and recommendations for further research [version 1; peer review: 2 approved]. F1000Res. 2017; 6: 231. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChalkidou K, Glassman A, Marten R, et al.: Priority-setting for achieving universal health coverage. Bull World Health Organ. 2016; 94(6): 462–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChalkidou K, Gutiérrez-Ibarluzea I: Key messages from Setting Priorities Fairly: Sustainable Policies for Effective Resource Allocation. [version 1; not peer reviewed]. F1000Res. 2018; 7: 1621. (document). Publisher Full Text\n\nHollingworth S, Gyansa-Lutterodt M, Dsane-Selby L, et al.: Implementing health technology assessment in Ghana to support universal health coverage: building relationships that focus on people, policy, and process. Int J Technol Assess Health Care. 2020; 36(1): 8–11. PubMed Abstract | Publisher Full Text\n\nLi R: Mapping of priority-setting and HTA:Questionnaire [version 1; not peer reviewed]. F1000Research. 2017; 6: 1458. (document). Publisher Full Text\n\nHollingworth S, Ruiz F, Gad M, et al.: iDSI HTA survey SSA Data sharing. The University of Queensland. Data Collection. 2020. http://www.doi.org/10.14264/uql.2020.178\n\nHollingworth S, Downey L, Ruiz FJ, et al.: What do we need to know? Data sources to support evidence-based decisions using health technology assessment in Ghana. Health Res Policy Syst. 2020; 18(1): 41. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: 2015 Global Survey on Health Technology Assessment by National Authorities. Main findings. Geneva, Switzerland: WHO. 2015. Reference Source\n\nMundy L, Trowman R, Kearney B: OVERCOMING THE BARRIERS TO ACHIEVING UNIVERSAL HEALTH CARE IN THE ASIAN REGION. Int J Technol Assess Health Care. 2018; 34(4): 352–9. PubMed Abstract | Publisher Full Text\n\nGad M, Lord J, Chalkidou K, et al.: Supporting the Development of Evidence-Informed Policy Options: An Economic Evaluation of Hypertension Management in Ghana. Value Health. 2020; 23(2): 171–179. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDoherty JE, Wilkinson T, Edoka I, et al.: Strengthening expertise for health technology assessment and priority-setting in Africa. Glob Health Action. 2017; 10(1): 1370194. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMacQuilkan K, Baker P, Downey L, et al.: Strengthening health technology assessment systems in the global south: a comparative analysis of the HTA journeys of China, India and South Africa. Glob Health Action. 2018; 11(1): 1527556. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Bank: West African Medicines Regulatory Harmonization. 2019. (Accessed 11 November 2019). Reference Source\n\nAfrican Union Development Agency: African Medicines Regulatory Harmonisation (AMRH). 2019. (Accessed 11 November 2019). Reference Source"
}
|
[
{
"id": "63457",
"date": "18 May 2020",
"name": "Evidence Nyamadzawo",
"expertise": [
"Reviewer Expertise Maxillofacial and Oral Surgery Resident & Health Technology Assessment Researcher."
],
"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 reports the results of an initial survey of Health Technology Assessment (HTA) stakeholders in sub-Saharan Africa (SSA). The authors aimed to identify where and how HTA methodologies can improve health system priority-setting and universal health coverage efforts at national level.\nThe authors are experts on HTA and have a wealth of experience in priority-setting, health systems policy, and global health.\nIn this interesting and important article, they have painted the current HTA landscape in SSA and highlighted areas in need of further investigations. Capacity-building efforts for HTA in SSA can now be refined based on the critical areas highlighted in this initial survey.\nThe limitations of this survey have been acknowledged. I think the low response rate and incomplete answers are a reflection of the stage of development of HTA in SSA.\nSpecific comments are provided below:\nThe authorship of the article could have included African researchers currently on the continent on a full-time basis to help with local capacity development and international collaboration.\n\nAbstract: just semantics and preferences. \"...tool to support..\" may sound better as \"...tool for supporting..\"\n\nMethods: the authors state that \"We used an existing framework..\" I think they should have provided more information on this \"existing survey\". Was the survey used before and what were the findings?\n\nGhana is mentioned as having given most of the responses and I know they have done a lot of work on local HTA use. The article could have given more detail on the developments in Ghana. It may help others to learn from such examples on the continent.\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? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7380",
"date": "11 Nov 2021",
"name": "Samantha A. Hollingworth",
"role": "Author Response",
"response": "1. The authorship of the article could have included African researchers currently on the continent on a full-time basis to help with local capacity development and international collaboration. R: Text inserted: potential collaborators were likely respondents. 2. Abstract: just semantics and preferences. \"...tool to support..\" may sound better as \"...tool for supporting..\" R: Done. 3. Methods: the authors state that \"We used an existing framework..\" I think they should have provided more information on this \"existing survey\". Was the survey used before and what were the findings? R: Cited a reference (#8). 4. Ghana is mentioned as having given most of the responses and I know they have done a lot of work on local HTA use. The article could have given more detail on the developments in Ghana. It may help others to learn from such examples on the continent. R: References to other countries inserted."
}
]
},
{
"id": "63459",
"date": "19 Jun 2020",
"name": "Rebecca Addo",
"expertise": [
"Reviewer Expertise Health technology assessment",
"economic evaluation and quality of life."
],
"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 great article that used an online survey to explore the perception and views of SSA respondents in the need for HTA, demand for HTA and supply of HTA. Survey response rate was low, however responses were from participants across 14 countries in SSA thus fairly representative of the HTA landscape in SSA. Almost half of the respondents were from Ghana, where progress has been made towards the use of HTA in the health system. Respondents considered HTA was most importantly needed for informing the design of basic health benefits package (for national health insurance schemes) and development of clinical guidelines and disease management pathways. Stakeholders perceived as potential users of HTA were those from the ministry of health, public health insurance bodies. Whilst some respondents were of the view that they could provide expertise and skills for HTA, the majority were of the view that there were limited local human capacity, data and other infrastructures to support HTA.\nSpecific comments to improving the research paper are summarised below:\nThe title of the article is suggestive of assessing capacity for HTA in terms of data, human and other infrastructure for HTA. However, the results are indicative of assessing what respondents perceived as the potential use, potential users and production of and barriers to producing HTA.\n\nThe abstract mentions 51 respondents completing the survey but the results note that only 30 fully completed. The authors should note whether partially completed surveys were included in the analysis or otherwise and provide justification for the choice.\n\nIt will be informative to provide a list of the countries that responded to the survey and also a list of where they worked.\n\nGiven that the majority of respondents were from Ghana, perhaps authors should provide some reasons/speculations as to why this was the case. Could it be as a result of Ghanaian respondents being more aware of HTA due to the recent involvement with iDSi projects for HTA and progress made towards using HTA for formal decision making in the country?\n\nThe authors should comment on whether the responses are likely to be biased by the general knowledge and awareness of respondents about HTA. Members of AfHEA and the majority of African health economists and policy analysts are mainly involved in health financing and not economic evaluation and HTA.\n\nIt will be interesting to know the differences in responses between respondents from Ghana countries that may have some ongoing work towards the use of HTA for health decision making and those that do not. Another area to consider is the differences in responses between respondents according to their area of work.\n\nThere are some studies from SSA that have explored the perceptions of decision-makers towards the use economic evaluations and HTA for decision making that covered the themes presented in this paper that the authors could have cited to support their findings. One study in Ghana (Addo et al., 20201) and the other Ethiopia (Zegeye et al., 20172).\n\nThe discussion mentions Ghana transitioning from reliance upon donor assistance for health. Perhaps the authors should add more context and how that may contribute to the current landscape of HTA in Ghana.\n\nLastly, the authors mention refining the survey tool in future iterations as it appears some questions were not entirely understood. Was this limitation considered in the data analysis? This point should be noted as a limitation of the study as it may have affected the responses and subsequent results presented in this paper. Also the authors should note what 'refinement' they intend to make to the survey tool - is it content wise, or rewording, etc.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate? 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": [
{
"c_id": "7382",
"date": "11 Nov 2021",
"name": "Samantha A. Hollingworth",
"role": "Author Response",
"response": "1. The title of the article is suggestive of assessing capacity for HTA in terms of data, human and other infrastructure for HTA. However, the results are indicative of assessing what respondents perceived as the potential use, potential users and production of and barriers to producing HTA. R: No changes made to the title. 2. The abstract mentions 51 respondents completing the survey but the results note that only 30 fully completed. The authors should note whether partially completed surveys were included in the analysis or otherwise and provide justification for the choice. R: Confirmed that there were 51 responses but only 30 were complete responses that were analysed. Text edited accordingly. 3. It will be informative to provide a list of the countries that responded to the survey and also a list of where they worked. R: Available in the dataset. 4. Given that the majority of respondents were from Ghana, perhaps authors should provide some reasons/speculations as to why this was the case. Could it be as a result of Ghanaian respondents being more aware of HTA due to the recent involvement with iDSi projects for HTA and progress made towards using HTA for formal decision making in the country? R: Yes. 5. The authors should comment on whether the responses are likely to be biased by the general knowledge and awareness of respondents about HTA. Members of AfHEA and the majority of African health economists and policy analysts are mainly involved in health financing and not economic evaluation and HTA. R: Text edited to “Some respondents may have known more about HTA than others which may have biased the results.” 6. It will be interesting to know the differences in responses between respondents from Ghana countries that may have some ongoing work towards the use of HTA for health decision making and those that do not. Another area to consider is the differences in responses between respondents according to their area of work. R: We agree. Please see dataset for more information. This could be explored in a later survey with more respondents. 7. There are some studies from SSA that have explored the perceptions of decision-makers towards the use economic evaluations and HTA for decision making that covered the themes presented in this paper that the authors could have cited to support their findings. One study in Ghana (Addo et al., 20201) and the other Ethiopia (Zegeye et al., 20172). R: We have cited the suggested studies and included a further two studies: Addo R, Hall J, Haas M, Goodall S: The knowledge and attitude of Ghanaian decision-makers and researchers towards health technology assessment. Soc Sci Med. 2020; 250: Zegeye EA, Mbonigaba J, Kaye SB, Wilkinson T: Economic Evaluation in Ethiopian Healthcare Sector Decision Making: Perception, Practice and Barriers. Appl Health Econ Health Policy. 2017; 15 (1): 33-43 Hollingworth, S., Fenny, A. P., Yu, S.-Y., Ruiz, F., & Chalkidou, K. (2021). Health technology assessment in sub-Saharan Africa: a descriptive analysis and narrative synthesis. Cost Effectiveness and Resource Allocation, 19(1), 39. https://doi.org/10.1186/s12962-021-00293-5 Uzochukwu, B. S. C., Okeke, C., O'Brien, N., Ruiz, F., Sombie, I., & Hollingworth, S. (2020). Health technology assessment and priority setting for universal health coverage: a qualitative study of stakeholders' capacity, needs, policy areas of demand and perspectives in Nigeria. Global Health, 16(1), 58. https://doi.org/10.1186/s12992-020-00583-2"
}
]
}
] | 1
|
https://f1000research.com/articles/9-364
|
https://f1000research.com/articles/10-1143/v1
|
11 Nov 21
|
{
"type": "Research Article",
"title": "An intelligent decision support system for crop yield prediction using hybrid machine learning algorithms",
"authors": [
"Kalaiarasi Sonai Muthu Anbananthen",
"Sridevi Subbiah",
"Deisy Chelliah",
"Prithika Sivakumar",
"Varsha Somasundaram",
"Kethaarini Harshana Velshankar",
"M.K.A.Ahamed Khan",
"Sridevi Subbiah",
"Deisy Chelliah",
"Prithika Sivakumar",
"Varsha Somasundaram",
"Kethaarini Harshana Velshankar",
"M.K.A.Ahamed Khan"
],
"abstract": "Background: In recent times, digitization is gaining importance in different domains of knowledge such as agriculture, medicine, recommendation platforms, the Internet of Things (IoT), and weather forecasting. In agriculture, crop yield estimation is essential for improving productivity and decision-making processes such as financial market forecasting, and addressing food security issues. The main objective of the article is to predict and improve the accuracy of crop yield forecasting using hybrid machine learning (ML) algorithms. Methods: This article proposes hybrid ML algorithms that use specialized ensembling methods such as stacked generalization, gradient boosting, random forest, and least absolute shrinkage and selection operator (LASSO) regression. Stacked generalization is a new model which learns how to best combine the predictions from two or more models trained on the dataset. To demonstrate the applications of the proposed algorithm, aerial-intel datasets from the github data science repository are used. Results: Based on the experimental results done on the agricultural data, the following observations have been made. The performance of the individual algorithm and hybrid ML algorithms are compared using cross-validation to identify the most promising performers for the agricultural dataset. The accuracy of random forest regressor, gradient boosted tree regression, and stacked generalization ensemble methods are 87.71%, 86.98%, and 88.89% respectively. Conclusions: The proposed stacked generalization ML algorithm statistically outperforms with an accuracy of 88.89% and hence demonstrates that the proposed approach is an effective algorithm for predicting crop yield. The system also gives fast and accurate responses to the farmers.",
"keywords": [
"Machine Learning",
"Prediction",
"Crop",
"Stacked Generalization",
"Random Forest",
"Regression"
],
"content": "Introduction\n\nThe tremendous increases in population and random climatic changes have laid down a great challenge to the agricultural sector in terms of the unavailability of food, productivity, and sustainability. Although farmers are skilled in the cultivation of crops, there is a huge gap between scientific and technological knowledge, and their availability in rural areas. One of the key challenges for a country's food security is climate change and its effects in the form of extreme weather events. The increase in temperature of 1-2.5 degrees Celsius forecast for 2030 is likely to have serious effects on crop yields (Bhanumathi et al., 2019) as it allows changes in photosynthesis, increases the respiration rate of plants, and affects pest populations.\n\nOne of the goals proposed to be achieved by 2030 is “no hunger” and the other goal is “promoting sustainable agriculture” (Holzapfel and Brüntrup, 2017). Sustainable agriculture helps to empower small farmers, end poverty, improve the financial growth of the country, and to promote gender equality. The present scenario is alarming. To ensure sustainable access to nutritious food universally, countries would force continuous food production and agricultural practices (Ramesh and Vardhan, 2015).\n\nTimely and economic agricultural observance is essential to attain these goals. In this context, crop yield estimation is crucial for checking and making higher cognitive processes like crop insurance, money market foretelling, and addressing food security problems (Patil and Shirdhonkar, 2017). With the drastic improvement in technology, the objective of the present study is to use the machine learning algorithms (Medar et al., 2019) and control systems to change the procedure and enhance the productivity (Sriram et al., 2019) of crops (Zingade et al., 2017).\n\nFormerly, machine learning (ML) algorithms like linear regression and multiple linear regression have been used to make crop yield predictions (Manjula and Djodiltachoumy, 2017). This article proposes improved ML algorithms that use specialized ensemble methods such as stacked generalization, gradient boosting, random forest, and least absolute shrinkage and selection operator (LASSO) regression. Our goal is to develop a web application in order to provide the farmers/users an approximation on how much amount of crop yield will be produced depending upon the given input and also find the relationship between yield (dependent variable) and other independent variables.\n\nThe remaining section of the article contains the literature survey, proposed method, results, discussion, conclusion, and recommendations for future work.\n\n\nLiterature review\n\nA convolutional neural network - recurrent neural network (CNN-RNN) framework for crop yield prediction was introduced by Saeed Khaki et al., (2020). In this article, other models like random forest (RF), deep fully neural networks (DFNN), and LASSO algorithms were compared with CNN-RNN in predicting the corn and soybean yield. The forecasting was done throughout the Corn Belt within the United States for the years 2016, 2017, and 2018. The results were based on three categories, having soil, weather, and management as the attributes, and the accuracy for corn and soybean was 87.82% and 87.09% respectively.\n\nTo predict the crop yield, a random-forest classifier was used by Hajir Almahdi (2020) and Ramesh (2020). In their article, a graphical web-based interface was designed for a farmer to know the yield of crops beforehand cultivation. The dataset contains details about the crop production of Maharashtra where the study was conducted.\n\nA backpropagation artificial neural network model was proposed by Meena and Singh (2013) for forecasting the crop yield. Unlike the fuzzy models, physical factors for yield forecasts were used. The annual forecast evaluation reports (AFER) are compared and have been reduced from 11.40% to 3.82%.\n\nAn empirical analysis for crop yield forecasting was done by Dharmaraja et al. (2020) as an attempt to focus on forecasting the yield of ‘bajra’ or the pearl millet crop through implementing appropriate statistical models such as regression and time-series models. Models like auto-regressive integrated moving average (ARIMA) and an ARIMA model with an exogenous variable (ARIMAX) were also used for prediction. The ARIMAX model produced the best outcome for 'bajra’ compared to the regression time series model.\n\nA crop yield prediction using ML was proposed by Nishant et al. (2020). They used stacked regression for crop yield production, based on an additional factor of soil nutrients. Efficient neural network (ENeT), LASSO, and kernel ridge algorithms had minimal errors of 4%, 2%, and 1% respectively. A web page was used as an interface to display the predicted result.\n\nMobile based applications such as uzhavan (https://apps.apple.com/in/app/uzhavan/id1405906962), Kisan (https://apps.apple.com/in/app/kisan/id1297223018), and the agri app (https://play.google.com/store/apps/details?id=com.criyagen&hl=en) provide facilities to the farmer for knowing the information about the scheme components, subsidy patterns, seeds and fertilizers. From the above literature, it is observed that the integration of an ML algorithm along with the web application or mobile application is missing. To address this issue, this article proposes a web page interface through which crop yield can be predicted with the applications of stacked generalization and random forest algorithms.\n\n\nMethods\n\nSelecting appropriate data is a very important part of any machine learning algorithms or statistics. In the proposed system, Aerialintel datasets from the github data science repository were utilised to forecast crop yields (Aerial Intelligence, 2017). Many researchers including Sriram Rakshith et al. (2019) and Jameshan (2017) have used this dataset and derived useful insights from it. It consists of two years’ winter wheat data for several counties in the United States of American for the years. 2013 and 2014, in total holding 26 attributes and over three hundred thousand records. The attributes mainly focus information about crop and climate data as outlined below.\n\nThe climatic parameters include precipitation, temperature, cloud cover, vapor pressure, and wet day frequency. The data in these files are geolocated to specific lat-longs and counties. The framework of the proposed work for this study using these datasets is shown in Figure 1. The framework contains the following modules: data preprocessing, feature extraction, and decision support system (DSS). DSS module includes predictions and performance evaluation.\n\nPredictions can be done by stacked regressor and performance evaluation can be done by checking the accuracy of dss. The detailed explanation about performance evaluation has been discussed in the discussion section.\n\nIn this phase, the collected dataset was explored, and data preprocessing techniques such as imputation of missing values and Haversine distance have been used. The details about the original dataset are shown in Table 1. Attributes precipIntensity, pressure, and visibility contain missing values. The number of missing values of the above attributes are 1, 254 and 30 respectively. Since the data are collected from different states in the United States, a global average cannot be used for imputing missing values. Therefore, the data from the same day and the closest neighboring location has been used to replace the null values by calculating the haversian distance between the two points. Basic statistics features like mean, variance, and quartiles values are computed for all the attributes. From which, it is found that the attribute “PrecipTypeIsOther” can be dropped as they hold no predictive power, since all the statistical values are around zero. Pairwise positive correlations between different features will aid the removal of features from models, as adding highly correlated features dilutes the model's predictive potential. Correlation coefficients have been estimated for all the possible combinations. From the correlation matrix, it has been observed that attributes like apparentemperaturemin, apparenttemperaturemax, and precipintensitymax etc have been removed since it is highly correlated with attributes like temperaturemax, temperaturemin, and precipAccumulation. The correlation between the attributes is given in the result section. After the removal of highly correlated attributes, the dataset contains the following attributes: latitude, longitude, precipAccumulation, temperaturemax, temperaturemin, ndvi,windspeed, country, state and date. Attributes such as State, and Date are removed because their inclusion would result in overfitting and a lack of generalization (Gandhi et al., 2016; Mythra et al., 2018). Features like length of day and elevation plays an important role in crop yield prediction (Nishant et al., 2020). These features are the derived features, it is not available in the original dataset. Hence these two features of length of day and elevation were added in order to account for the amount of sunlight available to the plants at different locations. This can be done through astral package in python, version 3.8.8 (https://www.python.org/downloads/release/python-388/). After data preprocessing and feature extraction, the dataset contains 12 features including derived attributes. These features are longitude, latitude, elevation, length_of_day, total_precipitation, minitemp, maxitemp, ndvi, windspeed, meantemp, stdtemp and yield. The results of the data preprocessing and feature extraction is shown in Figures 4–6. The original dataset contains two years of winter wheat data for several countries in the United States of America for 2013 and 2014 together with python code for data preprocessing techniques such as correlation estimation and scatter matrix is uploaded in Github (https://github.com/HangulAlien/intelligent-decision-support-system) (HangulAlien, 2021).\n\nBased on Hajir Almahdi (2020) and Dharmaraja et al. (2020), the whole data set is divided into two parts: that is, 70% of the data set is used for training the model and 30% of the data is reserved for testing the model. In the 2013 wheat dataset, around 124,000 records were considered for training purpose and 53,000 records (containing the period from March to May 2014) were considered for testing purpose. In the 2014 wheat dataset, around 127,000 records were considered for training purpose and 54,000 records (containing the period from March to May 2015) were considered for testing purpose. While developing the machine learning model, both the datasets i.e., 2013 and 2014 datasets are combined.\n\nA simple correlation study of the final featured data demonstrates that there was no strong linear correlation between the input features and the target output. However, some of them were linearly correlated to each other, which led to the conclusion that linear models such as linear regression could not be the best model for this dataset and problem. Hence, it was decided to execute many algorithms such as random forest (RF), stacked generalization, gradient boosted tree (GBT) regression, and LASSO regression algorithms (Bhanu Kiran et al., 2020). The efficiency of the model is tested using k-fold cross-validation (Shah et al., 2018; Champaneri et al., 2020).\n\nIn the proposed framework, the preprocessed dataset (contains 12 attributes), training and testing period is same for all the algorithms.\n\nRandom forest (RF) regression: The RF algorithm is a supervised learning model composed of multiple decision trees having the same nodes. It builds several decision trees and merges the decisions of several other decision trees to achieve a solution, which constitutes the mean of all these decision trees. The decision tree algorithm comprises traditional algorithms such as Iterative Dichotomiser (ID3), C 4.5 (which is a successor of ID3) and classification and regression tree (CART), etc. The performance of the algorithm can be measured by mean squared error (MSE).\n\nwhere N is the number of records, fi is the value returned by the model, and yi is the actual value for the given data point.\n\nLASSO Regression: LASSO regression is a form of linear regression that uses shrinkage. It performs both selections of variables and regularization in order to enhance accuracy. The LASSO model encourages simple, sparse models.\n\nThis precise form of regression is well-acceptable for models displaying excessive degrees of multi-collinearity or whilst one needs to automate certain components of model selection, like variable selection/parameter elimination.\n\nGradient boosted tree (GBT) regression: The GBT regression trees model is one of the most successful machine learning models for predictive study, which optimizes the result value in the successive steps in every iteration of the decision tree by adjusting the values of weights, or biases coefficients applied to the input variable. Gradient boosting involves three elements; namely, a loss function to be optimized, a weak learner to make predictions, and an additive model to add weak learners to minimize the loss function.\n\nwhere Jm is the number of terminal nodes in trees, Rjm is the region under study, γjm is the optimal value, and x is the training value.\n\nStacked regression: Stacking regressions is a method of combining multiple regressors to increase accuracy. The workflow of stacked regression is shown in Figure 2. It uses several meta-algorithms in order to learn how to combine the best predictions from two or more base algorithms. Here, by cross-validation and least square for non-negative values, the coefficient of the stack is found to give a result. It is found to be effective when compared with traditional ML algorithms and random forest. In the proposed work, the algorithms for random forest, LASSO regression, and GBT were used in the stacked regression. In Figure 2, R1, R2 … Rn represents the model which is generated after training. Based on the training model and testing data, the prediction models -P1,P2, … Pn is generated. The individual regression models are trained based on the same training set; then the meta-regressor is fitted based on the meta-features of the individual regression models in the ensemble learning. Meta-regression is a type of meta-analysis that customs regression analysis to combine, compare, and synthesize research findings from multiple experiments to provide a better response.\n\nThe Python integrated development environment (IDE) was utilised to find the machine learning solution for agricultural yield prediction using packages such as os, pickle, time, matplotlib, pandas, basemap, sklearn, numpy, and astral. Python pickle module is used for serializing and de-serializing a Python object structure. Pickle is used to “serializes” the object first before writing it to file. It is the way of converting a python object into a character stream. jsonify() is a helper method provided by Flask to properly return JSON data. Render_template is used to produce the output from a template file based on jinja2 engine. Render_template is typically imported directly from the flask package. Astral package is used to calculating the times of various aspects of the sun and phases of the moon.\n\nThe web-based model was deployed using flask, The flask framework's goal is to provide a graphical user interface for accessing information. In the proposed work, the best performing model i.e., stacked generalization is loaded in the flask framework to cross verify the performance or accuracy of the algorithm. When we provide inputs in the webpage, the stacked generalization model runs and provide the required output, i.e., yield prediction. The following input features: longitude, latitude, elevation, length_of_day, total_precipitation, minitemp, maxitemp, ndvi, windspeed, meantemp, and stdtemp are given in the web page to find the yield prediction. If the user enters the location details, wind speed and temperature details, they can obtain the yield prediction details. Around 100,000 records are considered for the testing purpose which includes combined data of 2013 and 2014 aerial intelligence (2017) datasets. Any novice users can access the webpage at any time from any location. The web interface is shown in Figure 3. The creation of the interactive page contains the following steps:\n\n➢ Install the flask package available in python- version 3.8.8 (https://www.python.org/downloads/release/python-388/).\n\n➢ Create a HTML file to display the front-end design of the web page\n\n➢ Create a python file that contains the following: generate a new route “/join” with “get and post” methods. Take the input from the web input box through request.form[<'name'>] . Perform the manipulations in the function and return the value as a JSON format to the web.\n\n➢ Create a route “/” and return to html file from the function. Then run the python file and click on the link that it provides after running.\n\n➢ The webpage takes the input from the web to flask and print the results back to the web page.\n\n\nResults\n\nFigure 4 represents the geographical distribution of data corresponds to the years 2013 and 2014. This graph represents the yield of crops in the particular region based on the collected dataset. The red color denotes maximum yield while it decreases towards blue color. In the graph, the year representing the yield prediction and the number of records in the region are mentioned. The number of records mentioned in different colors starting from blue to red which resprents lowest to highest count of the record. Since the dataset is huge, here both scatter matrices and correlation matrix are used to find the correlation between two variables, is shown in Figures 5 and 6. To demonstrate the purpose of the scatter matrix, four features such as temperaruremin, tempertauremax, apparanttemperaturemin and apparanttemperaturemax is considered. As a result, a 4*4 scatter matrix has been formed and it is shown in Figure 5. In the matrix, diagonal value represents histogram of the above four attributes. Other than diagonal value represents, correlation between the attributes. For example, the first row represents the correlation between apparanttemperaturemax and the remaining attributes such as apparanttemperaturemin,tempertauremax and temperaruremin. From the first row, it is observed that apparanttemperaturemax is correlated with other three attributes, since the y value is increased if there is an increase in x value as well, as it contains very few outlier data. Similar to the first row, the correlation between the attributes can be taken from the second, third, and fourth rows. From the matrix, it is observed that all attributes are correlated with each other. The correlation between the 12 attributes is shown in Figure 6. In the correlation matrix, highly correlated features are denoted in red and less correlated features are denoted in blue. In the correlation matrix, the diagonal represents correlation of the univariate data. First row in the correlation matrix denotes how the attribute “longitude” is correlated with the other 11 attributes. From the first row of the figure, it is inferred that the attribute longitude is negatively correlated (blue color in Figure 6) with the attributes latitude, ratiomndvi30, and elevation. The attribute longitude has no correlation with the attributes total_precipitation and yield. The attribute longitude is positively correlated with the attributes minnat30, mean_wind_speed,std_temperature_diff, and mean_tempeaturediff. The attribute longitude is strongly correlated (red color in Figure 6) with the attributes LOD and maxmat30. Four regression-based algorithms were used to find the crop yield. They are random forest regression, gradient boosted tree regression, LASSO regression, and stacked generalization ensemble method. The relative efficiencies of these four models were compared using cross-validation as outlined in the methods section. The performance was measured by varying the hyper-parameter settings. In most of the cases, stacked generalization performed the best, followed by random forest, and gradient boosted tree regression. The overall comparison of the algorithms is shown in Table 2.\n\nWhen optimizing the parameters, the best pairs of hyper-parameters were found, from which the performance can be increased. The learning curve of the stacked regressor and random forest is shown in Figure 7. The proposed work is trained and tested. Based on the results obtained from the testing set, the comparison of the proposed algorithms has been done.\n\nThe proposed ensembling methods of stacked generalization, gradient boosting, random forest, and LASSO regression have been implemented using the same training dataset. Among these algorithms, random forest – 87.71% and stacked generalization – 88.89% yield slightly better accuracy than Kaur et al. (2020), who have implemented random forest, gradient boosted regression, nearest neighbor regression, and support vector machine with the polynomial kernel where the accuracy of the algorithms is 87.5%, 80.11%, 78%, and 34%, respectively.\n\n\nDiscussion\n\nThe correlation matrix (Figure 5) and the scatter matrix (Figure 5) is used to find highly connected features (Figure 6). Attributes like apparentemperaturemin, apparenttemperaturemax, and precipintensitymax have been removed since it is highly correlated with attributes like temperaturemax, temperaturemin, and precipAccumulation. Features like day length and elevation are added since they play an important role in crop yield prediction (Nishant et al., 2020). After data preprocessing techniques such as imputation of missing values, attribute elimination, and adding the new attributes, the dataset contains 12 attributes. The algorithms RF, stacked generalization, GBT regression, and LASSO regression is used to predict crop yield. The performance of these algorithms is shown in Table 2. The performance of each model is evaluated separately, and then the performance of the stacked regressor is evaluated. Among these algorithms, stacked regressor yield better results. The mean absolute percentage error is ~ 5%. Based on the experimental results outlined in the previous section, the following observations have been made. The accuracy of random forest regressor, gradient boosted tree regression, and stacked generalization ensemble methods are 87.71%, 86.98%, and 88.89 % respectively. The proposed stacked generalization ML algorithm statistically outperforms with an accuracy of 88.89% and hence demonstrates that the proposed approach is an effective algorithm. The learning curve (shown in Figure 7) for the training is above the validation score. This indicates the goodness of the random forest and stacked generalization model. The learning curve of the stacked generalization model (Figure 8) showed little over-fitting but compared to other models, the overall accuracy and variance produce stronger results. The final model's R2 value is ~ 0.85 with a root mean square error (RMSE) of 5.2. The accuracy of the proposed algorithm is comparatively better than the existing work proposed by Kaur et al. ,2020. In the earlier literature (Nishant et al., 2020 and Medar et al., 2019), yield prediction was done by accepting input parameters in the terminal and not in the web interface. The farmers don’t have knowledge and don’t know how to use the terminal. In the proposed framework, the above issue has been resolved by use of the web interface. In the literature (Kaur et al., 2020), they maily focused on latitude, longitude, temperature and humidity. They are not considering the derived attributes like elevation and the length_of_day. In the proposed work, including the above features totally 11 features longitude, latitude, elevation, length_of_day, total_precipitation, minitemp, maxitemp, ndvi, windspeed, meantemp, stdtemp are considered for predicting the crop yield. The testing dataset that supports to check the performance of the web interface. The interactive web interface is used to find the crop yield prediction by accepting the inputs from the user as shown in Figure 3. The limitation of the study is that the proposed work uses United States datasets by considering the crop yield for the year 2013 and 2014, where recent datasets have been considered for better understanding and checking the accuracy in the real time.\n\n\nConclusions\n\nBased on the climatic input parameters, the present experiment provided a demonstration of the possible use of four regression-based algorithms to predict crop yield. The algorithms are random forest regression, gradient boosted tree regression, LASSO regression, and stacked generalization ensemble method. In comparison of these algorithms, one concludes that the stacked ensemble model performed the best, followed by others for the given dataset.\n\nSince this proposed system is a web-based system, input variables and modules can be easily changed as new features can be added based on their future needs. The system also gives fast and accurate responses to the farmers.\n\nSuggestion for future studies: Our future work is to examine hybrid machine learning such as random forest, support vector machine, multiple regressor, logistic regressor and deep learning algorithms, such as deep convolution neural network (DCNN), and long short-term memory (LSTM) which might provide a fast and accurate solution to this problem. Future work will include considering the large recent datasets from different countries for predicting the crop yield in advance, leaf disease prediction, and predicting the quality of the fruits etc. and the results will be tested by the farmers and the agricultural experts.\n\n\nData availability\n\nZenodo: HangulAlien/intelligent-decision-support-system: Crop Prediction. https://doi.org/10.5281/zenodo.5533487 (HangulAlien, 2021).\n\nThe project contains the following underlying data:\n\n• Python file. (Contains code for Random forest, Gradient boosted tree regression, Lasso regression and stacked generalization).\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\nSource code available from: https://github.com/HangulAlien/intelligent-decision-support-system.\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.5533487.\n\nLicense: Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).",
"appendix": "References\n\nAerial Intelligence: Data-science-exercise.2017. (Accessed on March 01,2021).Reference Source\n\nBhanu Kiran D, Priyanka J, Poojitha S, et al.: Crop Yield Prediction using Regression. Int. Res. J. Eng. Techno. (IRJET). 2020; 7(5): 3896–3899.\n\nBhanumathi B, Vineeth M, Rohit N: Crop Yield Prediction and Efficient use of Fertilizers. IEEE International Conference on Communication and Signal Processing (ICCSP). 2019; pp. 769–773.\n\nChampaneri M, Chachpara DC, Chaitanya: Crop yield prediction using machine learning. Int. J. Sci. Res. (IJSR). 2020; 9(2): 645–648.\n\nDharmaraja S, Jain V, Anjoy P, et al.: Empirical Analysis for Crop Yield Forecasting in India. Agric Res. 2020; 9: 132–138. Publisher Full Text\n\nGandhi N, Armstrong L: Rice crop yield forecasting of tropical wet and dry climatic zone of India using data mining techniques. IEEE International Conference on Advances in Computer Applications (ICACA). 2016; pp. 357–363.\n\nHajir Almahdi: Machine Learning nano-degree capstone project Data-science-exercise.2020. (Accessed on March 10,2021).Reference Source\n\nHangulAlien.: HangulAlien/intelligent-decision-support-system: Crop Prediction (Version 1). Zenodo. 2021. Publisher Full Text\n\nHolzapfel S, Brüntrup M: SDG 2 (Zero Hunger) in the context of the German Sustainable Development Strategy: are we leaving the starving behind? Briefing Paper, No. 13/2017.2017.\n\nJameshan: Wheat yield prediction for United States by environmental features.2017. (Accessed on March 01, 2021).Reference Source\n\nKaur R, Havish K, Dutt TK, et al.: Agrocompanion: A Smart Farming Approach Based on Iot and Machine Learning. Int. J. Innov. Techn. Explor. Eng. (IJITEE). 2020; 9(12): 254–262. Publisher Full Text\n\nManjula E, Djodiltachoumy S: A Model for Prediction of Crop Yield. Int. J. Compu. Intell. Inform. 2017; 6(4): 298–305.\n\nMedar R, Rajpurohit V, Shweta S: Crop Yield Prediction using Machine Learning Techniques. IEEE 5th International Conference for Convergence in Technology (I2CT). 2019; pp. 1–5.\n\nMeena M, Singh PK: Crop Yield Forecasting Using Neural Networks. Swarm, Evolutionary, and Memetic Computing. SEMCCO 2013. Lecture Notes in Computer Science, 82, Springer, Cham. 2013; pp. 319–331. Publisher Full Text\n\nMythra N, Velayudham A, Shamila ES, et al.: A Survey on Crop Yield Prediction using Data Mining. Int. J. Comp. Trends and Technol. 2018; 65(1): 1–7. Publisher Full Text\n\nNishant PS, Sai Venkat P, Avinash BL, et al.: Crop Yield Prediction based on Indian Agriculture using Machine Learning. International Conference for Emerging Technology (INCET), Belgaum, India. 2020; pp. 1–4.\n\nPatil D, Shirdhonkar MS: Rice Crop Yield Prediction using Data Mining Techniques: An Overview. Int. J. Adv. Res. Comp. Sci. Softw. Eng. 2017; 7(5): 427–431. Publisher Full Text\n\nSaeed K, Lizhi W, Archontoulis Sotirios V: A CNN-RNN Framework for Crop Yield Prediction. Front. Plant Sci. 2020; 10: 1,750–1,755.\n\nShah A, Dubey A, Hemnani V, et al.: Smart Farming System: Crop Yield Prediction Using Regression Techniques. Proceedings of International Conference on Wireless Communication. January 2018; pp. 49–56. Springer.\n\nSriram Rakshith K, Deepak G, Rajesh M, et al.: A Survey on Crop Prediction using Machine Learning Approach. Int. J. Res. App. Sci. & Eng. Techno. (IJRASET). 2019; 7(4): 3231–3234.\n\nRamesh D, Vardhan BV: Analysis of crop yield prediction using data mining techniques. Int. J. Res. Eng. Techn. 2015; 04: 470–473. Publisher Full Text\n\nRamesh A: Data Analytics:2020. (Accessed on April 30,2021). Reference Source\n\nZingade DS, Buchade O, Mehta N, et al.: Crop Prediction System using Machine Learning. Int. J. Adv. Engin. Res. Develop. Special Issue on Recent Trends in Data Eng. (IJAERD). 2017; 4(5): 01–06."
}
|
[
{
"id": "102293",
"date": "20 Dec 2021",
"name": "Millie Pant",
"expertise": [
"Reviewer Expertise Numerical optimization",
"artificial intelligence",
"data analysis"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors have proposed an article entitled: An intelligent decision support system for crop yield prediction using hybrid machine learning algorithms.\nIt is an interesting study and is relevant to the present scenario.\nI would suggest the authors to extend the review part a bit. Presently, it only discusses papers of 2020 and one paper of 2013. It will be good if the authors present a good range of review articles.\nIn the opening sentence in the introduction, \"increases\" should be replaced with increase and \"climatic\" should be replaced with climate. Likewise there are other grammatical errors that may be corrected before submitting the final version.\nMaybe the authors can add a table mentioning the characteristics of the algorithms used in the paper.\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": "99828",
"date": "20 Dec 2021",
"name": "Farrikh Alzami",
"expertise": [
"Reviewer Expertise Data mining",
"machine learning",
"pattern recognition"
],
"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 is well organized and easy to read to understand the content\nThe paper used data which are collected from different states in the United States, a global average cannot be used for imputing missing values. Therefore, they applied the Haversian distance between the two points, for replacing the null values.\n\nThe authors stated that there is no strong linear correlation between the input features and the target output in the dataset. Hence, they decided to execute many algorithms such as random forest (RF), stacked generalization, gradient boosted tree (GBT) regression, and LASSO regression algorithms. And finally they proposed the Stacked regression model which is a method of combining multiple regressors and compared its performance with other models.\n\nThe authors compared the data set using Scatter matrix for the 12 sample features. They identified highly correlated features and less correlated features using heat map data visualization method.\nThe authors concluded that the stacked ensemble model outperforms with an accuracy of 88.89% than Random forest (87.71%) and Gradient Boosted tree (86.98%).\nThe paper also stated the future works. Thus, I accept the paper without any modifications.\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": "99829",
"date": "20 Dec 2021",
"name": "Durai Raj Vincent",
"expertise": [
"Reviewer Expertise AI",
"ML",
"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\nThis work on crop yield prediction is nicely presented with much clarity.\nThe role of the crop yield prediction was explained well in the introduction section.\n\nAerialintel datasets from the GitHub data science repository were utilized to forecast crop yields. The existing attributes, the reason for the elimination of certain attributes like \"apparentemperaturemin\", \"apparenttemperaturemax\", etc, and the reason for the inclusion of the attributes like length of day and elevation are explained in data reprocessing and feature extraction section.\n\nFigure 1 gives an overview of the entire work and it is easy to follow.\n\nThe working of stacked generalization, gradient boosting, random forest, and least absolute shrinkage and selection operator (LASSO) regression for crop yield prediction was explained appropriately along with the equation.\n\nThe author also explained the purpose and need of a web-based model. The web-based model was deployed using a flask.\n\nIn the results and discussion section, the performance of the algorithms has been compared using accuracy and the learning curve.\n\nThe following comment can be considered to further strengthen the work.\nThe need for the current work was clearly mentioned in the Literature Review section by comparing with existing articles and existing mobile applications. However, many references are taken from conference proceedings, not from high-impact journals. The authors should consider references from high impact journal publications on crop yield prediction. For example, the following articles by this reviewer: Elavarasan et al. 20181, Elavarasan and Vincent 2021a2, Elavarasan and Vincent 2021b3.\nFinally, I conclude that the flow and contents are clear and the language is easy to understand. This article is suitable for indexing.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-1143
|
https://f1000research.com/articles/10-582/v1
|
16 Jul 21
|
{
"type": "Research Article",
"title": "Factors associated with knowledge, attitudes and preventive practices towards COVID-19 in health care professionals in Lima, Peru",
"authors": [
"Oriana Rivera-Lozada",
"Cesar Augusto Galvez",
"Elvis Castro-Alzate",
"Cesar Antonio Bonilla-Asalde",
"Cesar Augusto Galvez",
"Elvis Castro-Alzate",
"Cesar Antonio Bonilla-Asalde"
],
"abstract": "Background: Nowadays, we are facing a disease caused by SARS-CoV-2, known globally as COVID-19, which is considered a threat to global health due to its high contagiousness and rapid spread. Methods: Analytical cross-sectional study in 302 health professionals. An online questionnaire consisting of questions about knowledge, attitudes and practices (KAP) towards COVID-19 was applied. Socio-demographic, occupational and comorbidities factors were explored. Simple and multiple logistic regression models were used to identify factors associated with KAP. Results: Of the total, 25.2%, 31.5% and 37.4% had high levels of knowledge, preventive practices and risk perception attitudes respectively. Being married (aOR=6.75), having a master's degree (aOR= 0.41), having a working day with less than ten hours (ORa=0.49) and obesity (aOR=0.38) were associated with a low level of knowledge of COVID-19. The variables associated with preventive practices were being over the age of 50 (aOR=0.52), working in the hospitalization area (aOR=1.86) and having comorbidities such as arterial hypertension (aOR=0.28) and obesity (aOR=0.35). In relation to negative attitudes towards COVID 19, it was found that physical contact with patients with a confirmed diagnosis (aOR=1.84) and having asthma (aOR=2.13) were associated with these attitudes. Conclusion: Being married, having a master's degree, working less than ten hours were associated with having a low level of knowledge of COVID-19. Being older than 50, working in the hospitalization area were associated with preventive practices. Physical contact with COVID-19 patients was associated with negative attitudes.",
"keywords": [
"Health Knowledge",
"Attitudes and Practice",
"Health Personnel",
"Coronavirus infections",
"Peru"
],
"content": "Introduction\n\nWe are currently facing a disease caused by the SARS-CoV-2 virus, known globally as coronavirus disease-2019 (COVID-19), which is considered a threat to global health due to its high contagiousness and rapid spread.1 According to the World Health Organization (WHO), 159,896,332 cases of this disease and more than 3,321888 deaths were reported worldwide between its emergence in late 2019, and May 12, 2021.2 Perú, like other Latin America countries, has been widely affected by the increase in confirmed cases. On May 12, 2021, the Ministry of Health (MINSA) reported 1,858,239 cases and 64,691 deaths, which makes Peru the nation with the sixth highest number of patients in the world.3 However, there was a discrepancy between what was reported by MINSA and the figures reported by the National Death Registry Information System (Sistema Informático Nacional de Defunciones, SINADEF) since this institution reported 130,195 cases on the same date.\n\nIn Perú, health professionals are a population group at high risk of contracting COVID-19, because they are on the frontline in the fight against the disease. This disease is highly infectious; there is no specific treatment, and access to vaccination is still limited.4,5 Consequently, healthcare professionals must acquire sufficient knowledge to treat patients in an efficient and timely manner and, at the same time, protect themselves from contracting the disease.\n\nIt should be emphasized that, during the pandemic, healthcare professionals are being overworked in addition to feeling afraid of contracting the disease.6-8 This makes it more critical for any country to overcome the disease and protect healthcare professionals at the same time.7\n\nConsequently, a key element in the fight against the pandemic is to follow the guidelines established by organizations such as the World Health Organization (WHO) and MINSA. Given the challenges Perú is facing, adequate dissemination of information among health professionals is important so they can be updated with recent advances in managing the disease.\n\nHence, low levels of knowledge, attitudes and practices (KAP) in regard to the implementation of preventive measures against the disease2-6,9 might cause serious public health problems, since health personnel must assume responsibility for care and control of the pandemic.7-10\n\nPrevious studies have reported that having low levels of knowledge, risk perception attitudes and preventive practices leads to a negative impact on the behavior towards the disease in health professionals.11-16 Therefore, it is essential to know what factors are associated with KAP to face COVID-19, providing evidence that is potentially useful for healthcare facilities to improve health interventions, which will reduce occupational exposure to COVID-19 in health professionals.\n\n\nMethods\n\nThe study used an analytical cross-sectional design. The sample population consisted of 302 health professionals who worked in healthcare facilities in Lima-Callao, and who also taught at the Faculty of Health Sciences of Norbert Wiener University, distributed across eight academic professional schools (APS) (Human medicine, Nursing, Obstetrics, Medical technology, Odontology, Human Nutrition, Psychology and Postgraduate School) in the second half of 2020. The instrument was administered in the August-December period, in 2020.\n\nThe sample size was calculated probabilistically in two stages. In the first stage, the sample size was determined; in the second, the number of sample elements in each of the strata was calculated through proportional allocation. The sample size was divided by the population size and multiplied by the size of each stratum (APS). Thus, the size of the stratum was directly proportional to the sample size and the sampling was carried out by randomly selecting participants, using the list of health professionals of the academic schools that are part of the study population. Human medicine, Nursing and Obstetrics were the schools with the most representation, with 37.1% 14.4% and 14.3%, respectively.\n\nTo achieve our study objectives, we used the following selection criteria: health professionals working in a health facility in Lima-Callao who, additionally, were teaching at the faculty of Health Sciences or at the Postgraduate School of the Norbert Wiener University.\n\nThe questionnaire, described in the following pages, was validated by the judgment of ten experts, including pulmonologists, infectious disease specialists and epidemiologists, who determined their applicability to healthcare professionals in Perú.\n\nThe questionnaire to measure factors of interest had 20 questions that included sociodemographic factors (age, gender, marital status, number of children, level of education, religion and transportation), occupational factors (work area, working hours, contact with COVID-19 patients, relatives with suspected COVID-19 and physical contact with COVID-19 patients), comorbidity factors (diabetes, hypertension, asthma, cardiovascular diseases, obesity and overweight).\n\nThe competencies of health professionals on caring for COVID-19 patients were measured through their level of knowledge, preventive practices and risk perception attitudes. Regarding the level of knowledge on COVID-19, the WHO guidelines for clinical management of COVID-1917 and the questionnaire developed by Bhagavathula et al.18 were considered. To this end, a survey of 44 questions was used to explore professionals’ knowledge on the disease’s etiology, symptoms, transmission, diagnosis, and prevention; the test score ranged from 0 to 44 points. These questions were answered on a true/false and “don’t know” basis. Correct questions scored one point and incorrect or unanswered answers scored zero; scores were converted into percentiles, a percentile ≥ 75% was categorized as high knowledge (33 or more correct answers) and <75% as low level of knowledge (fewer than 33 correct answers). The reliability of the questionnaire was 0.51, which was obtained through the use of the KR-20 to measure internal consistency, and is considered an accepted value to develop research processes.19\n\nRegarding the formulation of preventive practices-related questions, these were based on COVID-19 clinical management guidelines by WHO17 and the Kim and Choi questionnaire.20 Eleven questions considered practices such as hand washing, social distancing, surface disinfection, use of personal protective equipment, response to possible contagion. The answers were formulated on a Likert scale, which were subsequently recategorized into a “yes” or “no” dichotomous scale, where one point was assigned to an appropriate preventive practice and zero points to an inappropriate preventive practice. Scoring ranged from 0 to 11 points; a percentile ≥ 75% was categorized as high level of preventive practices (eight or more correct answers) and <75% as low level of preventive practices (fewer than eight correct answers). The instrument obtained a reliability coefficient of 0.78 through the KR-20 internal consistency index, and is therefore considered an acceptable level to develop research processes.19\n\nThe attitude-related questions associated to risk perception were based on Zhang’s questionnaire,21 which considered seven questions addressing factors such as confidence in defeating the virus, fear of infecting the family, concern that the equipment could not work, physical and mental exhaustion. The answers were formulated on a Likert scale and were subsequently ranked on a dichotomous “yes” or “no” scale. One point was assigned to an affirmative response and zero points to a negative response; scoring ranged from 0 to 7 points. A percentile ≥ 75% was categorized as high level of risk perception (five or more correct answers) and <75% as low level of risk perception (fewer than five correct answers). The questionnaire obtained a reliability coefficient of 0.77 using the KR-20 internal consistency index, and is considered an acceptable level to develop research processes.19\n\nData collection was carried out through the distribution of an online questionnaire using Google Forms. Before filling out the questionnaire, everything was clearly and precisely explained via e-mail: the objectives of the study, voluntary participation, respect for confidentiality, the use of the obtained results and the description of the contact data. The surveys were anonymous and the data were treated with strict confidentiality; therefore, the completion of the questionnaires implied the informed consent of the professionals to participate in the study.\n\nData analysis was performed in three phases. The first phase included descriptive analysis of the variables, using frequencies of the categorical variables. The second phase considered bivariate analysis, where the association between variables was evaluated by means of contingency tables, using odds ratios (OR) with their corresponding 95% CI confidence interval; for the statistical significance of the contingency tables, we used Fisher´s exact test when more than 20% of cells had expected frequencies < 5. Finally, in the third phase, a binary logistic regression analysis was performed to determine the factors associated with low levels of knowledge, risk perception attitudes and preventive practices toward COVID-19 infection in health professionals. The analyses were performed using SPSS version 26 (IBM) statistics program with a license provided by University of Valle (Cali, Colombia).\n\nEthical standards were respected throughout the research process; the Institutional Research Ethics Committee of the Norbert Wiener University approved the study protocol and informed consent procedures with file No. -181-2020.\n\n\nResults\n\nInformation about 302 health professionals who were providing healthcare services during the period August-December 2020 was obtained. Regarding epidemiological variables, 64.9% were female and the median age was 46 years old (IQR 42-51), with greater participation of those under 50 old (73.5%). Regarding marital status, 87.4% (n = 264) were married or cohabiting, 7.0% (n = 21) were divorced and 5.6% (n = 17) were single, 91.4% (n = 276) had children. Regarding professions, 52.9% were physicians, 35.1% were nurses and 11.92% were obstetricians. The level of education corresponded to Master’s degree (79.1%), Doctorate (11.9%) and specialty (8.9%).\n\nRegarding the area of work, the participants worked in outpatient consultation (32.8%), internal medicine department at the hospital (28.1%), intensive care unit (15.9%), emergency (13.9%) and clinical laboratory departments (9.3%). The median number of years of service was five (IQR 3-8) and the median daily working time was eight hours (IQR 7-8).\n\nIn the case of level of knowledge, it was established that 25.2% showed scores ≥ the 75th percentile, the parameter which allowed us to establish a high level of knowledge about COVID 19. Responses with the lowest scores were those related to the severity of the disease according to age groups (42.7%), time of subsistence of the virus (50%) and the need for specialized hospitals to care for suspicion or diagnosis of infection (55.6%).\n\nIn the case of preventive practices, 31.5% (n = 95) obtained scores above the 75th percentile, indicating a high level. A low level was identified in practices such as the use of disposable gloves in the workplace (45.0%), use of disposable gowns (42.1%), use of personal protective equipment (PPE) (25.2%) and decontamination of surfaces (7.7%).\n\nThe level of risk perception attitudes towards COVID 19 was analyzed with an inverse scale, determining the frequency of low levels of manifestation of negative attitudes (fear of contagion, fear that relatives might contract the disease, fear that personal protective equipment might not work, fear of death) like confidence, fear, concern and physical and mental fatigue. A total of 37.4% (n = 113) obtained scores above the 75th percentile, with a predominance of fear of becoming infected (49.7%), returning home and infecting the family (45%) and fear of dying from COVID 19 (49.7%).\n\nThrough a bivariate analysis, it was possible to establish that being married was a risk factor for having low levels of knowledge (OR = 7.01; CI: 1.64-29.85). The study showed, in addition, some preventive factors: having a Master’s degree (OR = 0.496; CI 0.27-0.90); working more than nine hours a day (OR = 0.36 CI: 0.16-0.75) and having relatives with diagnosed COVID-19 (OR = 0.47; CI 0.24-0.92).\n\nRegarding preventive practices, it was shown that the use of public transport (OR = 1.68; CI 1.03-2.77), working in the hospital’s internal medicine department (OR = 2.11 CI 1.25-3.56) are risk factors for having a low level of preventive practices. However, we found some preventive factors such as being older than 50 (OR = 0.45; CI 0.24-0.83), experiencing comorbid conditions like hypertension (OR = 0.27; CI 0.08-0.94) and obesity (OR = 0.34; CI 0.14-0.79).\n\nRegarding risk perception attitudes, the findings revealed risk factors such as having relatives with suspected COVID-19 (OR = 1.50; CI 1.08-2.64), having had contact with patients diagnosed with COVID-19 (OR = 1.92; CI 1.05-3.08) and having asthma as a comorbid condition (OR = 2.29; CI 1.17-4.50) (Tables 1 and 2).\n\n* Fisher exact test.\n\nThe numbers in bold represent measures of association (Odds Ratio and statistical significance p < 0.05).\n\nLogistic regression analysis identified that being married (adjusted OR = 6.75, 95%CI 1.46-31.2) was a risk factor for a low level of knowledge of COVID 19. Preventive factors, such as having completed a Master’s degree (adjusted OR = 0.41, 95%CI 0.21-0.80), working more than 9 hours a day (adjusted OR = 0.49, 95%CI 0.25-0.95), presenting with obesity as a comorbidity condition (adjusted OR = 0.38, 95%CI 0.15-0.95) were also found. Multivariate analysis allowed us to estimate a coefficient of determination of 0.16, which explained 16% of the variance of the level of knowledge.\n\nIn relation to preventive practices, it was found that working in the hospital’s internal medicine department (adjusted OR = 1.86, 95%CI 1.08-3.18) was a predictor variable of risk for low level of preventive practices. In addition, protective factors such as being older than 50 (adjusted OR = 0.52, 95%CI 0.27-0.98), presenting with comorbidities such as hypertension (adjusted OR = 0.28, 95% CI 0.08-0.99) and obesity (adjusted OR = 0.35, 95%CI 0.14-0.83) were found. Multivariate analysis allowed us to estimate a coefficient of determination of 0.19, which explained 19% of the variance in the level of preventive practices.\n\nFinally, regarding risk perception attitudes towards COVID-19, physical contact with patients with a confirmed diagnosis (adjusted OR = 1.84, 95%CI 1.14-2.97) and presenting with asthma as a comorbidity condition (adjusted OR = 2.13, 95%CI 1.081-4.22) were found as predictor variables. Multivariate analysis allowed us to estimate a coefficient of determination of 0.23, which explained 23% of the variance in the level of risk perception attitudes (Table 3).\n\n\nDiscussion\n\nOur study revealed that healthcare professionals in Perú have insufficient knowledge about COVID-19 (more than 70% did not have a high level of knowledge), in contrast to a study in Nigeria,22 where fewer than 20% of health professionals showed insufficient knowledge. Although frontline healthcare staff are expected to have a high level of knowledge of SARS-CoV-2, our study found a large knowledge gap regarding the severity of the disease according to age group and duration of virus persistence. Knowledge of the severity of the disease according to age group represents a weak link in clinical management, since therapeutic management is prioritized according to the risk of contracting a disease or its complications.23 Regarding the persistence of the SARS-CoV-2 virus, it is important to highlight it can survive at least 72 hours on plastic surfaces and stainless steel.24 This is fundamental in the prevention of person-to-person or patient-to-healthcare worker transmission during clinical care.\n\nThe present study revealed that being married represents a higher probability of having a low level of knowledge. Authors such as Naser et al.,25 and Rani et al.,26 have shown associations between marital status and low levels of knowledge of COVID-19 in health professionals in Saudi Arabia, where low levels of knowledge were found in single health professionals, as opposed to married health professionals, which can be explained by cultural aspects of Eastern countries such as believing that children and young adults are at a lower risk of contracting the disease, attending crowded places such as markets and mosques, in addition to their low acceptance of the use of masks.25,26 These results are different from what we found in our study, where a low level of knowledge in married health professional was shown, which can be explained by the fact that the proportion of single population was low (12.6%).\n\nIn addition, regarding the methodological aspects of the present study, one factor that may affect the results is the low participation of single people under 40 to the study, which corresponds to the age at which continuous or post-graduate training processes are carried out.\n\nHowever, this association was not observed in the level of practices and attitudes. This could be due to social reasons, as married people might have less time to do COVID-19 training courses, unlike single people who might have more free time to acquire such knowledge. However, the level of practices and attitudes would not change, which could be due to the experience acquired in healthcare.\n\nIt was found that some factors such as having a Master’s degree, working more than nine hours and having relatives diagnosed with COVID-19 were preventive factors against having a low level of knowledge. This could be happening because self-learning, such as that employed when studying for a Master’s program, plays a key role in the process of acquiring COVID-19 knowledge. Similar studies in physicians found that younger physicians and those who had not worked with patients for a long time had lower COVID-19 knowledge scores.27 Presenting with comorbidity conditions was associated with good levels of knowledge, attitudes and practices towards COVID-19, which may be due to the fact that being part of a population at risk demands a greater level of care and attention to this disease compared to other groups that are not at risk.28 The presence of comorbidity conditions contributes to the inclusion of self-care behaviors by health professionals, based on their personal and professional experience and, thus, they can minimize the risk of contagion in their workplace.\n\nStudies conducted in some Asian countries found that health professionals had a high level of knowledge of COVID 19, but had low levels of preventive practices, which allows them to affirm that knowledge is not a determining factor in developing preventive practices and attitudes, and that other measures should be implemented, such as improvement of the work environment and access to adequate PPE.28,30-32 In our research, it became evident that 75% had low levels of knowledge and preventive practices, despite the fact that about six months had passed since the notification of the first case of COVID 19 in Perú. The explanation for this situation could be related to the fact that much of the information on the pandemic circulating in the academic media came from the opinion of “experts”, social networks or the media, which lacked scientific rigor.\n\nIt is known that healthcare professionals who have received instructions on donning and discarding PPE could cause a decrease in the risk of making errors, as along with professionals who have had active training with spoken instructions and computer simulation on correct PPE removal.33 A study in Jordan found that there was an association between biosafety at work and good biosafety practice at home, with a biosafety score at work of 73% (considered low by the researchers).31 The only way to control new potentially deadly epidemics such as the one we are experiencing, and from an early stage, is to educate the population and especially healthcare personnel to adopt optimal behavior of biosafety practices and maximum PPE protection.34,35\n\nIn relation to preventive practices, we could identify an association with epidemiological variables such as age, i.e. being older than 50. This suggests that an increase in knowledge may lead to better attitudes and practices. In this case, it is known that COVID-19 affects people of any age, but people over 60 are more severely affected,36 which may imply that older healthcare professionals, knowing that they are a population at a higher risk of contracting this disease, may follow better recommendations regarding preventive practices against COVID-19. Similarly, with respect to occupational factors, an association with being part of the hospital personnel was identified; a possible explanation may be that due to the serious clinical conditions of patients with COVID-19 in hospitals, the involved physicians and health personnel made greater efforts to have preventive practices against contagion.\n\nIn the present study, we found that certain groups of medical professionals have little knowledge about COVID-19, which is why the importance of ensuring the delivery of knowledgeable information to medical professionals should be emphasized. These low levels of knowledge would explain why Perú has one of the highest rates of medical professionals infected with COVID-19. This should be taken into account by front line care teams, physician managers and, in general, all health professionals in order to eliminate knowledge gaps and improve COVID-19 knowledge scores, attitudes and practices.\n\nKnowledge allows the establishment of prevention strategies to avoid the spread of the virus, and also facilitates the development of positive attitudes towards the acquisition of self-care habits at work as well as respect for the rights of patients diagnosed with COVID-19, and the recognition of the effectiveness of the treatment plan and coping behaviors.37 In addition, exposure to the virus in the workplace implies a mental burden and could have a negative impact on control measures,38,39 which increases the risk of infection. In the present study, among the risk perception attitudes, fear of becoming infected predominated, which coincides with the findings of Zhang et al., Abdel et al., and Maleki et al.,39,41 who found that between 85% and 92% of healthcare workers expressed fear of transmitting the disease to their family members. Therefore, it can be concluded that the perception of risk is a determining factor for the modification of attitudes in the work environment and the restructuring of healthy and safe behaviors during the working day,38,39 which impacts on family and social relations.\n\nThese results contrast with the findings of Abdelhafiz et al.,43 who stated that stigma associated with the disease is based on fear associated with mortality and its transmission capacity. This could explain the association between the level of negative attitudes in those with relatives with suspected COVID-19, and having had contact with patients diagnosed with COVID-19. Although it may seem irrelevant, stigma is important because it can lead to public reluctance to seek medical care and the underreporting of cases, which can influence the increase in confirmed cases in a scenario characterized by community transmission. Thus, to combat stigma, it is necessary to develop appropriate education strategies framed in health policies and launching de-stigmatization programs in hospitals.43\n\nThe main limitation of this study was that the attitudes and practices of health professionals may be overestimated, as they may answer interview questions in a way that they believe is socially acceptable rather than completely accurate, because of “social desirability”.44,45 However, we believe that this could not have affected the measurement of knowledge. Another limitation was the low percentage of surveyed health professionals working at the hospital and in the Intensive Care Unit; in addition, we could not survey another group of health professionals who were working in more complex health institutions. Therefore, we cannot infer their level of KAP.\n\nIn conclusion, being married, having a Master’s degree, and working more than nine hours a day were associated with a low level of knowledge of COVID-19 in health professionals. Being older than 50, and working at the hospital, were associated with preventive practices. Physical contact with patients with COVID-19 was associated with the report of negative attitudes towards COVID-19. We recommend that universities and health institutions incorporate comprehensive training programs that seek to improve knowledge and promote preventive measures against COVID-19.\n\n\nData availability\n\nZenodo: Factors associated with knowledge, attitudes and preventive practices towards COVID-19 in health care professionals in Lima, Peru https://doi.org/10.5281/zenodo.4780623.46\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
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PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Health Organization: Emerging respiratory viruses, including COVID-19: methods for detection, prevention, response, and control.2020. [2020-02-01]. Reference Source\n\nBhagavathula AS, Aldhaleei WA, Rahmani J, et al.: Knowledge and Perceptions of COVID-19 Among Health Care Workers: Cross-Sectional Study. JMIR Public Heal Surveill. 2020 Apr 30 [cited 2020 Jun 29]; 6(2): e19160. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGarcía Cadena CH, Landero Hernández R, González Ramírez GT: Estadística con SPSS y metodología de la investigación. México: Trillas2006. (pp. 139–166).\n\nKim JS, Choi JS: Middle East respiratory syndrome–related knowledge, preventive behaviours and risk perception among nursing students during outbreak. J Clin Nurs. 2016; 25(17-18): 2542–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZhang M, Zhou M, Tang F, et al.: Knowledge, attitude, and practice regarding COVID-19 among healthcare workers in Henan, China. J Hosp Infect. 2020; 105(2): 183–187. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTsiga-Ahmed FI, Amole TG, Musa BM, et al.: COVID 19: Evaluating the Knowledge, Attitude and Preventive Practices of Healthcare Workers in Northern Nigeria. Int J MCH AIDS. 2021; 10(1): 88–97. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPerrotta F, Corbi G, Mazzeo G, et al.: COVID-19 and the elderly: insights into pathogenesis and clinical decision-making. Aging Clin Exp Res. 2020; 32(8): 1599–1608. PubMed Abstract | Publisher Full Text | Free Full Text\n\nOtter JA, Donskey C, Yezli S, et al.: Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. J Hosp Infect. 2016; 92(3): 235–250. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNaser AY, Dahmash EZ, Alsairafi ZK, et al.: Knowledge and Practices during the COVID-19 Outbreak in the Middle East: A Cross-Sectional Study. Int J Environ Res Public Health . 2021; 18: 4699. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRani M, Sharma I, Sharma S, et al.: Exploring the knowledge, attitude, and practice of health-care professionals on coronavirus (COVID-19) pandemic infection. J Educ Health Promot. 2021; 10: 115. Published 2021 Mar 31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDesalegn Z, Deyessa N, Teka B, et al.: Evaluation of COVID-19 related knowledge and preparedness in health professionals at selected health facilities in a resource-limited setting in Addis Ababa, Ethiopia. PloS one. 2021; 16(2): e0244050. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAddis SG, Nega AD, Miretu DG: Knowledge, attitude and practice of patients with chronic diseases towards COVID-19 pandemic in Dessie town hospitals, Northeast Ethiopia. Diabetes Metab Syndr. 2021; 15(3): 847–856. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSilva JS, Batista de Carvalho AR, Leite HC, et al.: Reflexiones sobre los riesgos ocupacionales en trabajadores de salud en tiempos pandémicos por COVID-19. Rev Cubana Enferm. 2020 [citado 22 Jun 2021]; 36(2): [aprox. 0 p.]. Reference Source\n\nRizki SA, Kurniawan J, Budimulia P, et al.: Knowledge, Attitude, and Practice in Indonesian Health Care Workers Regarding COVID-19. Asia Pac J Public Health. 2021: 10105395211011017. PubMed Abstract | Publisher Full Text\n\nRamadan M, Hasan Z, Saleh T, et al.: Beyond Knowledge: Evaluating the Practices and Precautionary Measures towards COVID-19 among Medical Doctors in Jordan. Int J Clin Pract. 2021: e14122. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWang J, Zhou M, Liu F: Reasons for healthcare workers becoming infected with novel coronavirus disease 2019 (COVID-19) in China. J Hosp Infect. 2020; 105(1): 100–101. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVerbeek JH, Ijaz S, Mischke C, et al.: Personal protective equipment for preventing highly infectious diseases due to exposure to contaminated body fluids in healthcare staff. Cochrane Database Syst Rev. 2016; 4: Cd011621. PubMed Abstract | Publisher Full Text\n\nWilliams L, Rasmussen S, Kleczkowski A, et al.: Protection motivation theory and social distancing behaviour in response to a simulated infectious disease epidemic. Psychol Health Med. 2015; 20(7): 832–837. PubMed Abstract | Publisher Full Text\n\nMortada E, Abdel-Azeem A, Al Showair A, et al.: Preventive Behaviors Towards Covid-19 Pandemic Among Healthcare Providers in Saudi Arabia Using the Protection Motivation Theory. Risk Manag Healthc Policy. 2021; 14: 685–694. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDantas F: Resultados terapêuticos da homeopatia em pacientes suspeitos ou confirmados de COVID-19 no Brasil: Protocolo para estudo observacional prospectivo. Resultados terapêuticos da homeopatia em pacientes suspeitos ou confirmados de COVID-19 no Brasil: Protocolo para estudo observacional prospectivo. 2020. p. 46.\n\nMcEachan R, Taylor N, Harrison R, et al.: Meta-Analysis of the Reasoned Action Approach (RAA) to Understanding Health Behaviors. Ann Behav Med. 2016; 50(4): 592–612. PubMed Abstract | Publisher Full Text | Free Full Text\n\nThe national institute for occupational safety and health NIOSH: Guidelines for Protecting the Safety and Health of Health Care Workers Revision.2014. Retrieved June 10, 2020. Reference Source\n\nYesilgul G, Cicek H, Avci M, et al.: Nurses’ knowledge levels and perceptions regarding occupational risks and hazards. Int J Caring Sci. 2018; 11(2): 1117–1124.\n\nZhang M, Zhou M, Tang F, et al.: Knowledge, attitude, and practice regarding COVID-19 among healthcare workers in Henan, China. J Hosp Infect. 2020; 105(2): 183–187. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaleki S, Najafi F, Farhadi K, et al.: Knowledge, attitude and behavior of health care workers in the prevention of COVID-19.2020.\n\nAbdel Wahed WY, Hefzy EM, Ahmed MI, et al.: Assessment of Knowledge, Attitudes, and Perception of Health Care Workers Regarding COVID-19, A Cross-Sectional Study from Egypt. J Community Health. 2020; 45(6): 1242–1251. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAbdelhafiz AS, Mohammed Z, Ibrahim ME, et al.: Knowledge, Perceptions, and Attitude of Egyptians Towards the Novel Coronavirus Disease (COVID-19). J Community Health. 2020; 45(5): 881–890. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMaude RR, Jongdeepaisal M, Skuntaniyom S, et al.: Improving knowledge, attitudes and practice to prevent COVID-19 transmission in healthcare workers and the public in Thailand. BMC Public Health. 2021; 21(1): 749. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBonilla-Asalde CA, Rivera-Lozada IC, Bonilla-Pizarro DN, et al.: Health sciences students’ competencies in addressing COVID 19: The challenge of returning to clinical practice. Pakistan J Med Heal Sci. 2020; 14(3): 1005–1012.\n\nLozada OR, Bonilla CA: Factors associated with knowledge, attitudes and preventive practices towards COVID-19 in health care professionals in Lima, Peru.2021. Publisher Full Text"
}
|
[
{
"id": "89965",
"date": "03 Aug 2021",
"name": "Rubia Consuelo Cobo Rendón",
"expertise": [
"Reviewer Expertise Psychology",
"well-being and health"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is a significant study as this manuscript contributes to the identification of factors associated with knowledge, attitudes and preventive practices towards COVID-19 in health care professionals in Lima, Peru. The findings in the study are of value for further research and institutional action associated with the results found in Peru and Latin America.\n\nFollowing the review, I describe the following suggestions:\nAbstract:\nIt is suggested to improve the presentation of the conclusions, they look like a repetition of the results.\n\nThe implications of the findings found could be deepened.\n\nIntroduction:\nPresentation relevant to the reality of the context studied. It is suggested to deepen the ideas on the justification of the research, with the information presented in the paragraph: \"Hence, low levels of knowledge, attitudes and practices (KAP) in regard to the implementation of preventive measures against the disease2-6,9 might cause serious public health problems, since health personnel must assume responsibility for care and control of the pandemic.7-10\".\n\nInclude the objective of the study in the last paragraph.\n\nMethod:\n\nIt is important to describe the health context (pandemic) in which the study participants presented themselves at the time of answering the questionnaire.\n\nStudy procedure and tool:\nInclude the category \"Pandemic-associated factors before\" the phrase: \"relatives with suspected COVID-19 and physical contact with COVID-19 patients)\", e.g. \"relatives with suspected COVID-19 and physical contact with COVID-19 patients\".\n\nThe Results and Discussion are well described. Punctuation and spelling throughout the manuscript should be checked.\n\nReviewer suggestion is appreciated. Best wishes for future work.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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": "7221",
"date": "20 Oct 2021",
"name": "ORIANA RIVERA LOZADA",
"role": "Author Response",
"response": "This is a significant study as this manuscript contributes to the identification of factors associated with knowledge, attitudes and preventive practices towards COVID-19 in health care professionals in Lima, Peru. The findings in the study are of value for further research and institutional action associated with the results found in Peru and Latin America. Following the review, I describe the following suggestions: Abstract: It is suggested to improve the presentation of the conclusions, they look like a repetition of the results. Author response: The conclusion in the abstract was improved: Our study revealed that health professionals have an insufficient level of knowledge of COVID-19. This is why we recommend implementing strategies such as health literacy programs among health care workers. Thus, they can help develop positive attitudes towards the acquisition of self-care habits at work that, in turn, improve their confidence so that health care workers can provide adequate care for their patients and protect themselves. The implications of the findings found could be deepened. Author response: They were deepened in the discussion since we cannot extend much in the abstract. Presentation relevant to the reality of the context studied. It is suggested to deepen the ideas on the justification of the research, with the information presented in the paragraph: \"Hence, low levels of knowledge, attitudes and practices (KAP) in regard to the implementation of preventive measures against the disease2-6,9 might cause serious public health problems, since health personnel must assume responsibility for care and control of the pandemic.7-10\". Include the objective of the study in the last paragraph. Author response: The introduction was enhanced, taking into account the suggestions. Method: It is important to describe the health context (pandemic) in which the study participants presented themselves at the time of answering the questionnaire. Author response: It was added. Study procedure and tool: Include the category \"Pandemic-associated factors before\" the phrase: \"relatives with suspected COVID-19 and physical contact with COVID-19 patients)\", e.g. \"relatives with suspected COVID-19 and physical contact with COVID-19 patients\". Author response: It was added."
}
]
},
{
"id": "89964",
"date": "11 Aug 2021",
"name": "Jaime A. Yanez",
"expertise": [
"Reviewer Expertise COVID-19",
"epidemiology",
"pharmacology",
"toxicology",
"drug development",
"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\nABSTRACT\nIt is customary to report not only the aOR but also the CI, as well as the p-value, please include.\n\nINTRODUCTION\nIt feels short. There is a need to mention what has been studied and published so far about COVID-19 in Peru and there are plenty of papers related to COVID-19 in Peru. For instance, there is no mention of the effects the lack of KAP has already caused in Peru. Examples of some studies include:\nInfodemic1,2,3\n\nSelf-medication4,5\n\nMedicinal plants use6,7,8,9\n\nUse of unproven treatments such as chlorine dioxide6,10\n\nIssues in children with the development of MIS-C11,12,13,14\n\nImpact in mental health15,16,17,18,19\n\nTechnostress20\n\nIssues in adequate implementation of public health measures21,22,23\n\nFurthermore, Peru is leading some interesting aspects compared to Latin America in the implementation of telemedicine24,25,26,27\n\nMETHODS\nPlease indicate in the Study setting and design the exact dates that the survey was available for responses.\n\nWhat exclusion criteria were used?\n\nPlease deepen the study population and size. It is not clear if 302 respondents were a sufficient sample size for this study. Also, indicate what power were the authors looking for.\n\nIt is really hard to follow how big was the instrument. Please include the full survey as an Annex to understand the instrument and for other researchers to replicate it.\n\nRESULTS\nChange the word \"epidemiological\" for \"demographic\" in the following sentence: Regarding epidemiological variables...\n\nPlease include the demographic data in a table, which is customary for cross-sectional studies.\n\nClarify the value that represented the 75th percentile in this sentence: In the case of preventive practices, 31.5% (n = 95) obtained scores above the 75th percentile. Please include cut-off values for the surveys used.\n\nThe same comment as above for the level of risk perception.\n\nPlease include the p-value for the results of the bivariate analysis.\n\nTable 3, the constants are not necessary to be reported, nor the degrees of freedom for a dichotomous variable.\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": "7220",
"date": "20 Oct 2021",
"name": "ORIANA RIVERA LOZADA",
"role": "Author Response",
"response": "ABSTRACT It is customary to report not only the aOR but also the CI, as well as the p-value, please include. Author response: They were added in the abstract. INTRODUCTION It feels short. There is a need to mention what has been studied and published so far about COVID-19 in Peru and there are plenty of papers related to COVID-19 in Peru. For instance, there is no mention of the effects the lack of KAP has already caused in Peru. Examples of some studies include: Infodemic1,2,3 Self-medication4,5 Medicinal plants use6,7,8,9 Use of unproven treatments such as chlorine dioxide6,10 Issues in children with the development of MIS-C11,12,13,14 Impact in mental health15,16,17,18,19 Technostress20 Issues in adequate implementation of public health measures21,22,23 Furthermore, Peru is leading some interesting aspects compared to Latin America in the implementation of telemedicine24,25,26,27 Author response: The introduction was modified, taking into account the references suggested by the reviewer. METHODS Please indicate in the Study setting and design the exact dates that the survey was available for responses. Author response: The period was specified in the Study setting and design section (01 August-15 December 2020). What exclusion criteria were used? Author response: We explained this in the Study population and size section: “To achieve the objectives of our study, we used the following selection criteria: health professionals working at a health center in Lima-Callao who, in addition, were teaching at the Faculty of Health Sciences or at the Graduate School of Norbert Wiener University. The exclusion criteria considered work at the university for less than one year.” Please deepen the study population and size. It is not clear if 302 respondents were a sufficient sample size for this study. Also, indicate what power were the authors looking for. Author response: It was specified in the Study population and size section “The sample size was calculated probabilistically in two stages. In the first stage, we determined the sample. For this study, the sample frame was 672 teachers, who were registered in the database of the human resources area of the university. For the calculation of the sample, an expected 50% prevalence was considered, using a confidence level of 97% and an error percentage of 3% and we could obtain an estimated sample of 277 participants. In the second stage, the number of sample elements in each of the strata was calculated through proportional allocation. This was done by dividing the sample size by the population size and then multiplying by the size of each of the strata (APS). Thus, the size of the stratum was directly proportional to the sample size. Sampling was performed through random selection of participants, since the list of health professionals from the academic professional schools (APS) that were part of the study population was available.” It is really hard to follow how big was the instrument. Please include the full survey as an Annex to understand the instrument and for other researchers to replicate it. Author response: It was added in annexes. RESULTS Change the word \"epidemiological\" for \"demographic\" in the following sentence: Regarding epidemiological variables Author response: It was corrected: “Information about 302 health professionals who were providing healthcare services during the period August-December 2020 was obtained. Regarding demographic variables, 64.9% were female and the median age was 46 years old (IQR 42-51)”. Please include the demographic data in a table, which is customary for cross-sectional studies. Author response: We added Table 1 with the demographic data of the population. Clarify the value that represented the 75th percentile in this sentence: In the case of preventive practices, 31.5% (n = 95) obtained scores above the 75th percentile. Please include cut-off values for the surveys used. The same comment as above for the level of risk perception. Author response: The values were included. In the case of level of knowledge, 25.2% showed scores ≥ the 75th percentile, where the cut-off point was in the scores greater than or equal to 34, a parameter that permitted us to establish a high level of knowledge of COVID-19. The responses with the lowest scores were those related to the severity of the disease according to age groups (42.7%), time of subsistence of the virus (50%), and the need for specialized hospitals to care for suspected or diagnosed infection (55.6%). In the case of preventive practices, 31.5% (n = 95) obtained scores above the 75th percentile (the cut-off point was the scores greater than or equal to 11), which indicated a high level. A low level of practices was identified, among them, we had the use of disposable gloves in the workplace (45.0%), the use of disposable gowns (42.1%), the use of personal protective equipment (PPE) (25.2%), and the decontamination of surfaces (7.7%). The level of risk perception attitudes towards COVID 19 was analyzed with an inverse scale and we could determine the frequency of low levels of manifestation of negative attitudes (fear of contagion, fear that family members could contract the disease, fear that personal protective equipment could not work, fear of death) such as confidence, fear, concern, and physical and mental fatigue. A total of 37.4% (n = 113) had scores above the 75th percentile (cut-off point greater than or equal to 5), with a predominance of fear of becoming infected (49.7%), returning home, and infecting the family (45%) and fear of dying from COVID 19 (49.7%). Please include the p-value for the results of the bivariate analysis Author response: nIt was included. Table 3, the constants are not necessary to be reported, nor the degrees of freedom for a dichotomous variable. Author response: We took the constants and the degrees of freedom out of the table."
}
]
}
] | 1
|
https://f1000research.com/articles/10-582
|
https://f1000research.com/articles/10-1140/v1
|
10 Nov 21
|
{
"type": "Research Article",
"title": "Spectrophotometric study of Solvent extraction of Pb (II) and Cd (II) by aminooctyldiphosphonic acid",
"authors": [
"IKHOU Djamila",
"M'hamed Kaid",
"ZIANI Hanane",
"Didier Villemein",
"IKHOU Djamila",
"ZIANI Hanane",
"Didier Villemein"
],
"abstract": "This study has investigated the solvent extraction of cadmium and lead ions from an aqueous solution in nitrate medium using aminooctyldiphosphonic acid (AODPA) as extractant in chloroform. In order to establish spectrophotometrically the concentration of metal ion in the aqueous phase before and after extraction, the Arsenazo III method was used. The effects of several extraction parameters on the extraction of these metals ions including volume ratio between the aqueous and organic phases (1–5), extraction kinetic time (0–30 min), molar ratio Q (1–5), addition of HNO3 (pH =2–6), addition of KNO3 (0.01 – 1M), temperature (10–40°C) and the synergetic effect by adding TOPO (solvating agent) were evaluated. Thermodynamic parameters including the Gibbs free energy (ΔG0),enthalpy (ΔH0), and entropy (ΔS0) were calculated. Performed experiments showed that Pb (II) can be extracted till 73% when Cd (II) can be recovered completely after two cycles. The extraction of both metallic ions was spontaneous, endothermic and with a slight randomness. Positive synergetic effect was observed at a chelating agent/TOPO ratio of 3. It is a very encouraging result which can lead us to recover cadmium and lower the concentration of lead from wastewater.",
"keywords": [
"Aminooctylylphosphonic acid",
"solvent extraction",
"ion-exchange mechanism",
"Pb (II)",
"Cd (II)"
],
"content": "Introduction\n\nThe most rejected heavy metals are very polluting and dangerous. Lead and its inorganic derivatives are classified as category 2B (potentially carcinogenic to humans).1 Lead modifies the cellular functioning by disrupting different physiological processes. It can thus cause blood anemia and renal effects (renal failure). Exposure to lead can affect the central nervous system (developmental delay, irritability, sleep disorders, loss of memory) and have long-term effects on fertility.2 The effects of lead are generally amplified in the fetus and child (congenital abnormalities, persistent neurobehavioral deficits).2,3 Cadmium, used in several industrial and agricultural processes as well as mining activities and designed carcinogenic by the United States (US) National Toxicology Program can increase the contamination of water and wastewaters around the world.4,5 Cadmium can produce or increase the incidence of non-hereditary adverse effects in offspring.6 Inhalation, ingestion or skin penetration, even in very small quantities, can cause irritation in the stomach, leading to vomiting and diarrhea, renal insufficiency and, at high doses, chronic bronchitis, fibrosis, emphysema, damage to the bone system, kidney stones and increased blood pressure.7–10\n\nIn order to eliminate or at least reduce the effects of these cations, many processes have been developed to face dangers towards human health and environment.\n\nThe use of the extraction process was widely used thus occupying a special place (for analytical purposes, in the processing of nuclear raw materials and in industries related to the fuel cycle). Solvent extraction consists of treating aqueous industrial waste before it is released into the environment. This process is a very efficient way of upgrading or rendering industrial wastes inert, and to treat discharges contaminated with lead and cadmium, and is generally aimed at recovering these metals, in order to reuse them and thus reduce their eco-toxicological impact.11-13\n\nThe aim of our work was to determine the optimal parameters, at which the extraction yield was maximum, of the solvent extraction of lead (II) and cadmium (II) from an aqueous solution in nitrate medium by a new chelating agent- aminooctyldiphosphonic acid (AAODMDP), dissolved in chloroform, synthesized under microwaves.14\n\n\nMethods\n\nThis study was conducted in April 2020 in our laboratory and LCMT Caen (France). The experimental procedure and metal cations analysis is detailed below. In brief after preparing aqueous and organic solutions, contact between the solutions was done. The two phases were separated gravimetrically, and 1 mL of aqueous solution was taken for UV/V analysis.\n\nFor synergetic effect, the organic phase was a mixture of our chelating agent (AODMDPA) and a solvating agent (tri octyl phosphine oxide) at different volume ratio.\n\nThe reagents used in this study (with supplier and catalogue number) were: Lead nitrate tetrahydrate Pb (NO3)2 4H2O (99%, Riedel De Haen, 10099-74-8), Cadmium nitrate tetrahydrate Cd (NO3)2 4H2O (99%, Riedel De Haen, 10022-68-1), Arsenazo III C22H18AS2N4O14S2 (99%, Aldrich, 216-788-6), Nitric acid (65%, Panreac, 7697 37 2), Acétic acid CH3COOH (80%, prolabo, 64-19-7), Sodium Acétate CH3COONa (98%, prolabo, 6131-90-4), Potassium nitrate KNO3 (99%, Riedel De Haen, 7757-79-1),Chloroform CHCl3 (99% Riedel De Haen, 67-66-3), Aminooctane C8H19N (Aldrich, 111-86-4), Phosphorus acid (H3PO3, Aldrich, 13598-36-2), Hydrochloric acid (HCl, Riedel de Haen, 7647-01-0) , Formaldehyde (HCHO, Aldrich, 50-00-0), Acetone (C3H6O, Aldrich, 67-64-1), Tri octyl phosphine oxide TOPO ((C8H17)3PO, 78-50-2) and aminooctyldiphosphonic acid (AODPA).14 Microwave irradiations were performed using microwave oven Synthewave 402 (Prolabo) working at a frequency of 2450 MHz. Nuclear magnetic resonance (NMR) spectra were done on a Fourier Bruker AC multinuclear spectrometer. Ultraviolet–visible spectrophotometry (UV/Vis) spectra were obtained using the UV/Visdouble beam Optizen 3220UVspectrometer, a digital pH meter type Consort C863 to follow solution pH.\n\nA mixture of aminooctane (C4H11N) (4.96 mL, 30.0 mmol), phosphorus acid (H3PO3) (5.02 g, 60.0 mmol), water (3.0 mL) and hydrochloric acid (HCL) 37% (3.0 mL) was irradiated (in a microwave oven) in a glass cylinder reactor fitted with a cooler at 240 W for 2 min. After adding formaldehyde (HCHO) 37% (4.8 mL, 64.46 mmol) rapidly, the mixture was irradiated for 12 min at 240 W. After cooling and evaporation for 5 min, the precipitate was filtered and the white solid was washed with acetone and water.\n\nThe product had the following properties: Yield (92 %), mp > 240°C, Formula: C10H25NO6P2, 1H NMR (D2O, Na2CO3):1.07 (t, 3H, CH3), 1.15 (m, 12H, CH2), 3.2 (d, 2JHP = 9,01 NCH2-P), 3.46 (m, 2H, N-CH2); 31P NMR (D2O, Na2CO3): d/H3PO4 (ppm) s, 6.7; 13CNMR (D2O, Na2CO3): 19 (s, C1), 25.4 (s, C2), 27.3(s, C3), 31.7 (s, C3), 51 (d, 2JCP = 137.7, NCH2-P); IR (υ Cm−1): 2925(νasCH), 1333 (Deformation of (CH2)n: n > 4) 1120 (νs P-OH), 1044 (νs P=O), 938 (νsCm υ P-O) (s:symetric, as: antisymetric); pKa: 2.75, 8.73, 9.35, (9.67). These values indicated that in the water–acetone media, the first proton was strong and the other protons were weak.\n\nAfter dissolving aminooctyldiphosphonic acid in chloroform, the obtained organic solutions were used for extraction studies. Aqueous metal solutions were prepared by dissolving Pb (NO3)2 4H2O and Cd (NO3)2 4H2O in distilled water. The first stage consisted of achieving curves of standardization of the absorbance according to the concentration of Pb2+ and Cd2+. The concentrations were in the range 10−6-10−3 mol. L−1. Pb2+ and Cd 2+ analyses in the aqueous phase after extraction was performed by the Arsenazo III spectrophotometric method which consists of using this chromogenic reagent to form ion-arsenazo III complex. After separation of the organic from the aqueous phase, Arsenazo III was added to the later to form Arsenazo-Ion complex, which was placed in a quartz cuvette after adjusting the aqueous solution pH with buffer solution. The absorbance was learnt at λmax = 610 nm for Pb2+ (pH = 4)15 and λmax = 600 nm for Cd2+ (pH = 9.5),16 the second stage involved optimizing factors of extraction. The volume ratio Vaq/Vorg (the two phases: aqueous and organic; were mixed with different volumes) was carried out to establish the optimal yield of extraction and avoid emulsions, followed by the extraction kinetics (the two phases were stirred for different time). This was carried out to determine the necessary optimal time to reach the extraction equilibrium and for which the yield is maximal. The effect of different concentrations of the extractant (10−3M - 10−6M) on the extraction of the metallic ions was studied. The effect of the ionic strength (a salt (KNO3) was added to the aqueous phase) and medium acidity (adding an acid (HNO3) to the aqueous phase at a specific pH) were investigated adding salt or acids to aqueous solutions respectively. Synergetic effect was investigated by adding a solvating agent (Tri octyl phosphine oxide) to the chelating agent (AODPA) in the organic phase then determine the synergetic coefficient.\n\n\nResults and discussion\n\nIn order to easily determine the different extraction factors, emulsions must be avoided. The distribution coefficient, D, and the extraction yield, Y, defined as follows,10 will be used to discuss the extraction results:\n\nWith the variables being as follows: Abi, Abf are the initial and final absorbance of aqueous solutions before and after extraction respectively.\n\nA parameter that appeared essential is the effect of the stirring speed. We noted that a medium stirring speed gave the highest extraction yield for both cations (Figure 1 and 2).27 This can be explained by the fact that at the lowest speed, and taking into account the ionic radius of Pb2+ or Cd2+, the mass transfer is not favored. Also, at the highest stirring speed, the two cations seemed to be des-extracted which will help us in the des-extraction process.\n\nrpm = rotations per minute.\n\n[Cd2+] = 5 × 10−4 M, Vaq/Vorg = 1, T = 25°C.\n\nThe effect of volume ratio on the extraction yield of Pb2+ or Cd2+ was investigated using lead and cadmium nitrate aqueous solutions of 5×10−4 M. A concentration of 10−3 M of the organic phase was prepared by dissolving aminooctyl diphosphonic acid in chloroform. The results are indicated in Figure 3.\n\nOrganic phase [AODMDPA] = M, [Cd2+] = [Pb2+] = M, 600 rpm, T = 25°C.\n\nA volume ratio of 1 (which gave the maximum extraction yield) was used in the following experiences since the best-obtained yield of 40% and 25% were obtained, under this ratio, for Pb (II) and Cd (II) respectively. It is observed from Figure 3 that the higher the volume ratio, the lowest yield was, caused probably by a repulsion effect between the metal ions.\n\nThe extraction kinetics results are shown in Figure 4. The variation of the stirring time between 0 and 30 minutes showed that the maximum yield of 32% was obtained for Pb2+ after 15 minutes, and 10 minutes was necessary for the Cd+2. Thus, Pb2+ has greater resistance to mass transfer than Cd2+. This can be explained according to the atomic properties of the ionic radius of lead (1.2 A°) compared to that of cadmium (0.97 A°)\n\n[Pb2+] = [Cd2+] = 5 × 10−4 M, (Vaq/Vorg) = 1, 600 rpm, T = 25°C.\n\nThe molar ratio, Q, was used to investigate the extraction yield of the two metal ions. It is expressed as:\n\nIt can be seen in Figure 5, that the extraction of the two metal cations decreases with increasing AODMDPA concentration in the organic phase. The best extraction yields obtained were 55 % and 32% for Cd2+ and Pb2+ ions, respectively, at a molar ratio Q = 1.\n\n[Pb2+] = [Cd2+] = 5 × 10−4 M, Vaq/Vorg = 1, 600rpm, T = 25°.\n\nIonic strength measures the electric field tension in a solution. To verify the influence of ionic strength on the output of extraction, we modified the aqueous phase by the addition of KNO3 and HNO3.\n\nInfluence of the addition of potassium nitrate (KNO3)\n\nThe concentrations of KNO3 were taken equal to 0.01 M, 0.1 M and 1 M. The obtained results are shown in Figures 6 and 7. According to the results, we found that there was an increase in the extraction yield of Pb2+ ions whatever the quantity of KNO3 added to the system. A higher extraction percentage of lead ions in the presence of potassium nitrate can be attributed to the formation of stable complexes of Pb2+ in the aqueous phase in the presence of the latter salt.17 However, Additions of KNO3 reduce the extraction yield in the case of Cd+2. This may be due to the competition between Cd2+ and K+ ions, which is in accordance with the literature.18\n\n[Pb2+] = 5×10−4 M, Vaq/Vorg = 1, T = 25°C.\n\n[Cd2+] = 5 × 10−4 M, Vaq/Vorg = 1, T = 25°C.\n\nInfluence of the addition of nitric acid (HNO3)\n\nThe effect of nitric acid addition to the aqueous phase before extraction was investigated, in the range of pH 2 – 3, on the extraction of 5×10−4 M of metallic cations. The results are shown in Figures 8 and 9. It was noted that the acidic medium disadvantages the lead ions extraction whereas, that of cadmium ions was seen to be favoured. Similar results were obtained in previous papers.19,20\n\n[Pb2+] = 5 × 10−4 M, Vaq/Vorg = 1, T = 25°C.\n\nEvolution of the extraction yield of Cadmium according to Q with the addition of HNO3 - [Cd2+] = 5 × 10−4 M, Vaq/Vorg = 1, T = 25°C.\n\nAnother important variable affecting lead and cadmium recovery was studied. In Figures 10, 11, other extraction steps were realized. It was noted that Cd2+ can be recovered completely when Pb2+ reached 73% after two steps.\n\n[Pb2+] = 5×10−4 M, Vaq/Vorg = 1, T = 25°C.\n\n[Cd2+] = 5 × 10−4 M, Vaq/Vorg = 1, T = 25°C.\n\nThe extraction yield was studied in the range of 10 to 40 ± 1°C. The results are given in Figure 12.\n\nEffect of temperature of the extraction yield of Lead and Cadmium, [AODMDPA] = 10−3M [Pb2+] = [Cd2+] = 5 × 10−4 M, (Vaq/Vorg) = 1.\n\nFrom Figure 8, it noticed that an increase in the temperature from 10°C to 40°C favoured extraction yield. It allows us to predict the Pb2+ and Cd2+ des-extraction at high temperatures. This may be associated with the increase in the release of water molecules upon dehydration of ions during extraction. This is in good agreement with the results found in the literature.21,22\n\nPlots of the ln K values as a function of the inverse temperature [1/T (K)] in the range 283–313 K gave a straight line (Figure 13). The thermodynamic parameters can be determined by the following expressions23:\n\nVariation in Ln Kin function 1/T for Lead and Cadmium extraction with AODMDPA.\n\nFrom these equations (1) and (2) we pull the following equation (3) to calculate ∆H° and ∆S° while drawing the curve LnK according to the temperature.\n\nThe numerical values of ΔH0, ΔS0 are computed from the slope.24 The negative value of Gibbs free energy as shown in Table 1 indicates the spontaneous nature of extraction, while positive value of ΔH0 reflects the endothermic extraction behavior. The positive value of ΔS0 may be due to the increase in randomness around the chelating function.25\n\nIn order to study the synergetic effect, Tri octyl phosphine oxide TOPO (solvating agent) was added to our extractant (chelating agent) at 298 K. The synergetic coefficients were obtained as described by M. Taube and al.26\n\nDifferent phosphonic/TOPO volume ratios were tested presenting negative coefficients maybe because of steric and competition phenomena in the organic phase. The best synergetic coefficient was obtained at a phosphonic acid/TOPO volume ratio of 3 (Figures 14 and 15). The synergistic enhancement is attributed to the formation of complexes with the two extractants. Different positive synergetic coefficients are gathered in Table 2 showing that whatever the molar ratio, a positive synergetic coefficient was obtained.\n\n[Cd2+] = 5 × 10−4 M, (Vaq/Vorg) = 1; (AODMDPA: TOPO = 3: 1), T = 25°C.\n\n[Pb2+] = 5 × 10−4 M, (Vaq/Vorg) = 1;(AODMDPA: TOPO = 3: 1), T = 25°C.\n\nQ: molar ratio Q1: Q = 1, Q2: Q = 2, Q3: Q = 3, Q4: Q = 4, Q5: Q = 5.\n\nD1: Distribution factor using TOPO alone. D2: Distribution factor using AODMDPA alone.\n\nS: Synergetic factor S=logD1+2D1+D2.\n\n\nConclusion\n\nA new phosphonic acid extractant named aminooctylphosphonic acid easily synthesized under microwave using low-cost chemicals. Complete achievement of Cd2+ can be reached when Pb2+ extraction reaches 73% after two cycles. A positive synergetic effect was observed at an AODMDPA/TOPO ratio of 3. It is a very encouraging result that can lead us to recover Cd2+ and lower the concentration of Pb2+ from wastewater.\n\n\nData availability\n\nOpen Science Framework: Spectrophotometric study of Solvent extraction of Pb (II) and Cd (II) by aminooctyldiphosphonic acid. https://doi.org/10.17605/OSF.IO/FMHT4.27\n\nThis project contains the following underlying data:\n\n- NMR Spectra\n\n- Raw tables\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\nMartin S, Griswold W: Human health effects of heavy metals. Environ. Sci. Technol. Briefs Citizens. 2009; 15: 1–6.\n\nMason, Lisa H, Jordan P, et al.: Pb neurotoxicity: neuropsychological effects of lead toxicity. BioMed Res Int. 2014; 8.ID 840547\n\nDashtian K, Zare-Dorabei R: An easily organic–inorganic hybrid optical sensor based on dithizone impregnation on mesoporous SBA-15 for simultaneous detection and removal of Pb (II) ions from water samples: response-surface methodology. Appl. Organomet. Chem. 2017; 31: e3842. Publisher Full Text\n\nSienkiewicz J: Effect of heavy-metals industry on plant communities. Sci. Total. Environ. 1986; 55: 339–349.\n\nGupta N, Khan DK, Snatra SC: An assessment of heavy metal contamination in vegetables grown in wastewater irrigated areas of Titagarh, West Bengal, India. Bull. Environ. Contam. Toxicol. 2007; 80: 115–118. PubMed Abstract | Publisher Full Text\n\nRahimzadeh MR, Rahimzadeh MR, Kazemi S, et al.: Cadmium toxicity and treatment: An update. Caspian J Intern Med. 2017 Summer; 8(3): 135–145. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGupta VK, Yola ML, Atar N, et al.: A novel sensitive Cu (II) and Cd (II) nanosensor platform: Graphene oxide terminatedp-aminophenyl modified glassy carbon surface. Electrochimica Acta . 2013; 112: 541–548.\n\nPat C: Polyamine compounds containing phosphonic, sulfonic and carboxylic radicals and their preparing process. China Pat. 2000; 1243833; CAN 133:271319.\n\nEur. Pat: Method and compositions for controlling calcium sulfate scaling in mining circuits. Eur. Pat. 1993; 538026; CAN 119:55656.\n\nTewari PK, Singh AK: Preconcentration of lead with amberlite XAD-2 and XAD-7 based chelating resins for its determination by flame atomic absorption spectrometry. Talanta. 2002; 56(4): 735–744. PubMed Abstract | Publisher Full Text\n\nSeubert A, Klingenberg A: Sulfoacylated macroporous polystyrene-divinylbenzene: a new type of cation exchanger for the analysis of multivalent metal cations. J. Chromatogr. 1997; A 782,2: 149–157. Publisher Full Text\n\nDidi MA, Kaid M, Villemin D: Dodecylhydroxydiphosphonic acid for solvent extraction. Solvent Extr Ion Exch. 2008; 26(2): 113–127. Publisher Full Text\n\nM’hamed K, Mohamed AD, Didier V: Poly (aminomethylenephosphonic) acid for solvent extraction of metal ions. Chemistry & Chemical Engineering, Biotechnology, Food Industry. 2011; 12,269–280.\n\nBoulenouar I, Kaid M’h, Abbes O, et al.: Solvent Extraction of Lanthanum (III) and Europium (III) from Nitrate Media by Aminooctyldimethylene Diphosphonic Acid. Solvent Extraction Res Devel., Japan . 2016; 23(1): 51–61. Publisher Full Text\n\nMichalova V, Kuleva N: Arsenazo III as a spectrophotometric reagent for deter mination of lead. Talanta . 1979; 27: 63–66. Publisher Full Text\n\nMichalova V, Yuroukova L: Arsenazo III as a spectrophotometric reagent for zinc and cadmium Analytica chimica acta. Elsivier Sci. 1973; 68: 73–82. Publisher Full Text\n\nSoltani H, Yaftian MR, Zamani A, et al.: Selective Liquid-Liquid Extraction of Lead Ions Using Newly Synthesized Extractant 2-(Dibutylcarbamoyl) benzoic Acid. Anal. Bioanal. Chem. Res. 2015; 2(2): 91–98. Publisher Full Text\n\nJha MK, Kumar V, Jeong J, et al.: Review on solvent extraction of cadmium from various solutions. Hydrometallurgy. 2012: 111–112, 1–9.\n\nKonczyk J, Kozlowski C, Walkowiak W: Lead (II) removal from aqueous solutions by solvent extraction with tetracarboxylresorcin[4]arene. Physicochem. Probl. Miner. Process. 2013; 49(1): 213–222. Publisher Full Text\n\nSonmez E, Sonmez F, Kumbasar RA, et al.: Synergistic and selective extraction of Cd2+ from acidic solution containing Cd2+,Co2+, Ni2+by triisooctylamine (TIOA) and tributyl phosphate (TBP). J Industrial Engineering Chemistry . 2012; 18: 1286–1292. Publisher Full Text\n\nHuang C: Rare earth coordination chemistry: fundamentals and applications. Singapore: John Wiley & Sons (Asia) Pte Ltd.; 2010. p. 1–39.\n\nKolarik Z: Gmelin handbook of inorganic chemistry . 8th ed. Berlin: Springer-Verlag; 1982; 34–227.\n\nYaftian MR, Hassanzadeh L, Eshraghi ME, et al.: Solvent extraction of thorium (IV) and europium (III) ions by diphenyl-N,N-dimethylcarbamoylmethylphosphine oxide from aqueous nitrate media. Sep Purif Technol. 2003; 31: 261–268. Publisher Full Text\n\nChen D, Chen J, Luan X, et al.: Characterization of anion–cationic surfactants modified montmorillonite and its application for the removal of methyl orange. Chemical Engineering J . 2011; 171: 1150–1158. Publisher Full Text\n\nSoltani H, Yaftian MR, Zamani A, et al.: Selective Liquid-Liquid Extraction of Lead Ions Using Newly SynthesizedExtractant 2-(Dibutylcarbamoyl) benzoic Acid. Anal. Bioanal. Chem. Res. 2015; 2(2): 91–98.\n\nTaube M, Siekierski S: Nukleonika, General remarks on synergic effects in the extraction of uranium and plutonium compounds. Nukleonika. 1961; 6: 489–502.\n\nMhamed K, Djamila I, Hanane Z, et al.: Spectrophotometric study of Solvent extraction of Pb (II) and Cd (II) by aminooctyldiphosphonic acid.2021, August 12. Publisher Full Text"
}
|
[
{
"id": "148149",
"date": "20 Sep 2022",
"name": "Mohamed Abdelkrim Hasnaoui",
"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\nPage 3 : Extraction procedure:\nAuthors should give the definition of Q the “molar ratio”and why it’s fixed to 1, 2, 3 , 4 and 5. It’s mentioned that different concentrations of the extractant (10-3M to 10-6 M) have been studied. These values are not compatible with the Q ratios given on figures 1 and 2, when [M2+]= 5.10-4M) (M= Pb2+ or Cd2+). If the concentration of the cation is fixed, the concentration of the extractant should vary from 5.10-4 to 25 10-4.\n\nPage 4 : Results and discussion\nIt’s more convenient to start with stirring time (Kinetic) in order to get the optimal time of extraction.\n\nThe parameter time has not been mentioned anywhere. Once this parameter is fixed, the volume ratio must be investigated followed by volume ration and molar ratio.\n\nThe investigation of the volume ratio (figure 3), has the molar ratio is close to 2 (see concentration of M2+ and organic phase). This parameter “volume ratio” should be investigated again at Q=1 for a convenient comparative study.\n\nThe comparison of the maximum %yield obtained, it can be seen a substantial difference. The maximum %yield of Cd2+ extraction reached 83 % (figure 2) when only 55% (figure 5) was obtained at ( 600rpm; Va/Vorg=1, and Q=1 fixed). (see table below). It can also be seen that the maximum of %yield of cadmium obtained after 10 mn is close to 31 % (figure 4), while 83% was obtained when stirring speed was investigated (figure 2). This Result needs more interpretation. See table: https://f1000researchdata.s3.amazonaws.com/linked/452329.Table.png\n\nEffect of KNO3 addition:\nOn figure 6, it’s mentioned that the max %Yield obtained for free-KNO3 solution ( initial Pb2+) when, Va/Vorg=1, 600rpm and Q=1, is lower than mentioned on figure 1 ( 32 %).\n\nOn page 7 ”..can be attributed to the formation of stable complexes of Pb2+ in the aqueous phase in the presence of the latter salt..” : the authors tried to explain the augmentation of the yield of Pb2+ by the stability of the complex in the presence of KNO3. The authors are invited to explain why only for weak concentration 0,01M, the complex is stable?\n\nLikewise, for better comparison the study should be investigated even at molar ratio Q=1. Because, it can be shown, that for the free-KNO3 solution, %Yield of cadmium is close to 65 %, while it reached 81 % when molar ratio Q=1 (figure 1). This lead to suppose that probably higher yield than 92% will be obtained at Q=1.\n\nInfluence of temperature:\n\nOn page 8: “..It allows us to predict the Pb2+ and Cd2+ des-extraction at high temperatures..” . There is no extremum for the two curves to predict the des-extraction by extrapolation, the study should be extended to others temperature higher than 40°.\n\nThe procedure to keep the temperature constant should be given in experimental section.\n\nConclusion\nRephrase the conclusion in a way that covers all the results obtained.\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? No\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
},
{
"id": "158212",
"date": "19 Dec 2022",
"name": "Yehezkiel Steven Kurniawan",
"expertise": [
"Reviewer Expertise Solvent extraction",
"Metal separation",
"Separation engineering",
"Metal-organic framework",
"Heterocyclic compounds"
],
"suggestion": "Not Approved",
"report": "Not Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1) The authors describe the harmful effects of lead(II) and cadmium(II) ions in the introduction but no explanation of why the authors use aminooctyldiphosponic acid structure as the extraction agent.\n2) As a new compound, the HRMS measurement of aminooctyldiphosponic acid shall be reported.\n3) Statistical error bars were reported in Figure 2 but other Figures do not show any error bars. Please revise the other Figures with error bars.\n4) The authors give a small portion of the discussion of the experimental results and focus on reporting the experimental data without enough explanation/description.\n5) How to recover the extraction reagent? Did the authors do the stripping experiment?\n\nIs the work clearly and accurately presented and does it cite the current literature? Partly\n\nIs the study design appropriate and is the work technically sound? No\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\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/10-1140
|
https://f1000research.com/articles/10-1139/v1
|
10 Nov 21
|
{
"type": "Research Article",
"title": "Polymer tiles from polyethylene terephthalate (PET) wastes and fly ash: mechanical properties and durability",
"authors": [
"Taiwo O. Omosebi",
"Noor Faisal Abass",
"Noor Faisal Abass"
],
"abstract": "Background: Plastic waste (PW) is becoming increasingly hazardous to the environment as a result of its massive production, causing significant damage to both the ecosystem and its inhabitants. Managing plastic waste is a global concern due to its non-biodegradable nature. However, it is important to handle PWs properly to curtail the environmental emissions associated with their incineration and dumping into landfills. This research investigates the possibility of producing tiles from polyethylene terephthalate (PET) waste bottles and fly ash. The mechanical properties, as well as the chemical resistance of the manufactured PET polymer tiles, are reported in this study. Methods: PET waste was used in varying proportions (from 30% to 100%) by sand weight. The shredded PET waste was heated at 230 oC before being suitably blended with fly ash. It was then poured into the designated mold, removed after one hour, and cooled for 24 hours before testing. Results: The assessment of the physical and mechanical properties of the materials revealed that the tiles produced with 30% PET content performed better in terms of material density and strength compared to the samples with higher PET content. The highest compressive strength being 6.88 MPa. Based on the results of the tests, the produced PET tiles have a low water absorption efficiency of 80% lower when compare to cement and ceramic tiles (the water absorption values are between 0.98% and 0.09%). Conclusions: The results from this study indicate that PET waste bottles can be used to produce long-lasting, durable, and extremely low water absorption eco-friendly tiles for both residential and commercial applications. This prospect of tile production using polyethylene terephthalate (PET) waste and fly ash would not only minimize the cost of building products but will also act as a waste diversion to mitigate environmental emissions caused by plastic waste disposal.",
"keywords": [
"plastic wastes",
"pollution",
"aggregates",
"mechanical properties",
"polymer tiles"
],
"content": "Introduction\n\nPlastic is a synthetic, solid, hydrocarbon-based polymer; it can either be a thermoplastic or thermosetting material. Thermoplastic is a plastic material that can soften upon heating and harden when cooled; hence, it can be molded into different shapes. Thermosetting materials cannot be remelted when they solidify; they are mainly used as Bakelite.1 Plastics are in common use due to their lightweight, soft nature, flexibility, non-corrosiveness, and durability. Plastics are comfortable packing materials and containers but wastes from plastics are a major cause of environmental pollution; they emit poisonous gases upon incineration and are not biodegradable.2 Plastic materials are reportedly carcinogenic as they contain chlorine and other carcinogens. The burning of plastic waste produces toxic gases such as phosgene, carbon monoxide, chlorine, sulfur dioxide, nitrogen oxide, and other deadly dioxins that are harmful to the environment. Since plastic wastes account for the highest percentage of waste produced globally, there is a need to ensure proper management of such waste.3,4 Plastics are commonly used as packing materials, but their wastes can be used in the construction industries to produce construction materials, such as floor tiles, roof tiles, building blocks, etc. This can reduce construction costs and minimize environmental pollution. For instance, plastic wastes can be mixed with sand and other additives to produce constructional materials.5 Presently, recycled plastic wastes are gradually replacing natural materials such as fiber, metal, wood/timber, and sand, thereby preserving the natural environment. Proper management of solid wastes through recycling into new products will help to promote a sustainable environment, conservation of natural resources, and cheap raw materials.4 On the other hand, the lack of adequate management of solid wastes will add to the existing environmental problem; hence, solid wastes must be properly managed by recycling them into new useful products.6 Being that plastic wastes cannot decompose easily and are produced in huge quantities, their deposition into landfills may not be a permanent solution.7,8\n\nRecycling is currently not an easy management strategy for plastic materials because it is a labor and capital-intensive process.9 Previously, plastics were considered environmentally friendly materials that save energy, reduce raw material extraction, and fight climate change. However, the rate of plastic waste generation has increased tremendously, and management has become a serious issue. Consequently, researchers have suggested the use of plastic wastes in concrete production for two major reasons: first, to resolve the environmental problem associated with their disposal and second, to reduce construction costs since they are available in great quantities.9 Cement is generally used as a binder in the construction industry; however, the high cost of cement has prevented many people from building their houses and has hindered the advancement of the construction sector.10,11 Hence, it is important to find a suitable replacement for this expensive and essential building material.12,13\n\nPolyethylene terephthalate (PET) bottles are now used as binders in the manufacture of a wide range of building materials, including tiles. Shredded plastic waste is a recycled material that has received a lot of attention in the construction industry.11 Several studies have documented the potential suitability of plastic waste as construction materials. For example, Mehdi et al.14 reported that high-density polythene (HDPE) plastics can be used to make roof tiles when combined with sand. The results of their study revealed that composite tiles made with 70% HDPE had better performance and quality after analysis. Several experimental studies on the use of recycled PET bottles as a substitute for natural aggregates in concrete have recently been published,14 and as resin in polymer concrete.15 Akinwumi et al.16 documented the production of stabilized soil blocks from shredded plastic waste and their study opined that 1% finely shredded PET waste (size 6.3 microns) by weight could be used for successful block stabilization. Mustafa et al. [2019], investigated the use of PET waste as a partial replacement for fine aggregates in the production of high-impact resistance building materials. The impact resistance increased by 39% in mortars made with a 20% plastic material. Kumi-Larbi et al.17 reported the successful production of sand blocks using plastic waste and the findings of their study revealed that solid and durable sand blocks can be produced without the use of extra water, using only plastic waste.\n\nYang et al.18 also investigated the feasibility of producing eco-friendly door panels by combining plastic waste with wood dust. In a particular study, Al-Hadithi and Hilal21 used shredded PET waste to make roof tiles and discovered that the compressive strength of the sample decreased as the PET volume increased. Borg et al.20 used PET fibers in concrete and discovered that at higher PET fiber contents, PET fibers significantly decreased the compressive strength of the sample. Al-Hadithi and Hilal21 tested the use of plastic waste fibers in the construction of self-compacting concrete and discovered that the compressive strength of the sample increased as the plastic waste content increased. This study aims to examine the viability of utilizing PET waste as a binder in full replacement of cement to produce tiles. The main objectives of this study are to evaluate the possibility of recycling PET waste to produce tiles, as well as to examine the physical and mechanical performance of the PET polymer tiles.\n\n\nMethods\n\nThe materials used in making the composite tiles were sourced locally; the locally sourced materials included plastic wastes, metal mold, wood stirrer, sieve, hand gloves, coal pot, face mask, and engine oil. The PET wastes used in this study were shredded plastic bottle wastes collected from a Waste Resource Management Company located at 14000 Bukit Mertajam, Penang, Malaysia. The fly ash used was supplied to the School of Housing, Building, and Planning Resource Laboratory, Universiti Sains Malaysia. The shredded PET wastes were heated and melted inside an aluminum pot at a temperature of 230 °C before the addition of fine dried fly ash into the melted plastic wastes at different percentages. The mixture was homogenized and poured into a 5 cm thick iron mold that had been lubricated with engine oil for easy removal. The edge of the mold was banged continuously for proper compression. After one hour, the samples were de-molded, cooled, and cured at ambient temperature for forty-eight hours before testing (see Table 1). Table 2 shows the chemical composition of the obtained fly ash. The following chemicals: acetone, benzene, acetic acid, hydrochloric acid (HCl), carbon tetrachloride (CCl4), sodium carbonate, and sodium chloride were used and supplied by the School of Housing, Building, and Planning to determine the chemical tolerance of the polymer tiles produced.\n\nThe compressive strength of plastic composite tiles was determined using the Instron Universal Testing Machine (UTM 5967) (Instron Norwood, USA) and the ASTM D638 specification which involved casting of the homogenously mixed PET paste and fly ash into a standard cube for compression testing of size 50 × 50 × 50 mm. Samples with lengths of 50 mm, widths of 50 mm, and thicknesses of 50 mm were prepared for strength testing for this test, the samples were tested on the Instron Universal Machine after de-molding and cooling for 48 hours at room temperature to determine their compressive strength.\n\nThe chemical resistance test was performed on the samples in accordance with ASTM D543-14 by cutting the sample tiles into 20 × 20 × 20 mm sizes and soaking them in a different chemical solution for a period of seven days. The purpose of this test was to evaluate the sample’s resistance to various chemical reagents. The chemicals used for this study were acetone, benzene, acetic acid, hydrochloric acid (HCl), carbon tetrachloride (CCl4), sodium carbonate, and sodium chloride with 5% dilution.\n\nFurthermore, the ASTM D570 standard method was used to determine the relative water absorption rate of the polymer tiles sample after immersion in water for 72 hours. The percentage change in weight of the sample was calculated and recorded, all experiments were carried out at room temperature.\n\nThe flexural strength of the PET polymer tiles was determined using ASTM D 72-64-15. For the testing, three prismoids measuring 40 × 40 × 160 mm3 were made from each batch of PET polymer paste. The prism specimen was placed on the ELE International Flexural Testing Machine loading frame with the assurance that the specimen to be examined is centered and parallel with the two longitudinal levers located below and above the machine arms. The specimens were subjected to bending tests using a bending test machine loaded at a continuous rate of 50 N/s until they failed, and the failure load was recorded. The ultimate flexural strength was calculated by taking the average of three specimens from the same batch.\n\nThe average density of tile specimens was discovered by taking the measurement of the weight of sample of the polymer tiles and the diameter of the specimen. The polymer tile is prepared and poured into a prism cube size 50 × 50 mm. Three to five samples of each mix are selected for the test. The weight of each sample was recorded. The density was calculated using the equation:\n\nWhere j is the sample weight and d is the diameter of the sample size.\n\nWhile the porosity was measured in accordance with the RILEM guidelines.22 Cylinder specimens with diameters of 50 mm and heights varying from 35 to 40 mm were cast. The samples were dried in an oven for 78 hours at 105 ± 2 degrees Celsius. They were then cooled in a desiccator for 24 hours. The weight of the oven dried samples was calculated and denoted as Wd. The sample was then placed in a dissector filled with de-aired and de-ionized water until it was completely immersed in water. The samples were held under a steady vacuum for 78 hours before being allowed to equilibrate. The weight of the samples was determined in both the air (Wa) and the water (Ww). The absolute porosity, P for the samples is calculated using:\n\n\nResults and discussion\n\nPET polymer tiles produced with 30% PET and 70% fly ash achieved the highest value (0.98%) while those produced with 100 PET and 90% PET + 10% fly ash presented the lowest values (see Figure 1). This means that the water absorption of the PET polymer tiles is directly a function of the PET content but inversely related to the fly ash content.\n\nThe density of the PET polymer tile was determined, and the result showed PT1, PT2, PT3, PT4, and PT5 (Table 1) are 1688, 1575.2, 1370.4, 1181.6, and 1070.3 kg/m3 respectively. The PET polymer tiles produced with 100% PET had the lowest density (1070.3 kg/m3) while those produced with 30% PET content had the highest density (1688.0 kg/m3) as shown in Figure 2. Therefore, increases in the PET content decreased the density of the PET polymer tile. Notably, other studies previously indicated that an increase in PET content reduced the density of the resulting composites.19,23\n\nThe PET plastic composites produced with 30% PET content presented the highest porosity value (4.14%) while those containing 90% PET achieved the lowest porosity value of 0.39% (see Figure 3). The porosity values fall consistently as the fly ash percentage decreases, yet the percent porosity of PT 5, which contains pure PET (no fly ash), is higher than PT 3 and PT 4, which contain 30% and 10% fly ash, respectively. This means that the presence of fly ash in the PET tiles has an effect on the porosity value of the PET polymer tiles but should not exceed 10% in a particular mix. Rilem23 made a similar observation.\n\nPET composite that contains 100% PET exhibited the lowest compressive strength value (0.012 MPa) while those produced with 30% PET content had the highest compressive strength value (6.88 MPa) as shown in Figure 4. The compressive strength values (6.88, 5.49, 4.36, 2.94, and 0.012 MPa respectively) steadily increased with the fly ash content but decreased with increasing PET content. The results show that increasing the PET waste content reduces the compressive strength of the composite.18,19,21,23\n\nThe flexural strength of the PET polymer tiles was calculated in accordance with ASTM D 72-64-15, and the results are shown in Figure 5. The sample with 100% PET content had the lowest flexural strength, while the sample with 30% PET content had the highest (6.75 MPa). This shows that the flexural strength improved as PET content decreased but increased as fly ash content increased. Because of this behavioral adjustment, the flexural strength of the PET polymer tile is dependent on the PET material. A similar observation was also previously reported and showed that flexural strength decreased as the amount of plastic waste in a structure increased.19–21\n\nChemical resistance tests were performed on the samples in accordance with ASTM D543-14 guidelines. The samples were prepared with length = 20 mm, width = 20 mm, and thickness = 10 mm, then weighed and immersed in various chemicals: hydrochloric acid (HCl), sodium chloride (NaCl), sodium carbonate (Na2CO3), acetone, benzene, acetic acid, and carbon tetrachloride (CCl4). The experiment was carried out at room temperature for 168 hours. Following the soaking time, the samples were removed, rinsed with distilled water, and air-dried before measuring the weight and dimensions of the soaked samples and comparing them to the weight and size of the non-soaked samples. Comparative findings revealed no significant changes in sample weights or measurements after seven days of soaking in different chemicals; this finding is consistent with Dhawan et al.23\n\n\nConclusions\n\nBased on the experimental results, the following conclusions were reached:\n\n• A higher PET content in the tile reduces water absorption. The percentage of water absorption decreased from 0.98% to 0.1%.\n\n• Samples with 100% PET content had the lowest average density (1070.3 kg/m3), while samples with 30% PET content had the highest density (1688.0 kg/m3). When compared to control samples, density increased steadily with increasing fly ash content but decreased with an increasing percentage of PET waste.\n\n• The compressive and flexural strength of the PET polymer tiles decreased as the PET content increased. The compressive strength decreased from 6.88 MPa for samples with 30% PET content to 0.012 MPa for samples with 100% PET content, while the flexural strength decreased from 6.75 MPa for samples with 30% PET content to 0 (brittle) for samples with 100% and 90% PET content.\n\n• PET polymer tile tolerance in different chemical solutions has been demonstrated, with no significant changes in weight or dimensions found after seven days of soaking in different chemicals.\n\nThese results from this study indicate that PET waste bottles can be used to produce long-lasting, good strength, minimal water absorption, and eco-friendly tiles for both residential and commercial applications. This prospect of tile production using polyethylene terephthalate (PET) waste and fly ash would not only minimize the cost of building products but will also act as a waste diversion to mitigate environmental emissions caused by plastic waste disposal.",
"appendix": "Acknowledgements\n\nAuthors are thankful to the Dean of the School of Housing, Building, and Planning, Universiti of Sains Malaysia for providing materials needed for this research.\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\nReferences\n\nAkçaözoğlu S: Evaluation of waste plastics as recycled plastic composite materials. J Waste Management. Edorium; 2015; Vol. 1, pp. 16–19. Publisher Full Text\n\nTaiwo O, O, Abas NF: Mechanical Properties and Durability of PET waste Aggregates in Roof Tiles Production. Int J Recent Technol Eng . 2021; 9(5): 300–304. Publisher Full Text\n\nWahid SA, Rawi SM, Desa NM: Utilization of Plastic Bottle Waste in Sand Bricks. J Basic Appl Sci Res. 2015; 5(1): 35–44. 2090-4304.\n\nSadiq MM, Khattak MR: An Overview of Plastic Waste Management. J Emerging Technol Innovative Res (JETIR). Delhi: Plastic Waste Management Institutes, Central Pollution Control Board; 1999; 2(6). Publisher Full Text\n\nAnslem EO, Eneh: Application of Recycled Plastics and Its Components in the Built Environment. BEST: Int J Management. Delhi: Information Technology and Engineering; 2015; Vol. 3, Issue 3, pp. 9–16. 2348-0513.\n\nShiri ND, Varun Kajava P, Ranjan HV, et al.: Processing of Waste Plastics into Building Materials Using a Plastic Extruder and Compression Testing of Plastic Bricks. J Mech Eng Automation. 2015; 5(3B): 39–42. Publisher Full Text\n\nPatil PS, Mali JR, Tapkire GV, et al.: Innovative techniques of waste plastic used in concrete. J Mech Eng Auto. 2015; 5: 1800–1803. Publisher Full Text\n\nEPA 430-R-11-005: Inventory of U.S. Greenhouse Gas Emissions and Sinks: (1990–2009). U.S. Environmental Protection Agency homepage. U.S.; 2011. Reference Source\n\nMelik B, Habib T, Asroun A: Properties of Waste Tire Rubber Powder. Eng Technol Appl Sci Res. 2014; 4(4): 669–672. Publisher Full Text\n\nKonin A: Use of plastic wastes as a binding material in the manufacture of tiles: a case study of wastes with a basis of polypropylene. Material structures J RILEM. 2011; 1381–1387. Publisher Full Text\n\nLaryea S, Agypong SA, Leiringer R, et al.: 4th West African Built Environment Research (WABER) Conference (pp. 1231-1237).Abuja, Nigeria: West African Built Environment Research (WABER) Conference.\n\nRamaraj AP, Nagammal AN: Exploring the Current Practices of Post-Consumer PET Bottles and The Innovative Applications as A Sustainable Building Material. 30th International Plea Conference. Ahmedabad: Cept University Press; 2014; pp. 16–18.\n\nVelumani P, Karthik SG: Development of Eco-Friendly Pressed Roof Tiles: A Prologue Study. Int J Sci Eng Res. 2017; 8(12): 2030–2033.\n\nHarini BV: Use of Recycled Plastic Waste as a partial replacement for fine aggregate in Concrete. International Journal of Innovative Research in Science, Engineering, and Technology. 2015; pp. 85–96. Publisher Full Text\n\nNiaki MH, Fereidoon A, Ahangari MG: Effect of Basalt, Silica Sand and Fly Ash on the Mechanical Properties of Quaternary Polymer Concretes. Bull. Mater. Sci. 2018; 41: 69 © Indian Academy of Sciences. Publisher Full Text\n\nAkinwumi II, Domo-spiff AH, Salami A: Case Studies Construction Materials Marine plastic pollution and affordable housing challenge: shredded waste plastic stabilized soil for producing compressed earth bricks. Case Stud. Constr, Mater. 2019; 11. e00241. Publisher Full Text\n\nKumi-Larbi A, Yunana D, Kamsoulounm P, et al.: Recycling waste plastics in developing contries: use of low-density polyethylene water sachets to form plastic bonded sand blocks. Waste Manag. 2018; 80: 112–118. Publisher Full Text\n\nYang Y, Boom R, Irion B, et al.: Recycling of composite materials. Chem. Eng. Process. Process Intensif. 2012; 51: 53–68. Publisher Full Text\n\nBamigboye GO, Adedeji AA, Olukanni DO, et al.: Reliability of Gravel in Place of Granite in Concrete Production. J Eng Appl Sci . 2017; 12(20): 5121–5128. Publisher Full Text\n\nBorg RP, Baldacchino O, Ferrara L: Early age performance and mechanical characteristics of recycled PET fiber reinforced concrete. Construction and Building Materials. 2016; 108. pp. 29–47. Reference Source\n\nAL-Hadithi AI, Hilal NN: The possibility of enhancing some properties of self-compacting concrete by adding waste plastic fibres. J Buil Eng. 2016; 8A: 20–28. Publisher Full Text\n\nRilem C: 11.3. Absorption of water by immersion under vacuum. Mater Struct . 1984; 17(101): 391–394.\n\nDhawan, Bisht BMS, Rajeev Kumar, et al.: Recycling of plastic waste into tiles with reduced flammability and improved tensile strength. Process Safety and Environmental Protection. 2019; 124: 299–307. Advanced Engineering, 2(6), pp. 42–46. Publisher Full Text"
}
|
[
{
"id": "238560",
"date": "13 Feb 2024",
"name": "Shahbaz Dandin",
"expertise": [
"Reviewer Expertise Materials"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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: 1. The PET melting process, requiring 260 degrees Celsius, is a lengthy one. It's essential to explore how this method aligns economically with conventional materials.\n2. The results and discussions lack explanations for variations in various parameters considered in this paper.\n3. The discussion session should encompass comparisons with waste materials from existing literature.\n4. This research could benefit from considering binding parameters when mixing flash and melted PET bottles in different proportions.\n5. The research limitations need to be succinctly outlined.\n6. Melting a mass quantity of PET at 260 degrees Celsius poses significant challenges. What are your environmental concerns in this scenario?\n7. The latest literature exploring the behavior of PET and fly ash, such as ref [1,2,3] could have been considered in 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?\nI cannot comment. A qualified statistician is required.\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? No",
"responses": []
},
{
"id": "238552",
"date": "15 Feb 2024",
"name": "Fathoni Usman",
"expertise": [
"Reviewer Expertise Structure and materials"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nElaborate and add citations for the following statement: Plastic materials are reportedly carcinogenic as they contain chlorine and other carcinogens.\nThere is too much common sense in the 1st paragraph of the Introduction. Kindly focus on PET waste and its problems.\nHow did you melt the PET and how did you handle the mixing with PET and producing the homogenously mixed PET paste and fly ash? How did you mould it? Kindly elaborate a detail descriptive paragraph on it.\nThe compressive strength of plastic composite tiles was determined using the Instron Universal Testing Machine (UTM 5967) (Instron Norwood, USA) and the ASTM D638. The compressive testing for plastic material is supposed to be following ASTM D695. ASTM D638 for tensile test.\nKindly check the following statement (Is RIlem the name of the author?): Rilem23 made a similar observation.\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?\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": []
},
{
"id": "238557",
"date": "19 Feb 2024",
"name": "Seema Raj",
"expertise": [
"Reviewer Expertise Waste management in bricks/tiles",
"Biodiesel",
"phytormediation and water treatment"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\n1. The title of the manuscript should be more attractive. 2. The investigators have done many characterizations, but in abstract they have only emphasized on Compressive strength and water absorption. They should rewrite the abstract in more precise way and also mentioned the optimum results. 3. Table 1 should be more elaborated with respect to composition of samples. 4. The investigators didn't provide any SEM results or image of tiles. 5. In methodology the investigators should provide the type of PET waste they have used (granular or flaky) 6. In Chemical resistance heading the investigators immersed samples in many chemicals, they should reflect results with respect to efflorescence. 7. Recent references 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? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Partly\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nNot applicable\n\nAre all the source data underlying the results available to ensure full reproducibility? Partly\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1139
|
https://f1000research.com/articles/10-1138/v1
|
10 Nov 21
|
{
"type": "Research Article",
"title": "Evaluation of the effect of soft drinks on the surface roughness of dental enamel in natural human teeth",
"authors": [
"Ibrahim Al-Amri",
"Roula Albounni",
"Sultan Binalrimal",
"Roula Albounni",
"Sultan Binalrimal"
],
"abstract": "Background: Exposing enamel to soft drinks and beverages causes changes in the microscopical morphology. Changes in the physical characteristics, like hardness and surface roughness, were studied with various parameters. Factors such as pH, exposed duration, and other content of the soft drinks have different effects on the enamel. Methods: Thirty-six human premolar teeth were randomly divided into three groups (n=12). Group 1 consisted of teeth which were immersed in artificial saliva (control), group 2 consisted of teeth which were immersed in Pepsi, and group 3 consisted of teeth which were immersed in Mirinda. After the preparation of samples and necessary measures, surface roughness was measured using the profilometer. Baseline measurements were taken. Reading two and reading three were taken after exposing the specimens for three days and 15 days, respectively. All of the collected data were compared statistically using SPSS and presented in tables and graphs. Results: At the baseline, the surface roughness value was the same for all three groups. On the 3rd day, the Mirinda group showed more surface roughness compared to that of the test and Pepsi groups, which was statistically significant. On the 15th day, both the Pepsi and Mirinda groups showed increased surface roughness compared to that of the control, which was statistically significant. Conclusions: Within the limitation of this study, it can be concluded that surface roughness increased when teeth were exposed to both soft drinks",
"keywords": [
"Soft drinks",
"surface roughness",
"dental enamel",
"pH"
],
"content": "Introduction\n\nModern-day food and drink has a deleterious effect on the oral cavity including the tooth; though enamel is considered to be the hardest part of the body, exposure to many foods and beverages has been shown to have a negative impact on the enamel.1 Though the enamel surface appears to be flat, it is not. It has a wavy structure because at places where Retzius’ striae end such striae overlap in the form of steps, with the appearance of shallow grooves referred to as perikymata. With its organic and inorganic structure, enamel shows pronounced hardness, but it is also fragile at the same time and similar to glass. Exposure to several environmental factors including food and beverages makes this strongest part of the body susceptible to breakdown.2\n\nTooth wear is thus considered as an additive, multifactorial lifelong event which is of great concern because it is irreversible.3 Among these, tooth erosion has taken a major toll on management of tooth wear. Tooth substance loss associated with erosion by acidic foods and soft drinks is an increasing social problem because it is frequently linked with individuals’ lifestyle and eating habits.1 Consumption of these beverages and soft drinks has increased worldwide, especially in the younger generation, which leads to the early loss of teeth, and is a serious concern. This impact on oral health, and teeth as such, has led to much research to find out the exact factors associated with this and thus how to overcome this effect.4\n\nIn the modern world, with the influence of the western world, this increased consumption of soft drinks and carbonated beverages is becoming a problem. These soft drinks are becoming popular because of added content to these drinks, which increase the palatability or taste. The major added content to these soft drinks is citric acid, phosphoric acid, and malic acid.5 If the soft drink is the external factor for the alteration in tooth enamel to occur, there are also intrinsic factors, such as eating disorders or bulimia and/or gastric reflux, which result in the output of gastric content into the oral cavity. This leads to a loss of tooth substance or erosion of the tooth on the lingual aspect of the teeth, sparing the buccal aspect.1\n\nWithin the available literature, it was found that several factors influence the behavior of enamel when it is exposed to soft drinks and beverages. These factors are pH, acidic species, calcium and phosphate contents, and exposure time.1,6,7 For enamel demineralization to occur, the pH on the enamel surface must fall below 5.5. Many available soft drinks have a pH value well below 5.5. Several studies3,4 have been published on the pH values of soft drinks, as an indicator of their erosive potential; though it is an important component of the soft drink to be related to the erosion, the response can be modified by other factors like calcium and phosphate content and the amount of time the enamel is in contact with the soft drinks.1\n\nTo date, many studies have mainly concentrated on two factors, pH and the physical characteristics of the enamel. This property has been evaluated by measurement of the roughness of enamel.4,8 Certain quantitative evaluations, using various devices like the profilometer, have been the standard for research activities which define the loss of substance which occurs due to exposure to soft drinks. However, many studies lack an explanation for the time-bound exposure of these agents and their effect on loss of tooth substance. Thus, the present study is undertaken to investigate the effect of soft drinks on the surface roughness of dental enamel and compare the effect of two kinds of soft drinks (Pepsi and Mirinda) on the surface roughness of dental enamel in two time periods.\n\n\nMethods\n\nA total of 36 extracted human premolar teeth, which were extracted for orthodontic treatment at the dental hospital of Riyadh Elm University, were taken. The study was approved by the Institutional Review Board (IRB) of Riyadh Elm University (IRB approval number FPGRP/2020/516/304/300) and consent was waived by the committee. Teeth were carefully cleaned with distilled water and a soft brush then stored in distilled water. Teeth were sectioned, first longitudinally from mesial to distal of the central fissure, and second transversely 2mm below the cementoenamel junction (CEJ) using a slow speed saw machine with a diamond disc to separate the buccal surface of the tooth. The buccal surfaces were then embedded in acrylic resin to keep them free from acrylic resin in order to obtain the surface roughness. After placing all samples in acrylic resin mold, teeth were randomly divided into three groups:\n\nGroup 1 (n = 12): Teeth immersed in 150 ml artificial saliva (control group) (the composition of the artificial saliva was a combination of water and the following: carboxymethylcellulose [CMC], glycerin, minerals such as phosphates, calcium, fluoride, and xylitol. It also contains preservatives to maintain shelf life and flavoring agents to give them a pleasant taste).9\n\nGroup 2 (n = 12): Teeth immersed in 150 ml of Pepsi (the composition of Pepsi is carbonated water, sugar, color [caramel E150d], acid [phosphoric acid] and flavorings [including caffeine]).\n\nGroup 3 (n = 12): Teeth immersed in 150 ml of Mirinda (the composition of Mirinda is carbonated water, high fructose corn syrup and/or sugar, citric acid, purity gum, potassium benzoate and potassium sorbate [preserves freshness], ester gum, natural flavor, yellow 6, ascorbic acid and calcium disodium EDTA [to protect flavor] and sodium citrate).\n\nThe control groups were immersed in artificial saliva, the test soft drink groups (Pepsi and Mirinda) were changed daily, and the samples were immersed at 37° C. Baseline measurements for all of the samples were taken with the profilometer, and the baseline data was recorded in a special form to be analyzed later.\n\nA respective number of samples were immersed in the control solution and two test beverages according to the aforementioned division of all samples, for two periods of time, first for three days and then for 15 days in the second round. After each period all samples were washed with distilled water then subjected to roughness measurements using the same device, then all results were recorded in the same form for each group. Characterization and imaging were performed using a Contour GT-K 3D Optical Microscope (Bruker®), and 3D non-contact surface metrology with interferometry. A 5× Michelson magnification lens with a field of view of 1.5 × 1.5 mm, a Gaussian Regression Filter, a scan speed of 1×, and thresholding of 4 was set for this study.\n\nSamples were placed on the stage and manually adjusted to give an image on the monitor screen. The microscope uses Vision 64 (Bruker®) software which controls the instrument settings, data analyses, and graphical output. The measurement was performed using vertical scanning interferometry which uses a broadband (normally white) light source which is effective for measuring objects with rough surfaces, as well as those with adjacent pixel-height differences greater than 135 nm. Each sample was scanned at three intervals and averaged accordingly to determine the roughness value.\n\nDescriptive statistics such as mean and standard deviation were used. One-way repeated measurement ANOVA (analysis of variance) or two-way ANOVA was used to compare the effect of solutions and time by the average Ra. Tukey’s multiple comparison test was used when ANOVA showed a significant difference.\n\nData was analyzed using statistical package for the social sciences (SPSS) version 20.0 (SPSS Inc., Chicago, II, USA). A p-value of ≤0.05 was considered statistically significant.\n\n\nResults\n\nThe analysis showed there was a significant interaction between the reading factor and solution factor (p < 0.0001) (Table 1). The mean ± sd baseline readings were 1.097 ± 0.245, 1.187 ± 0.260, and 1.187 ± 0.255 for the control group, Pepsi, and Mirinda, respectively. The ANOVA shows that there was no significant difference among solutions in their roughness means (p = 0.634).\n\nAdditionally, within reading two, the solutions’ mean ± slandered deviation of roughness was 1.339 ± 0.209 for control, 1.580 ± 0.249 for Pepsi, and 1.90 ± 0.330 for Mirinda. However, ANOVA showed that at least one of the solutions was significantly different in roughness from the other (p < 0.001). Tukey’s multiple comparison test indicated that the Mirinda group had significantly higher mean roughness than the Pepsi and control groups (p < 0.05). Also, the Tukey post hoc test did not find a significant difference between the average roughness of the control and Pepsi groups (p = 0.085).\n\nHowever, within reading three the solutions’ mean readings were 1.172 ± 0.425, 1.987 ± 0.832, and 2.559 ± 0.783 for control, Pepsi, and Mirinda, respectively. ANOVA showed that at least one of the solutions was significantly different in terms of mean roughness from the others (p < 0.001). As a consequence, the multiple compression test indicated that the Pepsi and Mirinda groups had significantly higher mean roughness than the control group (p < 0.05), and there was no significant difference between the average roughness of the Pepsi and Mirinda groups (p = 0.139) (Table 2 and Figure 1).\n\nOne-way ANOVA was used to study the effect of reading or time by comparing the roughness average within each solution. However, within the control solution the reading means were 1.097 ± 0.246, 1.339 ± 0.209, and 1.172 ± 0.425 for the baseline reading, reading two, and reading three, respectively. ANOVA showed no significant difference among readings in terms of roughness (p = 0.158).\n\nAdditionally, within the Pepsi group, the readings of roughness were 1.187 ± 0.260 for the baseline reading, 1.580 ± 0.249 for reading two, and 1.987 ± 0.332 for reading three, However, ANOVA showed that at least one of the readings was significantly different in roughness from the others (p < 0.001). Furthermore, the multiple compression test indicated that reading three has significantly higher mean roughness than the baseline reading (p < 0.05), but there was no significant difference between the average roughness of reading two and reading three (p = 0.153).\n\nMoreover, within the Mirinda solution, the reading means were 1.187 ± 0.255, 1.967 ± 0.330, and 2.559 ± 0.780 for the baseline, reading two, and reading three, respectively. ANOVA showed that at least one of the readings was significantly different to the others in terms of roughness (p < 0.001). As a result, the multiple compression test indicated that reading two and reading three had significantly higher roughness than the baseline reading (p < 0.05), and there was no significant difference between the roughness of reading two and reading three (p = 0.139) (Table 3 and Figure 2).\n\n\nDiscussion\n\nIn modern society, consumption of carbonated beverages is so common that it has replaced drinking water, which has led to many ill effects and has been discussed in many studies.1 Enamel, though the hardest part of the body, is still a vulnerable structure when exposed to chemicals, like those found in soft drinks and beverages. Among the factors which are associated with this are pH and other factors like calcium and the phosphate content of the soft drinks. Changing the viscosity has shown a positive effect and reduction in the erosion of the enamel.10\n\nThe present study utilized the commonly consumed beverages in the Saudi market which are Pepsi and Mirinda. Timed exposure to the test specimens and artificial saliva was taken, with three days and 15 days as a time interval which will help to co-relate the timed exposure that may occur in the oral cavity. Surface roughness is one of the parameters used to assess the effect of soft drinks on enamel. Other aspects like hardness also have been studied. However, surface roughness is the initial change in the enamel that appears due to exposure to soft drinks and beverages. To measure this a profilometer, which has been commonly used in many previous studies, has been utilized.4,11\n\nThe surface roughness of all the samples measured at the baseline showed no difference. However, the samples compared at three days have shown that the soft drink Mirinda causes a comparatively rougher surface than the other substances. These results are similar to the results of previous studies. The reason for this could be due to the composition of Mirinda compared to Pepsi. It is very well known that the most common type of acid used in soft drinks is citric acid, which has greater erosive potential. Citric acids and/or citrates are added as buffering and flavoring agents, but they can concurrently bind to calcium and phosphorus thereby promoting increased titratable acidity levels.12\n\nIt was shown that most carbonated beverages have a pH of 2.6.3 However, the actual pH may vary in different soft drinks (which is the trade or brand secret) and may lead to surface changes seen which are different in three days compared to the Pepsi and control groups. One earlier study has shown that Coca-Cola has the lowest pH of all the test drinks, so it shows the highest change in surface roughness.13 A study where they have compared cola and orange juice has shown that the eroded surfaces in cola and orange juice groups were visibly roughened and had lost their luster as compared to the control surface.11 Similarly, Barac et al. also showed results similar to the present study.11 In the present study roughness was measured at the end of the third day, while the above studies have had exposure times of 30 minutes and 60 minutes. Though there is a time difference, the results of the study have shown the same outcome with all the drinks showing surface roughness.\n\nIn the present study surface roughness was assessed again on the 15th day. The results of the study have shown that both the test groups, Pepsi and Mirinda, showed higher roughness compared to the control group. Again, these results were similar to previous studies. Trivedi et al. measured surface roughness at the 14 day point in their study, and the high-energy sports drink and non-carbonated beverage showed a highly significant difference compared to the control.12 Similarly, an in vitro study by Navarro et al. which measured bond strength, bracket microleakage, and adhesive remnant on intact and sealed enamel in 15 days also resulted in more roughness and a change in the hardness of the enamel, which led to the decreased bond strength and microleakage.14 Thus, the present study results are comparable to the previous results.\n\nIn the present study, it was found that there was no difference in surface roughness at day 15 for both the Pepsi and Mirinda groups. These results are similar to the study done by Barac et al.11 They found that roughness parameters with Coca-Cola had the strongest erosion potential during the 15 min of exposure, while Coca-Cola and orange juice showed similar results during 30- and 60-min exposures. There was no difference between 60 minutes and 10 days’ exposure. However, this result was in contrast to the study by Rajeev and Lewis, where they found that the maximum roughness was seen at 10 days with lime juice and lime soda. The difference in the result is due to the variations in the beverages and amount of exposure to these beverages.3\n\nA change in surface roughness in the hardness of the enamel is common after exposure to soft drinks. This has been proven in the current and previous studies. To overcome and reduce the effect of soft drinks, many measures and treatment modalities have been attempted. All studies have shown favorable results. They have used fluoride, casein phosphopeptide-amorf calcium phosphate, and acidulated phosphate fluoride gel,15 CPP-ACPF and nano-hydroxyapatite,16 air-abrasion pre-treatment with bioactive glass 45S5,17 and many other treatments. These research reports show the seriousness of the surface roughness problem associated with soft drinks.\n\nThis study report, with three days and 15 days of exposure, shows that one needs to be well aware of the effect of soft drinks on enamel. Dentists need to educate patients regarding these soft drinks and ways to reduce the exposure to them. The limitations are, mimicking the oral mouth environment and salivary pH which affect the roughness property strongly, compositions of the enamel and its properties differ between vital and non-vital teeth, and personal oral hygiene and dental habits could be an important factor that affects the result.\n\n\nConclusions\n\nWithin the limitations of the study, there are significant differences between the surface roughness of the samples exposed to Pepsi and Mirinda on the third day. However, the Miranda sample showed the roughest surface. There is a statistically significant difference between the control and test samples (Pepsi and Mirinda) at 15 days of exposure, with both showing similar roughness.\n\n\nData availability\n\nHarvard Dataverse: Evaluation of the effect of soft drinks on the surface roughness of dental enamel in natural human teeth. https://doi.org/10.7910/DVN/VJC52A.18\n\nThis project contains the following underlying data:\n\n• data sheet.tab (profilometer measurement results)\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\nLussi A, Schlueter N, Rakhmatullina E, et al.: Dental erosion--an overview with emphasis on chemical and histopathological aspects. Caries Res. 2011; 45 Suppl 1: 2–12. PubMed Abstract | Publisher Full Text\n\nLutovac M, Popova OV, Macanovic G, et al.: Testing the Effect of Aggressive Beverage on the Damage of Enamel Structure. Open Access Maced J Med Sci. 2017; 5(7): 987–93. PubMed Abstract | Publisher Full Text | Free Full Text\n\nRajeev G, Lewis AJ, Srikant N: A time based objective evaluation of the erosive effects of various beverages on enamel and cementum of deciduous and permanent teeth. J Clin Exp Dent. 2020; 12(1): e1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFujii M, Kitasako Y, Sadr A, et al.: Roughness and pH changes of enamel surface induced by soft drinks in vitro-applications of stylus profilometry, focus variation 3D scanning microscopy and micro pH sensor. Dent. Mater. J. 2011; 30(3): 404–10. PubMed Abstract | Publisher Full Text\n\nKregiel D: Health safety of soft drinks: contents, containers, and microorganisms. Biomed. Res. Int. 2015; 2015: 128697. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMeurman JH, ten Cate JM : Pathogenesis and modifying factors of dental erosion. Eur. J. Oral Sci. 1996; 104(2 (Pt 2)): 199–206. PubMed Abstract | Publisher Full Text\n\nten Cate JM , Imfeld T: Dental erosion, summary. Eur. J. Oral Sci. 1996; 104(2 (Pt 2)): 241–4. PubMed Abstract | Publisher Full Text\n\nJoshi N, Patil NP, Patil SB: The abrasive effect of a porcelain and a nickel-chromium alloy on the wear of human enamel and the influence of a carbonated beverage on the rate of wear. J. Prosthodont. 2010; 19(3): 212–7. PubMed Abstract | Publisher Full Text\n\nPytko-Polonczyk JJ, Jakubik A, Przeklasa-Bierowiec A, et al.: Artificial saliva and its use in biological experiments. J. Physiol. Pharmacol. 2017; 68(6): 807–13. PubMed Abstract\n\nXavier AM, Rai K, Hegde AM, et al.: A spectroscopic and surface microhardness study on enamel exposed to beverages supplemented with lower iron concentrations. J. Clin. Pediatr. Dent. 2015; 39(2): 161–7. PubMed Abstract | Publisher Full Text\n\nBarac R, Gasic J, Trutic N, et al.: Erosive Effect of Different Soft Drinks on Enamel Surface in vitro: Application of Stylus Profilometry. Med. Princ. Pract. 2015; 24(5): 451–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nTrivedi K, Bhaskar V, Ganesh M, et al.: Erosive potential of commonly used beverages, medicated syrup, and their effects on dental enamel with and without restoration: An in vitro study. J. Pharm. Bioallied Sci. 2015; 7(Suppl 2): S474–80. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKarda B, Jindal R, Mahajan S, et al.: To Analyse the Erosive Potential of Commercially Available Drinks on Dental Enamel and Various Tooth Coloured Restorative Materials - An In-vitro Study. J. Clin. Diagn. Res. 2016; 10(5): Zc117–21. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNavarro R, Vicente A, Ortiz AJ, et al.: The effects of two soft drinks on bond strength, bracket microleakage, and adhesive remnant on intact and sealed enamel. Eur. J. Orthod. 2011; 33(1): 60–5. PubMed Abstract | Publisher Full Text\n\nMaden EA, Acar Ö, Altun C, et al.: The Effect of Casein Phosphopeptide-Amorf Calcium Phosphate and Acidulated Phosphate Fluoride Gel on Dental Erosion in Primary Teeth: An in vitro Study. J. Clin. Pediatr. Dent. 2017; 41(4): 275–79. PubMed Abstract | Publisher Full Text\n\nDionysopoulos D, Tolidis K, Sfeikos T: Effect of CPP-ACPF and Nano-hydroxyapatite Preventive Treatments on the Susceptibility of Enamel to Erosive Challenge. Oral Health Prev. Dent. 2019; 17(4): 357–64. PubMed Abstract | Publisher Full Text\n\nDionysopoulos D, Tolidis K, Sfeikos T: Effect of air-abrasion pre-treatment with bioactive glass 45S5 on enamel surface loss after erosion/abrasion challenge. Dent. Mater. 2019; 35(9): e193–203. PubMed Abstract | Publisher Full Text\n\nAl-Amri I: Evaluation of the effect of soft drinks on the surface roughness of dental enamel in natural human teeth.2021. Harvard Dataverse, V2. Publisher Full Text"
}
|
[
{
"id": "99678",
"date": "09 Feb 2022",
"name": "Khalifa Sulaiman Al-Khalifa",
"expertise": [
"Reviewer Expertise Cariology",
"Dental Public Health",
"Quality of life"
],
"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 investigated the effect of soft drinks on the surface roughness of dental enamel in natural human teeth. The topic is interesting, and the manuscript is well written. The introduction covered the main ideas investigated in the study. All data of surface roughness are available, and the discussion explained the results thoroughly.\nHowever, some minor comments are suggested for the authors to consider:\nIn the discussion, give a brief account of the limitations of your study.\nOne of the limitations is the sample size which may not be optimal. Adequate sample size will result in more reliable, valid, and generalizable results. The authors also did not mention sample size/power calculation: determining the optimal sample size for a study assures an adequate power to detect statistical significance. If study is underpowered, it will be statistically inconclusive and may make the whole protocol a failure.\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": "99681",
"date": "09 Feb 2022",
"name": "Manuel S Thomas",
"expertise": [
"Reviewer Expertise dental materials",
"restorative dentistry"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nChanges in dietary habits, especially increased consumption of acidic food and drinks have been attributed to a steep increase in the prevalence of dental erosion over the years.1 This article reinforces the fact that carbonated drinks can cause enamel erosion, especially when consumed for a prolonged period. Therefore, it is imperative that oral health care providers recognize the dietary pattern of their patients and give them sound oral care instructions.2\nApart from the pH of the drink, other aspects like dissociation constant (pKa), titratable acidity, buffering capacity, the concentration of calcium, phosphate, and fluoride ions as well as the degree of saturation of the product are also significant factors determining the erosive potential of the drink.3 In addition to measuring the surface roughness of the enamel, other aspects such as weight loss, degree and depth of demineralization, and surface hardness will shed light on the destructive nature of dietary products on enamel. Accordingly, these topics could be considered as areas of potential future research.\nIn this study 3D non-contact surface metrology was used to measure the enamel surface roughness. This is a non-damaging quantitative technique, unlike contact methods like stylus surface profilometer. Therefore, the method used in this study is ideal for measuring repeated values in the same area. [ref 4]. Another point to note in this study is that the enamel surface was exposed to the beverage for a prolonged period of time (up to 15 days). This longer duration of exposure can provide more insight into the effects of frequent consumption of these beverages on the enamel surface hardness.\nThere are two spelling errors that I have highlighted in the pdf (page no. 6, paragraphs 4 and 5). I have also mentioned a couple of suggestions in the PDF [these are highlighted in yellow].\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/10-1138
|
https://f1000research.com/articles/10-1137/v1
|
10 Nov 21
|
{
"type": "Research Article",
"title": "[18F]Fluoromethylcholine PET/CT for CNS lymphoma assessment: a new tool",
"authors": [
"Kirsty Marshall",
"Bhupinder Sharma",
"Thomas Millard",
"Sahil Chhabda",
"Fayed Sheikh",
"Emily Guilhem",
"Joel Cunningham",
"Yong Du",
"Emma Alexander",
"David Cunningham",
"Ayoma Attygalle",
"Ian Chau",
"Sunil Iyengar",
"Dima El-Sharkawi",
"Kirsty Marshall",
"Bhupinder Sharma",
"Thomas Millard",
"Sahil Chhabda",
"Fayed Sheikh",
"Emily Guilhem",
"Joel Cunningham",
"Yong Du",
"Emma Alexander",
"David Cunningham",
"Ayoma Attygalle",
"Ian Chau",
"Sunil Iyengar"
],
"abstract": "Background Central nervous system (CNS) lymphomas are a rare subset of lymphoma, which are associated with a poor outcome. The gold standard for CNS imaging is with gadolinium-enhanced magnetic resonance imaging (MRI); however, there are a number of limitations, including some patients with small persistent abnormalities from scarring due to focal haemorrhage or from a previous biopsy, which can be difficult to discern from residual tumour. [18F]Fluoromethylcholine positron emission tomography–computed tomography (FCH-PET/CT) uses an analogue of choline, which due to the upregulation of choline kinase in tumour cells, allows increased uptake of FCH. As there is minimal background grey matter uptake of FCH, FCH-PET/CT can be used in CNS imaging and provide a useful tool for response assessment. Methods This is a cohort study, where we identified 40 patients with a diagnosis of primary or secondary CNS lymphoma between 1st November 2011 and 10th October 2019. Results 26 of the 40 patients (65%) had concordant results. Of the discordant results, 11 out of 14 had partial response (PR) on MRI but showed a metabolic complete response (mCR) on FCH-PET. The overall response rates (ORR) were similar between the two modalities (90% for MRI versus 95% with FCT-PET/CT). Conclusion We conclude that FCH-PET/CT is a reasonable alternative mode of imaging to gadolinium-enhanced MRI brain imaging, providing a new tool for assessment of CNS lymphoma.",
"keywords": [
"CNS lymphoma",
"imaging",
"response assessment."
],
"content": "Introduction\n\nPrimary central nervous system lymphoma (PCNSL) is a rare type of B cell lymphoma, accounting for 1–2% of all lymphomas1 and approximately 4% of newly diagnosed CNS tumours.2 Secondary CNS involvement occurs in 2.3–10% of patients with systemic diffuse large B-cell lymphoma (DLBCL)3 but can also occur in other lymphoma subtypes.\n\nDespite recent advances in treatment, with the addition of thiotepa to the methotrexate-cytarabine backbone,4 prognosis for PCNSL remains poor with 2-year overall survival rates of between 42 and 69%, and only a fifth of patients being alive at 5 years.5 For secondary CNSL, the prognosis is even more dire, with median OS of 10 months.6 It is challenging to decipher which patient will do poorly, as only age and performance status having an impact on prognosis. Unlike other lymphoma types, most noticeably Hodgkin’s lymphoma,7 metabolic imaging has no role in response assessment and the associated prognostic impact and is confined to diagnostic staging to exclude concurrent systemic disease.8\n\nThe gold standard for CNS imaging is with gadolinium-enhanced magnetic resonance imaging (MRI).9 However, MRI has its limitations. When used in end-of-treatment (EOT) imaging, some patients will have small persistent abnormalities from scarring due to focal haemorrhage or from a previous biopsy, which be difficult to discern from residual tumour and is currently classified as unconfirmed complete response (CRu).9 There have also been recent safety concerns over exposure to gadolinium-based contrast agents (GBCAs) with case reports of the development of nephrogenic systemic fibrosis,10 as well as gadolinium deposits in other organs.11 This led to the European Medicines Agency (EMA) restricting or suspending the use of linear gadolinium products in 2017.12\n\nCholine positron emission tomography–computed tomography (PET/CT) uses analogues of choline as a radiotracer. Choline can be labelled with either [18F] fluoromethyl (18FCH) or [11C] carbon (11CH3). FCH was first developed as a radiotracer for PET imaging in 2000. Choline is a precursor of phospholipids, which upon entry to the cell, is phosphorylated by the enzyme choline kinase.13 The expression of choline kinase is upregulated in tumour cells and allows increased uptake of the choline tracer.14 There is evidence that MYC, which regulates lipid metabolism and can be overexpressed or translocated in high-grade lymphomas, plays a part in the increased uptake.15 MYC over-expression a poor prognosis in PCNSL with patients having a 5-fold higher 5-year risk of progression and/or death than those without.16 When Bcl-2 is also over-expressed (so called double expressor) the risk is 13-fold higher.\n\nAs there is minimal background grey matter uptake of the tracer, FCH-PET/CT can be used to detect tumours with a high lesion-to-CNS background ratio and has been used in diagnosis and follow up imaging in brain tumours, particularly high-grade gliomas.14 There are case reports of both systemic and CNS lymphoma showing FCH-PET/CT avidity, including incidental lymphoma picked up during imaging for prostate cancer17 and histology proven CNS lymphoma in brain tumour series.18 This contrasts with the lack of utility of the 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET/CT for CNS lymphoma analysis, due to high FDG physiological activity levels within the grey-white matter. Although high-grade CNS lymphomas do have a standard uptake value maximum (SUVmax) greater than background grey-white matter at diagnosis (average SUVmax 13.5±5.4 compared to background SUVmax of 5.3±1.2),19 for interim and EOT scanning the higher physiological background levels limit accurate detection of residual active disease.\n\nOur centre has been using FCH-PET/CT alongside MRI for CNS lymphoma assessment since 201120 following approval by the Administration of Radioactive Substances Advisory Committee (ARSAC). Our primary objective to to assess concordance between FCH-PET/CT and MRI.\n\n\nMethods\n\nTo assess concordance between FCH-PET/CT and gold standard MRI, our centre conducted a retrospective cohort analysis of patients who had EOT response assessment conducted using both modalities between 1st November 2011 and 10th October 2019 at the Royal Marsden Hospital, London. Approval for this study (approval number 782), including ethical approval was obtained from the Committee for Clinical Review (CCR). Patients with a histopathological or specialist neuroradiological (where biopsy was not feasible) diagnosis of primary or secondary CNS lymphoma who had an EOT MRI and FCH-PET/CT were identified from a radiology database. Patients who did not complete treatment, or had the imaging performed after consolidative therapy were excluded. Patient characteristics, clinical information, and survival data were collected from the electronic patient recorded (EPR). MRI and FCH-PET/CT reports were collected from EPR and PACS. EOT response was classified as either complete response (CR) for MRI/metabolic complete response (mCR) for FCH-PET/CT, partial response (PR), stable disease (SD) or disease progression (PD). MRI response was reported as per the International Primary CNS Lymphoma Collaborative Group (IPCG).4 For FCH-PET/CT, PR is defined as reduction in activity (SUVmax), PD is an increase in SUVmax, SD as no change in SUVmax, and mCR is defined as no activity. Statistical analysis was performed using IBM SPSS version 27 (RRID:SCR_019096), JASP (RRID:SCR_015823) is an open-access alternative. Survival analysis was evaluated using log-rank test.\n\n\nResults\n\nA total of 40 patients met the inclusion criteria. Patient characteristics are shown in Table 1. PCNSL was the most common type of CNS lymphoma, and MATRix regimen the most common type of chemotherapy used. 16 patients (40%) were consolidated after EOT imaging, with autologous stem cell transplant (ASCT) being the preferred method.\n\n14 patients (35%) had discordant results on EOT imaging. The majority of discordant cases (11 out of 14) were patients who had PR on MRI but showed CMR on FCH-PET/CT. In the remaining discordant three cases, two had PD on MRI with PR on FCH-PET/CT and one had CR on MRI and PR on FCH-PET/CT. Figure 1 shows examples of two concordant cases and one discordant case.\n\nTop row. Histology – large B-cell lymphoma, composed of sheets of large atypical lymphoid cells, (haemtoxylin and eosin [H&E] stain) that are CD20 positive (inset). This patient had concordant MRI and FCH-PET/CT imaging findings throughout treatment. The baseline coronal CE T1W MRI demonstrates an enhancing lesion within the right thalamus and a focus of increased tracer uptake in the same region on the contemporaneous coronal FCH-PET/CT image (white circles). These areas of enhancement and tracer uptake had both resolved on the EOT imaging, consistent with radiological CR. Follow up imaging demonstrates a new focus of enhancement and corresponding tracer uptake within the left thalamus and cerebral peduncle on the coronal CE T1W MRI and FCH-PET/CT images, respectively (white circles). Middle row. Histology - large B-cell lymphoma, composed of sheets of large atypical lymphoid cells (H&E stain) that are CD20 positive (inset). This patient had discordant findings between imaging modalities. The baseline axial CE T1W MRI shows an enhancing mass within the right medial temporal lobe and posterior insula (red circle). The contemporaneous choline PET-CT is concordant, demonstrating increased uptake in the same anatomical location (red circle). Partial response is achieved on the EOT CE T1W MRI as illustrated by interval reduction in size of the mass although some pathological enhancement remains (amber circle, this area was not hyperintense on the pre-contrast T1W imaging - not shown). The EOT choline PET-CT is discordant, showing metabolic complete response (amber circle). Follow up imaging shows resolution of the mesial temporal and insular enhancement (green circle) and ongoing normal physiological FCH tracer uptake in the cranium on the maximum intensity projection FCH-PET/CT reconstruction, consistent with radiological CR. Bottom rows. Histology - large B-cell lymphoma, composed of sheets of large atypical lymphoid cells, (H&E stain, top panel) that are CD20 positive (middle panel) and display a high Ki 67 proliferation index (lower panel). This patient had a partial response which was concordant between modalities throughout treatment. The baseline axial CE T1W MRIs depict an enhancing lesion within the right side of the splenium of the corpus callosum (top, white arrows) and the left cingulate gyrus (bottom, blue arrows) with corresponding increased uptake on the axial FCH-PET/CT in the same regions. The splenial lesion has resolved on both the EOT MRI and FCH-PET/CT (top) but the left-sided lesion is still present on both modalities (bottom, blue arrows). Follow up imaging shows recurrence of the right-sided splenial lesion on both modalities (white arrows).\n\nAbbreviations: CR = complete response, PR = partial response. CE T1W = contrast-enhanced T1 weighted. EOT = end of treatment.\n\nFor the whole cohort, the overall response rates (ORR) were similar between the two modalities. The ORR for MRI was 90%, with 16 patients (40%) achieving CR and 20 (50%) achieving PR. FCH-PET/CT had a slightly higher ORR of 95%, with 26 (65%) patients achieving mCR and 12 (30%) achieving PR.\n\nA total of 17 patients subsequently progressed (47%). The progression-free survival (PFS) was 78% at 100 days and 51% at 2 years. Overall survival (OS) was 61%.\n\n\nDiscussion\n\nTo our knowledge, this is the first published study for FCH-PET/CT imaging in CNS lymphoma.21 Our results showed a concordance rate of 65% between FCH-PET and MRI. 11 out of 14 discordant cases were in patients who achieved a PR by MRI, but were in mCR on FCH-PET/CT. This group had a clinical course similar to the patients who achieved a CR/mCR on both. One theory is that the residual enhancement seen on MRI was scarring or post-treatment changes and may have been better classified as CRu.\n\nThere are no studies with direct comparison. A similar study by Ahn et al.22 looked at the prognostic value of metabolic imaging, using 11C-methionine (11C-MET) rather than FCH as a tracer. Imaging was done after four cycles of methotrexate-containing chemotherapy and again after completion of chemotherapy. The concordance at interim imaging between 11C-MET PET/CT and MRI was 89%, with four cases achieving CMR on 11C-MET PET/CT who had residual lesions on MRI. There are limited studies looking at the effect of FDG-PET/CT on prognosis. Bursen et al.23 showed PET negativity (defined as SUV uptake below physiologic background uptake) after two cycles of methotrexate-containing chemotherapy is associated with improved PFS but not OS. This conflicts with results from Jo et al.24 who showed improved PFS only with EOT and not interim scanning. Again, there was no difference in OS.\n\nOur study does have limitations. Our numbers are small and consist of a combination of primary and secondary CNSL as well as relapsed cases, which have different expected outcomes. There was also considerable variation in treatment and consolidation regimens, with the addition of thiotepa from 2016 onwards for young, fit patients. Therefore, the prognostic value of FCH-PET/CT could not be studied using this cohort. Further work is being done by our group to assess the prognostic value of FCH-PET/CT in patients with PCNSL who undergo ASCT.25\n\nWe conclude that FCH-PET/CT is an important a new tool for assessment of CNS lymphoma. At the current time, its use may be limited to patients who have a contraindication to MRI.26 Further studies are warranted evaluating the potential role for FCH-PET/CT in CNS lymphoma, including assessment of whether FCH PET/CT is superior to MRI in predicting persistent disease or identifying patients that need consolidation therapy.\n\n\nData availability\n\nOSF: Underlying data for ‘[18F] Fluoromethylcholine PET/CT for CNS lymphoma assessment: a new tool’ https://doi.org/10.17605/OSF.IO/KTNDG.27\n\nThe project contains the following underlying data:\n\nData file 1: Patient database.\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\nAuthor contributions\n\nKM wrote the initial draft of the manuscript. KM, SC, FS, EG, BS collected data. AA provided histopathology images. BS, SC, FS, EG provided radiology images. All authors contributed to design, review and redrafting of the manuscript.",
"appendix": "Acknowledgements\n\nThe authors acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre (London, UK).\n\n\nReferences\n\nLiu D, Liu X, Ba Z, et al.: Delayed Contrast Enhancement in Magnetic Resonance Imaging and Vascular Morphology of Primary Diffuse Large B-Cell Lymphoma (DLBCL) of the Central Nervous System (CNS): A Retrospective Study. Med. Sci. Monit. 2019; 25: 3321–3328. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVillano JL, Koshy M, Shaikh H, et al.: Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br. J. Cancer. 2011; 105(9): 1414–1418. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHerr MM, Barr PM, Rich DQ, et al.: Clinical Features, Treatment, and Survival of Secondary Central Nervous System Lymphoma. Blood. 2014; 124(21): 5389. Publisher Full Text\n\nFerreri AJM, Cwynarski K, Pulczynski E, et al.: Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial. Lancet Haematol. 2016; 3: e217–e227. Publisher Full Text\n\nRoth R, Martus P, Thiel E, et al.: Long-term survival in patients with primary CNS lymphoma: Results from the G-PCNSL-SG1 trial. J. Clin. Oncol. 2015; 33(15): 2032–2032. Publisher Full Text\n\nFerreri AJM, Donadoni G, Cabras MG, et al.: High Doses of Antimetabolites Followed by High-Dose Sequential Chemoimmunotherapy and Autologous Stem-Cell Transplantation in Patients With Systemic B-Cell Lymphoma and Secondary CNS Involvement: Final Results of a Multicenter Phase II Trial. J. Clin. Oncol. 2015; 33(33): 3903–3910. Publisher Full Text\n\nRyan C, Lynch RC, Ranjana HA: Risk-Adapted Treatment of Advanced Hodgkin Lymphoma With PET-CT. Am. Soc. Clin. Oncol. Educ. Book. 2016; 36: 376–385.\n\nHoang-Xuan K, Bessel E, Bromberg J, et al.: Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol. 2015; 16: e322–e332. Publisher Full Text\n\nAbrey LE, Batchelor TT, Ferreri AJM, et al.: Report of an International Workshop to Standardize Baseline Evaluation and Response Criteria for Primary CNS Lymphoma. J. Clin. Oncol. 2005; 23(22): 5034–5043. PubMed Abstract | Publisher Full Text\n\nYoung LK, Matthew SZ, Houston JG: Absence of potential gadolinium toxicity symptoms following 22,897 gadoteric acid (Dotarem®) examinations, including 3,209 performed on renally insufficient individuals. Eur. Radiol. 2019; 29: 1922–1930. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMcDonald RJ, McDonald JS, Kallnes DF, et al.: Intracranial Gadolinium Deposition after Contrast-enhanced MR Imaging. Radiology. 2015; 275(3): 772–782. PubMed Abstract | Publisher Full Text\n\nEuropean Medicines Agency: EMA’s final opinion confirms restrictions on use of linear gadolinium agents in body scans.2017. Reference Source\n\nGiovannini E, Lazzeri P, Milano A, et al.: Clinical Applications of Choline PET/CT in Brain Tumours. Curr. Pharm. Des. 2015; 21(1): 121–127.\n\nLam WWC, Ng DCE, Wong WY, et al.: Promising role of [18F] fluorocholine PET/CT vs [18F] flurodeoxyglucose PET/CT in primary brain tumors- Early experience. Clin. Neurol. Neurosurg. 2011; 113: 156–161. PubMed Abstract | Publisher Full Text\n\nXiong J, Wang L, Fei XC, et al.: MYC is a positive regulator of choline metabolism and impedes mitophagy-dependent necroptosis in diffuse large B-cell lymphoma. Blood Cancer J. 2017; 7: 582. Publisher Full Text\n\nHatzl S, Posch F, Deutsch A, et al.: Immunohistochemistry for c-myc and bcl-2 overexpression improves risk stratification in primary central nervous system lymphoma. Hematol. Oncol. 2020; 38: 277–283. Publisher Full Text\n\nDe Leiris N, Riou L, Leenhardt J, et al.: 18F-Choline and 18F-FDG PET/CT in a Patient With Diffuse Large B-Cell Lymphoma and Recurrent Prostate Cancer. Clin. Nucl. Med. 2018; 43: 471–472.\n\nUtriainen M, Komu M, Vuorinen V, et al.: Evaluation of brain tumour metabolism with [11C] choline PET and 1H-MRS. J. Neuro-Oncol. 2003; 62: 329–338. PubMed Abstract | Publisher Full Text\n\nKawai N, Zhen HN, Miyake K, et al.: PrognosticPrognostic value of pretreatment 18F-FDG PET in patients with primary central nervous system lymphoma: SUV-based assessment. J. Neuro-Oncol. 2010; 100: 225–232. Publisher Full Text\n\nCunningham J, Iyengar S, Sharma B: Evolution of lymphoma staging and response evaluation: current limitations and future directions. Nat. Rev. Clin. Oncol. 2017; 14: 631–645. PubMed Abstract | Publisher Full Text\n\nMarshall K, Du Y, Zerizer I, et al.: 18Fluoromethylcholine –positron emission tomography computed tomography is not inferior to gadolinium-enhanced magnetic resonance imaging in central nervous system lymphoma imaging. BJHaem. 2020; 189(S1): 218.\n\nAhn SY, Kwon SY, Jung SH, et al.: Prognostic Significance of Interim 11C-Methionine PET/CT in Primary Central Nervous System Lymphoma. Clin. Nucl. Med. 2018; 43(8): 259–264.\n\nBirsen R, Blanc E, Williems L, et al.: Prognostic value of early 18F-FDG PET scanning evaluation in immunocompetent primary CNS lymphoma patients. Oncotarget. 2018; 9(24): 16822–16831. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJo JC, Yoon DH, Kim S, et al.: Interim 18F-FGD PET/CT may not predict the outcome in primary central nervous system lymphoma patients treated with sequential treatment with methotrexate and cytarabine. Ann. Hematol. 2017; 96: 1509–1515. PubMed Abstract | Publisher Full Text\n\nSammour F, Nicholson E, Anthias C, et al.: 18Fluoromethylcholine PET/CT to predict outcomes of patients pre and post autologous stem cell transplantation (ASCT) for CNS lymphoma – a new CNS lymphoma imaging tool. EBMT. 47th Annual Meeting (virtual). 14-17 March 2021.\n\nMillard T, Chau I, Iyengar S, et al.: 18 F-choline radiotracer positron emission tomography as a new means to monitor central nervous system lymphoma. Br. J. Haematol. 2021 Jun; 193(6): 1026. Publisher Full Text\n\nMarshall K, Sharma B, Millard T, et al.: Underlying data for ‘[18F] Fluoromethylcholine PET/CT for CNS lymphoma assessment: a new tool’.Publisher Full Text"
}
|
[
{
"id": "118906",
"date": "31 Jan 2022",
"name": "Irfan Kayani",
"expertise": [
"Reviewer Expertise radionuclide imaging",
"lymphoma imaging",
"PET/CT"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThis is an interesting study assessing the use of Fluoromethylcholine PET in CNS lymphoma suggesting that it may have a useful clinical role. As the authors state the main limitations of the study are the small sample size, heterogeneous tumour population, and treatment.\nMethods and Results:\nIt would be useful to know the SUVmax / SUVr values for each scan\n\nAs PR status on Fcholine seems to fail to predict outcome could the authors comment on whether this might be improved by using a different method of assessment, e.g. quantitative analysis\n\nDiscussion: Is concise, well written, and on the whole balanced except for two points:\nThis is useful as a preliminary study suggesting a possible role for Fluoromethylcholine, and as the authors suggest most likely as an alternative in those who cannot have MRI. However, this would require further supportive data from future trials before clinical use.\n\nA major feature of the results of this study was the high discordance in patients with a partial response on MRI but complete response on Fluoromethylcholine, The authors state that the clinical course of these patients was similar to those with a complete response on both imaging modalities and suggest the possibility that this may be due to residual enhancement on MRI secondary to scarring/post-treatment changes mimicking persistent tumour. However, looking at the underlying data table shows that 6 of 11 patients with partial response MR/CR Fcholine relapsed compared to 4 of 9 patients with partial response MR/PR Fcholine. Therefore another interpretation is that Fcholine status was not able to usefully differentiate patients with PR status on MRI indicating an unclear role for Fcholine. This may be due to the mentioned limitations of the study but is relevant as it is an obvious potential clinical use.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1137
|
https://f1000research.com/articles/10-793/v1
|
11 Aug 21
|
{
"type": "Research Article",
"title": "Effects of sociodemographic and socioeconomic factors on stroke development in Lebanese patients with atrial fibrillation: a cross-sectional study",
"authors": [
"Diana Malaeb",
"Souheil Hallit",
"Nada Dia",
"Sarah Cherri",
"Imad Maatouk",
"George Nawas",
"Pascale Salameh",
"Hassan Hosseini",
"Diana Malaeb",
"Souheil Hallit",
"Sarah Cherri",
"Imad Maatouk",
"George Nawas",
"Pascale Salameh",
"Hassan Hosseini"
],
"abstract": "Background: Non-communicable diseases, the major cause of death and disability, are susceptible to modifiable and non-modifiable risk factors. Atrial fibrillation (AF) increases the risk of stroke by 4-5 times and can lead to cardiovascular mortality. This study was conducted to assess the effects of different sociodemographic factors on stroke development in patients with AF. Methods: A cross-sectional study was conducted between January and June 2018 on patients recruited from Lebanese community pharmacies. The CHA2DS2-VASc scoring system is utilized as a stroke risk stratification tool in AF patients. Participants with a previous physician diagnosis of AF, documented on medical records, were included in this study. Results: A total of 524 patients were enrolled in the study with a mean age of 58.75 (± SD) ± 13.59 years with hypertension (78.38%) being the most predominant disease. The results showed that obesity (Beta=0.610, p-value =0.011), retirement and unemployment compared to employment (Beta=1.440 and 1.440, p-value=0.001 respectively), divorced/widow compared to married (Beta=1.380, p-value =0.001) were significantly associated with higher CHA2DS2-VASc scores whereas high versus low socio-economic status (Beta=-1.030, p=0.009) and high school education versus primary education level (Beta=-0.490, p-value=0.025) were significantly associated with lower CHA2DS2-VASc scores. Conclusions: The study highlights that the CHA2DS2-VASc score is affected by the presence of various sociodemographic and socioeconomic characteristics in patients with AF. Thus, screening for those factors may predict the progression of cardiovascular disease and may provide an optimal intervention.",
"keywords": [
"Stroke",
"Lebanon",
"sociodemographic",
"CHA2DS2-VASc score"
],
"content": "List of abbreviations\n\nAF Atrial fibrillation\n\nM Mean\n\nNCD Non-communicable diseases\n\nSD Standard deviation\n\nTIA Transient ischemic attack or prior stroke\n\nWHO World health organization\n\n\nIntroduction\n\nNon-communicable diseases (NCDs), also known as chronic diseases, are responsible for the premature death of 41 million people globally, accounting for 71% of all deaths annually.1 According to the World Health Organization (WHO), ischemic heart disease and stroke are the world’s biggest killers in 2016, accounting for 15.2 million deaths worldwide.1 The global crude death rate per 100,000 population of high-income, upper and lower-middle-income countries due to stroke is the second-highest following ischemic heart disease.2,3 In Lebanon, NCDs are the major cause of death and disability and are expected to be responsible for 91% of deaths by 2025.4,5\n\nNCDs are susceptible to modifiable and non-modifiable risk factors that are known to trigger their development. Some behavioral changes can be implemented to halt disease progression as the cessation of nicotine, enhancement in physical activity and adherence to a healthy diet.1,6 On the other hand, other factors cannot be altered to modify disease development as age, gender, and previous medical conditions.\n\nAtrial fibrillation (AF) increases the risk of stroke by 4-5 times and is estimated to account for ~15% of the 15 million strokes that occur worldwide every year.7–9 Stroke is expected to increase 2.5 times over the next 40 years due to the increased numbers of older individuals.7–9 The characteristics of patients with AF in the Gulf and Middle East region is different from the West due to the high prevalence of obesity, diabetes, and smoking in oil-rich countries.7 The risk of stroke development in AF patients is assessed through the CHA2DS2-VASc model which depends on demographic and clinical risk factors.10 The CHA2DS2-VASc score allows health care professionals to quickly assess stroke risk and recommend appropriate therapy to prevent further disease progression.10\n\nSociodemographic and socioeconomic aspects can affect cardiovascular outcomes as certain ethnic groups (African-American/Black), low-income status, low educational level, and unemployment are recognized to negatively impact cardiovascular health.11,12 In Lebanon, 15% of the population live below the poverty line and 54% in the moderate middle class in 2013. In addition, 54.3% of the Lebanese population aged above 25 years had a secondary level of education in 2017, and the unemployment rate was reported to be 6.2% in 2018.13\n\nThere is strong evidence that elucidates that socioeconomic determinants are factors that affect cardiovascular diseases indicating an inverse relationship between socioeconomic status and the occurrence of cardiac diseases. Initially, cardiovascular risk factors and diseases were higher in populations with higher socioeconomic status, but then there was a gradual change where the risk factors were higher in groups with lower socioeconomic status groups.14\n\nFurther studies have shown that higher socioeconomic status patients with non-communicable diseases have access to various medical treatments and have greater accessibility to more specialized hospitals with better-prescribed medicines in comparison to the lower socioeconomic status.15\n\nIn addition to the socioeconomic status, it has been indicated that structural aspects of an individual's social relationships can predict all-cause mortality from cardiovascular diseases. It has been highlighted that all of the various unmarried states manifested as being single never married, being separated/divorced and being widowed have been all associated with elevated mortality risk from cardiovascular events.16 As far as we know, few studies have been conducted on Lebanese cardiac patients, such as assessing the level of knowledge on warfarin and assessing the impact of pharmacist counseling, but no study has been conducted that evaluated the impact of sociodemographic factors on cardiac disease progression.17\n\nAlthough the CHA2DS2-VASc scoring system has been widely adopted as a stroke risk stratification tool in AF patients, it does not take into consideration several of the socioeconomic and sociodemographic factors that contribute to poor cardiovascular outcomes. Accordingly, this study was designed to assess the effect of sociodemographic and socioeconomic factors on CHA2DS2-VASc score on Lebanese patients with AF.\n\n\nMethods\n\nA cross-sectional study was conducted on patients recruited from different Lebanese community pharmacies distributed in different Lebanese geographic districts between January and June 2018. The pharmacies were chosen by simple randomization from the list of pharmacies provided by the Lebanese Order of Pharmacists. The questionnaire was administered face-to-face by trained researchers, who had training before the start of the data collection to ensure the quality of research. All participants who presented to the community pharmacies were screened for possible enrollment in the study and included if they had a previous physician-diagnosed AF documented on their electronic medical profile available in the community pharmacies. No attempt was made to verify the accuracy of the physician’s diagnosis. Excluded from the analysis were patients who could not answer the questionnaire adequately either due to a decreased mental alertness or a decreased cognitive function (cognitive disorders, sedated patients, Alzheimer’s disease, etc.). A copy of the questionnaire can be found in the Extended data.\n\nThe first part of the questionnaire aimed at collecting the patient’s demographic data such as age, gender, work status (employed, retired, unemployed), socioeconomic status (low, moderate, high) and education (primary, middle or high school). The second part included a detailed assessment of the patient’s factors to assess the CHA2DS2-VASc score. The score calculation is performed on all enrolled patients through an assessment of the following criteria: patients aged ≥65 years, female gender, heart failure, prior stroke or transient ischemic stroke (TIA), hypertension, diabetes mellitus, vascular disease, coronary heart disease or peripheral artery disease.18 All medical diseases were assessed by checking the detailed previous medical conditions along with the prescribed medications documented on medical profiles. These factors were incorporated into a CHA2DS2-VASc model where each element received 1 point except those aged ≥75 years and those who had a history of stroke or TIA who received 2 points. The CHA2DS2-VASc score can range from 0 to 9. The score’s interpretation is categorized into “low” if the score is zero, “low-moderate” if the score is one, and “moderate-high” if the score ≥2.19 Some of the questions under the sociodemographic characteristics (as socioeconomic status, educational level, and social history) in the questionnaire were left unanswered either because the patient did not remember or did not understand what was asked. Sources of bias were addressed by minimizing investigators interference in the data collection, patients were recruited in a way to represent the different Lebanese geographic characteristics, and information related to medical history was retrieved from the electronic medical profiles.\n\nBased on a 70% enrolled cardiac patients who were illiterate20 and in the absence of similar studies in Lebanon, the minimal sample size calculated according to the Epi Info software version 7.2 (population survey) was 323 participants to ensure a confidence level of 95%.\n\nAn independent person who was unaware of the goals of this research conducted the data coding and analysis using the version 23.0 of the Statistical Package for Social Sciences (SPSS) software. Continuous variables were presented as mean (M) and standard deviation (SD), and the categorical variables were presented as frequency (percentage). The statistical analysis adjusted for the missing values by accounting for the valid percentage in the results output. The Student t-test was used to compare the means of the maximum two groups; for means of three and above, the ANOVA test was applied. In the case of non-homogeneity, non-parametric tests substituted the parametric tests. Variables with a p < 0.05 in the bivariate analysis were included in the linear regression to assess its association with the dependent variable, the CHA2DS2-VASc score. Potential confounders have been eliminated when p > 0.2 to avoid misleading results. P < 0.05 was considered statistically significant.\n\nThe methods were performed in accordance with the latest relevant guidelines and regulations. The study design was approved by the ethics committee at the Lebanese International University. Written informed consent was obtained from all enrolled patients before the start of the study and their personal identifying information was removed from the data set to respect their autonomy and confidentiality.\n\n\nResults\n\nOut of the 800 questionnaires distributed, 524 patients (65.5%) had AF and were consequently enrolled in the study. Lack of diagnosis by an AF physician is a potential factor for non-enrollment. The sociodemographic and socioeconomic factors of patients included in this study are summarized in Table 1. The mean age of the participants was 58.75 ± 13.59 years, with the majority being males (61.15%) and from rural areas (63.22%). Around 57.2% attended at least high school and 42.02% had a medium economic status. The majority of the studied population (75.6%) had a CHA2DS2-VASc score of ≥2. As for the past medical history, hypertension (78.38%) and dyslipidemia (67.57%) were the most prevalent concomitant conditions. The mean score (± standard deviation) of the CHA2DS2-VASc score was 3.07 ± 1.92; out of 524, 206 (39.3%) had a CHA2DS2-VASc score that is at least equal to the mean.\n\nThe results of the bivariate analysis showed a significantly higher CHA2DS2-VASc score in case of divorce or death of a spouse (p = 0.001). A higher mean score was found in cases of unemployment or retirement compared to employment (p = 0.001). A lower mean score was significantly associated with a higher socioeconomic status (p = 0.001) as well as higher education (p = 0.001). Obesity was significantly associated with a high mean score (p = 0.006) (Table 2).\n\nThe results of the linear regression showed that obesity (Beta = 0.610, p = 0.011), retirement and unemployment compared to employment (Beta = 1.440, p = 0.001 each), divorced/widow compared to married (Beta = 1.380, p = 0.001), were significantly associated with higher CHA2DS2-VASc scores whereas high versus low socio-economic status (Beta = −1.030, p = 0.009) and high school education versus primary education level (Beta = −0.490, p = 0.025) were significantly associated with lower CHA2DS2-VASc scores (Table 3).\n\n† Reference.\n\nβ, beta; 95% CI, 95 percent confidence interval; BMI, body mass index.\n\n\nDiscussion\n\nThis cross-sectional study was conducted to investigate the impact of sociodemographic and socioeconomic characteristics on CHA2DS2-VASc score in Lebanese AF patients. Sociodemographic characteristics may directly affect the development of cardiovascular disease that are not currently accounted for in the CHA2DS2-VASc score criteria. The findings of our study show that obesity, retirement and unemployment compared to employment, and divorced/widow compared to married were significantly associated with higher CHA2DS2-VASc scores whereas high versus low socio-economic status and high school education versus primary education level were significantly associated with lower CHA2DS2-VASc scores.\n\nOur results showed that both jobless and retired participants were associated with higher CHA2DS2-VASc scores compared to patients with jobs, which is consistent with the results of another study.21,22 The factors responsible for the increased risk amongst the unemployed are of various causes, which can involve behavioral and lifestyle risk factors, such as smoking, poor diet, alcohol consumption and lack of exercise, all of which increase the risk of cardiovascular disease development and complications.23 In addition to increased smoking and alcohol consumption by unemployed patients, there are other causes, such as financial insecurity and adverse socioeconomic status, which lead to inappropriate health behaviors. Unemployed individuals may not have adequate financial support and/or decreased social involvement which increases the risk of developing cardiovascular and psychological diseases. It has been described that there is a strong correlation between unemployment and the negative effects on cardiovascular and psychological morbidity due to the activation of certain biological factors that are closely linked with acute cardiac events and depression.24\n\nIn addition, jobless participants were found to have a higher risk of obesity, lower fruit and vegetable consumption, and restricted physical activity.25,26 A cross-sectional study in a rural Malay population in Malaysia showed being unemployed or a housewife is associated with metabolic syndrome.27\n\nOur study showed that lower socioeconomic status is associated with higher CHA2DS2-VASc score which is consistent with the results of another study.28 It is explained that lower socioeconomic status is usually correlated with poor health as the socioeconomic status reflects the level of education, income, and type of occupation. According to a population-based study of 11,247 Australian adults aged ≥25 years, and women with lower education were associated with a higher risk of metabolic disorders manifested by hyperinsulinemia, hypertriglyceridemia, abdominal obesity and hypertension that trigger the risk of cardiovascular occurrence.29 According to the literature, a low educational level is associated with poor health because of the limited access, and lack of comprehensive understanding of health-related information.26 Furthermore, lower socioeconomic factors are not only associated with higher metabolic disorders but are correlated with engagement in a variety of behaviors that exert a detrimental and constructive effect on health.30–32\n\nThe previous findings can be explained by the fact that people from the low socioeconomic factors have a lack of motivation and less hope for the future and as a result, they tend to engage with pleasurable activities to help cope with their situations all of which increase the risk of cardiac disorders.33–35\n\nOur results concluded that obese participants have higher CHA2DS2-VASc scores compared to normal-weight patients which are reflected in previous studies.27,36 The literature sheds light that the prevalence of diabetes, hypertension, and dyslipidemia increase with obesity which are all known established risk factors for cardiovascular development.37\n\nIt is established that obesity influences the pathogenesis of atherosclerosis through the association with metabolic and inflammatory systems.38 The adipose tissue secretes proteins that are known to regulate biological and physiological states and play a vital role in obesity, atherosclerosis pathogenesis, metabolic derangements, and inflammatory process.39\n\nOur results showed that widowed and divorced status were significantly associated with higher CHA2DS2-VASc score which is consistent with the results of a recent meta-analysis.40 There are several mechanisms postulated to explain the protective effect of marital status on cardiovascular diseases. Social causation theory suggests that individuals benefit from spousal support41 where living with another person, specifically the partner, allows for earlier recognition and response to warning symptoms.42,43 It was further discussed that single patients had longer delays in seeking medical consultation,42,44,45 were more likely to be non-adherent to medications.46 In addition, partners exert a positive effect on the quality of life depicted through the engagement of health behaviors such as a healthy lifestyle and greater financial resources, especially in households with a dual-income making better healthcare more accessible.42,47,48 Another reason that explains the effect of marriage on cardiovascular diseases is the stress-related theory, which suggests that partner loss or poor-quality relationships may have a detrimental impact on the economic, behavioral and emotional well-being of an individual that increases susceptibility to diseases.49 Specifically, biological stress may ultimately worsen cardiovascular risk factors such as hypertension, impaired vagal tone, hyperlipidemia, diabetes, and the progression of atherosclerosis.50 It is further highlighted that married status can exert a buffering role through the informational or emotional resources from a spouse promoting adaptive behavior and reducing the excessive neuroendocrine response to acute or chronic stressors translated to a reduced risk of cardiovascular diseases.51\n\n\nLimitations\n\nOur study has some limitations: first, the questionnaire used was not validated and self-applied based on subjective assessment of the respondent, so the information could be biased given that recall bias might influence individuals’ responses. Although the patients were recruited from different Lebanese geographic areas yet they might not be representative of the whole Lebanese areas which can hinder generalizing the results to the entire population. In addition, the refusal of some patients to participate in the study might have led to unintended selection bias. Our study has elucidated a preliminary possible association between sociodemographic factors and risk of stroke development among AF patients in Lebanese patients where some risk factors might be population-specific since disease profiles may be different in terms of lifestyle, genetics and demography. A better planned longitudinal study may be of value since the study is cross-sectional where it is impossible to know which comes first, the illness or the socioeconomic factor. Finally, there was no control group. The strengths of our study were the enrollment of a large sample of subjects and the utilization of the validated tool CHA2DS2-VASc score to assess the odds of stroke in patients with AF.\n\n\nConclusion\n\nThis study highlighted the fact that non-communicable diseases should not be assessed through the past or present medical history only; it should rather be evaluated through a thorough investigation of socioeconomic and sociodemographic factors. The findings of this study support the fact that work, economic, and marital status may modify the odds of non-communicable disease in patients with baseline cardiac disease. Consequently, the study raises the need for the integral role pharmacists have in educating and minimizing the influence of socioeconomic factors other than those included in the current guidelines and which can increase the risk for developing cardiovascular disease.\n\n\nData availability\n\nOSF: Effects of Sociodemographic and Socioeconomic Factors on Stroke Development in Lebanese Patients with Atrial Fibrillation: a cross-sectional study. https://doi.org/10.17605/OSF.IO/PJC6A.52\n\nThis project contains the following underlying data.\n\n- Data_Anonymous_Results_stroke with Afib_Dr Diana Malaeb_2020.sav\n\nOSF: Effects of Sociodemographic and Socioeconomic Factors on Stroke Development in Lebanese Patients with Atrial Fibrillation: a cross-sectional study. https://doi.org/10.17605/OSF.IO/PJC6A.52\n\nThis project contains the following extended data.\n\n- Questionnaire_Stroke with Afib_Dr Diana Malaeb_2020.doc\n\n- Formulas used in the analysis_Stroke with Afib_Dr Diana Malaeb_2020.docx\n\n- Data key_CV score_Dr Diana Malaeb_2020.docx\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 all the patients who participated in this study.\n\n\nReferences\n\nWorld Health Organization: Noncommunicable diseases - Key Facts.2018. Reference Source\n\nWorld Health Organization: The top 10 causes of death.2018. Reference Source\n\nWorld Health Organization: Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000-2016.2018. Reference Source\n\nRamahi TM: Cardiovascular disease in the Asia Middle East region: global trends and local implications. Asia Pac J Public Health. 2010; 22(3 Suppl): 83s–9s. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Noncommunicable Diseases (NCD) Country Profiles.2018. Reference Source\n\nForouzanfar MH, A A, Alexander LT, et al.: Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. 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PubMed Abstract | Publisher Full Text | Free Full Text\n\nMendis S, Abegunde D, Yusuf S, et al.: WHO study on prevention of recurrences of myocardial infarction and stroke (WHO-PREMISE). Bull World Health Organ. 2005; 83: 820–9. PubMed Abstract | Free Full Text\n\nMolloy GJ, Stamatakis E, Randall G, et al.: Marital status, gender and cardiovascular mortality: behavioural, psychological distress and metabolic explanations. Soc Sci Med. 2009; 69(2): 223–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nChoumane NS, Malaeb DN, Malaeb B, et al.: A multicenter, prospective study evaluating the impact of the clinical pharmacist-physician counselling on warfarin therapy management in Lebanon. BMC Health Serv Res. 2018; 18(1): 80. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSamaha A, Zouein F, Gebbawi M, et al.: Associations of lifestyle and dietary habits with hyperlipidemia in Lebanon.2017. Publisher Full Text\n\nLane DA, Lip GY: Use of the CHA(2)DS(2)-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation. 2012; 126(7): 860–5. PubMed Abstract | Publisher Full Text\n\nJanati A, Matlabi H, Allahverdipour H, et al.: Socioeconomic Status and Coronary Heart Disease. Health Promot Perspect. 2011; 1: 105–10. PubMed Abstract | Publisher Full Text | Free Full Text\n\nParsons C, Patel SI, Cha S, et al.: CHA(2)DS(2)-VASc Score: A Predictor of Thromboembolic Events and Mortality in Patients With an Implantable Monitoring Device Without Atrial Fibrillation. Mayo Clin Proc. 2017; 92(3): 360–9. PubMed Abstract | Publisher Full Text | Free Full Text\n\nZagozdzon P, Zaborski L, Ejsmont J: Survival and cause-specific mortality among unemployed individuals in Poland during economic transition. J Public Health (Oxf). 2009; 31(1): 138–46. PubMed Abstract | Publisher Full Text\n\nMontgomery S, Cook D, Bartley M, et al.: Unemployment, cigarette smoking, alcohol consumption and body weight in young British men. Europ J Public Health. 1998; 8. Publisher Full Text\n\nEmpana JP, Sykes DH, Luc G, et al.: Contributions of depressive mood and circulating inflammatory markers to coronary heart disease in healthy European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation. 2005; 111(18): 2299–305. PubMed Abstract | Publisher Full Text\n\nKee C, Jamaiyah H, Safiza MN, et al.: Abdominal Obesity in Malaysian Adults: National Health and Morbidity Survey III (NHMS III, 2006). Malays J Nutr. 2008; 14(2). PubMed Abstract\n\nSafiza N, Khor GL, Shahar S, et al.: The Third National Health and Morbidity Survey (NHMS III) 2006: nutritional status of adults aged 18 years and above. Malay J Nutri. 2008; 14: 1–87.\n\nMohamed H, Mitra A, Mohd Zainuddin LR, et al.: Women Are at a Higher Risk of Metabolic Syndrome in Rural Malaysia. Women Health. 2013; 53: 335–48. PubMed Abstract | Publisher Full Text\n\nGhazali SM, Seman Z, Cheong KC, et al.: Sociodemographic factors associated with multiple cardiovascular risk factors among Malaysian adults. BMC Public Health. 2015; 15(1): 68. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKavanagh A, Bentley RJ, Turrell G, et al.: Socioeconomic position, gender, health behaviours and biomarkers of cardiovascular disease and diabetes. Soc Sci Med. 2010; 71(6): 1150–60. PubMed Abstract | Publisher Full Text\n\nHiscock R, Bauld L, Amos A, et al.: Socioeconomic status and smoking: a review. Ann N Y Acad Sci. 2012; 1248(1): 107–23. PubMed Abstract | Publisher Full Text\n\nKeyes KM, Hasin DS: Socio-economic status and problem alcohol use: the positive relationship between income and the DSM-IV alcohol abuse diagnosis. Addiction. 2008; 103(7): 1120–30. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGrittner U, Kuntsche S, Graham K, et al.: Social Inequalities and Gender Differences in the Experience of Alcohol-Related Problems. Alcohol Alcohol. 2012; 47(5): 597–605. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCutler DM, Lleras-Muney A, Vogl T: Socioeconomic status and health: dimensions and mechanisms. National Bureau Econ Res. 2008. Report No.: 0898-2937. Publisher Full Text\n\nLantz PM, House JS, Mero RP, et al.: Stress, life events, and socioeconomic disparities in health: results from the Americans' Changing Lives Study. J Health Soc Behav. 2005; 46(3): 274–88. PubMed Abstract | Publisher Full Text\n\nLayte R, Whelan CT: Explaining social class inequalities in smoking: the role of education, self-efficacy, and deprivation. Europ Soc Rev. 2009; 25(4): 399–410. Publisher Full Text\n\nMohamud WN, Ismail AA, Sharifuddin A, et al.: Prevalence of metabolic syndrome and its risk factors in adult Malaysians: results of a nationwide survey. Diabetes Res Clin Pract. 2011; 91(2): 239–45. PubMed Abstract | Publisher Full Text\n\nSelvarajah S, Haniff J, Kaur G, et al.: Clustering of cardiovascular risk factors in a middle-income country: a call for urgency. Eur J Prev Cardiol. 2013; 20(2): 368–75. PubMed Abstract | Publisher Full Text\n\nUnamuno X, Gómez-Ambrosi J, Rodríguez A, et al.: Adipokine dysregulation and adipose tissue inflammation in human obesity. Eur J Clin Invest. 2018; 48(9): e12997. PubMed Abstract | Publisher Full Text\n\nJoão AL, Reis F, Fernandes R: The incretin system ABCs in obesity and diabetes - novel therapeutic strategies for weight loss and beyond. Obes Rev. 2016; 17(7): 553–72. PubMed Abstract | Publisher Full Text\n\nWong CW, Kwok CS, Narain A, et al.: Marital status and risk of cardiovascular diseases: a systematic review and meta-analysis. Heart. 2018; 104(23): 1937. PubMed Abstract | Publisher Full Text\n\nFournier S, Muller O, Ludman A, et al.: Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Swiss Medical Weekly. 2013; 143: 0. PubMed Abstract | Publisher Full Text\n\nKilpi F, Konttinen H, Silventoinen K, et al.: Living arrangements as determinants of myocardial infarction incidence and survival: A prospective register study of over 300,000 Finnish men and women. Soc Sci Med. 2015; 133: 93–100. PubMed Abstract | Publisher Full Text\n\nSorlie PD, Coady S, Lin C, et al.: Factors associated with out-of-hospital coronary heart disease death: the national longitudinal mortality study. Ann Epidemiol. 2004; 14(7): 447–52. PubMed Abstract | Publisher Full Text\n\nAustin D, Yan AT, Spratt JC, et al.: Patient characteristics associated with self-presentation, treatment delay and survival following primary percutaneous coronary intervention. Eur Heart J Acute Cardiovasc Care. 2014; 3(3): 214–22. PubMed Abstract | Publisher Full Text\n\nHadi Khafaji HA, Al Habib K, Asaad N, et al.: Marital status and outcome of patients presenting with acute coronary syndrome: an observational report. Clin Cardiol. 2012; 35(12): 741–48. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWu J-R, Lennie TA, Chung ML, et al.: Medication adherence mediates the relationship between marital status and cardiac event-free survival in patients with heart failure. Heart Lung. 2012; 41(2): 107–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDupre M, Nelson A: Marital history and survival after a heart attack. Soc Sci Med. 2016; 170. PubMed Abstract | Publisher Full Text | Free Full Text\n\nFloud S, Balkwill A, Canoy D, et al.: Marital status and ischemic heart disease incidence and mortality in women: a large prospective study. BMC Med. 2014; 12(1): 42. PubMed Abstract | Publisher Full Text | Free Full Text\n\nQuinones PA, Kirchberger I, Heier M, et al.: Marital status shows a strong protective effect on long-term mortality among first acute myocardial infarction-survivors with diagnosed hyperlipidemia--findings from the MONICA/KORA myocardial infarction registry. BMC Public Health. 2014; 14: 98. PubMed Abstract | Publisher Full Text | Free Full Text\n\nVujcic I, Vlajinac H, Dubljanin E, et al.: Long-term prognostic significance of living alone and other risk factors in patients with acute myocardial infarction. Ir J Med Sci. 2015; 184(1): 153–8. PubMed Abstract | Publisher Full Text\n\nAkimova E, Pushkarev G, Smaznov V, et al.: Socio-economic risk factors for cardiovascular death: Data from 12-year prospective epidemiologic study. Russian J Cardiol. 2015; 110: 7.\n\nDia N: Effects of Sociodemographic and Socioeconomic Factors on Stroke Development in Lebanese Patients with Atrial Fibrillation: A Cross-Sectional Study. OSF. 2021. Publisher Full Text"
}
|
[
{
"id": "92211",
"date": "23 Aug 2021",
"name": "Feras Jirjees",
"expertise": [
"Reviewer Expertise Pharmacotherapeutics",
"Cardiovascular diseases",
"Diabetes",
"and medication adherence"
],
"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 was written in a scientific manner. There are several important points in this study. There are some corrections, especially in the writing, that I would ask the authors to make.\nAbstract:\nIntroduction: “4-5” should be “4 to 5”. Aim: the authors should add “socioeconomic factors” to the aim of the study. Results: “with a mean age of 58.75 (± SD) ± 13.59 years” should be written as “with a mean age (± SD) of 58.75 ± 13.59 years”.\n\nIntroduction:\nPage 3:\nParagraph 3: “~15%”, it is better as \"approximately 15%\" (no symbol). Paragraph 3: “Gulf and Middle East region”, Gulf countries are part of the Middle East region; therefore, it should be the “Middle East countries”.\n\nPage 4: Ethics approval and consent to participate:\nNo ethics approval number or code, please add it.\n\nResults:\nPage 4, Sociodemographic characteristics:\nNumber or percentage should either have one digit after decimal or two digits\nPage 5, Table 1:\nAge: add (years).\nPage 8, Conclusion: “…. the study raises the need for the integral role pharmacists have in educating …” It should be healthcare providers instead of pharmacists alone.\nFinally, in general, please use \"socioeconomic\" instead of “socio-economic” in all of the manuscript.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? 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": "7132",
"date": "10 Nov 2021",
"name": "Nada Dia",
"role": "Author Response",
"response": "Dear Dr. Jirjees, Thank you for your time and input. All the requested modifications were applied. Nonetheless, the ethics approval number was not listed because in 2018 the Lebanese International University did not release numbers for any accepted study. Kindly let us know if further information is needed. Sincerely, Nada Dia"
}
]
},
{
"id": "92213",
"date": "23 Aug 2021",
"name": "Seif El-Hadidi",
"expertise": [
"Reviewer Expertise Cardiology",
"Drug-therapy optimisation & Guideline-led Prescribing",
"Critical Care Medicine",
"Infectious Diseases",
"Pharmacoepidemiology."
],
"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\n- This article is of good quality, fit for indexing and citation. - The article is well-written and raises an interesting question. - However, I have some weak points for revision before final indexing.\nSome citations can be added as inserted below. - 1a) Sabry et al. (20211): This paper is nearly of similar content regarding the social determinants but in COVID-19 among the population of a low-middle Income country. - 1b) PIPHFrEF is a very good statement for meds that are harmful in cardiac diseases & particularly, HF where AF is a prognostic factor (El Hadidi et al., 20202). - 1c) The role of pharmacists in NCD management might not be well elaborated in the Middle East. El Hadidi et al. (20203) might be a good reference for pharmacists' role in NCD in limited resources.\n\nThe real questionnaire should be attached as supplement material (even if in Arabic/French Language) for reproducibility.\n\nI prefer to change the term \"jobless\" to \"unemployed\" as I think it is more ethical.\n\nI prefer to briefly define the criteria/criterion/reference of high/low socioeconomic levels in USD.\n\nSome English writings in the intro need to be revised before submission e.g. sentences should not start with abbreviations.\n\nIn the 4th paragraph of the intro, a very brief comparison of Lebanon people to a neighbouring country might be needed.\n\nOverall, this manuscript will be very interesting after doing the above recommendations and insertion of the recommended citations.\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": "7133",
"date": "10 Nov 2021",
"name": "Nada Dia",
"role": "Author Response",
"response": "Dear Dr. El-Hadidi, Thank you for your time and valuable input. Whenever possible, the articles you refer to were added to the section of references. The questionnaire was not attached as it is mentioned in the extended data. A study similar to the one we conducted in Lebanon was hard. Hence comparison was not possible. The remaining changes were applied as requested. Kindly let us know if further questions/improvements were needed. Sincerely, Nada dia and the co-authors"
}
]
},
{
"id": "92214",
"date": "26 Aug 2021",
"name": "Muna Barakat",
"expertise": [
"Reviewer Expertise Clinical practice"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThank you for giving me this opportunity in reviewing the article ”Effects of sociodemographic and socioeconomic factors on stroke development in Lebanese patients with atrial fibrillation: a cross-sectional study”. The article is really interesting and informative as it highlights a vital problem in the community. The findings thus should be used as a tool to enhance patient counselling about the risk factors including diseases and life style measures that should be implemented to minimize the occurrence of chronic diseases.\n\nNo further comments were raised, and I believe it is suitable to index.\n\nIs the work clearly and accurately presented and does it cite the current literature? Yes\n\nIs the study design appropriate and is the work technically sound? Yes\n\nAre sufficient details of methods and analysis provided to allow replication by others? Yes\n\nIf applicable, is the statistical analysis and its interpretation appropriate?\nYes\n\nAre all the source data underlying the results available to ensure full reproducibility? Yes\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": [
{
"c_id": "7134",
"date": "10 Nov 2021",
"name": "Nada Dia",
"role": "Author Response",
"response": "Dear Dr. Barakat, Thank you so much for your time and input. The co-authors and I were happy to read your feedback. Sincerely, Nada Dia and the co-authors"
}
]
}
] | 1
|
https://f1000research.com/articles/10-793
|
https://f1000research.com/articles/9-1376/v1
|
26 Nov 20
|
{
"type": "Study Protocol",
"title": "Mental distress and quality of life following provision of vascular imaging results of the coronary and carotid arteries to asymptomatic adults: a scoping review protocol",
"authors": [
"Reindolf Anokye",
"Ben Jackson",
"James Dimmock",
"Joanne M. Dickson",
"Lauren C. Blekkenhorst",
"Jonathan M. Hodgson",
"Joshua R. Lewis",
"Mandy Stanley",
"Ben Jackson",
"James Dimmock",
"Joanne M. Dickson",
"Lauren C. Blekkenhorst",
"Jonathan M. Hodgson",
"Joshua R. Lewis",
"Mandy Stanley"
],
"abstract": "Background: Non-invasive screening for atherosclerosis or asymptomatic cardiovascular disease of the coronary and carotid arteries is commonly undertaken, and research has been focussed on how results from these screenings lead to behaviour change. However, no review has focused on the effects of these results on mental distress and quality of life. This protocol will outline how a scoping review will be conducted to map all available evidence on mental distress or quality of life outcomes following the provision of vascular imaging results of the coronary and carotid arteries. Methods: Arksey and O’Malley’s (2005) framework will guide the scoping review. Databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be searched using MeSH terms such as \"Coronary stenosis\", \"Carotid Stenosis\", \"Psychological Distress\" and \"Quality of Life\" and related terms. Two investigators will screen title and abstract and all articles meeting inclusion criteria will be extracted. Data on authors, publication year, country of origin, aims/purpose, methodology, intervention, outcome measures as well as key findings that relate to the scoping review questions will be extracted for each included study. The findings will be presented using tables and thematic narrative synthesis. The scoping review will not produce a pooled estimate of the impact of vascular imaging results on mental distress and quality of life but will present information from the included studies related to mental distress and QOL. Conclusion: The review will highlight and address gaps in knowledge and provide direction for future investigations.",
"keywords": [
"Mental distress",
"Quality of life",
"Non-invasive vascular imaging",
"Asymptomatic adults",
"Scoping review"
],
"content": "Introduction\n\nCardiovascular disease (CVD) refers to diseases of the blood vessels, and in particular the heart, brain and peripheral vasculature1. CVDs due to atherosclerosis include cerebrovascular events such as stroke, ischaemic heart disease events such as heart attacks, and peripheral arterial diseases causing peripheral claudication1. CVD is the leading cause of death and disability globally1,2 with an estimated 17.9 million people dying from CVDs in 2016, representing 31% of all global deaths. Of these CVD-related deaths, 85% were due to heart attack and stroke or their sequelae2. By 2030, it is estimated that more than 22.2 million people will die annually from CVDs3.\n\nAtherosclerosis before clinical events, or “asymptomatic CVD”, can be easily visualised using a range of imaging methods, with the most common being computed tomography of the coronary arteries to calculate coronary artery calcification (CAC) or carotid ultrasound to identify carotid plaques and assess intimal medial thickness4. Imaging of the arteries to identify asymptomatic CVD is becoming commonplace in medical practice5, and provides asymptomatic individuals with a visible and tangible illustration of an otherwise hidden disease process, even before distinctive symptoms appear6. Such information can improve an individual’s knowledge of the disease which may enable them to increase control over, and improve their health7. Increased knowledge may also lead to personal and social benefits, such as enabling effective community action and contributing to developing one's social capital8,9. However, diagnostic information or results related to a disease (depending on how the situation is evaluated) may also affect an individual’s sense of well-being10 or lead to mental distress6,11,12. For example, previous studies have reported that women who undergo mammography screening may be susceptible to mental distress following the provision of results13–21.\n\nMental distress is frequently used as an outcome measure in psychological and medical research22. It includes distress expressed inwardly (anxiety, depression and impulsivity) and distress expressed outwardly (psychoticism, impulsivity and aggression)23 or a measure of obsession-compulsion, and interpersonal sensitivity23,24. Whereas, Quality of Life (QOL) encompasses a person’s psychological state, appraisals of physical health, personal beliefs as well as social relationships25. It is often measured in research using physical and mental health summary scores26. These two broad concepts (mental distress and QOL) are the outcomes of interest for this scoping review.\n\nThe scoping review was informed by Witte’s27 extended parallel process model (EPPM) and cognitive stress appraisal theory28. Based on the constructs of the EPPM27, the provision of information—in particular, negative information—about a person’s coronary artery calcium and carotid plaque (and the potential implications of this condition) is likely to stimulate subjective ‘threat’ appraisals (i.e., perceived susceptibility to, and severity of, CVD)29. Depending on interactions between that threat appraisal and individuals’ efficacy appraisals, individuals may react to screening information by (a) adopting danger control responses (including attitudes, beliefs, behavioural intentions, and/or behaviours) that align with message recommendations, or (b) adopting fear control processes (such as denial, reactance, and avoidance) intended to reduce fear rather than take protective action30. Behavioural intentions and/or behaviours such as increasing physical activity, health responsibility, good nutrition, and stress management could impact health outcomes31. Behavioural intentions and/or behaviours are also associated with lifestyle related disease burden such as CVD32 which could undermine QOL33. Cognitive stress appraisal theory28 also proposes that individuals primarily evaluate circumstances/situations as ‘challenging’ (i.e., threat that can be overcome or met) or ‘threatening’ (i.e., anticipated loss/harm)28. Positive cognitive stress appraisal (i.e. appraising a situation as a challenge to be resolved and setting goals to achieve that) may contribute to prevention of depression and improved QOL34. Negative appraisals of stress—viewing an issue such as detected atherosclerotic plaque in the arteries as a threat and believing that resolving it is beyond one’s abilities—may, however, lead to mental distress35–37.\n\nBased on the EPPM and cognitive stress appraisal frameworks, we therefore hypothesized that; (a) population screening to detect atherosclerotic plaque in the coronary or carotid arteries can influence QOL, and (b) population screening to detect atherosclerotic plaque in the coronary or carotid arteries can cause mental distress. To date, however, the available evidence that may support (or refute) these hypotheses has not been scrutinised or reported in any coherent manner. Hence, there is a need for a scoping review to synthesize the state of scientific literature on this subject.\n\nScoping reviews aim to map key concepts, main sources and types of evidence available in a research area and can be undertaken where an area is complex or has not been comprehensively reviewed before38. Previous reviews reported very little evidence relating to QOL or mental distress following provision of vascular imaging results to asymptomatic adults7,39–42. It is important, therefore, to collate evidence relating to the findings available in this field, how studies in this field have been conducted, the key characteristics of studies, and important knowledge gaps. As such, this scoping review will comprehensively map the evidence on mental distress and QOL outcomes following provision of vascular imaging results of the coronary or carotid arteries to asymptomatic adults. We will also report other details of included studies that we deem important in this scoping review (e.g. the information provided during counselling and whether the counselling could reduce distress or any information included in the results that shaped the nature of the response).\n\n\nStudy rationale and guiding question\n\nThere is great interest (and value) in providing people with vascular imaging results of the coronary and carotid arteries to prompt healthful behaviour change and better management of CVD7,40. However, the provision of the imaging results may produce markedly different emotions—and as a result, downstream behaviours—depending upon the way in which they are received and appraised. Also, the uncertainty about a possible future threat (due to coronary artery calcium and carotid plaque) may cause anxiety43. There is theoretical justification to anticipate that information aimed at prompting healthful behaviour change and better management of CVD may stimulate negative psychosocial outcomes or mental distress such as anxiety or depression impairing QOL. Accordingly, it is important to identify which research questions have and have not been addressed in this area. Also, by highlighting the extent of findings on distress and/or QOL, a scoping review could support the development of strategies designed to mitigate or prevent distress during and following such screening exercises.\n\nThe aim of this review is to map all available evidence on mental distress and QOL outcomes among participants who were screened for atherosclerosis by non-invasive methods and provided with their own coronary or carotid artery vascular imaging results. This scoping review will address this research question:\n\n1. What is the state of scientific literature on mental distress and quality of life outcomes following provision of vascular imaging results of the coronary and carotid arteries, and what are the gaps in that literature?\n\nTable 1 further clarifies the core elements of the questions guiding the conduct of this scoping review.\n\nQOL, quality of life.\n\n\nProtocol\n\nStudy design. The framework developed by Arksey and O’Malley44 will be used for this scoping review. The framework involves 5 stages: (1) identifying the research question; (2) identifying relevant studies; (3) study selection; (4) charting the data; and (5) collating, summarizing and reporting the results. The reporting of this scoping review will also be guided by the PRISMA extension for scoping review reporting checklist45.\n\nInformation sources and search strategy. The main purpose of a scoping review is to comprehensively identify primary studies (published and unpublished) and reviews suitable for answering the review questions. To achieve this, databases such as MEDLINE (Clarivate), APA PsychINFO, EMBASE, Social Work Abstracts, Psychology and Behavioural Sciences Collection, and Cumulative Index to Nursing and Allied Health Literature (CINAHL), will be searched for articles of relevance. Further manual searching of reference lists in identified articles will be undertaken to include other studies of relevance. We will also search relevant grey literature databases such as Open Grey and Open Access Theses and Dissertations (OATD) to identify relevant studies.\n\nApproach to developing search strategy. Different sources (e.g. MeSH headings and thesaurus) will be used to identify terms and synonyms to comprehensively cover the research questions as much as possible46–49. The proposed search strategy was developed in consultation with an academic librarian (Table 2) for MEDLINE using MesH terms such as \"Coronary stenosis\", \"Carotid Stenosis\", \"Psychological Distress\" and \"Quality of Life\". We also used Boolean operators “AND” to narrow search results to include only relevant results containing required keywords and “OR” to expand search results and combine synonyms. Other keywords such as behaviour, lifestyle, motivation, risk perception, medication adherence and smoking cessation were included to capture all relevant studies as mental health and QOL outcomes are unlikely to be primary or secondary outcomes and thus reported in the title or abstract. This search strategy will be modified for use in other databases. Due to the exploratory nature of scoping reviews and the need to ensure a comprehensive search of relevant literature, an iterative approach to search strategies will be employed44. This implies that the search strategy will be updated as we discover new terms as we work through the review.\n\nMeSH, Medical Subject Headings; CAC, Coronary Artery Calcium.\n\nThese terms will be searched as keywords in the title and abstract headings and no date limits will be applied. Search results will be downloaded, imported and saved as Microsoft Word and PDF documents. Database outputs will be compared to check for the existence of any duplicates.\n\nDatabases and records will be screened using the eligibility criteria (see below) and studies not meeting the criteria will be excluded. The process for identification, screening, eligibility and studies to be included is displayed in Figure 1. The process of searching and selection will be reported in the main review using a PRISMA flowchart50.\n\nThe screening will begin with title and abstract screening by two investigators (RA and JRL) who will independently screen the titles and abstracts for all retrieved records for inclusion and to agree on exclusions. This process will be piloted using a sample of abstracts to ensure that this approach will be efficient enough to capture all relevant articles. Any articles that meet the inclusion criteria or that cannot be excluded will be retained for full text review. For the second stage, two investigators (RA and JRL) will each independently screen the full text of articles to determine if they meet the inclusion criteria and conflicts will be resolved by an independent reviewer (LCB).\n\nData from included studies will be extracted. There will be no critical appraisal of quality of studies, but we will comment on key methodological issues within the studies. We are not critically appraising results as this scoping review (and scoping reviews in general) will not produce critically appraised and synthesised data but an overview of existing evidence51.\n\nInclusion criteria\n\nThe following inclusion criteria will apply:\n\na) Study characteristics\n\nStudies must be of adults who are 18 years and over and asymptomatic (not screened due to clinical symptoms such as chest pain or angina) and without pre-existing CVD (e.g. stroke, myocardial infarction, peripheral arterial disease or transient ischemic attack). Studies must report follow-up assessment and a mental distress or QOL outcome after participants received information related to their own coronary artery calcification or carotid stenosis/plaque.\n\nb) Study types\n\nStudy types that will be included for this scoping review are empirical studies of any type. No year of publication and language restrictions will be applied.\n\nConcepts\n\ni) Imaging results\n\nInformation regarding the state of arteries, extent of stenosis, extent of coronary artery calcification, or carotid/atherosclerotic plaques, coronary calcium score, arterial wall irregularities or obstructive artery walls conveyed to study participants.\n\nii) Mental distress\n\nStudies must report mental distress expressed inwardly (anxiety, depression and impulsivity), distress expressed outwardly (psychoticism, impulsivity and aggression), obsession-compulsion or interpersonal sensitivity.\n\niii) Quality of life\n\nStudies must report QOL as an outcome or should include QOL as an outcome measure.\n\nc) Context\n\nThis scoping review will include studies conducted in any geographical location among any racial/ethnic group and gender. Studies will be included irrespective of their settings.\n\nExclusion criteria\n\na) Study types, participants and imaging methods\n\nStudies in symptomatic patients undergoing invasive imaging for diagnostic purposes will be excluded. Other studies that will be excluded are studies providing imaging results of other vascular diseases/conditions such as Aneurysm or Endoleak; Angiodysplasia; Angioedema; Angiomatosis (Bacillary Angiomatosis, Klippel-Trenaunay-Weber Syndrome, Sturge-Weber Syndrome, von Hippel-Lindau Disease); Arteriovenous Malformations; Capillary Leak Syndrome; Ischemic Colitis; Compartment Syndromes; Diabetic Angiopathies; Hand-Arm Vibration Syndrome; Hemorrhoids; Hemostatic Disorders; Hyperemia; Hepatic Veno-Occlusive Disease; Hypotension; Peliosis Hepatis; Ischemic Optic Neuropathy; Pulmonary Veno-Occlusive Disease; Scimitar Syndrome; Retinal Vein Occlusion;Pulmonary Vein Stenosis; Splenic Infarction; Superior Vena Cava Syndrome; Telangiectasis; Varicocele; Thoracic Outlet Syndrome; Varicose Veins; Vascular Fistula; Vascular Neoplasms; Vascular System Injuries; Vasculitis as well as Vasoplegia and Venous Insufficiency.\n\nb) Outcomes\n\nStudies without outcomes considered as mental distress will be excluded. We will also exclude studies where mental distress/psychiatric assessments were performed only before vascular imaging procedure and not after provision of imaging results. Studies that did not report QOL as an outcome will also be excluded.\n\nA draft data extraction chart will be developed and piloted with a selection of identified studies. The diagrammatic or tabular form of presentation or charting will be used for this study. The potential chart categories may consist of authors information (names, year of publication, study location), participant characteristics (age, gender), research design, methods, instruments/techniques/clinical assessments used to gather data coronary artery calcification, carotid plaque/stenosis, mental distress, and quality of life and aims/purpose of the extracted studies (Table 3). We will also extract data on how vascular imaging results were provided and whether there was additional counselling or support mechanisms.\n\nQOL, quality of life.\n\nEndNote X9 will be used as a reference management tool and to avoid duplications. Microsoft Excel and Word will be used to manage data within the review team.\n\nThis review will employ thematic and numeric approaches to summarise studies. A thematic approach will be used to summarise the main and sub-themes that will emerge after the scoping exercise. A numeric approach will also be used to summarise results of the scoping review by presenting the quantity of each emerging concept (e.g. worry was used interchangeably with anxiety (n=2) or most of the studies (n=25) measured depression using the Center for Epidemiological Studies Depression (C-ESD) instrument). The scoping review will not produce a pooled estimate of the impact of vascular imaging results on mental distress and quality of life as we aim to preliminary assess the potential size, scope and gaps in available literature.\n\nResults on the state of scientific literature will be reported and the gaps in the literature will be identified. There will be further discussion on the implications of the results for practice and future research.\n\nThe findings from this review will be submitted to peer-reviewed journals to be considered for publication and may be presented at scientific conferences. Also, we aim to share our results with key stakeholders to influence policy and practice.\n\n\nStudy status\n\nStart date of search: August 2020; anticipated date of completing review: December, 2020\n\nCurrent study status:\n\nPreliminary searches: Yes\n\nPiloting search strategy: Yes\n\nPilot screening of search results: Yes\n\nStudy selection process piloting: Yes\n\nFormal screening of search results against eligibility criteria: Not started\n\nData extraction: Not started\n\nData analysis and interpretation: Not started\n\n\nConclusion\n\nThe purpose of this protocol is to describe the methodological considerations that will guide the completion of a scoping review that will summarise the extent, range and nature of studies on mental distress and quality of life outcomes reported among asymptomatic adults following the provision of vascular imaging results. This comprehensive review will help advance knowledge about potential negative effects of screening for asymptomatic CVD to elicit healthful behaviour changes. It could also possibly enable the development of strategies to prevent distress. The results of this review will help advance knowledge in this field and will be useful for future medical practice when providing vascular imaging results to patients, cardiovascular research, and future clinical trials providing vascular imaging results to participants. This scoping review will be limited to studies reporting coronary or carotid artery plaque screening only as these are the commonly used structural vascular imaging modalities for large screening initiatives of asymptomatic individuals.\n\n\nEthics approval and consent to participate\n\nThere will be no formal ethical application and ethical review as no primary data will be collected.\n\n\nData availability\n\nNo data are associated with this article.",
"appendix": "References\n\nMendis S, Puska P, Norrving B, et al.: Global atlas on cardiovascular disease prevention and control. World Health Organization; 2011. Reference Source\n\nWorld Health Organization: Cardiovascular diseases (CVDs): fact sheet 2017. Diambil dari. 2017; Reference Source\n\nWorld Health Organization: Global status report on noncommunicable diseases 2010. Geneva: WHO; 2011. World Health Organization. 2016. Reference Source\n\nGoff DC Jr, Lloyd-Jones DM, Bennett G, et al.: 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014; 63(25 Pt B): 2935–59. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBuxton DB, Antman M, Danthi N, et al.: Report of the National Heart, Lung, and Blood Institute working group on the translation of cardiovascular molecular imaging. Circulation. 2011; 123(19): 2157–63. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDevcich DA, Ellis CJ, Waltham N, et al.: Seeing what's happening on the inside: patients' views of the value of diagnostic cardiac computed tomography angiography. Br J Health Psychol. 2014; 19(4): 810–22. PubMed Abstract | Publisher Full Text\n\nMamudu HM, Paul TK, Veeranki SP, et al.: The effects of coronary artery calcium screening on behavioral modification, risk perception, and medication adherence among asymptomatic adults: a systematic review. Atherosclerosis. 2014; 236(2): 338–50. PubMed Abstract | Publisher Full Text\n\nNutbeam D: Health literacy as a public health goal: a challenge for contemporary health education and communication strategies into the 21st century. Health Promotion International. 2000; 15(3): 259–67. Publisher Full Text\n\nWorld Health Organization: Health Promotion Track 2: health literacy and health behaviour. 7th Global Conference on Health Promotion: track themes. Accessed on; 2015. Reference Source\n\nMushlin AI, Mooney C, Grow V, et al.: The value of diagnostic information to patients with suspected multiple sclerosis. Rochester-Toronto MRI Study Group. Arch Neurol. 1994; 51(1): 67–72. PubMed Abstract | Publisher Full Text\n\nMushlin AI, Kern LM, Paris M, et al.: The value of diagnostic information to patients with chest pain suggestive of coronary artery disease. Med Decis Making. 2005; 25(2): 149–57. PubMed Abstract | Publisher Full Text\n\nPeel E, Parry O, Douglas M, et al.: Diagnosis of type 2 diabetes: a qualitative analysis of patients' emotional reactions and views about information provision. Patient Educ Couns. 2004; 53(3): 269–75. PubMed Abstract | Publisher Full Text\n\nBarton MB, Morley DS, Moore S, et al.: Decreasing women's anxieties after abnormal mammograms: a controlled trial. J Natl Cancer Inst. 2004; 96(7): 529–38. PubMed Abstract | Publisher Full Text\n\nBrett J, Austoker J, Ong G: Do women who undergo further investigation for breast screening suffer adverse psychological consequences? A multi-centre follow-up study comparing different breast screening result groups five months after their last breast screening appointment. J Public Health Med. 1998; 20(4): 396–403. PubMed Abstract | Publisher Full Text\n\nBrett J, Austoker J: Women who are recalled for further investigation for breast screening: psychological consequences 3 years after recall and factors affecting re-attendance. J Public Health Med. 2001; 23(4): 292–300. PubMed Abstract | Publisher Full Text\n\nOng G, Austoker J, Brett J: Breast screening: adverse psychological consequences one month after placing women on early recall because of a diagnostic uncertainty. A multicentre study. J Med Screen. 1997; 4(3): 158–68. PubMed Abstract | Publisher Full Text\n\nMeystre-Agustoni G, Paccaud F, Jeannin A, et al.: Anxiety in a cohort of Swiss women participating in a mammographic screening programme. J Med Screen. 2001; 8(4): 213–9. PubMed Abstract | Publisher Full Text\n\nOlsson P, Armelius K, Nordahl G, et al.: Women with false positive screening mammograms: how do they cope? J Med Screen. 1999; 6(2): 89–93. PubMed Abstract | Publisher Full Text\n\nLerman C, Track B, Rimer BK, et al.: Psychological and behavioral implications of abnormal mammograms. Ann Intern Med. 1991; 114(8): 657–61. PubMed Abstract | Publisher Full Text\n\nAro AR, Absetz SP, van Elderen TM, et al.: False-positive findings in mammography screening induces short-term distress - breast cancer-specific concern prevails longer. Eur J Cancer. 2000; 36(9): 1089–97. PubMed Abstract | Publisher Full Text\n\nLerman C, Trock B, Rimer BK, et al.: Psychological side effects of breast cancer screening. Health Psychol. 1991; 10(4): 259–67. PubMed Abstract | Publisher Full Text\n\nOlsen LR, Mortensen EL, Bech P: Mental distress in the Danish general population. Acta Psychiatr Scand. 2006; 113(6): 477–84. PubMed Abstract | Publisher Full Text\n\nOlsen LR, Mortensen EL, Bech P: The SCL-90 and SCL-90R versions validated by item response models in a Danish community sample. Acta Psychiatr Scand. 2004; 110(3): 225–9. PubMed Abstract | Publisher Full Text\n\nGoldberg DP, Hillier VF: A scaled version of the General Health Questionnaire. Psychol Med. 1979; 9(1): 139–45. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: WHOQOL: measuring quality of life. Division of Mental Health and Prevention of Substance Abuse; 1997. Reference Source\n\nWare JE Jr: SF-36 health survey update. Spine (Phila Pa 1976). 2000; 25(24): 3130–9. PubMed Abstract | Publisher Full Text\n\nWitte K: Fear control and danger control: A test of the extended parallel process model (EPPM). Communications Monographs. 1994; 61(2): 113–34. Publisher Full Text\n\nLazarus RS: Thoughts on the relations between emotion and cognition. Am Psychol. 1982; 37(9): 1019. Publisher Full Text\n\nWitte K: Putting the fear back into fear appeals: The extended parallel process model. Communications Monographs. 1992; 59(4): 329–49. Publisher Full Text\n\nWitte K: Fear as motivator, fear as inhibitor: Using the extended parallel process model to explain fear appeal successes and failures. Handbook of communication and emotion. Elsevier; 1996; 423–50. Publisher Full Text\n\nCockerham WC: Health lifestyle theory and the convergence of agency and structure. J Health Soc Behav. 2005; 46(1): 51–67. PubMed Abstract | Publisher Full Text\n\nWorld Health Organization: Global action plan for the prevention and control of noncommunicable diseases 2013-2020. 2013. Reference Source\n\nWang W, Lau Y, Chow A, et al.: Health-related quality of life and social support among Chinese patients with coronary heart disease in mainland China. Eur J Cardiovasc Nurs. 2014; 13(1): 48–54. PubMed Abstract | Publisher Full Text\n\nTohmiya N, Tadaka E, Arimoto A: Cross-sectional study of cognitive stress appraisal and related factors among workers in metropolitan areas of Japan. BMJ Open. 2018; 8(6): e019404. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLazarus RS: Psychological stress and the coping process. 1966. Reference Source\n\nLazarus RS, Stress SF: Appraisal and Coping New York. springer publishing company; 1984\n\nCarpenter R: A review of instruments on cognitive appraisal of stress. Arch Psychiatr Nurs. 2016; 30(2): 271–9. PubMed Abstract | Publisher Full Text\n\nMays N, Roberts E, Popay J: Synthesising research evidence. Studying the organisation and delivery of health services: Research methods. 2001; 220. Reference Source\n\nHackam DG, Shojania KG, Spence JD, et al.: Influence of noninvasive cardiovascular imaging in primary prevention: systematic review and meta-analysis of randomized trials. Arch Intern Med. 2011; 171(11): 977–82. PubMed Abstract | Publisher Full Text\n\nRodondi N, Auer R, de Bosset Sulzer V, et al.: Atherosclerosis screening by noninvasive imaging for cardiovascular prevention: a systematic review. J Gen Intern Med. 2012; 27(2): 220–31. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHollands GJ, Hankins M, Marteau TM: Visual feedback of individuals' medical imaging results for changing health behaviour. Cochrane Database Syst Rev. 2010; (1): CD007434. PubMed Abstract | Publisher Full Text\n\nBize R, Burnand B, Mueller Y, et al.: Biomedical risk assessment as an aid for smoking cessation. Cochrane Database Syst Rev. 2012; 12: CD004705. PubMed Abstract | Publisher Full Text\n\nGrupe DW, Nitschke JB: Uncertainty and anticipation in anxiety: an integrated neurobiological and psychological perspective. Nat Rev Neurosci. 2013; 14(7): 488–501. PubMed Abstract | Publisher Full Text | Free Full Text\n\nArksey H, O'Malley L: Scoping studies: towards a methodological framework. Int J Soc Res Methodol. 2005; 8(1): 19–32. Publisher Full Text\n\nTricco AC, Lillie E, Zarin W, et al.: PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation. Ann Intern Med. 2018; 169(7): 467–73. PubMed Abstract | Publisher Full Text\n\nLefebvre C, Manheimer E, Glanville J: Searching for studies. Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series. 2008; 95–150. Publisher Full Text\n\nHausner E, Guddat C, Hermanns T, et al.: Development of search strategies for systematic reviews: validation showed the noninferiority of the objective approach. J Clin Epidemiol. 2015; 68(2): 191–9. PubMed Abstract | Publisher Full Text\n\nDe Vet H, Eisinga A, Riphagen I, et al.: Chapter 7: searching for studies. Cochrane handbook for systematic reviews of diagnostic test accuracy version 04 [updated September 2008] The Cochrane Collaboration. 2008.\n\nKristensen FB, Hørder M: Health technology assessment handbook: Danish Institute for Health Technology Assessment; 2001\n\nLiberati A, Altman DG, Tetzlaff J, et al.: The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009; 62(10): e1–e34. PubMed Abstract | Publisher Full Text\n\nPeters MD, Godfrey CM, Khalil H, et al.: Guidance for conducting systematic scoping reviews. Int J Evid Based Healthc. 2015; 13(3): 141–6. PubMed Abstract | Publisher Full Text"
}
|
[
{
"id": "77059",
"date": "08 Mar 2021",
"name": "Md Mahbub Hossain",
"expertise": [
"Reviewer Expertise Psychosocial Epidemiology",
"Evidence-based Mental Health",
"Mental Health Policies and 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\nWe want to express our gratitude to the authors who have chosen to work on such an important area of health science. With the growing burden of cardiovascular diseases, it is necessary to understand how such diagnoses may impact mental health and overall wellbeing in affected individuals. This prospective scoping review is likely to add great value; however, there are a few concerns that require to be addressed before the review protocol is indexed, and more importantly before the review is conducted.\nFirst, the authors planned to use the framework by Arksey and O'Malley, which is one of the most widely used frameworks for scoping reviews. However, this framework has undergone further improvements by Levac et al. (2010)1 and Peters et al. (2015, 2017)2,3,4. The authors may consider using the updated frameworks or give the rationale for using the current one over the more recent versions.\nSecond, in Table 1, the authors mentioned adults and international within core elements such as \"perspective\" and \"setting,\" respectively. A researcher and/or a practitioner may wish to know where the population belonged to in the primary studies, which can be local/global as well as community/clinical settings. I'd suggest using \"population\" for adults and expanding the concept of \"setting\" to the community and/or clinical settings while keeping the search terms and the scope of the review as global. This would bring more clarity and might make more sense from a systematic assessment perspective on the evidence.\nThird, the authors must explain what \"mental distress\" and \"quality of life\" are. These concepts have varying definitions from different disciplines. It may not be feasible to do another review to summarize what they mean; however, it would be useful to have at least a working definition of these concepts that refers to some of the leading articles explaining these terms. Such explanations would be helpful to present and discuss the findings of the review in the future. However, the protocol must mention these clearly before the review begins.\nLastly, in the concepts section, the authors mentioned that \"studies must report\" mental distress and quality of life. The use of \"must\" in both concepts creates a dilemma that is they will recruit articles if they (must) include both these concepts. We found this idea less practical. Rather, an article may report either \"mental distress\" or \"quality of life,\" and the authors may present both as the summarized evidence, which would provide a better \"map\" of the evidence landscape. We would humbly request the authors to make necessary changes that reflect the true objective of the review, as they feel appropriate.\n\nIs the rationale for, and objectives of, the study clearly described? Yes\n\nIs the study design appropriate for the research question? Partly\n\nAre sufficient details of the methods provided to allow replication by others? Partly\n\nAre the datasets clearly presented in a useable and accessible format? Not applicable",
"responses": [
{
"c_id": "6677",
"date": "28 May 2021",
"name": "Reindolf Anokye",
"role": "Author Response",
"response": "We want to express our gratitude to the authors who have chosen to work on such an important area of health science. With the growing burden of cardiovascular diseases, it is necessary to understand how such diagnoses may impact mental health and overall wellbeing in affected individuals. This prospective scoping review is likely to add great value; however, there are a few concerns that require to be addressed before the review protocol is indexed, and more importantly before the review is conducted. Response: We would like to thank the reviewers for their time and valuable comments when reviewing the manuscript. We have extensively revised the manuscript to address the comments and feedback. First, the authors planned to use the framework by Arksey and O'Malley, which is one of the most widely used frameworks for scoping reviews. However, this framework has undergone further improvements by Levac et al. (2010) and Peters et al. (2015, 2017). The authors may consider using the updated frameworks or give the rationale for using the current one over the more recent versions. Response: We agree that the updated framework would better suit this study and provide a better approach to the design of the study including collating, summarizing and reporting the results. The framework has been updated in the manuscript. Please see the study design section for details of the updated framework. Second, in Table 1, the authors mentioned adults and international within core elements such as \"perspective\" and \"setting,\" respectively. A researcher and/or a practitioner may wish to know where the population belonged to in the primary studies, which can be local/global as well as community/clinical settings. I'd suggest using \"population\" for adults and expanding the concept of \"setting\" to the community and/or clinical settings while keeping the search terms and the scope of the review as global. This would bring more clarity and might make more sense from a systematic assessment perspective on the evidence. Response: Table 1 has been updated as per comments under ‘study rationale and guiding question’ section of the manuscript. We have now expanded the concept of “setting” to include community and/or clinical settings and also using “population” for adults while keeping the scope of the review global. Third, the authors must explain what \"mental distress\" and \"quality of life\" are. These concepts have varying definitions from different disciplines. It may not be feasible to do another review to summarize what they mean; however, it would be useful to have at least a working definition of these concepts that refers to some of the leading articles explaining these terms. Such explanations would be helpful to present and discuss the findings of the review in the future. However, the protocol must mention these clearly before the review begins. Response: We agree that \"mental distress\" and \"quality of life\" could have been explained better in the manuscript. We have replaced mental distress with psychological distress in the manuscript even though articles using mental distress will still be included in the review. Although mental distress and psychological distress are often used interchangeably, psychological distress is well defined in the literature and is perhaps more easily understood. We have also expanded our definition of quality of life and indicated that our focus is on health-related quality of life. The explanation or definition for psychological distress and health-related quality of life can be found in the third paragraph of the introduction section of the manuscript. Lastly, in the concepts section, the authors mentioned that \"studies must report\" mental distress and quality of life. The use of \"must\" in both concepts creates a dilemma that is they will recruit articles if they (must) include both these concepts. We found this idea less practical. Rather, an article may report either \"mental distress\" or \"quality of life,\" and the authors may present both as the summarized evidence, which would provide a better \"map\" of the evidence landscape. We would humbly request the authors to make necessary changes that reflect the true objective of the review, as they feel appropriate. Response: We have replaced \"studies must report\" with “an article may report” psychological distress and/or quality of life/health-related quality of life for inclusion in the review. This can be found in the concepts section of the manuscript."
}
]
}
] | 1
|
https://f1000research.com/articles/9-1376
|
https://f1000research.com/articles/10-549/v1
|
08 Jul 21
|
{
"type": "Brief Report",
"title": "Implementation challenges from a prospective, interventional biopsy-based study of Environmental Enteropathy in rural Pakistan",
"authors": [
"Sheraz Ahmed",
"Najeeha Iqbal",
"Kamran Sadiq",
"Fayaz Umrani",
"Arjumand Rizvi",
"Zehra Jamil",
"Sana Syed",
"Marium Khan",
"Junaid Iqbal",
"Shahida Qureshi",
"Aneeta Hotwani",
"Najeeb Rahman",
"Sean Moore",
"Asad Ali",
"Sheraz Ahmed",
"Najeeha Iqbal",
"Kamran Sadiq",
"Fayaz Umrani",
"Arjumand Rizvi",
"Zehra Jamil",
"Sana Syed",
"Marium Khan",
"Junaid Iqbal",
"Shahida Qureshi",
"Aneeta Hotwani",
"Najeeb Rahman",
"Sean Moore"
],
"abstract": "The Study of Environmental Enteropathy (EE) and Malnutrition in Pakistan (SEEM) is a community intervention trial designed to understand the pathophysiology of EE and its associated clinical phenotypes in children less than two years of age. Undernutrition is the underlying cause of three million deaths annually, accounting for 45% of all deaths among children under five years of age. Linear growth stunting affects a further 165 million. In Pakistan, where our study is focused, an estimated one in three children are underweight and nearly half are stunted. This manuscript summarizes the challenges faced by the field team and the solutions employed for achieving our research objectives at the rural field site, Matiari. Our study design involved a longitudinal collection of field data and biological samples which required constant engagement of field staff with the participating families. Challenges faced in SEEM included: 1) quality assurance parameters of anthropometry data; 2) 24-hour food recall data collection; 3) clinical management of acutely sick children enrolled in our study; 4) obtaining informed consent for upper gastrointestinal endoscopy (an invasive procedure); and 5) biological sample collection (blood, urine, stool) from malnourished children at the community level. We accomplished our goal of enrolling 350 malnourished children and 50 well-nourished children with a more than 95% success rate of collecting blood, urine and stool specimens. We collected 72% microbiome stool samples within 30 minutes of the child passing stool. We conducted an upper gastrointestinal biopsy in 63 children.\n\nBroadly, solutions to these challenges included good governance, the establishment of credibility, and the development of a longitudinal bidirectional relationship embedded in trust and effective communication with the caretakers of the children enrolled in our study.\n\nContinuous monitoring, regular training of staff, and effective teamwork were key factors that led to the successful execution of our study.",
"keywords": [
"Field Implementation",
"environmental enteropathy",
"biomarkers",
"data collection",
"malnutrition",
"stunting",
"microbiome"
],
"content": "Abbreviations\n\nEE: Environmental Enteropathy\n\nSEEM: Study of Environmental Enteropathy (EE) and Malnutrition\n\nAKU: Aga Khan University\n\nIDRL: Infectious Diseases Pediatric Research Laboratory\n\nERC: Ethics Review Committee\n\nWHZ: Weight-for-Height\n\nWAZ: Weight for Age\n\nHAZ: Height-for-Age\n\nWHO: World Health Organization\n\nRUTF: Ready-to-use Therapeutic Food\n\nRUSF: Ready-to-use Supplementary Food\n\nMAM: Moderate Acute Malnutrition\n\nSAM: Severe Acute Malnutrition\n\nUGI: Upper Gastrointestinal\n\nINR: International Normalized Ratio\n\nHFIAS: Household Food In-security and Access Scale\n\nUNICEF: United Nations International Children's Emergency Fund\n\nMAL-ED: Malnutrition and Enteric Disease Study\n\nCHWs: Community Health Workers\n\nLMICs: Low- and Middle-income countries\n\nIMCI: Integrated Management of Childhood Illnesses\n\nMUAC: Mid Upper Arm Circumference\n\nENA: Emergency Nutrition Assessment\n\nL:R Lactulose: Rhamnose\n\n\nIntroduction\n\nMalnutrition is defined as an imbalance of nutrient intake that results in either overnutrition (manifested as obesity) or undernutrition (manifested as stunting, wasting, and/or underweight). Undernutrition is directly or indirectly responsible for almost half of deaths in children under five years of age in low and middle-income countries (LMIC) with severe implications for child survival and individual intellectual development, and adverse national economic consequences. Southeast Asia carries half of the global burden for stunting (length for age Z score<-2; 22%) and wasting (weight for length Z score<-2; 7.5%) in children under five years of age.1 Stunted Pakistani children comprise ~45% of all stunted South East Asian children, attributing to the third-highest percentage of stunting worldwide.2 Among various factors, poverty and food insecurity in these areas are the main risk factors for undernutrition, which is further aggravated by poor sanitation and unhygienic living conditions. Stunting is mediated in large part by EE, a subclinical disorder characterized by non-specific intestinal inflammation with or without overt diarrhea episodes.3 It is a process driven by repeated exposure to entero-pathogens, and exposure to environmental contaminants/toxins. The hallmarks of EE pathophysiology are believed to be gut barrier dysfunction, non-specific inflammation, and malabsorption.\n\n\nMethods\n\nWe implemented SEEM in the rural district of Pakistan; the primary objective was to test the biomarkers of EE in malnourished and well-nourished children. Matiari is a rural district that is 185km/115 miles north of the city Karachi, where the Aga Khan University (AKU) flagship campus is based. Its total population is 0.769 million with approximately 143,000 households in around 1600 villages.4 The major source of economic growth in this area is from agriculture-related activities. Matiari is subdivided into 18 Union Councils (the equivalent of municipalities in the United States), which are its administrative subunits. The average population per union council is 30,000 people with an average household size of 6.7 persons. The Department of Pediatrics and Child Health of AKU has been conducting community-based research projects in this district since 2002 and our research team has successfully implemented several large community-based trials on maternal, neonatal, and child health.5–15 In our current study, SEEM, collection of field data and laboratory samples (blood, urine, and stool) involved traveling to the residence of the families versus the use of a field office as a central sample and data collection point. This decision was driven by feasibility given that our study population primarily lived in widely scattered villages from where access was limited due to poor road and public transportation infrastructure. It was logistically difficult to ask parents to bring their children to a field office or any fixed facility for sample collection.\n\nThe Matiari district shoulders an immense burden of maternal, neonatal, and childhood illnesses as evidenced by a stillbirth rate of 42·8 (40·5–45·2)/1000 total births, neonatal mortality of 46.9 (44.4–49.4)/1000 live births, and a maternal mortality ratio of 259 (198–319)/100,000 live births.16 The Matiari site has a field laboratory with basic equipment needed for processing biological urine, blood, and stool samples and is staffed by technicians trained at AKU that receive periodical refresher training via regular visits to our central research coordinating facility - the AKU Infectious Diseases Pediatric Research Laboratory (IDRL) at Karachi. The site is also equipped with an electronic Data Management Unit (DMU) which enables both electronic transcriptions of the data collected in the field on hard/paper copies, and direct electronic data collection via portable tablets through customized applications. Furthermore, the DMU has data storage servers that enable data synchronization with central servers at AKU, Karachi. We have previously successfully conducted several studies on maternal and child health at this study site.5–15 However, we found SEEM to be unique in terms of the additional biological specimens and data collection processes we had to implement given that these samples would then be processed for high throughput sensitive ‘omics analyses such as microbial RNA and metabolomics.\n\nThe study protocol was approved by the Aga Khan University Ethics Review Committee (ERC, 3836-Ped-ERC-15) in December 2015, and the study is registered on clinicaltrials.gov (ID: NCT03588013).17\n\nThis was a community intervention study.\n\nThe primary objective of the SEEM study was to understand the clinical phenotypes of children at risk for EE in order to identify predictive ‘omic profiles along with detailed microbiome and transcriptomics as potential therapeutic targets. A cohort of 416 children was selected for a longitudinal study; 365 of whom were diagnosed with acute malnutrition or wasting (defined as weight-for-height Z (WHZ) score < -2) while 51 healthy controls or well-nourished children (defined as WHZ score ≥ 0 and height-for-age Z (HAZ) score ≥ -1 on two consecutive follow-ups from three to six months) were recruited. Our detailed study methods and results have been published.18,19 In brief, birth surveillance was established in which parents registered their newborns within 30 days of birth followed by monthly anthropometric assessment until six months of age. Between the time of birth registration and six months of age, data regarding young infant feeding practices, morbidity, and health-seeking behavior in the case of illness was also collected. Anthropometry measurements including height, weight, and mid-upper arm circumference (MUAC) of both parents and children, with an additional measure of head circumference were recorded from our sample of children. Anthropometry data collected between three and six months was used to calculate WHZ scores based on World Health Organization (WHO) growth reference standards;20 children were enrolled as cases and controls based on criteria defined above. At the time of enrollment, we collected data of the Household Food Insecurity and Access Scale,21 illnesses and treatment received, socioeconomic status, maternal and paternal education (Table 1). Enrolled children were then followed weekly for morbidity data (diarrhea, respiratory tract infection, antibiotic use, and hospitalization) and monthly for anthropometric measurements. Blood, stool, and urine samples were collected at the time of enrollment and at nine months of age for biomarker assessment. Breast milk samples from mothers were also collected once at the time of enrollment for oligosaccharides assessment.\n\nBetween six and nine months of age, nutritional education counseling was provided monthly to cases i.e. acute malnourished children. At nine months, if the child had a persistent WHZ score < -2, a chick-pea-based and locally made Ready-to-use Supplementary Food known as AchaMum was initiated for two months as per WHO guidelines for the management of moderate acute malnutrition.22 For severe acute malnutrition, however, while the WHO recommendation is for Ready-to-use Therapeutic Food (RUTF), we provided AchaMum according to a child’s weight (similar to RUTF) due to logistic and administrative issues in importing RUTF. If the child’s WHZ score consistently remained < -2 after the intervention, he/she was referred for further clinical assessment by a pediatric gastroenterologist for the screening of celiac disease and detailed luminal evaluation via an upper gastrointestinal (UGI) endoscopy.\n\nImplementation challenges:\n\n1. Collection of 24 hours food intake frequency data\n\nA 24 hours food recall data was collected through a specialized structured instrument designed to collect all food items consumed by the child in the last 24 hours. This provided a quantitative estimate of the non-breast milk food intake. The form was administered between six and 24 months on every alternate month. This data was collected by an experienced dietitian or an individual with knowledge regarding food preparation techniques, portion sizes, recipes, and food intake. Six community health workers (CHWs) conducted the dietary intake form after getting training in the Naushahro Feroze district, an area where a similar food recall form was administered as part of the Malnutrition and Enteric Disease Study (MAL-ED) cohort.23\n\nAs the mothers in this area participate in fieldwork including crop harvesting, it was challenging to find optimal times to contact and interview them. We also found that some families temporarily migrated to different villages in response to employment opportunities. If a new recipe was found, which was not mentioned in the existing MAL-ED coding list, then CHWs cooked these recipes in the field office kitchen with the same method as cooked per the report by the mothers. The purpose of this activity was to identify the caloric value of each food item mentioned in the recipe. It was not only the data collection that was challenging but converting this data into a quantitative form for data analysis was a huge task. For this, the CHWs had to work for several hours on every single form to search for the codes already assigned to food items by the MAL-ED team and to assign new codes for new food items.\n\n2. Management of acute childhood illnesses\n\nAll sick enrolled children were visited at their homes and assessed by study physicians as per Integrated Management of Childhood Illnesses guidelines.24 Medications were prescribed for mild-to-moderate and serious illnesses, the child was referred to the nearest healthcare facility with facilitated transport.\n\n3. Anthropometry measurements and quality assurance\n\nWeighing machines were monitored by daily standardization through calibrated weights of 0.5,1, 2, and 5 kilograms. Performance of CHWs was monitored in several ways: 1) standardization sessions were performed every three months to ensure reliability, precision & accuracy; 2) repeated measurements were taken from each child to increase the accuracy and precision, for 3-5% of the participants these repeat measurements were performed within 24-72 hours of the first measurement; 3) if measurements differed between two consecutive follow-ups, these were anthropometric measurements were recorded daily and outlier readings were then verified independently by the field team monitors, and 4) real-time feedback was provided to the field worker identified as responsible for the error. Furthermore, we employed the use of the Emergency Nutrition Assessment software25 for digit preference of weight, height and MUAC measurements, and these scores were reviewed weekly.\n\n4. Upper GI endoscopy consent\n\nAfter a nutritional intervention, children who did not adequately respond (WHZ remained < -2) were thus selected for further evaluation. This included a detailed clinical workup and, if indicated, an upper GI endoscopy with biopsies as per pediatric gastroenterology guidelines.26,27 Challenges encountered in the group of children selected for UGI endoscopies included: 1) 13 out of 89 biopsies had to be postponed as children were deemed unfit for anesthesia (seven children suffered from flu, fever and runny nose; three suffered from low hemoglobin levels; one had diarrhea; one had low platelets, and in one case the mother was too ill to accompany her child to Karachi). Children with low hemoglobin were prescribed oral iron until their hemoglobin levels reached an acceptable level (i.e. hemoglobin >=9mg/dl) for procedure eligibility; 2) 13 children (12.7%) were determined to be ineligible due to pre-existing diseases and disorders, which included tuberculosis, neurological disorders, thalassemia, congenital anomaly and, epilepsy; and 3) obtaining consent for the procedure from the parents required need of an additional explanation of risks and benefits of the procedure. As per protocol, the parents were re-consented by the pediatric gastroenterologist when they arrived at the AKU Hospital before the procedure.\n\n5. Laboratory samples collection challenges\n\nBreast milk sample collection\n\nSugars found in breast milk are known to serve as prebiotics and help in establishing the health-promoting gut microbes in infants. The presence of female study physicians led to a reduction of anxiety and addressed the fears the mothers were harboring. The sample was transported to and stored at Matiari field lab at 2-8°C.\n\nStool samples collection for microbiome testing\n\nFecal sample collection for the purpose of microbiome analyses was performed for the first time in our study in a rural setting in Pakistan. This required the development of new feasibility measures and modification of transport protocols. An important aspect of fecal sample collection in the microbiome collection protocol, given the rapid degradation of bacterial RNA species at room temperature, includes a critical time window i.e. stool samples had to be collected and cryopreserved ideally within 30 minutes. This was particularly challenging given that the households could be up to 90 minutes’ drive from the field office. To allow rapid freezing of samples, dry cryo-shippers were procured to facilitate transportation back to the central IDRL at AKU, Karachi, a vehicle was modified to enable transportation of the field-site collection staff and the dry shipper along with the ability to park as close to the collection site as possible for appropriate rapid storage and cryo-preservation. Further challenges faced included multiple visits, at times due to diarrhea, insufficient quantity of stool produced and the challenge of sitting in open courtyards by CHWs and children during extreme weather conditions for several hours at a time. We found that the provision of access to a cellphone helped coordinate the best time for stool collection.\n\nUrine sample collection for Lactulose: Rhamnose test\n\nThe lactulose: rhamnose (L:R) is a dual sugar absorption assay used to assess increased intestinal permeability as a surrogate measure of EE.28 The L:R test is performed by preparing oral lactulose and rhamnose solutions for the child to drink.29 Urine samples are obtained while fasting (before intake of lactulose and rhamnose), at 30, 60, and finally at 90 minutes after intake. These urine samples are then tested for the excretion of sugars.29 The biggest challenge was the collection of a fasting urine sample as it was difficult for mothers to keep their infants in a fasting state. The CHWs counseled and coordinated appropriate times for the collection of fasting samples and this aided in the sample collection. Additionally, the collection of urine samples at multiple time points required close monitoring. This process took several hours to complete. Furthermore, Matiari has average summer temperatures ranging from 38°C to 41°C,30 which leads to decreased urine sample collection in summer due to dehydration. This environmental limitation was a significant barrier in conducting the L: R sample collection.\n\n\nResults\n\nWe registered 2679 newborns within 30 days of their birth from March 2016 to October 2017. CHWs referred 712 children to study physicians between three and six months for inclusion in the study as malnourished children. The study physician enrolled 365 (51%) acute malnourished children in which laboratory specimens were collected in 346 (95%) children. Blood was collected in 341(93%) children, urine and stool/microbiome samples in 346 (95%) children, and breastmilk samples from mothers of 318 (87%) children (Figure 1). We also enrolled 51 well-nourished children in which we collected blood samples in 50 children, urine, stool and microbiome samples in 49(96%) children, and breastmilk samples from mothers of 48 (94%) children. We received a total of 6536 sick calls from the community from February 2017 to December 2018 and all sick kids were visited by study physicians within 24-72 hours (Figure 2). From June 2016 to December 2018, we successfully filled 24 hours of food recall form in 90% of targeted follow-up visits (4612/5025). We collected 2656 stool and microbiome samples from enrolled children from the period of May 2016 to December 2018 and we were successfully able to preserve 73.2% of our samples in liquid nitrogen within 30 minutes of defecation (Figure 3). We attempted 311 urine L:R tests in which our success rate of collecting urine samples was 272(87%) with a 13% failure rate (Figure 4). We successfully carried out UGI endoscopies in 63 children out of 89 eligible children.\n\nParticipants flow diagram showing registration, enrollment and laboratory specimens’ collection at enrollment and then at 9 months of child’s health.\n\nMonth wise data of sick children visited by study physicians from February 2017 to December 2017 (total visits = 6536).\n\nA pie chart showing the microbiome flash-frozen stool sample collection time difference in percentage (%) from the time stool passed (discovered by mother) to time placed in dry shipper from May 2016 to December 2018 (number of samples collected=2656).\n\nMonth wise data of urine Lactose Rahmanose tests conducted successfully versus test failure from January 2017 to December 2018. Total samples collected were 311.\n\n\nDiscussion\n\nThe growing prevalence of undernutrition in LMICs has resulted in a high proportion of stunted and wasted children in these regions.1 EE, a subclinical disorder characterized by non-specific intestinal inflammation with or without overt diarrheal episodes, is a major contributor to stunting in this setting.3 SEEM has been implemented in rural Pakistan to advance our understanding of the pathophysiology of EE and to identify biomarkers related to the disease through following a birth cohort of malnourished and well-nourished children up to two years of age. Our group has faced several field challenges in implementing SEEM and this paper recognizes these challenges and highlights the field team’s efforts to successfully encourage participation and effectively and efficiently complete data collection. Further, it highlights the creation of an engaged study site in which the community was involved in the development of the study framework, in regard to data collection, to ensure efficient data and sample collection.\n\nThe field team was particularly successful in respecting parental time and comfort to collect data efficiently. For example, collecting data regarding food recall had proved challenging as the mothers were determined as the best respondents and their availability varied due to their occupation. Most of these women were involved in fieldwork, e.g. crop harvesting, and at times would have to move to a different region for farming-related reasons. Thus, scheduling interviews proved difficult, however, the field team created a data collection schedule determined on the mothers’ availabilities, therefore, ensuring effective food recall. Further, the field team maintained an understanding and respected that some mothers may be uncomfortable with sharing breastfeeding details or with how breast milk samples were handled, therefore female CHWs and physicians led this effort. Lastly, similar to previous studies,31 day-to-day variation in food recipes proved to be a limitation. We found that cooking food under supervision ensured the better collection of dietary recall data and breast milk samples and helped overcome this limitation.\n\nAdditionally, our field team also understood the social and economic restrictions that made it difficult for parents to bring their children to the AKU laboratory to provide samples. In lieu of this, the team visited the homes of participants to obtain the relevant data and samples; this team included an experienced phlebotomist to collect blood samples. Such efforts provided feasibility for the patients to participate in the study without adding a burden on the parents.\n\nAnother key challenge faced was the collection and transport of stool samples for microbiome analysis; appropriate sample acquirement and storage conditions affect the microbiome. Similar to Smith et al.,32 we devised a cryopreservation-based method to transfer the stool samples from Matiari to the AKU laboratory in Karachi. Our stool collection protocol consisted of cryopreserving the stool samples and transporting them in a specific vehicle suitable for dry shipment; this enabled long-term sample storage. Additionally, along with conducting necessary interviews and visits for data and sample collection, our team also counseled the parents regarding the microbiome and its importance – the parents were actively engaged, and the increased awareness made it easier to collect stool samples at the appropriate times.\n\nLastly, a unique aspect of our study was the use of electronic tablets for data collection. Most hospitals and research studies conducted in Pakistan make use of paper charts for all forms of data collection. Our use of electronic tablets was not unique for a rural setting but also enabled researchers to store data on a backend server which made data collection easier and that it would not be lost. Our experience and findings from this study can be replicated in similar research sites based in low- and middle-income countries not only in the context of environmental enteropathy but also in studies requiring community-based data and laboratory sample collection. This manuscript presents a summary of the challenges and lessons learned by our study staff in the implementation of field activities in accordance with the study protocol of SEEM and in the maintenance of continuous quality in-field data collection procedures. We found that efficient management and strong communication with the field staff allowed us to meet our goals of delivering quality samples leading us to achieve our study targets. Furthermore, regular training schedules, a multilayered monitoring system, weekly progress meetings between the field staff, principal investigator and other collaborators led to the implementation of new field management protocols which allowed us to creatively solve the unique challenges and barriers encountered during this study. Our experience and findings from this study can be replicated to similar research sites based in LMICs not only in the context of EE but also in studies requiring community-based data and laboratory sample collection.\n\n\nEthics approval\n\nAga Khan University Hospital ethical review committee approved the study in 2015 with ERC number 3836-Ped-ERC-15\n\n\nConsent to participate\n\nInformed consent was received from parents/legal gaurdians of children for participation in this study and for their data to be published\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": "Competing interests\n\n\n\nNo competing interests were disclosed.\n\n\nGrant information\n\nThe study was funded by the Bill and Melinda Gates foundation (AA: OPP1138727, SRM: OPP1144149. Dr. Asad Ali received the funding. The funding agency had no role in the design of the study and collection, analysis, and interpretation of data and in writing this manuscript.\n\nThe funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n\n\nAcknowledgments\n\nWe would like to acknowledge mothers of enrolled children in Matiari for providing us time and data for this study. We would also like to thank all our CHWs for implementing this challenging project at the field site.\n\n\nReferences\n\nUNICEF-WHO-The World Bank Group: Joint child malnutrition estimates - Levels and trends (2018 edition). Geneva: UNICEF-WHO-The World Bank Group; 2018.\n\nNational Institute of Population Studies (NIPS) [Pakistan] and ICF International: Pakistan Demographic and Health Survey (PDHS) 2012-2013. Islamabad; 2013.\n\nSyed S, Ali A, Duggan C: Environmental enteric dysfunction in children. J Pediatr Gastroenterol Nutr. 2016 Jul; 63(1): 6–14. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPakistan Bureau of Statistics: Matiari district population and household detail: Census 2017. Islamabad: Pakistan Bureau of Statistics; 2018.\n\nBartlett LA, LeFevre AE, Mir F, et al.: The development and evaluation of a community-based clinical diagnosis tool and treatment regimen for postpartum sepsis in bangladesh and pakistan. Reprod Health. 2016 Feb 25; 13: 16,016-0124-1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHabib MA, Soofi S, Sheraz A, et al.: Zinc supplementation fails to increase the immunogenicity of oral poliovirus vaccine: A randomized controlled trial. Vaccine. 2015 Feb 4; 33(6): 819–25. PubMed Abstract | Publisher Full Text\n\nIqbal NT, Sadiq K, Syed S, et al.: Promising biomarkers of environmental enteric dysfunction: A prospective cohort study in pakistani children. Sci Rep. 2018 Feb 14; 8(1): 2966,018-21319-8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKhowaja AR, Mohiuddin S, Cohen AL, et al.: Pakistan Hib Vaccine Study Group. Effectiveness of haemophilus influenzae type b conjugate vaccine on radiologically-confirmed pneumonia in young children in pakistan. J Pediatr. 2013 Jul; 163(1 Suppl): S79,S85.e1. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoofi S, Ahmed S, Fox MP, et al.: Effectiveness of community case management of severe pneumonia with oral amoxicillin in children aged 2-59 months in matiari district, rural pakistan: A cluster-randomised controlled trial. Lancet. 2012 Feb 25; 379(9817): 729–37. PubMed Abstract | Publisher Full Text\n\nSoofi S, Cousens S, Iqbal SP, et al.: Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in pakistan: A cluster-randomised trial. Lancet. 2013 Jul 6; 382(9886): 29–40. PubMed Abstract | Publisher Full Text\n\nSyed S, Iqbal NT, Sadiq K, et al.: Serum anti-flagellin and anti-lipopolysaccharide immunoglobulins as predictors of linear growth faltering in pakistani infants at risk for environmental enteric dysfunction. PLoS One. 2018 Mar 6; 13(3): e0193768. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSyed S, Yeruva S, Herrmann J, et al.: Environmental enteropathy in undernourished pakistani children: Clinical and histomorphometric analyses. Am J Trop Med Hyg. 2018 Jun; 98(6): 1577–84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAhmed S, Ariff S, Soofi SB, et al.: Challenges in implementation of the ANISA protocol at the matiari site, pakistan. Pediatr Infect Dis J. 2016 May; 35(5 Suppl 1): S65–9. PubMed Abstract | Publisher Full Text\n\nBhutta ZA, Soofi S, Cousens S, et al.: Improvement of perinatal and newborn care in rural pakistan through community-based strategies: A cluster-randomised effectiveness trial. Lancet. 2011 Jan 29; 377(9763): 403–12. PubMed Abstract | Publisher Full Text\n\nHabib MA, Soofi S, Mach O, et al.: Effect of booster doses of poliovirus vaccine in previously vaccinated children, clinical trial results 2013. Vaccine. 2016 Jul 19; 34(33): 3803–9. PubMed Abstract | Publisher Full Text\n\nAlliance for Maternal and Newborn Health Improvement (AMANHI) mortality study group: Population-based rates, timing, and causes of maternal deaths, stillbirths, and neonatal deaths in south asia and sub-saharan africa: A multi-country prospective cohort study. Lancet Glob Health. 2018 Oct 22. PubMed Abstract | Publisher Full Text | Free Full Text\n\nClinicalTrials.gov: Study of Environmental Enteropathy and Malnutrition in Pakistan (SEEM). ClinicalTrials.gov July 2018.\n\nIqbal NT, Syed S, Sadiq K, et al.: Study of environmental enteropathy and malnutrition (SEEM) in pakistan: Protocols for biopsy based biomarker discovery and validation. BMC Pediatr. 2019 Jul 22; 19(1): 247,019-1564-x. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHaberman Y, Iqbal NT, Ghandikota S, et al.: Mucosal genomics implicate lymphocyte activation and lipid metabolism in refractory environmental enteric dysfunction. Gastroenterology. 2021 Jan 29. PubMed Abstract | Publisher Full Text\n\nWHO Multicentre Growth Reference Study Group: WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: Methods and development. Geneva: WHO; 2006.\n\nCoates J, Swindale A, Bilinsky P: Household Food Insecurity Access Scale (HFIAS) for Measurement of Household Food Access: Indicator Guide. Food and Nutrition Technical Assistance Project, Academy for Educational Development. Washington DC. [Internet].\n\nWorld Health Organization (WHO): Technical note on Supplementary foods for the management of moderate acute malnutrition in infants and children 6-59 months of age.Geneva: WHO; 2012.\n\nTurab A, Soofi SB, Ahmed I, et al.: Demographic, socioeconomic, and health characteristics of the MAL-ED network study site in rural pakistan. Clin Infect Dis. 2014 Nov 1; 59(Suppl 4): S304–9. PubMed Abstract | Publisher Full Text\n\nWHO-EMRO: Child and adolescent health; Integrated Management of Childhood Health.\n\nSMART: Emergency Nutrition Assessment. Canada: Action Against Hunger Canada and UNICEF; 2007.\n\nASGE Standards of Practice CommitteeLightdale JR, Acosta R, Shergill AK: Modifications in endoscopic practice for pediatric patients. Gastrointest Endosc. 2014 May; 79(5): 699–710. PubMed Abstract | Publisher Full Text\n\nTringali A, Thomson M, Dumonceau JM, et al.: Pediatric gastrointestinal endoscopy: European society of gastrointestinal endoscopy (ESGE) and european society for paediatric gastroenterology hepatology and nutrition (ESPGHAN) guideline executive summary. Endoscopy. 2017 Jan; 49(1): 83–91. PubMed Abstract | Publisher Full Text\n\nHarper KM, Mutasa M, Prendergast AJ, et al.: Environmental enteric dysfunction pathways and child stunting: A systematic review. PLoS Negl Trop Dis. 2018 Jan 19; 12(1): e0006205. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMishra A, Makharia GK: Techniques of functional and motility test: How to perform and interpret intestinal permeability. J Neurogastroenterol Motil. 2012 Oct; 18(4): 443–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWorld Weather Online: Matiari Monthly Climate Averages. Dubai: World Weather Online cited. September 2018: 13.\n\nInstitute of Medicine (US) Committee: Dietary Risk Assessment in the WIC Program.2002.\n\nSmith MI, Yatsunenko T, Manary MJ, et al.: Gut microbiomes of malawian twin pairs discordant for kwashiorkor. Science. 2013 Feb 1; 339(6119): 548–54. PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "95009",
"date": "11 Oct 2021",
"name": "Patrick Kaonga",
"expertise": [
"Reviewer Expertise Public Health",
"Epidemiology",
"biostatistics and 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\nThe paper examines an interesting and useful topic of Environmental Enteropathy (EE), which the cause is still not known but presumed due to continuous ingestion of entero-pathogens. This condition is common in resource-poor settings where a higher proportion of individuals are exposed to unsanitary environments. One major strength of this paper is the practice aspect of real field conditions which can be useful for implantation in a real world setting. It does fit the scope of the F1000 Research. Overall, it contributes to the advancement of knowledge on poverty-related conditions such EE and the challenges and possible mitigation factors related to sample collection especially among children from a community setting. The findings have the potential to help researchers, gastroenterologists and policymakers how to navigate challenges in data collection among children with EE.\n\nIn the abstract, the authors claim that “…three million deaths annually…” but it is not indicated the region where these deaths occur. This needs to be clarified. Similarly, the same applies to 165 million.\n\nIn the abstract, the authors have used the term “well-nourished children”. This needs to be defined in the context of the paper.\n\nThe authors claim that one of the solutions to the challenges is good governance. How did the authors arrive at this conclusion? The study does not seem to have explored this issue or more clarity is needed.\n\nIt is a good idea to arrange abbreviations in alphabetical order. The authors are advised to consider this.\n\nIt is a good idea for the aim of the study to appear at the end or towards the end of the introduction rather than in the methods section.\n\nIn the Pakistan context, what is the definition of a rural area? Probably the definition should have a citation. This may vary from country to country.\n\nAuthors should be consistent with the use of the words. For example, they have used laboratory or lab in certain parts of the manuscript.\n\nAuthors have indicated that technicians receive periodical refresher training. How often are these pieces of training? It is important to be specific so that the reader can relate this to the capacity to navigate challenges.\n\nThe authors indicated that they used the software “Emergency Nutrition Assessment Software” But even if the citation has been provided there is still a need to indicate company, city and country.\n\nUnder the sub-heading “Stool samples collection for microbiome testing” in line nine, a come should be included after the word further.\n\nUnder sub-heading “Urine sample collection for Lactulose: Rhamnose test” line three, “……at 30, 60, and finally at 90 minutes….” Consider removing “finally at” to improve the readability of the sentence.\n\nUnder figure 1, the line on the far right of the figure under assessment of well-nourishment, the line indicating the flow of information should be made straight.\n\nThe word “kids” should be replaced by the word children in the text. Children is a more formal word and appropriate. The word kid can be used for adults' worse behavior is immature. Similarly, see Figure 2. On the Y-axis the word kids have been used but in the same figure in the footnote the word children have been used.\n\nUnder figure 3, the blue colour representing the total sample (2656) should be removed since it is not appearing in the actual figure.\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? No source data required\n\nAre the conclusions drawn adequately supported by the results? Yes",
"responses": []
}
] | 1
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https://f1000research.com/articles/10-549
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https://f1000research.com/articles/10-655/v1
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26 Jul 21
|
{
"type": "Method Article",
"title": "Rapid detection of herpes simplex virus 2: a SYBR-Green-based real-time PCR assay",
"authors": [
"Modhusudon Shaha",
"Bithi Roy",
"Mohammad Ariful Islam",
"Bithi Roy",
"Mohammad Ariful Islam"
],
"abstract": "The prevalence of Herpes simplex virus 2 (HSV2) is increasing at an alarming rate in the world. Most of the HSV2 cases are not diagnosed properly, although a range of molecular and serological diagnoses exist. Herein, we have reported a very rapid detection method specific for HSV2 using real-time PCR. The primers specific for HSV2 were designed using the Primer-BLAST tool and 120 base pairs of the polymerase gene were amplified using real-time PCR with SYBR Green dye. The designed primer pair was found highly efficient in detecting only HSV2 DNA, but not HSV1. The threshold cycle (Ct) value for HSV2 reactions by designed primers was found to be an average of 22.55 for a standard copy number of viral DNA that may denote the efficiency of the primers. The melting temperature (Tm) of the amplicon using designed primers (82.60C) was also higher than that using reference primers (about 780C), indicating the high GC content of the amplified template. The designed primer pair will help clinicians to detect the HSV2 DNA specifically and diagnose the associated disease rapidly.",
"keywords": [
"Herpes simplex virus 2",
"real-time PCR",
"rapid diagnosis",
"primer design"
],
"content": "Introduction\n\nHerpes simplex virus 2 (HSV-2), a highly infectious pathogen, is a member of the Herpesviridae family consisting of a double-stranded DNA material.1,2 Globally, about 417 million people are infected by HSV-2, with a prevalence of 11.3%.3 The most common age group with HSV-2 diseases is 15-49 years of age, with a slightly higher rate of infection in women.3 HSV-2 infection is characterized by painful genital ulcers with vesicular rash (watery blisters), which are highly contagious and spread viruses to other hosts upon direct contact.4\n\nThe diagnosis of HSV2 is complex and costly in developing countries like Bangladesh. Moreover, due to the high similarity of HSV2 with other human herpes viruses (HHV) such as HSV1, it is tough to confirm the type of the diagnosed HHV. Nowadays, molecular analysis exists to determine specific types of HHV, but identification of the virus type is solely dependent on nucleotide sequencing. In this case, developing a new real-time polymerase chain reaction (RT-PCR) method for HSV-2 diagnosis can facilitate HSV2 detection.\n\nRT-PCR is the upgraded version of conventional PCR, invented by Kary Mullis in 1984, which aims to detect and quantify genes with dynamic expression profiles.5 Analysis by RT-PCR has several important steps including DNA extraction, designing primers and amplification.5 This study sheds light on the development of a RT-PCR assay to detect HSV2, which includes the design of compatible primers and amplification of HSV2 DNA using this primer set.\n\n\nMethods\n\nAppropriate primer design is a very important step to diagnose and quantify a specific microbial gene. An important, general step to design a primer set is to ensure the optimal melting temperature (Tm), balanced GC content, self-complementarity and self-3’ complementarity.6 There are several online tools to develop and design primers, such as NCBI’s Primer-BLAST.6 A known gene sequence of HSV2 virus collected from NCBI GenBank (MH697422.1, see Underlying data) was used for Primer-BLAST in the NCBI server keeping the parameters as default.\n\nUsing the online NCBI nucleotide Basic Local Alignment Search Tool (BLAST)6 several highly similar sequences of HSV1 and HSV2 were collected based on alignment score (quality of the alignment), query cover (nucleotide cover of searched sequence), Expected value (E, expected number of alignments by chance with a particular score; the lower the E value, the more significance the score) and identity with the reference sequence (Figure 1a), and then aligned using BioEdit software version 7.2, keeping HSV2 sequences at the top (Figure 1b). The primers obtained were then checked to find the best region to anneal with HSV2 but not HSV1 (in order to develop the primer specific for HSV2). The region with maximum nucleotide matches to the reference HSV2 sequences and minimum nucleotide matches to the HSV1 sequences was selected. Among all sets of primers tested, primer-3 was found the best regarding properties like a greater number of nucleotide mismatches with HSV1 sequences, self-complementarity (a predictor secondary structures between a single primer or primer pairs), higher Tm compared to other not-selected primers) and GC content (in good range 55-60%), and most importantly, 3’ self-complementarity (useful for predicting primer-dimers) (Figure 1c).\n\n(a) Collection of HSV sequences using NCBI-BLAST for designing a primer pair; (b) Alignment of HSV sequences and amplification region (selection region) using BioEdit software; (c) Different primer pair sets and associated properties; primer pair-3 was selected for further analysis.\n\nThe real-time PCR (based on SYBR Green fluorescent binding) with HSV1 and HSV2 template DNA were prepared using the designed primer pair (specific for HSV2) and control primer pair (common for both HSV1 and HSV2). In a 20ul reaction mix, 10ul of SYBR Green Master Mix (2X), 1ul of each reverse and forward primers at 6pM concentrations, 6ul of nuclease-free water and 2ul of template HSV2 DNA were added. The reagents were purchased from Qiagen (Germantown, MD, USA). The reaction conditions used to amplify the DNA were an initial 95°C for 20 seconds, 40 cycles of 3 seconds at 95°C and 30 seconds at 60°C, and a final cycle of 15 seconds at 95°C, 1 minute at 60°C and 15 seconds at 95°C.\n\n\nResults\n\nAbout 120 base pairs of HSV2 polymerase gene fragment were considered to be amplified using the designed primers, whereas in case of standard control primer pair both HSV1 and HSV2 were amplified (Figure 2a). The average threshold cycle (Ct) values for reaction by designed and control HSV2 primers were found to be 22.55 and 22.85 respectively, which indicates that the similar initial concentrations of DNA were amplified.7,8\n\n(a) Amplification curves of HSV1 and HSV2 using designed (own) and standard (reference) primers; a lagging stage, logging cycle and plateau are clearly visible; (b) Melt curve of HSV1 and HSV2 using designed (own) and reference (reference) primers.\n\nObserving the melting curve revealed that the designed primer was specific for HSV2. The peak of that amplification was stronger than that of reference primers, indicating the designed primers had a greater sensitivity to the HSV2 target gene than the reference primers (Figure 2b).9,10 The melting temperature (Tm) of the amplicon using the designed primers (82.6°C) was also higher than that of the reference primers (about 78°C). The explanation behind this may be a higher GC content of the product or larger fragments than the product amplified by reference primers.11 On the other hand, some unusual peaks for the negative controls were found in the melt curve, which have much higher Ct values (more than 35) and lower Tm of around 70-74°C, which indicates the possibilites of being either non-specific products or primer-dimers.12\n\nIn this assay, some secondary non-specific products or primer-dimers were observed in the melt curve, hence, the amplification reaction needs to be optimized. Increasing the annealing temperature of the reaction may reduce non-specific amplification of the product.13 Here, the annealing temperature of the reaction was 60°C; it would be better to use a slightly higher annealing temperature to get only the specific product. However, the annealing temperature should not be too high, as it would reduce the yield of the desired product.14 The optimal annealing temperature can easily be obtained using gradient real-time PCR.14 On the other hand, the concentration of primers can slightly be decreased to prevent the formation of primer-dimer if formed.13,15\n\nThe optimization of Magnesium ion (Mg2+) concentrations is also an important factor to achieve specific and desired product amplification.16 It has been documented that the higher the Mg2+ concentration, the higher the affinity of primers towards hybridization, leading to the formation of primer-dimers and non-specific priming.13,16 Furthermore, to verify the SYBR Green reaction specificity, an additional agarose gel electrophoresis can be performed using the product and non-specific bands, to confirm the presence of a single PCR product.14,17 As the SYBR Green fluorescent dye binds with double-stranded DNA and provides fluorescence at the same time as the amplification is running (hence being a real-time assay), all the steps of the protocol should be handled carefully and aseptically. That is why the lack of aseptic conditions may lead to the contamination of the reaction, giving rise to secondary non-specific products.18\n\n\nConclusions\n\nAccording to the results, the annealing temperature of the reaction should be slightly increased to get specific amplification of HSV2. Furthermore, the primer concentration needs to be decreased to prevent primer-dimer formation. On the other hand, the concentration of Mg2+ in the buffer system can also be reduced to promote the specificity and efficiency of the reaction. Observing the real-time PCR assay, I believe that my designed primers do not need to be altered as the specificity of determining HSV2 is good enough compared with other primers used.\n\nSome modifications to this assay such as proper optimization of the reaction and the use of a probe, specific to that gene, can render it appropriate to be used in a diagnostic laboratory.5 As SYBR Green assays detects all dsDNA, the introduction of a probe (consisting of fluorescent–labeled target-specific oligonucleotides that increase sensitivity and specificity) may establish this assay as a diagnostic test to detect HSV2. Furthermore, to establish this assay as a diagnostic test, positive control with a housekeeping gene (constitutive genes expressed in all cells) is necessary.19 This may promote the efficiency and reliability of this test.\n\n\nData availability\n\nFigshare: HSV-2 primer and qPCR Ct values, https://doi.org/10.6084/m9.figshare.14603934.v4.20\n\nThis project contains the designed HSV2 primer pair and the cycle threshold (Ct) values of HSV2- and HSV1-positive samples generated using qPCR.\n\nNCBI GenBank: Human alphaherpesvirus 2 isolate HSV2_1 DNA polymerase (UL30) gene, complete cds. Accession number: MH697422.1; https://www.ncbi.nlm.nih.gov/protein/MH697422.1.\n\nNCBI GenBank: Human herpesvirus 2 strain RR 60279 DNA polymerase gene, complete cds. Accession number: AY038366.1; https://www.ncbi.nlm.nih.gov/protein/AY038366.1.\n\nNCBI GenBank: HIV-1 clone MNT3-2-12 from USA gag protein (gag) gene, partial cds. Accession number: AY038267.1; https://www.ncbi.nlm.nih.gov/protein/AY038267.1.\n\nNCBI GenBank: Human herpesvirus 2 strain 1605/2007 DNA polymerase (UL30) gene, complete cds. Accession number: JQ352193.1; https://www.ncbi.nlm.nih.gov/protein/JQ352193.1.\n\nNCBI GenBank: Human herpesvirus 2 strain 1541/2008 DNA polymerase (UL30) gene, complete cds. Accession number: JQ352194.1; https://www.ncbi.nlm.nih.gov/protein/JQ352194.1.\n\nNCBI GenBank: Human herpesvirus 2 isolate HSV-2v_pat1 DNA polymerase (UL30) gene, complete cds. Accession number : JX905315.1; https://www.ncbi.nlm.nih.gov/protein/JX905315.1NCBI GenBank: Human herpesvirus 1 UL30 gene for DNA polymerase, complete cds. Accession number: AB072389.1; https://www.ncbi.nlm.nih.gov/protein/AB072389.1.\n\nNCBI GenBank: Human herpesvirus 1 gene for DNA polymerase, complete cds, clone: HSV-1 R98/0. Accession number: AB070847.2; https://www.ncbi.nlm.nih.gov/protein/AB070847.2.\n\nNCBI GenBank: Herpes simplex virus type 1 DNA polymerase gene. Accession number: X04771.1; https://www.ncbi.nlm.nih.gov/protein/X04771.1.\n\nNCBI GenBank: Herpes simplex virus type 1 strain ANG gene for DNA polymerase. Accession number: X04495.1; https://www.ncbi.nlm.nih.gov/protein/X04495.1.\n\nNCBI GenBank: Herpes simplex virus type 1 (KOS) ori-L region and polymerase (pol) gene, complete cds. Accession number: M10792.1; https://www.ncbi.nlm.nih.gov/protein/M10792.1.\n\nNCBI GenBank: Human herpesvirus 1 gene for DNA polymerase, complete cds, clone: HSV-1 R98/3. Accession number: AB070848.2; https://www.ncbi.nlm.nih.gov/protein/AB070848.2.\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\nDropulic LK, Cohen JI: The challenge of developing a herpes simplex virus 2 vaccine. Expert Rev Vaccines. 2012; 11: 1429–40. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWhitley R, Kimberlin DW, Prober CG: Pathogenesis and disease. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al. (ed), Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge; 2007.\n\nLooker KJ, Magaret AS, Turner KM, et al.: Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015; 10: e114989. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchiffer JT, Corey L: New concepts in understanding genital herpes. Curr Infect Dis Rep. 2009; 11: 457–64. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDeepak S, Kottapalli K, Rakwal R, et al.: Real-Time PCR: Revolutionizing Detection and Expression Analysis of Genes. Curr Genomics. 2007; 8: 234–51. PubMed Abstract | Publisher Full Text | Free Full Text\n\nYe J, Coulouris G, Zaretskaya I, et al.: Primer-BLAST: a tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics. 2012; 13: 134. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStowers CC, Haselton FR, Boczko EM: An Analysis of Quantitative PCR Reliability Through Replicates Using the C Method. J Biomed Sci Eng. 2010; 3: 459–69. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKessler HH, Muhlbauer G, Rinner B, et al.: Detection of Herpes simplex virus DNA by real-time PCR. J Clin Microbiol. 2000; 38: 2638–42. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHuang Q, Yue H, Zhang B, et al.: Development of a real-time quantitative PCR for detecting duck hepatitis a virus genotype C. J Clin Microbiol. 2012; 50: 3318–23. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGardella C, Huang ML, Wald A, et al.: Rapid polymerase chain reaction assay to detect herpes simplex virus in the genital tract of women in labor. Obstet Gynecol. 2010; 115: 1209–16. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMammedov TG, Pienaar E, Whitney SE, et al.: A Fundamental Study of the PCR Amplification of GC-Rich DNA Templates. Comput Biol Chem. 2008; 32: 452–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nWadle S, Lehnert M, Rubenwolf S, et al.: Real-time PCR probe optimization using design of experiments approach. Biomol Detect Quantif. 2016; 7: 1–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPonchel F, Toomes C, Bransfield K, et al.: Real-time PCR based on SYBR-Green I fluorescence: an alternative to the TaqMan assay for a relative quantification of gene rearrangements, gene amplifications and micro gene deletions. BMC Biotechnol. 2003; 3: 18. PubMed Abstract | Publisher Full Text | Free Full Text\n\nJuskowiak B: Nucleic acid-based fluorescent probes and their analytical potential. Anal Bioanal Chem. 2011; 399: 3157–76. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMikeska T, Dobrovic A: Validation of a primer optimisation matrix to improve the performance of reverse transcription - quantitative real-time PCR assays. BMC Res Notes. 2009; 2: 112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLorenz TC: Polymerase chain reaction: basic protocol plus troubleshooting and optimization strategies. J Vis Exp. 2012; 10.3791/3998: e3998. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGudnason H, Dufva M, Bang DD, et al.: Comparison of multiple DNA dyes for real-time PCR: effects of dye concentration and sequence composition on DNA amplification and melting temperature. Nucleic Acids Res. 2007; 35: e127. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEspy MJ, Uhl JR, Sloan LM, et al.: Real-time PCR in clinical microbiology: applications for routine laboratory testing. Clin Microbiol Rev. 2006; 19: 165–56. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKozera B, Rapacz M: Reference genes in real-time PCR. J Appl Genet. 2013; 54: 391–406. PubMed Abstract | Publisher Full Text | Free Full Text\n\nShaha M, Roy B, Islam MA: HSV-2 primer and qPCR Ct values. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "91924",
"date": "07 Sep 2021",
"name": "ASM Monjur Al Hossain",
"expertise": [
"Reviewer Expertise Drug delivery"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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, I would like to thank all the authors for their nice write up. The authors explained the methods clearly. In introduction, the authors clearly describe the background of the project. They sum up the conclusion nicely. They also included necessary citations. However, I have some queries for the researchers:\nIn the methods section, what are the default parameters used in the Primer-BLAST tool for designing the primer?\n\nWhat is the rationale behind selecting MH697422 as the reference one?\n\nWhat are the sequences of primer-3?\n\nIn the results section, have you tried using different Mg++ concentrations, higher melting temp. to check whether the non-specific melting curve was still there or not?\n\nAddressing these points, the manuscript can be indexed.\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": "7316",
"date": "25 Oct 2021",
"name": "Modhusudon Shaha",
"role": "Author Response",
"response": "Thank you so much for your constructive comments on this. To design the appropriate primers, we used the defaults parameters of Primer-BLAST tool of NCBI database. More specifically, max Tm difference of 3oC (min Tm- 67oC and max Tm 63oC), PCR product size of min 70 bp, and max 200 bp. With regards to the use of MH697422 as a reference sequence, this accession contains the complete sequence of DNA polymerase gene of HSV2, on which we were interested. The sequences of primer-3 are given in the data availability section which was deposited to Figshare. Additionally, the primer sequences are given below- Forward GATCTACAAGGTCCCGCTCG Reverse CACCATCCCGTTCACCTTGA Regarding question 4, we used a commercially available PCR master mix (described in the Methods section) for PCR amplification. Therefore, we did not use different Mg++ concentrations."
}
]
},
{
"id": "93395",
"date": "05 Oct 2021",
"name": "Joyanta Modak",
"expertise": [
"Reviewer Expertise My area of expertise is microbiology and molecular biology."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nShaha et al., aimed to develop a new primer for the detection of herpes simplex virus 2 using real-time PCR. They used the Primer-BLAST tool to design a primer that can detect only HSV2, not HSV1. However, they are few issues about the manuscript that needs to be addressed.\nTitle of the manuscript – this is not a rapid antigen test using a kit or immunochromatographic test that can be done in 5 minutes. So, the word “Rapid” should remove from the title.\n\nThere are quite a few published articles that developed a real-time PCR method for the detection of HSV2. In the introduction, authors should acknowledge previously published articles and should describe what is lacking the previous method and why they are developing new methods.\n\nWhat type of samples were used, e.g. clinical sample, extracted DNA, lab strains etc.\n\nHow many samples were used to validate the method?\n\nWhat are the sensitivity and specificity of the primer?\n\nPlease provide a table for the new and reference primer.\n\nAuthors should write results and discussions together instead of results alone.\n\nThe authors should highlight the limitation of the method such as the number of samples were used.\n\nPlease delete the word “my” in the conclusion.\n\nAuthors should consider improving the flow of writing.\n\nPlease update the references with the most recent articles.\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? 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? Yes",
"responses": [
{
"c_id": "7317",
"date": "09 Nov 2021",
"name": "Modhusudon Shaha",
"role": "Author Response",
"response": "Thank you so much for your thoughtful and constructive comments on the manuscript. Title of the manuscript – this is not a rapid antigen test using a kit or immunochromatographic test that can be done in 5 minutes. So, the word “Rapid” should remove from the title. Response: The title is revised as ‘Detection of herpes simplex virus 2: a SYBR-Green-based real-time PCR assay’. There are quite a few published articles that developed a real-time PCR method for the detection of HSV2. In the introduction, authors should acknowledge previously published articles and should describe what is lacking the previous method and why they are developing new methods. Response: The required section is updated as per the reviewer’s recommendation. What type of samples were used, e.g. clinical sample, extracted DNA, lab strains etc. Response: We used an HSV2 lab strain and extracted DNA to perform the PCR assay. It has been updated in the Methods section of the manuscript. How many samples were used to validate the method? Response: We performed three experiments to confirm the specificity of the used primers to HSV2 strains. We also cross-checked the results with an HSV1 lab strain. The detailed results were described in the Results section of the manuscript. What are the sensitivity and specificity of the primer? Response: The primers were of improved sensitivity and specificity compared to the standard primer set that was used to amplify both HSV1 and HSV2 DNAs (described in the Results section). As we tried to declare a new HSV2-specific primer set, we did not determine the sensitivity and specificity of the primers. Please provide a table for the new and reference primer. Response: The designed primers used for this study were given in the data availability section. Authors should write results and discussions together instead of results alone. Response: The Results section is updated as Results and Discussion. The authors should highlight the limitation of the method such as the number of samples were used. Response: The manuscript was updated with the inclusion of the limitation statement. Please delete the word “my” in the conclusion. Response: Required section is updated. Authors should consider improving the flow of writing. Response: The manuscript was checked again and revised accordingly."
}
]
}
] | 1
|
https://f1000research.com/articles/10-655
|
https://f1000research.com/articles/10-1132/v1
|
09 Nov 21
|
{
"type": "Software Tool Article",
"title": "KnowMore: an automated knowledge discovery tool for the FAIR SPARC datasets",
"authors": [
"Ryan Quey",
"Matthew A. Schiefer",
"Anmol Kiran",
"Bhavesh Patel",
"Ryan Quey",
"Matthew A. Schiefer",
"Anmol Kiran"
],
"abstract": "Background: This manuscript provides the methods and outcomes of KnowMore, the Grand Prize winning automated knowledge discovery tool developed by our team during the 2021 NIH SPARC FAIR Data Codeathon. The National Institutes of Health Stimulating Peripheral Activity to Relieve Conditions (NIH SPARC) program generates rich datasets from neuromodulation researches, curated according to the Findable, Accessible, Interoperable, and Reusable (FAIR) SPARC data standards. Currently, the process of simultaneously comparing and analyzing multiple SPARC datasets is tedious because it requires investigating each dataset of interest individually and downloading all of them to conduct cross-analyses. It is crucial to enhance this process to enable rapid discoveries across SPARC datasets. Methods: To fill this need, we created KnowMore, a tool integrated into the SPARC Portal that only requires the user to select their datasets of interest to launch an automated discovery process. KnowMore uses several SPARC resources (Pennsieve, o²S²PARC, SciCrunch, protocols.io, Biolucida), data science methods, and machine learning algorithms in the back end to generate various visualizations in the front end intended to help the user identify potential similarities, differences, and relations across the datasets. These visualizations can lead to a new discovery, new hypothesis, or simply guide the user to the next logical step in their discovery process. Results: The outcome of this project is a SPARC portal-ready code architecture that helps researchers to use SPARC datasets more efficiently and fully leverages their FAIR characteristics. The tool has been built and documented such that more data analysis methods and visualization items could be easily added. Conclusions: The potential for automated discoveries from SPARC datasets is huge given the unique SPARC data ecosystem promoting FAIR data practices, and KnowMore has only demonstrated a small highlight of what could be achieved to speed up discoveries from SPARC datasets.",
"keywords": [
"Data standards",
"Data Science",
"Metadata",
"Natural Language Processing",
"Knowledge graph",
"Cloud computing",
"Python"
],
"content": "Introduction\n\nThe National Institutes of Health’s (NIH’s) Stimulating Peripheral Activity to Relieve Conditions (SPARC) program seeks to accelerate the development of therapeutic devices that modulate electrical activity in nerves to improve organ function.1 A major focus of the SPARC program is to generate rich datasets that provide resources for understanding nerve-organ interactions and guiding the development of neuromodulation therapies. These datasets are publicly available through an open data platform, the SPARC Data Portal.2 As of July 2021, 115 datasets are available spanning multiple scales (cellular, tissue, organ level), organs (stomach, large intestine, small intestine, heart, bladder, urinary tract, lung, pancreas, spleen), species (pig, human, rat, mouse, dog), and data types (scaffold data, histology, immunohistochemistry, electrical impedance tomography, 3D microscopy, morphometric analyses, computer simulations of single axons or populations of axons, electrophysiological responses to electrical stimulation, etc.).\n\nTo ensure SPARC datasets are findable, accessible, interoperable, and reusable (FAIR), they are curated according to the SPARC Data Structure (SDS), the data standards designed by the SPARC Data Curation Team to capture the large variety of data generated by SPARC investigators.3,4 Accordingly, many resources are made available to SPARC researchers for making their data FAIR, such as the cloud data platform Pennsieve, the curated vocabulary selector and annotation platform SciCrunch, the open source computational modeling platform Open Online Simulations for Stimulating Peripheral Activity to Relieve Condition (o2S2PARC), the online microscopy image viewer Biolucida, and the data curation Software to Organize Data Automatically (SODA).5,6 As a result, the SPARC program provides a wealth of open and well-curated datasets that are accessible via the SPARC Data Portal. The portal provides several means of accessing data. A standard portal search feature is available. Alternatively, the user can find datasets by browsing through data categorized by organ system. The user can also use an interactive map to click on organs or nerves in animal models of interest and the portal provides links to associated datasets. These pathways make it easy to find datasets. Clicking a link to a dataset provides the user with details about the study and options to download all or subsets of the data files.\n\nWhile it is very easy to look at the details of any single SPARC dataset on the portal, there is currently no easy way to rapidly compare multiple datasets. Typically, a researcher wanting to find relations across datasets would have to do so manually by going through each dataset individually, i.e., read the description of each dataset, go through each protocol, browse files that are accessible from the browser, etc. Datasets that warrant further investigation must be downloaded for offline analyses and payment may be required for access to large datasets, according to Amazon Web Services (AWS) pricing. Depending on the formats of the data, this may require programming skills beyond that of many users. After spending time collating data in a form that allows comparison across the different datasets, the user may find that, in fact, the datasets did not contain the information they needed. This process of analyzing multiple datasets together is tedious, which ideally should not be the case since the SDS is designed to facilitate such analysis. Therefore, this process needs to be urgently improved to 1) enable rapid discoveries across SPARC datasets and 2) encourage more researchers to use the SPARC Data Portal.\n\nTo address this shortcoming, we developed KnowMore during the 2021 SPARC FAIR Codeathon7 (July 12th, 2021 – July 26th, 2021). KnowMore is an automated knowledge discovery tool integrated within the SPARC Portal. With minimal clicks, the user selects datasets of interest and KnowMore allows the user to visualize potential relations, similarities, differences, and correlations between the studies and associated datasets. This process, illustrated in Figure 1, is achieved by leveraging our knowledge of the SPARC data structure and metadata that allows us to perform text mining, generate a summary table, and plot data that is common across all selected datasets. The results are presented as several visualization items that provide the user with a quick means of identifying potential relations across the datasets. This manuscript describes the structure of KnowMore and provides an example of knowledge provided by the tool when applied to a set of three sample datasets that constituted our use case for demonstrating KnowMore during the 2021 SPARC FAIR Codeathon.\n\nNote that the tool is not currently integrated in the official SPARC Portal, but accessible through our fork of the sparc-app. It could be included into the official SPARC Portal after future consultation with SPARC.\n\n\nMethods\n\nThe overall workflow of KnowMore is shown in Figure 2. Our architecture consists of three main blocks that are independent:\n\n1. The front end of our app is based on a fork of the sparc-app (i.e. the front end of sparc.science) where we have integrated additional user interface elements and front end logic for KnowMore.8\n\n2. The back end consists of a Flask (a micro web framework written in Python programming language) application that listens to front end requests and launches the data processing jobs.\n\n3. The data processing and result generation are done through a MATLAB code (for ‘MAT’ data files) and a Python code (all other data types) that both run on the o2S2PARC platform, the SPARC supported cloud computing platform.9\n\nThe red rectangles highlight the major code blocks of KnowMore that were developed during the 2021 SPARC FAIR Codeathon.\n\nIn our front end of the sparc-app, we have integrated an “Add to KnowMore” button that is visible in the search result for each dataset and also available on the dataset page. By clicking on this button, the user can add their desired datasets for the analysis. Once all the datasets have been added, the user can go to the “KnowMore” tab we have included. On that page, the user can see a list of the selected datasets as well as a “Discover” button. A click on that button initiates the discovery process, where the Pennsieve IDs (i.e., the unique ID attributed to each dataset on sparc.science) of the selected datasets are sent to the Flask server, which then sends the IDs and our data processing Python script to o2S2PARC, using the o2S2PARC application programming interface (API).10 Once the script is fully executed, the results are sent back to the Flask server, which then transfers them to the front end where visualization items are generated. More details about the visualization items are provided in the next section.\n\nThe software architecture shown in Figure 2 was motivated by our aim of making KnowMore ready to on-board the SPARC Data Portal:\n\n• Integrating the front end of KnowMore will only require merging our fork of the sparc-app with the main branch sparc-app.\n\n• The back end of the sparc-app, the sparc-api, is built with Flask so the KnowMore back end is readily integrable.11\n\n• The data processing jobs are designed to run on o2S2PARC and do not require any type of integration as our back end ensures communication with o2S2PARC.\n\nMoreover, each of the three main elements of KnowMore is fully independent. While the front end will not be of much use on its own, having the back end fully interoperable is very valuable as our Flask application can be connected to any front end if needed (another analysis tool, website, software, etc.). The data processing and results generation jobs are also independent such that they can be used directly to get the visualization items. We have demonstrated that by developing a Jupyter Notebook that communicates directly with o2S2PARC to run the knowledge discovery jobs based on user-specified dataset IDs. Note that the data for the Knowledge Graph is obtained from Pennsieve/Scicrunch on the front end for efficiency but the same results can be generated in the back end as well. Thorough details for using the source code are available on the GitHub repository for this project.12\n\nThe output of KnowMore consists of multiple interactive visualization items displayed to the user so that they can progressively gain knowledge on the potential similarities, differences, and relations across the datasets. This output is intended to provide foundational information to the user so that they can rapidly make novel discoveries from SPARC datasets, generate new hypotheses, or simply decide on their next step (assess each dataset individually on the portal, download and analyze the datasets further, remove/add datasets to their analysis pool, etc.). A list of the visualization items is provided in Table 1, along with the potential knowledge that could be gained from each of them.\n\nThe source of the raw data for generating the visualization items are also listed.\n\nThe process of getting these outputs starts by getting the IDs of the datasets selected by the user, which are obtained using the Pennsieve API13 in the front end. From there, we leverage several SPARC-supported and recommended resources in our data processing Python Script to collect the raw data required to generate the above-mentioned outputs. These resources include the Pennsieve API,13 the Scicrunch Elasticsearch API,14 the protocols.io API,15 and the Biolucida API.16 We refer to the paper on the SPARC Data Resource Center (DRC) for more details about these resources and their role in the SPARC data ecosystem.6 Details about each of the visualization items are provided below. Each of these items can be easily saved from the front-end interface.\n\nKnowledge graph\n\nUsing the Pennsieve ID of each dataset, the following items are queried from SciCrunch Elasticsearch API14: Person (authors of the dataset), Affiliation (affiliation of the authors), and Award (funding source for the dataset). The visualization library Vega is used in the front end to display this information in an interactive knowledge graph, which instantly highlights high-level relations amongst the datasets.\n\nSummary table\n\nA summary table is built with information collected from the metadata.json file of each dataset, which is a standard file generated for each SPARC dataset when published, and the subjects and samples metadata files, which are standard metadata files prescribed for SPARC datasets by the SDS. The files are retrieved from the Pennsieve API within our Python code. The following items are parsed from the metadata.json file for each dataset: title of the dataset, subtitle of the dataset, publication date. The following items are parsed from the subjects’ metadata file for each dataset: number of subjects, species, age, sex. The following items are parsed from the samples metadata file: number of samples, specimen, type, specimen anatomical locations. The visualization library Plotly is used in the front end to display the results in an interactive table, which shows this information side-by-side for each dataset, thus enabling quick comparison in the study design of each dataset.\n\nKeywords\n\nText is obtained for each dataset from the description included in metadata.json file and the text from all the text files in the dataset using the Pennsieve API, and the text from the protocol on protocols.io associated with the dataset using the protocols.io API. The link to the protocol.io protocol is extracted from the metadata.json file of the dataset. All text is combined to create a paragraph for each dataset. The Natural Language Processing (NLP) Python library NLTK17 is then used to clean the text (e.g., remove stopwords). Biological keywords are identified using the spaCy python module and ScispaCy models.18,19 The frequency of biological words is counted for each dataset. The final frequency of the keywords is assigned based on lowest occurrence among the datasets and the twenty most frequent words are selected and displayed as a word cloud using the visualization library Vega. The minimum frequency of a keyword across the dataset is displayed when the cursor hovers over the word. These keywords conveniently allow the user to identify common themes across the datasets.\n\nCorrelation matrix and abstract\n\nThe correlation matrix demonstrates the putative relatedness between datasets.20,21 To generate the correlation matrix for the given datasets, pairwise similarity between datasets is calculated using the following Jaccard index equation22:\n\nParagraphs generated from datasets for the keywords identification are merged and divided into sentences. Each sentence is further divided into words and stopwords were removed. The frequency of each remaining word in a sentence is counted and converted into vectors where keywords represent the direction and frequencies represent the magnitude. The distance of two sentences is calculated using equation 1−cosθ where cosine similarity is expressed as follows:\n\nData plots\n\nIf data files in.mat format are found under the “derivative” folder, the data processing Python script extracts and saves them then provides them to our MATLAB script that is compiled and deployed on o2S2PARC. The script collates the data into a data table. The script next determines which columns in the data table can be used for plotting purposes. Columns containing categorical data are limited to the x-axis. Columns containing numerical data can be plotted on the x-axis or y-axis. Columns containing any other type of data are excluded. Plots are then generated for every variable that can be displayed on a y-axis against every variable that can be plotted on an x-axis. In addition to the plots, the MATLAB script outputs an Excel file that lists each of the plots created and the variables included in each plot. The Excel file also includes data for each plot. Additionally, the script creates a json file that includes all data for each plot. These plots quickly highlight to the user relations between similar quantities measured across datasets.\n\nImage clustering\n\nAn additional visualization item we aimed to provide to the user but could not complete during the Codeathon due to time constraints was a clustering of images across datasets, which may be particularly useful for histological data. All image data from SPARC datasets are stored on Biolucida. We currently have a function in place to retrieve image data from Biolucida given a Pennsieve dataset ID using the Biolucida API.16 In the future, image clustering and visualization components will be added in the Python script and front end, respectively, to provide an additional element to the user for comparing datasets.\n\n\nUse case\n\nKnowMore was developed and tested using three datasets available at sparc.science (Table 2). These datasets were selected because they have a common theme – quantified vagus nerve morphology – and span three species: rat, pig, and human. In principle, KnowMore is not specifically designed around these datasets and is coded to work with any user-selected datasets. However, for demonstration purposes, the data plots are currently limited to only appear when working with all or a subset of the three datasets listed in Table 2. Reasons for this are addressed in the Challenges section below and recommendations are put forth to expand the usability of this feature and increase the interoperability of SPARC datasets.\n\nInitiating a KnowMore analysis requires five steps:\n\n1. Use the search feature or browse for possible datasets of interest at sparc.science.\n\n2. As datasets are identified that the user wants to compare, click on the “Add to KnowMore” button, visible in the header of the datasets or the search results. This will add the datasets to the KnowMore analysis.\n\n3. Go to the KnowMore tab at the top of the webpage and check that all of the desired datasets are listed.\n\n4. Decide which output to display. All possible output is displayed by default.\n\n5. Click on the “Discover” button to initiate the automated analysis.\n\nThe number of datasets selected will affect the duration of time required to run the full discovery analysis. The use case with these three datasets takes about 4 min to generate all the visualization items.\n\nKnowledge graph\n\nThe Knowledge graph provides an interactive tool to visualize metadata across the three datasets (Figure 3). This provides the ability to quickly determine, for example, that all three datasets had four investigators in common (Cariello, Grill, Goldhagen, and Pelot) affiliated with the Department of Biomedical Engineering at Duke and that the human dataset had additional investigators (Ezzell and Clissold) affiliated with the Department of Cell Biology and Physiology at the University of North Carolina.\n\nSummary table\n\nThe Summary Table provides the user with key pieces of information from each study in tabular format (Table 3). From this table, the user can easily determine that datasets have several common metrics. However, perineurial thickness is not quantified in dataset 64.\n\nCommon keywords\n\nThe common keywords figure provides a graphical depiction of words that show up multiple times across the selected datasets (Figure 4). This size of the word in the image provides a visual representation of the weight (or frequency) of that word across the datasets. Not surprisingly, “nerve” is a large word as it shows up many times. Many other keywords highlight the quantified morphology across the datasets (diameter, cross-sectional area, fascicle, etc.).\n\nCorrelation matrix and abstract\n\nKnowMore generates a heatmap illustrating the correlation between the studies based on the words used in the text of these studies (Figure 5). This figure can guide the user in selecting highly correlated studies or eliminating studies that do not correlate well. Additionally, KnowMore generates a combined abstract that provides an overview of all datasets included in the study.\n\nData plots\n\nFor this use case, KnowMore also generates 20 scatter plots. Due to time constraints, these plots are currently generated in the backend as png files and then displayed in the front-end. Data points are color-coded to each dataset. Each axis is labeled with the variable being plotted. The variable name is obtained directly from the datasets. Three of the plots are presented here (Figure 6). Plot 3.4 reveals that pigs contain more fascicles in their vagus nerves than humans do, and humans contain more fascicles than rats. Plot 3.4 also reveals that pigs and rats have similar variability (spread) in their fascicle diameters whereas humans have a greater spread in their fascicle diameters. Finally, Plot 3.4 illustrates that humans can have larger fascicles than pigs. Plot 3.5 reveals that humans and pigs have similar-sized nerves, though pigs may, on average, have larger nerves. Plot 3.5 also reveals that the number of fascicles in the nerve may tend to be greater for nerves of larger diameter within each species. That is, there appears to be a positive correlation between the number of fascicles in the nerve and the diameter of the nerve. However, Plot 4.5 suggests that there may not be a trend between the fascicle diameter and the nerve diameter. Although these findings have been previously reported in some form,24 the Data Plots can become a very useful tool in helping researchers quickly understand the underlying data across multiple datasets.\n\n\nConclusions and next steps\n\nIn a few clicks to select datasets, KnowMore can provide both a high-level metanalysis and a granular comparison across two or more datasets on the SPARC portal. KnowMore outputs result at several levels depending on the needs of the researcher. One can quickly determine personnel, institutional, and funding relationships between datasets, and generate an overview of subjects included in the datasets and the techniques used to obtain data. Finally, if data are suitable for plotting, plots can reveal relationships within and across the studies that may reveal larger trends or help the researcher choose or eliminate particular datasets for more detailed analysis.\n\nSPARC has done an excellent job of standardizing the metadata associated with a study, and, as such, most of the KnowMore output is available across any selected studies. However, SPARC has not enforced standardization for tabular data. As such, the Data Plot output of KnowMore is currently limited to datasets that contain identical variable names and formats. This is an uncommon occurrence across datasets. Data can currently be stored in any number of formats. KnowMore’s Data Plot currently requires data to be stored in a MATLAB.mat file due to our use case, but this could be expanded to several other file formats. It would be preferable from a programming perspective if all data formats and variable naming are consistent, however, within MATLAB alone, data can be stored in multiple formats. Data may be stored in vectors/matrices; cells; cell arrays of vectors, matrices or more cells; structures; or tables, among other formats. Even small differences in variable names such as NerveDiam versus NerveDiameter versus DiameterOfNerve are not immediately reconcilable, though NLP may alleviate such inconsistencies. Without unified variable naming, comparisons across datasets become very challenging. Inconsistent variable names are not the only challenge, however. Even if variable names are identical, the values stored for that variable may be different from study to study. Without unified data types, comparisons across datasets become very challenging. To make the KnowMore Data Plot tool universal we propose standardization of commonly used variable names, data formats, data types, and data units. We also recommend the inclusion of key pieces of information that describe the data in the metadata. We have submitted these recommendations to SPARC and a copy of the document is available in our GitHub repository. This may require a significant amount of effort to convert previously uploaded datasets but should not put an exceptional burden on new studies. Data standardization across the SPARC platform would make the data ready for much broader analysis using more sophisticated big data tools that could provide insights that are otherwise obscured or not readily accessible.\n\nCurrently, the discovery process takes several minutes to run and display the visualization items (about 5 min for the use case). To improve performance, we suggest using multi-threading in the Python script; moving the.mat file processing directly into the Python script; collecting all required raw data (e.g., text) when a dataset is uploaded (e.g. save it in the metadata.json file) and even pre-process it (clean the text) so it is readily available during our discovery process. Image clustering components can be included in the future as well as any other visualization items that are deemed useful to the user. If the above-mentioned challenges with tabular data are addressed, the Data Plots feature of KnowMore can be generalized to work with any datasets.\n\nThe SPARC data ecosystem that is built to deliver FAIR datasets, provides a unique opportunity to automate knowledge discovery across datasets. During this project, we leveraged that ecosystem to demonstrated what can be achieved to increase the speed and convenience of discoveries across SPARC datasets. The tool we have developed is a statement of the power of FAIR practices and the effort of SPARC in that regard. We believe that we have only scratched the surface during the Codeathon and the opportunities are yet immense.\n\n\nSoftware availability\n\nSource code available from: https://github.com/SPARC-FAIR-Codeathon/KnowMore.12\n\nArchived source code at the time of publication: https://doi.org/10.5281/zenodo.5137255.28\n\nLicense: MIT\n\nThe repository and archive both contain detailed information for using the source code. They also contain a copy of our recommendation to SPARC for standardizing tabular data.",
"appendix": "Acknowledgments\n\nWe would like to thank the NIH SPARC Program and the SPARC Data Resource Center (DRC) teams for organizing the 2021 SPARC FAIR Codeathon. We would also like to thank the DRC teams for their guidance and help during this Codeathon.\n\n\nReferences\n\nNational Institutes of Health: Stimulating Peripheral Activity to Relieve Conditions (SPARC). (Accessed: 19th September 2020).Reference Source\n\nNational Institutes of Health: SPARC Data Portal. (Accessed: 19th September 2020).Reference Source\n\nWilkinson MD, et al.: The FAIR Guiding Principles for scientific data management and stewardship. Sci. Data. 2016; 3: 160018. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBandrowski A, et al.: SPARC Data Structure: Rationale and Design of a FAIR Standard for Biomedical Research Data. bioRxiv. 2021. 2021.02.10.430563.Publisher Full Text\n\nPatel B, Srivastava H, Aghasafari P, et al.: SPARC: SODA, an interactive software for curating SPARC datasets. FASEB J. 2020; 34: 1–1.\n\nOsanlouy M, et al.: The SPARC DRC: Building a Resource for the Autonomic Nervous System Community. Front. Physiol. 2021; 0: 929.\n\n2021 SPARC FAIR Codeathon. (Accessed: 1st August 2021).Reference Source\n\nNIH SPARC.: Web Application for the SPARC Portal. (Accessed: 1st August 2021).Reference Source\n\nIT’IS Foundation: Open Online Simulations for Stimulating Peripheral Activity to Relieve Conditions. (Accessed: 1st August 2021).Reference Source\n\nIT’IS Foundation: osparc API client. (Accessed: 1st August 2021).Reference Source\n\nNIH SPARC: SPARC Portal API. (Accessed: 1st August 2021).Reference Source\n\nPatel B, Quey R, Schiefer M, et al.: KnowMore: Automated Knowledge Discovery Tool for SPARC Datasets. (Accessed: 1st August 2021).Reference Source\n\nPennsieve: Pennsieve API. (Accessed: 1st August 2021).Reference Source\n\nFDI Lab: SciCrunch ElasticSearch API. (Accessed: 1st August 2021). Reference Source\n\nprotocols.io: protocols.io for Developers. (Accessed: 1st August 2021).Reference Source\n\nMBF Bioscience: Biolucida API v2021. (Accessed: 1st August 2021).Reference Source\n\nBird S, Klein E, Loper E: Natural language processing with Python: analyzing text with the natural language toolkit. O’Reilly Media, Inc; 2009.\n\nHonnibal, Matthew Montani I, Van Landeghem S, et al.: spaCy: Industrial-strength Natural Language Processing in Python.2020. Publisher Full Text\n\nNeumann M, King D, Beltagy I, et al.: ScispaCy: Fast and Robust Models for Biomedical Natural Language Processing.2019; 319–327. Publisher Full Text\n\nThakur N, Mehrotra D, Bansal A: Information Retrieval System Assigning Context to Documents by Relevance Feedback. Int. J. Comput. Appl. 2012; 58: 37–47. Publisher Full Text\n\nKotu V, Deshpande B: Classification. Data Science - Concepts and Practice. Morgan Kaufmann; 2019; 65–163. Publisher Full Text\n\nJaccard P: The distribution of the flora in the alpine zone. New Phytol. 1912; 11: 37–50. Publisher Full Text\n\nHagberg AA, Schult DA, Swart PJ: Exploring network structure, dynamics, and function using NetworkX. Proceedings of the 7th Python in Science Conference (SciPy2008). Varoquaux G, Vaught T, Millman J, editors. 2008; 11–15.\n\nPelot NA, et al.: Quantified Morphology of the Cervical and Subdiaphragmatic Vagus Nerves of Human, Pig, and Rat. Front. Neurosci. 2020; 0: 1148.\n\nPelot NA, Goldhagen GB, Cariello JE, et al.: Quantified Morphology of the Rat Vagus Nerve (Version 4).2020. Publisher Full Text\n\nPelot NA, Goldhagen GB, Cariello JE, et al.: Quantified Morphology of the Pig Vagus Nerve (Version 4).2020. Publisher Full Text\n\nPelot NA, et al.: Quantified Morphology of the Human Vagus Nerve with Anti-Claudin-1 (Version 6).2020. Publisher Full Text\n\nQuey R, Kiran A, Schiefer M, et al.: KnowMore: v1.0.0 - Automated Knowledge Discovery Tool for SPARC Datasets (v1.0.0). Zenodo. 2021. Publisher Full Text"
}
|
[
{
"id": "124523",
"date": "11 Mar 2022",
"name": "Thomas Donoghue",
"expertise": [
"Reviewer Expertise Neuroscience",
"data science",
"Python programming",
"data analysis"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nOverview\nIn this report, Quey et al develop a prototype software tool, KnowMore, to be used within the SPARC ecosystem of tools and datasets related to stimulating peripheral nerves and organs with the goal of improving organ function. The goal of KnowMore is to address the current limitation whereby it is difficult to directly compare different datasets available through the SPARC portal. Specifically, KnowMore is a data comparison dashboard, which allows for selecting different datasets, and then initializing a process which returns a series of visualizations and reports that can be used to compare between datasets. Notably, KnowMore was developed during a SPARC codeathon, such that what is described in this paper is a working prototype, but has not (yet?) been integrated into the main SPARC portal, and does not currently work across all available datasets.\nOverall, I think this manuscript reports a useful and important development of a system to compare between datasets, which addresses a meaningful need for better resources for comparing and combining datasets. The tool is specific to the SPARC context, as is well motivated by this paper, including the use of multiple related tools within this ecosystem. Technically, I find no obvious issues with this tool – the paper describes the main strategies employed, the code is available, the I was able to run the example usage noted in the paper. In that context, I find this is be a useful and valuable project, and broadly a successful paper reflecting that. My main overall comments, detailed below, reflect that though I appreciate the prototype tool and discussion in this paper, I am left slightly unclear with what the goal of this particular version of the paper is – whether the authors intend this paper to reflect a tool people should use, in which case more of roadmap regarding generalizing the tool should perhaps be offered, or whether it’s goal is more of a narrative description of “lessons learned” from attempting this kind of prototype, in which case further discussion on how to better support this kind of work in the future may be warranted.\nMain comments:\n1 – STATUS OF THE TOOL\n\nThis manuscript feels like it exists within two contexts, as it both introduces a new tool, and describes a project pursued during a hackathon. While this is clearly a sensible combination for the realities of this project, at times it is unclear if the reader should be reading this as a report on a new tool that they can go and use, and/or if this report is a narrative description of an example application in the general context of comparing between datasets, that future work should learn from. To the extent it’s more tool oriented, then it’s a limitation that this paper describes a prototype that, to my understanding, only works on a small number of datasets. As such, although the prototype is compelling, it is unclear if this is an actionable tool for people to generally use. In this context, it feels like a limitation that the paper does not clearly describe the roadmap for if / to what extent the tool will continue to be developed in order to become more generally useable. For example, it seems unclear if there will be development on this tool post-codeathon, and whether there is a plan for this tool to be merged with SPARC, or if and how people should try to use this tool in the interim. For example, if the goal is for people to use this, a possible short-term update would be to extend the tool to make the other visualizations that are not dependent on the data fields, such as the knowledge graph, work across all possible datasets. As far as I can tell, this does not currently work, limiting the actionable usage of this tool. If the tool is expected to be supported, and developed further, this could be made more clear.\n2 – STANDARDIZED DATA FORMATS\n\nTo the extent that this paper represents a narrative description of the “lessons learned” from working on this project in the context of a codeathon, then I think more could be said about the challenges that arose in order to present some useful commentary for future work on this topic. In particular, this paper notes that a major hurdle that was encountered in generalizing this tool is the lack of data standardization. It feels like the magnitude of this issue is perhaps understated. Data standardization is a large and difficult issue, and if one of the goals of this paper is to address issues such as this that arise in this kind of project, then perhaps this can be discussed further, both in terms of recognizing the scale of the issue at hand, and noting more details on what would need to happen for this to be properly addressed. As I work in a different field, I can’t speak to related discussion in the context of SPARC datasets, but in other areas, these are topics of extended debate, including the need to develop clear ontologies of terms that are accepted and used by the community (example: Yarkoni et al, 2019), and the need for standardized data files and formats that then embody these names, and associated technical tools for file I/O, validation, comparison, etc (example: Gorgolewski et al, 2016). I presume there is likely similar / related work more topical to the data under study here, that could be cited and further discussed. If a goal of this paper is to provide insights for future work on this topic, then more details in terms of what would be needed for the next generation of this tool would be valuable, as well as notes on relevant work and whether there are plans for these topics to be addressed within the SPARC ecosystem.\n3 – GOAL OF THE PAPER\nTo conclude, and integrate across the prior notes, I think an overall, potential update to the paper would be for the authors to explicitly consider and update the paper in terms of what they wish the reader to take away from this report. This might entail clarifying the status and future of the tool itself, and/or digging into this project as an example for future work. To be clear, I don’t think this requires updating the report with respect to everything I mentioned – it may be more sensible to choose an approach and focus on that. I also want to clarify these are potential ideas that may be useful, but aren’t meant to imply that I find anything explicitly of issue with the current draft, but that some minor amendments would serve to better describe and inform the reader of the status of the associated tool. Finally, I’d like to note that I think this kind of work is very important, but also difficult to do and often under-valued, so I would like to commend the authors on pursuing this kind of project.\nSigned, Thomas Donoghue, PhD\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Yes\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
},
{
"id": "139348",
"date": "21 Jun 2022",
"name": "Ammar Ammar",
"expertise": [
"Reviewer Expertise Bioinformatics",
"systems biology",
"data science",
"data analysis",
"FAIR",
"semantic web"
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIntroduction\nThe authors developed a software tool composed of three components (frontend, backend, and data processing scripts) to perform an analysis on a selected group of SPARC datasets by the user in order to visualize potential relations, similarities, differences, and correlations between the datasets. That is achieved by leveraging the SPARC data structure and metadata which allows us to perform text mining and different types of plots. The software extends an already available user interface to add knowledge discovery functionalities. Moreover, it is mainly a dashboard for data visualization which utilizes an API and the capabilities of a computational platform (o2S2PARC) besides several other resources to perform data analysis in the form of an asynchronous job-submission paradigm. The tool is useful and potentially will help increase the usability of SPARC datasets and the SPARC data portal by allowing users to discover dataset inter-relations and generate new insights from the combined analysis of multiple datasets.\nThe code is provided through GitHub, and versioned through Zenodo with a DOI. The requirements.txt provides specific package versions and the code functions are documented. Moreover, the analysis functionality can be used through Jupyter Notebooks without the GUI and the authors provided a full example (in the GitHub repository) on how to use it. The description of the software components and how it works is clear and sound.\nOverall, the manuscript describes an important and useful system that address the current limitations resembled in the difficult comparison between SPARC datasets and extracting useful insights from them or decide on their (re)usability. I find the project, even as a prototype, valuable and serve the intended purpose and the manuscript fulfills describing the software and demonstrating its work. However, I have some comments and recommendation addressed below.\nMajor updates\nI could not reproduce the example use case described in the manuscript. At first, step (1) under the “Setup” subtitle (page 7, of the pdf) says “Use the search feature or browse for possible datasets of interest at sparc.science” while KnowMore is not integrated into the main platform and alternatively provided as a Herokuapp demo which is not mentioned anywhere in the manuscript. I had to find it in the GitHub README file. The same misleading information is mentioned in Figure 1, the first thumbnail from the left. Next, after accessing the software using the Herokuapp link and selecting the three datasets, the results sections did not show up and the spinners kept spinning. Further investigation through the console and network tabs in the Google Chrome browser (latest version 102) revealed an HTTP error 500 for the call https://sparc-know-more-api.herokuapp.com/api/start-osparc-job/ and the following error message:\nosparc.exceptions.ApiException: (401) Reason: Unauthorized HTTP response headers: HTTPHeaderDict({'Content-Length': '38', 'Content-Type': 'application/json', 'Date': 'Mon, 20 Jun 2022 23:56:35 GMT', 'Server': 'uvicorn', 'Vary': 'Accept-Encoding, Accept-Encoding'}) HTTP response body: {\"errors\":[\"Invalid API credentials\"]}\nTherefore, I could not see the results mentioned in the manuscript.\n\nThe demo application should be at least working. Moreover, it would be helpful to provide an API credentials for testing purposes so users can try running the tool locally using Docker and Docker Compose. However, I could start the Flask backend server and got the response \"status: up\" on port 5000.\nMinor updates\nI could not find where to test the platform according to the use case section since the Herokuapp link is not mentioned anywhere in the manuscript. I recommend providing the test URL of the demo application under the “Setup” subtitle (Page 7), in step 1 and removing the currently mentioned URL “sparc.science” where the KnowMore tool is not integrated yet.\n\nThe plots in Figure 6 have no meaningful titles, it is not clear what is plotted in each plot. The plots need descriptive titles. It is true that the plots are described in the text but this will not be the case for real users when they will use the software.\n\nIn the GitHub repository, I see the code for the analysis provided under “assets/INPUT_FOLDER”. The naming makes no sense and gives no clue on why to put a main function script under such unrelated path. A better script files structuring can be used here to make the project hierarchy more understandable.\n\nI see in the GitHub repository a PDF file describing the measurements taken to provide FAIR software according to (Lamprecht et al. 2020)1. This is valuable information that should be described in the manuscript mentioning the measures taken to make the KnowMore tool FAIR.\n\nRecommendations\nThe KnowMore tool authors took serious efforts to make the software FAIR, but the software analysis output itself is still not FAIR. For instance, the tool does not provide its output in a machine-readable way and adopt a known controlled vocabulary. For example, the analysis results can be expressed (besides the visualization and the HTML output) as JSON-LD representation format that is injected in the HTML upon job completion. Furthermore, schema.org vocabulary can be used to describe the output of the comparison (to the extent that is supported by schema.org) which allows software agents to parse, understands and take actions based on the JSON-LD metadata in an automated way. The SPARC data portal main application (sparc.science) already does a remarkable FAIR job by using JSON-LD to describe the SPARC datasets metadata and uses globally unique identifiers for the datasets (DOI) and the creators (ORCID) besides provenance information like license and free-access status. So, it would be a great addition to KnowMore to adopt the same approach and provide such a machine-readable metadata to describe the dataset comparison and analysis results to make it more FAIR. Storing the analysis results and giving them a unique identifier for later retrieval is also a step toward more FAIR dataset comparison metadata.\n\nIs the rationale for developing the new software tool clearly explained? Yes\n\nIs the description of the software tool technically sound? Yes\n\nAre sufficient details of the code, methods and analysis (if applicable) provided to allow replication of the software development and its use by others? Partly\n\nIs sufficient information provided to allow interpretation of the expected output datasets and any results generated using the tool? Partly\n\nAre the conclusions about the tool and its performance adequately supported by the findings presented in the article? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1132
|
https://f1000research.com/articles/10-379/v1
|
12 May 21
|
{
"type": "Research Article",
"title": "Photophysical study and in vitro approach against Leishmania panamensis of dicloro-5,10,15,20-tetrakis(4-bromophenyl)porphyrinato Sn(IV)",
"authors": [
"Fabián Espitia-Almeida",
"Carlos Diaz-Uribe",
"William Vallejo",
"Doris Gómez-Camargo",
"Arnold R. Romero Bohórquez",
"Cristian Linares-Flores",
"Carlos Diaz-Uribe",
"William Vallejo",
"Doris Gómez-Camargo",
"Arnold R. Romero Bohórquez",
"Cristian Linares-Flores"
],
"abstract": "Background: Photodynamic therapy activity against different biological systems has been reported for porphyrins. Porphyrin modifications through peripheral groups and/or by metal insertion inside the ring are main alternatives for the improvement of its photo-physical properties. In this study, we synthesized and characterized 5,10,15,20-tetrakis(4-bromophenyl)porphyrin and the dicloro-5,10,15,20-tetrakis(4-bromophenyl)porphyrinato Sn(IV). Methods: Metal-free porphyrin was synthesized using the Alder method, while the Sn(IV)-porphyrin complex was prepared by combining metal-free porphyrin with stannous chloride in DMF; the reaction yields were 47% and 64% respectively. Metal-free porphyrin was characterized by UV-Vis, FT-IR, ESI-mass spectrometry and 13C-NMR. Additionally, the Sn(IV) -porphyrin complex was characterized using UV-Vis and FT-IR. Cyclic voltammetry tests in four different solvents. The fluorescence quantum yield (Φf) was measured using fluorescein as a standard, the singlet oxygen quantum yield (ΦD) was estimated using the standard 5,10,15,20-(tetraphenyl)porphyrin (H2TPP) and the quencher of singlet oxygen 1,3-diphenylisobenzofuran (DPBF). Results: UV-Vis assay showed typical Q and Soret bands for porphyrin and its metallo-porphyrin complex. Compounds showed photoluminescence at the visible range of electromagnetic spectrum. The inclusion of the metal in the porphyrin core changed the Φf from 0.15 to 0.05 and the ΦD increased from 0.55 to 0.59. Finally, the effect of the compounds on the viability of L. panamensis was evaluated by means of the MTT test. The results showed that both compounds decreased the viability of the parasite; this inhibitory activity was greater under light irradiation; the porphyrin compound had IC50 of 16.5 μM and the Sn(IV)-porphyrin complex had IC50 of 19.2 μM. Conclusion: The compounds were synthesized efficiently, their characterization was carried out by different spectroscopy techniques and their own signals were evidenced for both structures, both compounds decreased the cell viability of L. panamensis.",
"keywords": [
"Photodynamic therapy",
"porphyrin",
"Leishmania panamensis",
"Photophysical study",
"in vitro",
"porphyrinato"
],
"content": "Introduction\n\nPorphyrins and metalloporphyrins are versatile macrocyclic organic compounds, from the structural viewpoint; the porphyrin main skeleton consists of four pyrrole rings bound through their alpha carbons (α-C) with four aldehydes.1,2 These structural characteristics confer on the porphyrins a variety of properties such as high conjugation, symmetry, and planarity. Additionally, they acquire the ability to complex with a large number of metals in their interior through the coordination of the four pyrrolic nitrogen atoms submerged in the molecule.3,4 The conjugated and aromatic structure of porphyrins allows interactions between π electrons and different metals, facilitating the binding to their coordination centers.5 Porphyrins have absorption and intense electronic emission at wavelengths greater than 400 nm, small energy for HOMO-LUMO transitions and the ability to adjust their optical redox properties.6-10 All these properties make porphyrins relevant macromolecules in several chemistry fields (e.g. material science, optics, catalysis, transformation and storage of energy, medicine, pharmacology).11-17 In recent years, porphyrins have emerged as important promising photosensitizers in photodynamic therapy (PDT); porphyrin and its derivatives demonstrate great efficacy as both antibacterial and antiviral agents against different species due to its exceptional photodynamic properties.18,19 Porphyrins have potential applications in biological sciences, therefore, it is pertinent to develop simple synthetic pathways that lead to compounds with unique physical and chemical characteristics.\n\nNowadays different strategies to improve porphyrin photodynamic properties have been applied: (a) structural modification of the base ring with the addition of a variety of substituents at messo position, and (b) the inclusion of metals into the porphyrin core.20-22 The photophysical properties of porphyrins and their metallic-derivatives are affected for both the peripherally and/or axial substituents and the central metal into porphyrin core.23 The porphyrins and their metallic-derivatives act efficiently as sensitizing agents and they have presented phototoxic activity against different pathogens, such as bacteria, fungi, viruses and parasites.24-27 Different porphyrinic photosensitizers have reported anti-leishmanicidal activity against Leishmania tarentolae in promastigote stage (ethyl and diethyl carbaporphyrin), against amastigotes of L. panamensis, and promastigotes of L. major and L. braziliensis (β-substituted porphyrinic systems).28-32 Improved pharmacological responses have been found when incorporating metals in the macrocycle, as reported by Gomes et al. when evaluating the activity against L. amazonensis against derivatives metalated with Bi (III) and Sb (IV) (IC50 of 93.8 μM and 52.4 μM respective).33 Another Zn (II) metalated porphyrin derivative evaluated against promastigotes of L. braziliensis reduced parasite viability with greater efficiency than the metal-free derivative.34 This type of modification alters the steric and electronic nature of porphyrins giving rise to new molecules that have specific and unique properties, and it also presents a promising alternative for modifying photophysical properties of the compounds: (a) quantum singlet oxygen performance, (b) the range of the therapeutic window, (c) photostability and (d) lipophilicity could be improved.35\n\nAlthough, 5,10,15,20-tetrakis(4-bromophenyl)-porphyrin (compound 1) and dicloro-5,10,15,20-tetrakis(4-bromophenyl) porphyrinato Sn (IV) (compound 2) are commercially available, the reports about of its application as sensitizers in PDT are few. Therefore, in this study, we analyzed the photophysical behavior of (1) and (2) as regards their potential use in PDT against Leishmania panamensis.\n\n\nMethods\n\nAll reagents and solvents were purchased from Sigma Aldrich. We prepare the porphyrin 5,10,15,20-tetrakis(4-bromophenyl) porphyrin (1) based on Adler’s method,36 introducing a small modification that consisted of leaving the reaction for 8 hours at room temperature and stirring in an open container, using the oxidative power of oxygen to convert more of the chlorin by-product into porphyrin. In summary, equimolar amounts of pyrrole and 4-bromobenzaldehyde were mixed in propionic acid for 8 hours at ambient temperature under an atmosphere of air. Dicloro-5,10,15,20-tetrakis(4-bromophenyl) porphyrinato Sn (IV) (2) was synthesized by porphyrin precipitation in metal chloride solicitation (Figure 1). The formation of the final products was followed by thin layer chromatography on aluminum foil UV254 TLC, the mobile phase was petroleum ether-ethyl acetate (2:1). The compounds were characterized using 13C NMR spectra (Bruker AC-400 spectrometer); the 13C NMR chemical shifts are reported as ppm (δ), relative to CDCl3 (signal located at 7.29 ppm). Infrared spectrum was measured on the equipment ECO-ART alpha Bruker FTIR spectrometer. To perform UV-Vis spectrum (using a UV-2401PC UV-Vis spectrophotometer), we dissolved 2.0×10−5 g of each compound in ethyl acetate, and finally, we obtained the mass spectrum by dissolving the compound in methanol (using ESI-LC-MS/MS ion Trap amaZon, Bruker spectrometer). Furthermore, we measured fluorescence quantum yield (using a PTI um 40 fluorimeter) and singlet oxygen quantum yield,37 and electrochemical characterization was performed in four different dissolvents (Dimethylformamide-DMF, dichloromethane -DCM, dimethylsulfoxide-DMSO, tetrahydrofuran-THF) containing 1.0×10−1 M tetrabutylammonium perchlorate ((C4H9)4N(ClO4), Aldrich 98% purity) as a supporting electrolyte for all electrochemical measurements.\n\nCompound (1) was prepared by mixing 10 mmol pyrrole and 10 mmol 4-bromobenzaldehyde in 80 ml propionic acid for 8 hours at ambient temperature in an open container. The product was extracted from the reaction medium by adding 60 mL cold methanol and filtering by gravity, the filtrate was dried at room temperature, obtaining 1.4136 g of a purple solid that was finally purified using column chromatography (mobile phase; ether-ethyl acetate 20:2). Yield: 47.28%; melting point > 300°C; UV-Vis (ethyl acetate) 414, 512, 546, 591, 645; FT-IR (cm −1): N-H (3350), C=C (1470.28), C=N (1088.22), C-N (964.28); 13C NMR (CDCl3, 400 MHz): 118.86 (Ar), δ = 122.92 (Ar), δ = 130.22 (β-py), δ = 131.95 (Ar), δ = 135.95 (Ar ipso), δ = 140.91 (Ar-Br); (M+H) m/z = 930.9. These results concur with previous reports for this compound.37,38\n\nCompound (2) was prepared by mixing 0.5478 mmol of (1) with 2.2164 mmol SnCl2.2H2O in DMF (80 mL) for 4 hours at ambient temperature, and by stirring. After that, we added cold water and TBrPP-Sn (IV) precipitated; this solid was washed and dried at ambient temperature. The compound was purified by column chromatography (mobile phase; petroleum ether-ethyl acetate 5:1). Yield: 64.4%; melting point > 300°C; UV-Vis: 426, 560, 600. These results concur with previous reports for this compound.37,39\n\nFluorescence quantum yield (ϕf) was determined by the comparative method in a PTI um 40 fluorimeter. Using as a standard fluorescein dissolved in water, porphyrin (1) and metalloporphyrin (2) was dissolved in ethyl acetate. All fluorescences were determined taking as excitation wavelength the maximum of the Soret band, using a 2 nm slit and a 420-750 nm scan. The fluorescence quantum yield was calculated with the following eq. 1.37,40,41\n\nFx and Fest are the areas under the fluorescence emission curve of compounds (1), (2) and the standard. A x and A are sample absorbances and standard at the excitation wavelength. ɳ x and ɳ are the respective refractive indices of the solvents (ethyl acetate; ɳ = 1.3724, water; ɳ = 1.33336).\n\nSinglet oxygen quantum yield (Φ∆) of (1) and (2) was performed by the graphical method, using 1,3-diphenylisobenzofuran (DPDF) as singlet oxygen scavenger, and singlet oxygen generator standard 5,1,15,20-(tetraphenyl) porphyrin (H2TPP). The tests were carried out by preparing a 1×10-9 M solution of each compound in DMF in triplicate and calculated with eq. 2.37,40,41\n\nWhere: Φ∆standard is the singlet oxygen quantum yield of the H2TPP standard in DMF (0.64). W and Wstandard are the slopes of the degradation curves of the DPDF.\n\nCyclic voltammetry (CV) data were recorded using a single-compartment electrochemical cell with a maximum electrolyte volume of 10 mL. A CH Instruments (Model 600E) Electrochemical Analyzer was used for the electrochemical measurements. The working electrode was a glassy carbon 3 mm in diameter on Teflon R (CH Instruments). The reference electrode used was an Ag+/Ag electrode on Teflon R; we used a solution 1.0×10−3 M AgNO3 in electrolyte support; the auxiliary electrode was a platinum of 99.99% from CH Instruments. The electrochemical characterization was carried out using cyclic voltammetry and linear voltammetry. The peak current intensityipA, in cyclic voltammetry, is given by the Randles-Sevcik Eq.3:42\n\nwhere n is the number of electrons in the redox reaction, Acm2 is the area of the working electrode,Dcm2s−1 is the diffusion coefficient for the electroactive species, vVs−1 is the scan rate, and Cmolcm−3 is the concentration of the electroactive species in the electrode. The anodic and cathodic peak currents are equal, and the ratio ip,a/ip,c is 1.0. The half-wave potential, E1/2, is midway between the anodic and cathodic peak potentials, Eq. 4.\n\nLeishmania panamensis (UA140) was used in in vitro tests for the evaluation of the leishmanicidal potential of the compounds (1) and (2). Leishmanicidal activity was determined as the ability of the compounds to decrease the viability of the parasite, for this the MTT method is widely used in the literature (MTT Assay Protocols, Thermo Fisher Scientific). Conditions were previously standardized by our working group.37,43-45\n\nLeishmania panamensis (UA140) were cultured in RPMI-1640 supplemented with 10% fetal bovine serum, 1% glutamine and 1% antibiotics (200 U penicillin/200 μg Amikacin) under incubation conditions 5% CO2.37,45 The metacyclic promastigotes in the infectious stage were isolated from stationary cultures. The parasite viability was estimated by MTT assay.37,43-45 Anti-leishmanicidal activity was evaluated at different concentrations (1, 10, 50, 100 and 200 μM) of compound and positive control (Glucantime) under visible-light irradiation, at incubation times of 24, 48 and 72 hours.37 We used 6 Omnilux LED bulbs located at a close chamber, and an incident photon flow per unit volume Io was 5.7 × 10−7 Einstein*L−1s−1. Each trial was performed in triplicate. Plates were analyzed using SkanIt software. We applied an ANOVA test to determine the differences or similarities between treatments and positive control. In addition, a post hoc analysis was performed using Tukey statistics. Finally, differences were considered to be significant when p < 0.05.\n\n\nResults and discussion\n\nThe UV-Vis spectrum of (1) (Figure 2), shows a band of maximum absorption located at 414 nm (Soret band), generated by a1u(π)-eg*(π) transitions and four lower absorption Q band located at 515nm, 547nm, 588nm and 645 nm, which corresponds to a2u(π)-eg*(π) transitions.46,47 The UV-Vis spectrum of compound (2) shows one Soret band and only two Q bands. When the Sn (IV) ion coordinates nitrogen atoms inside the porphyrin ring, the porphyrin symmetry increases. Furthermore, the reduction in the number of Q bands indicates that the metal effectively entered the macrocycle.48 The intensity of the Q bands is correlated with the relative stability of the metalloporphyrin: when the signals are of low intensity, the metallocomposites are highly stable and their atoms are located in the square plane.49,50 Ohsaki et al. reported a similar change in the UV-Vis spectrum after tin (IV)-insertion into the porphyrin core synthesized in water at ambient temperature.51 Moreover, the Soret band for (2) had red shift from 414 nm to 425nm (near to 11 nm). The direct coordination between Sn (IV) ion and porphyrin core could extend conjugation from porphyrin to metal ion; in this case, the electronic excitation will require lower energy absorption due to increasing conjugation–this process requires longer wavelength than pure porphyrin.10,52 Figure 2 shows that (1) and (2) have photo-activity inside window 400 to 7000 nm. Although the compounds do not have a considered absorption in the red rank of the visible light spectrum from 600 nm to 800 nm (this radiation can reach a penetration depth of 8.0 mm inside tissue), they absorb radiation inside range 500-600 nm. This radiation penetrates approximately 4.0 mm, and such penetration capacity is suitable for potential application in cutaneous treatments.53\n\nDeamination of Փf\n\nInformation related to the efficiency of fluorescence emission is important to explain the inactivation pathway related to PDT.54 Figure 3 shows fluorescence emission for (1) and (2); both show photoluminescence at a visible range in the electromagnetic spectrum. As shown in Figure 3, fluorescence emission wavelength was located at 651 nm for both compounds, the energy transition did not change after the Sn (IV) ion insertion; however, fluorescence emission intensity was more high compound (1). This effect is due to the Sn (IV) ions insertion inside the porphyrin core decreases significantly fluorescence effect. As shown in Table 1, the Φf of (1) was three times greater than (2); the Sn (IV) ions inside the porphyrin core could increase the non-radiative decay of the excited singlet state of porphyrin,37 Sn (IV) ions within the porphyrin nucleus could increase disintegration by inter-system crossover (ISC), and this pathway is governed by orbital spin coupling at the central atoms; in this case, the insertion of Sn (IV) reduces the fluorescence emission.9,55,56 A similar effect was reported for cupper insertion inside meso-porphyrinic complexes.56,57\n\nDeamination of ՓΔ\n\nThe generation of singlet oxygen produced by (1) and (2) was quantified by chemical entrapment using DPBF. To estimate the ΦΔ, the degradation of DPBF was measured at 415 nm over time (Figure 4), the lower the absorbance, the greater the degradation of DPBF mediated by singlet oxygen. The complex Sn (IV)-porphyrin (2) presented higher ΦΔ compared to (1) (Table 1), the difference in ΦΔ between the compounds is 7%, and this difference is directly attributed to the insertion of the metal ion Sn (IV) inside the macrocycle. Sn (IV) would be generating greater stability of the triplet state of the molecule and improving the interaction with molecular oxygen, which is reflected as a greater translocation of the molecular oxygen spin and its subsequent conversion into singlet oxygen.4,59-62 These sensitizers show promise in PDT for its ΦΔ values, and could in the future be candidates in clinical trials like its counterpart Lutetium Texaphyrin, which has a ΦΔ as low as 0.11.63\n\nThe biological systems present microheterogeneity, caused by the coexistence of microphases such as aqueous polar and highly hydrophobic lipid.64,65 Therefore it is relevant to study the physicochemical properties of sensitizers at different media. We have studied the electrochemical behavior of (2) using cyclic voltammograms (CV) in four different solvents. Figure 5 shows CVs and Table 2 lists electrochemical parameters. Porphyrin had irreversible one-electron oxidation at Epa, which varies between 0.55 V for DMF and 1.0 V for THF, in addition to one quasi-reversible reduction peak between −1.01 V for THF and −1.41 for DMF (Figure 5a). The latter is clearer when DMF and DMSO are solvents. CVs (in detail) in DMSO, presenting three redox processes: (a) oxidation processes (I and II) related to the formation of monocationic and dicationic porphyrin spaces, (b) (a) oxidation processes (I and II) related to the formation of monocationic and dicationic porphyrin spaces, (b) reduction process (III) that results in the formation of the anionic porphyrin species66 (Figure 5b).\n\nThe conformational and structural changes observed in reversible electron transfer reactions can be examined through the potential differences between the first and second oxidation states.46,67 Table 2 shows the oxidation and reduction potentials. The couple III presented an almost reversible behavior accompanied by a separation of anodic-cathodic peaks ΔEp> 60 mV, in addition, it presented an anodic-cathodic peak potential ratio of approximately unity (1.0). This result is characteristic of a nearly reversible monoelectronic process. The electron-attractant character of the bromine substituents could be significantly influencing the electrochemical properties of the derivatives (1) and (2).68,69 Likewise, Table 2, shows a slight effect on ΔE1/2 by change of dissolution solvent. THF had the highest ΔE1/2 due to lower dielectric constant value (ε), and this solvent had smaller dielectric constant value (εDMSO=46.70, εDMF=36.70, εDCM=8,93 and εTHF=7.58) between all aprotic dipolar solvents under study herein. Our data on the potentials for oxidation and reduction of TBrPP-Sn (IV) (Table 2) are consistent with previous reports published in the literature on metalloporphyrin-like compounds.70,71\n\nWe studied the scanning speed effect on the current response of CVs for each solvent to determine if the redox process was controlled by diffusion or by adsorption. Figure 6a shows Cvs for (2) at different scanning speeds in DMF. Figure 6a shows an anode peak for all scan rates in the range 0.8-1.3 V for all solvents used. The relationship found between the scanning speed and the peak current was directly proportional with linear increase, and the peak potential anodically shifted; additionally, when the scanning speed was increased, the peak became broader. Figure 6b shows that the peak current correlated with the square root of the scan rate for each solvent studied. Table 3 shows R2 and linear equation fitting for each test. The fitting results indicated that the process is controlled by diffusion, then hydrodynamics of media (e.g. polarity, density, viscosity) determines the redox process rate.66-68 Furthermore, the linear fit of the line plot of Ip versus v1/2 indirectly indicates a relationship between the diffusion coefficient and DMSO; and DMF had the highest slope value, suggesting that the diffusion coefficient for these solvents was greater than the diffusion coefficient for THF and DCM. This result is associated with the value of the dielectric constant, as discussed.67,68\n\nFigure 7 shows dissolvent effect on electrochemical band gap value (2) for solvents studied in this work. The data obtained for the redox potentials (pH = 7.0 and room temperature) of the water separation reaction and the carbon dioxide reduction reactions to produce methane and methanol: Potential per redox couple; E (H2O/O2) = −5.26 eV; E (H +/H2) = −4.03 eV; E (CO2 / CH4) = −3.79 eV; E (CO2/CH3OH) = −3.65 eV.72 It is evident that the value of the electrochemical band gap depends on the polarity of the solvent, (2) had the smallest defective gap in THF. A requirement for the photosensitizer in PDT is the band gap; electrochemical characterization indicates that it is appropriate and suitable. Finally, the potentials described in Table 2 corresponding to the redox process of (2) are in agreement with other reports for processes based on rings in porphyrin complexes.72,73\n\nY-axis energy levels for the reduction and oxidation potentials of the dissociation reactions. pH = 7 y room temperature.\n\nA wide variety of molecules have been evaluated as possible therapy against Leishmania spp in recent years: (i) aluminum and zinc phthalocyanines (ii) methylene blue, 5-aminolevulinic acid and porphyrin. The field of research on new substances with challenging properties in medicine and pharmacology is an important topic, which has become more relevant due to the appearance of resistant and emerging microorganisms.74-76 The compounds (1) and (2) have been used to evaluate their effects on the viability of L. panamensis using the MTT method. The results are presented as cell viability of L. panamensis after exposure to different concentrations of (1) and (2) during incubation periods of 24, 48 and 72 hours, in darkness and under irradiation. The same procedure was done for the positive control (Glucantime).\n\nThe results show that (1) and (2) presented inhibitory activities on parasite viability (Figure 8). The decrease in the viability of L. panamensis was observed to a greater degree on the irradiated tests, this is due to the increased interaction capacity of the test compounds with oxygen, which induced the production of singlet oxygen.77,78\n\nThe contrary effect was evidenced for the reference standard, which reached better inhibitory activities on parasite viability in darkness. The highest effect leishmanicide was observed when the parasite was exposed to light for 24 hours and with concentrations of the compounds higher than 100 μM. Furthermore, the irradiation time (48–72) had no significant effect on viability (%) results compared to samples irradiated for 24 hours. The IC50 (Table 4) was determined using data found in the 24-hour test. Under irradiation, the IC50 of both compounds was lower compared to the positive control (Glucantime), with values of 16.5 and 19.5 μM respectively. The activation of sensitizers by light action ensures lower IC50 values. Besides, in the absence of light, the response was lower, thus being in line with findings of other reports.78 Our results also show that (1) and (2) cause damage to the parasite, decreasing its survival rate by 1.5 times compared to the standard, which could induce a reduction in the healing time of a lesion.\n\n\nConclusions\n\nIn the present study, we synthesized and characterized (1) and (2). Compound structures were confirmed by spectroscopic techniques (UV-Vis, FT-IR, 13C- NMR and ESI-mass). Sn (IV) ion insertion inside in the porphyrin core reduced significantly Փf 0.15 to 0.05. Furthermore, ΦΔ increased from 0.55 to 0.59 after metal insertion inside the porphyrin core. Electrochemical results showed that electrochemical properties were affected by the solvent dielectric constant, where THF had the highest ΔE1/2 due to a lower dielectric constant value. Moreover, the electrochemical assay showed a quasi-reversible reduction peak between −1.01 V in THF and −1.41 in DMF. The inhibitory results shown that (1) and (2) presented inhibitory activities on parasite viability. The highest inhibitory activity on the parasite was observed when the treatments were irradiated for 24 hours and with concentrations of the compounds of 200 μM, strengthening the hypothesis that parasite mortality is mediated by reactive oxygen species (especially singlet oxygen). These compounds were synthesized with low-cost methods and with acceptable synthesis yield, a fundamental aspect in the search for sensitizer candidates. The results of biological activity suggest these compounds could be applied in future applications of in vivo models as potential sensitizers of photodynamic therapy.\n\n\nData availability\n\nMendeley Data: Complementary material, http://dx.doi.org/10.17632/h2vmrdz4sg.1.79\n\nThis project contains the following underlying data:\n\n- 1. UV-Vis compound (1) and (2).xlsx [UV-Vis spectrum of compound 1 and 2]\n\n- 2. Gráficos, RENDIMIENTO CUÁNTICO DE FLUORESCENCIA.xlsx [Graphics, Quantum fluorescence yield of compound 1 and 2]\n\n- 2.1 Calculo de Qf.xlsx [Calculation of Quantum fluorescence yield (Qf) of compound 1 and 2]\n\n- 3. 1. Compound 1 (DMSO). Rendimiento Cuántico Oxígeno Singulete – copia.xlsx [Calculation of Quantum Yield Oxygen Single of Compound 1 in DMSO]\n\n- 3.2. Compound 2 (DMSO). Rendimiento Cuántico Oxígeno Singulete.xlsx [Calculation of Quantum Yield Oxygen Single of Compound 2 in DMSO]\n\n- 4. ESI-MS, Compound 1.jpg [Mass spectrum of Compound 1 in methanol]\n\n- 5. FT-IR, Compound 1.pdf [FT-IR spectrum of Compound 1]\n\n- 6. RMN 13C, Compound 1.mnova [RMN 13C spectrum of Compound 1 in CDCl3]\n\n- 7. Assay Biologoly_Compound 1 and 2_Luz vs L. Panamensis_Promastigote.xlsx [Assay Biological of Compound 1 and 2 in the presence of light against L. Panamensis promastigote]\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "Acknowledgments\n\nC.D.U. and W.V. thanks Universidad del Atlántico. F.E.A thanks COLCIENCIAS.\n\n\nReferences\n\nMarin D, Payerpaj S, Collier G, et al.: Efficient intersystem crossing using singly halogenated carbomethoxyphenyl porphyrins measured using delayed fluorescence, chemical quenching, and singlet oxygen emission. Phys Chem Chem Phys. 2015; 17: 29090. PubMed Abstract | Publisher Full Text\n\nOrtiz A, Collier G, Marin D, et al.: The effects of heavy atoms on the exciton diffusion properties in photoactive thin films of tetrakis(4-carbomethoxyphenyl)porphyrins. J Mater Chem C. 2015; 3: 1243. Publisher Full Text\n\nVecchi A, Galloni P, Floris B, et al.: Metallocenes meet porphyrinoids: Consequences of a “fusion”. Coord Chem Rev. 2015; 291: 95. Publisher Full Text\n\nAbada Z, Ferrié L, Akagah B, et al.: Synthesis and characterization of original N-meso chiral substituted diarylporphyrins. Tetrahedron Lett. 2012; 53: 6961. 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PubMed Abstract | Publisher Full Text\n\nGuillaumot D, Issawi M, Da Silva A, et al.: Synergistic enhancement of tolerance mechanisms in response to photoactivation of cationic tetra (N-methylpyridyl) porphyrins in tomato plantlets. J Photochem Photobiol B Biol. 2016; 156: 69. PubMed Abstract | Publisher Full Text\n\nZoltan T, Vargas F, López V, et al.: Influence of charge and metal coordination of meso-substituted porphyrins on bacterial photoinactivation. Spectrochim. Acta Part A Mol Biomol. Spectrosc. 2015; 135: 747. PubMed Abstract | Publisher Full Text\n\nAkilov O, Kosaka S, O'Riordan K, et al.: Parasiticidal effect of delta-aminolevulinic acid-based photodynamic therapy for cutaneous leishmaniasis is indirect and mediated through the killing of the host cells. Exp Dermatol. 2007; 16: 651. 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Publisher Full Text\n\nAratani N, Takagi A, Yanagawa Y, et al.: Giantmeso-meso-Linked Porphyrin Arrays of Micrometer Molecular Length and Their Fabrication. Chem A Eur J. 2005; 11: 3389. PubMed Abstract | Publisher Full Text\n\nWohrle D: The colours of life. An introduction to the chemistry of porphyrins and related compounds. Adv Mater. 1997; 9: 1191. Publisher Full Text\n\nGiovannetti R: The Use of Spectrophotometry UV-Vis for the Study of Porphyrins. In: Macro To Nano Spectroscopy. Dr Jamal U , Ed.; InTech; 2012; 987-953-51-0664-7. Publisher Full Text\n\nOhsaki Y, Thomas A, Kuttassery F, et al.: How does the tin (IV)-insertion to porphyrins proceed in water at ambient temperature?: Re-investigation by time dependent 1H NMR and detection of intermediates. Inorganica Chim Acta. 2018; 482: 914. Publisher Full Text\n\nKurniawan F, Miura Y, Kartasasmita R, et al.: In Silico Study, Synthesis, and Cytotoxic Activities of Porphyrin Derivatives. Pharmaceuticals. 2018; 11: 8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHanefeld U, Lefferts L: Catalysis: An integrated textbook for students. In: Ulf H, Lefferts L, Ed.; Wiley-Blackwell; 2018; 9783527341597.\n\nO’Connor A, Mc Gee M, Likar Y, et al.: Mechanism of cell death mediated by a BF2-chelated tetraaryl-azadipyrromethene photodynamic therapeutic: Dissection of the apoptotic pathway in vitro and in vivo. Int J Cancer. 2012; 130: 705. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMamardashvili G, Maltceva O, Lazovskiy D, et al.: Medium viscosity effect on fluorescent properties of Sn (IV)-tetra(4-sulfonatophenyl) porphyrin complexes in buffer solutions. J Mol Liq. 2019; 277: 1047. Publisher Full Text\n\nDiaz-Uribe C, Vallejo L, Miranda J: Photo-Fenton oxidation of phenol with Fe (III)-tetra-4-carboxyphenylporphyrin/SiO2 assisted with visible light. J Photochem Photobiol A Chem. 2014; 294: 75. Publisher Full Text\n\nKadish K, Smith K, Guilard R: The porphyrin handbook. In: Phthalocyanines: spectroscopic and electrochemical characterization Academic Press; 2003; Volume 16. , 9780080923901.\n\nBoscencu R, Oliveira A, Ferreira D, et al.: Synthesis and Spectral Evaluation of Some Unsymmetrical Mesoporphyrinic Complexes. Int J Mol Sci. 2012; 13: 8112. PubMed Abstract | Publisher Full Text | Free Full Text\n\nDube E, Nwaji N, Oluwole D, et al.: Investigation of photophysicochemical properties of zinc phthalocyanines conjugated to metallic nanoparticles. J Photochem Photobiol A Chem. 2017; 349: 148. Publisher Full Text\n\nOrmond A, Freeman H: Effects of substituents on the photophysical properties of symmetrical porphyrins. Dye Pigment. 2013; 96: 440. Publisher Full Text\n\nShao W, Wang H, He S, et al.: Photophysical Properties and Singlet Oxygen Generation of Three Sets of Halogenated Corroles. J Phys Chem B. 2012; 116: 14228. PubMed Abstract | Publisher Full Text\n\nBonnett R: Chemical Aspects of Photodynamic Therapy. 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}
|
[
{
"id": "85271",
"date": "24 May 2021",
"name": "John Mack",
"expertise": [
"Reviewer Expertise I carry out research that is relevant to all aspects of this study."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to 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 synthesis and further characterization of a Sn(IV) tetraarylporphyrin complex including its photosensitizer properties and in vitro studies of its activity against L. panamensis. The work has been carried out competently for the most part. The results are very much in line with expectations but are of sufficient interest in the context of the effect of the porphyrins on the viability of L. panamensis to merit publication on a platform like F1000. I recommend approval after minor revisions. I urge the authors to carefully consider the following points while preparing their revised manuscript:\n(a) The references should be brought up to date where appropriate. They appear to stop at around 2018 or so.\n(b) Were DMSO stock solutions used to solubilize the dyes for the in vitro studies? If so, the details must be provided.\n(c) Were filters used for the fluorescence measurements in Figure 3 and was a solvent baseline subtracted. The baseline should not rise like it does for compound 2. If not, the fluorescence quantum yields will have to be recalculated.\n(d) Can Figure 1 be redrafted in Chemdraw?\n(e) Decimal points should be used in the y-axis labels of Figure 2.\n(f) There is no need for \"(u.a.)\" in the y-axis title of Figure 4. Having absorbance values > 2 is problematic in this context in terms of the linear range of the spectrometer used, but if reasonable linearity was obtained there is probably no need to repeat the measurements.\n(g) The phrase \"have photo-activity inside window 400 to 7000 nm\" needs to be fixed.\n(h) The λabs values for the Q bands should also be provided in Table 1. λem would normally be preferred rather than λemi.\n(i) The authors should carefully re-evaluate whether their use of three significant figures in Table 2 is justified.\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": []
}
] | 1
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https://f1000research.com/articles/10-379
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https://f1000research.com/articles/10-697/v1
|
30 Jul 21
|
{
"type": "Software Tool Article",
"title": "rmcorrShiny: A web and standalone application for repeated measures correlation",
"authors": [
"Laura R. Marusich",
"Jonathan Z. Bakdash",
"Jonathan Z. Bakdash"
],
"abstract": "We describe a web and standalone Shiny app for calculating the common, linear within-individual association for repeated assessments of paired measures with multiple individuals: repeated measures correlation (rmcorr). This tool makes rmcorr more widely accessible, providing a graphical interface for performing and visualizing the output of analysis with rmcorr. In contrast to rmcorr, most widely used correlation techniques assume paired data are independent. Incorrectly analyzing repeated measures data as independent will likely produce misleading results. Using aggregation or separate models to address the issue of independence may obscure meaningful patterns and will also tend to reduce statistical power. rmcorrShiny (repeated measures correlation Shiny) provides a simple and accessible solution for computing the repeated measures correlation. It is available at: https://lmarusich.shinyapps.io/shiny_rmcorr/.",
"keywords": [
"repeated measures correlation",
"statistics",
"multilevel modeling",
"Shiny",
"correlation",
"regression",
"repeated measures",
"within-participants"
],
"content": "Introduction\n\nThe most common techniques for calculating the correlation between two variables (e.g., the Pearson correlation coefficient) assume that each pair of data points arises from an independent observation. Take, for example, a study that calculates the correlation between age and the volume of a specific brain region for a sample of people. In this example, each individual contributes a data point consisting of a brain volume and an age. However, it is not uncommon for studies to use repeated measures designs, such as a study by Raz et al.1 that collected the brain region volume and age at two different time points. Each participant in this study contributed two (repeated) data points of paired measures. Repeated measures of the same individual are no longer independent observations and should not be analyzed as such. Erroneously modeling repeated measures data as independent observations is surprisingly prevalent in published research, even though such results will generally be misleading.2-4 A common way to resolve this problem is to use aggregated data: first taking an average of the repeated measures data of each person so that every individual again contributes a single paired data point, and then calculating the correlation from these averages (between-participants). Another possibility is to use separate models to analyze each paired data point, removing the dependency. For example, the study by Raz et al.1 computed separate correlations between brain region volume and age at each of the two time points.\n\nInstead of aggregation or separate models, an alternative solution is to calculate the repeated measures correlation,5-7 which assesses the common intra-individual (within-participants) association for paired repeated measures data. The repeated measures correlation technique is conceptually similar to a null multilevel model, with a common (fixed effect) slope but varying (random effect) intercept for each individual. Calculating the repeated measures correlation has multiple potential benefits. It is simpler and more straightforward to implement than a multilevel model, with the potential for much greater statistical power than aggregation. In addition, repeated measures correlation can provide insights into patterns within individuals that may be obscured by aggregation or use of separate models.5\n\nWe previously developed the rmcorr package8 in R9 to make the repeated measures correlation technique widely available for researchers; it has since also been adapted as a function in the Pingouin statistics package10 for Python. However, the use of both of these packages requires some facility with programming languages, which may limit accessibility.\n\n\nMethods\n\nHere we introduce rmcorrShiny, a Shiny11 app, which provides an intuitive graphical interface for computing and plotting the repeated measures correlation. An example of the interface is shown in Figure 1.\n\nThe interface consists of two panels, corresponding roughly to input (left) and output (right), with each containing multiple subpanels or tabs. The left panel has tabs for Input: uploading data or using sample data, Data Options: selecting variables for analysis, and Plot Options: customizing labels and plot appearance. The right panel has tabs for Results: statistical output from rmcorr, Plot: corresponding visualization of the rmcorr results, R code: the custom R code generating the analysis and plot for the selected data/options, Processed Data: summary statistics on data and raw viewer, Download: buttons to download the plot and generated R code, and About: information about the app.\n\nThe primary features of rmcorrShiny include:\n\n• The ability to import data in a variety of different file formats or to use one of four included sample datasets, described below.\n\n• Options for bootstrapping the confidence interval (CI) for the rmcorr effect size.\n\n• The display of raw data and the output from rmcorr as well as formatted output for reporting scientific results.\n\n• Multiple options to generate and customize rmcorr plots, making use of the ggplot2 package12,13 and palettes from the RColorBrewer14 and pals15 packages.\n\n• Customized R code generated using the data and options chosen by the user that can be directly pasted and executed in R to produce the same output as in rmcorrShiny, or as a starting point for additional customization in R.\n\n• The ability to download plots (in multiple file formats) or a .zip file of all output.\n\nNote that many features in rmcorrShiny, including the panel interface, were based on modifications of code from the Raincloud-shiny app.16\n\nrmcorrShiny can be used in a web browser here, or the package can be installed from Github and run locally in R, using the following commands:\n\n\nUse case\n\nAs a use case, we use rmcorrShiny to compute and plot the repeated measures correlation of raz20051, one of the four included sample datasets. The right panel of Figure 2 shows the rmcorr plot for this data. Because a variety of patterns in data can produce similar or even identical statistical results for rmcorr, as well as other models, we highly recommend visualization to aid in interpreting results. In Figure 2, the x-axis is age and the y-axis is volume of a brain area, the cerebellar hemisphere. Each participant, plotted in a different color, contributes two paired data points representing two assessments of age and brain volume. Paired age and brain volume were measured twice per participant about five years apart. The corresponding lines depict the repeated measures correlation model. Note the large negative slope and close fit of the lines to many of the data points. This shows a strong pattern of a common decrease in the volume of this brain area over time, across different ages. The lower left corner of the plot shows the effect size for rmcorr and its p-value.\n\nAs mentioned previously, the pattern of results may vary, depending on whether the analysis is within- or between-individuals.17,18 This can be observed in the current example; when the raz2005 dataset is analyzed using aggregation or separate models (between-individual analyses), the magnitude of the negative association is diminished in comparison to rmcorr (within-individual analysis; see Figure 5 in Bakdash & Marusich5).\n\n\nLimitations\n\nrmcorrShiny has the advantage of making the useful and already fairly simple-to-use rmcorr technique even more accessible and easy to implement and interpret. However, its limitations are the same as rmcorr’s: it does not have all of the capabilities of multilevel modeling and thus it is not a replacement. We recommend using multilevel modeling if: there are more than two variables of interest (in addition to participants or subjects), data with more than two levels, simultaneous modeling of within- and between-participants is needed, visual patterns suggest varying slopes by individual and/or non-linear associations, or time needs to be explicitly included in the model (i.e., modeling change over time as a separate variable; note in Figure 2 age is a measure of time, but it is not a separate variable). For more information about multilevel modeling, see Aarts et al.2 and the About tab in rmcorrShiny.\n\n\nConclusion\n\nThis paper demonstrates the rmcorrShiny app for graphing and analyzing paired, repeated measures data without requiring programming knowledge. By increasing the accessibility of the rmcorr technique, we aim to increase analyses of patterns within-participants as an alternative to other approaches. Such approaches include incorrectly modeling repeated measures data as independent, which is highly problematic, as well as analyses performed only on aggregated data or using separate models. In particular, this app may be useful for visualization and analysis of a common linear pattern across participants and could be a informative precursor complementing multilevel modeling.\n\n\nData availability\n\nThe rmcorrShiny app contains sample datasets from four previously published papers.\n\n• bland1995: Health science data with repeated measures, by participant, of pH (degree of base or acidity) and PaCO2 (partial pressure of carbon dioxide).6\n\n• gilden2010: Psychology data of reaction time and accuracy for a visual search task by participant, in four repeated blocks (both dependent measures are averaged by block).19\n\n• marusich2016: Psychology data of dyads working together to capture High Value Targets (lower task time is better performance) and their averaged Mission Awareness Rating Scale (MARS) score for each block, repeated three times. MARS evaluates subjective situation awareness (”knowing what is going on”), higher values indicate better situation awareness.20\n\n• raz2005: Neuroscience data containing the volume of a brain area (cerebellar hemisphere) measured twice per participant at two different ages, approximately 5 years apart.1\n\nThe csv files for datasets can be directly downloaded from Github (https://github.com/lmarusich/rmcorrShiny/tree/master/inst/shiny).\n\n\nSoftware availability\n\n\n\n• Software available from: https://lmarusich.shinyapps.io/shiny_rmcorr/\n\n• Source code available from: https://github.com/lmarusich/rmcorrShiny\n\n• Archived source code at time of publication: http://doi.org/10.5281/zenodo.508296421\n\n• License: GPL-3",
"appendix": "Acknowledgements\n\nWe would like to thank Derek Anderson, Erin Zaroukian, Blaine Hoffman, and Andrew Tague for helpful feedback on the rmcorrShiny app.\n\nThe views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the U.S. Army Combat Capabilities Development Command Army Research Laboratory or the U.S. Government. The U.S. Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation.\n\n\nReferences\n\nRaz N, Lindenberger U, Rodrigue Karen M, et al.: Regional brain changes in aging healthy adults: General trends, individual differences and modifiers. Cereb Cortex. 2005; 15(11): 1676–1689. PubMed Abstract | Publisher Full Text\n\nAarts E, Verhage M, Veenvliet JV, et al.: A solution to dependency: Using multilevel analysis to accommodate nested data. Nat Neurosci. 2014; 17(4): 491–496. PubMed Abstract | Publisher Full Text\n\nLazic SE: The problem of pseudoreplication in neuroscientific studies: Is it affecting your analysis? BMC Neurosci. 2010; 11(1): 1–17. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBakdash JZ, Marusich LR, Kenworthy JB, et al.: Statistical significance filtering overestimates effects and impedes falsification: A critique of Endsley (2019). Front Psychol. 2020; 11: 1–12. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBakdash JZ, Marusich LR: Repeated measures correlation. Front Psychol. 2017; 8(456): 1–13. 1664-1078. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nBland JM, Altman DG: Statistics notes: Calculating correlation coefficients with repeated observations: Part 1–correlation within subjects. BMJ. 1995; 310(6977): 446. 0959-8138. Publisher Full Text Reference Source\n\nBland JM, Altman DG: Calculating correlation coefficients with repeated observations: Part 2–correlation between subjects. BMJ. 1995; 310(6980): 633. 0959-8138. PubMed Abstract | Publisher Full Text | Free Full Text Reference Source\n\nBakdash JZ, Marusich LR: rmcorr: Repeated Measures Correlation. 2021. R package version 0.4.3. Reference Source\n\nR Core Team: R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing2021. Reference Source\n\nVallat R: Pingouin: statistics in python. J Open Source Software. 2018; 3(31): 1026. Publisher Full Text\n\nChang W, Cheng J, Allaire JJ, et al.: shiny: Web Application Framework for R. 2021. R package version 1.6.0. Reference Source\n\nWickham H, Chang W, Henry L, et al.: ggplot2: Create Elegant Data Visualisations Using the Grammar of Graphics. 2020. R package version 3.3.2. Reference Source\n\nWickham H: ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag; 2016.978-3-319-24277-4. Reference Source\n\nNeuwirth E: RColorBrewer: ColorBrewer Palettes. 2014. R package version 1.1-2. Reference Source\n\nWright K: pals: Color Palettes, Colormaps, and Tools to Evaluate Them. 2019. R package version 1.6. Reference Source\n\nForn-Cuní G: Raincloud-shiny, March 2021.Reference Source\n\nKievit R, Frankenhuis WE, Waldorp L, et al.: Simpson’s paradox in psychological science: a practical guide. Front Psychol. 2013; 4: 513. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMolenaar PCM, Campbell CG: The new person-specific paradigm in psychology. Cur Dir Psychol Sci. 2009; 18(2): 112–117. Publisher Full Text\n\nGilden DL, Thornton TL, Marusich LR: The serial process in visual search. J Exp Psychol Hum Percept Perform. 2010; 36(3): 533. PubMed Abstract | Publisher Full Text\n\nMarusich LR, Bakdash JZ, Onal E, et al.: Effects of information availability on command-and-control decision making: performance, trust, and situation awareness. Hum factors. 2016; 58(2): 301–321. PubMed Abstract | Publisher Full Text\n\nMarusich LR, Bakdash JZ: lmarusich/rmcorrshiny: Initial release.July 2021. Publisher Full Text"
}
|
[
{
"id": "93336",
"date": "10 Sep 2021",
"name": "Ronan McGarrigle",
"expertise": [
"Reviewer Expertise Experimental Psychology",
"Cognitive 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\nThe authors outline the development of a user-friendly software tool ('rmcorrShiny') for running repeated-measures correlation (rmcorr) analysis without the need for any prior programming knowledge. The paper provides a compelling rationale for the development of this novel tool and all materials are shared in an open and transparent way. I believe this has the potential to be a highly useful resource for researchers across a variety of disciplines. I particularly enjoyed the seamless integration with ggplot2 in R to provide detailed and aesthetically-pleasing visualizations of the rmcorr data, which can be very easily created and modified by the user. I also liked the 'reportable results' section of the app, which I believe novice users will find especially useful. Overall, I believe this is an excellent resource that I look forward to using myself and have no doubt others will follow suit.\nI just have a few minor suggestions that I hope will help to promote the utility of this tool for researchers:\nAs mentioned above, I found the shiny app extremely intuitive and straight-forward to use. To test it with some of my own data, I uploaded two data sets. First, I uploaded a dataset from my own previous study for which I had run rmcorr analysis to see if the plots/findings would replicate on the app. I am pleased to report that all of the values provided in the 'results' section on the app were consistent with my own previous analyses, and the plot looked great! To test the app once more, this time I fabricated a dataset in excel (5 repeated measures, two variables, 10 subjects) and tried to plot/analyze the data once again using the app. The 'Results', 'Processed data', and 'R Code' sections all looked fine and appeared similar in format to both the previous analysis and the sample data provided on the app (the columns in the .csv file were correctly identified as variables, etc.). However, the plot tab did not appear to work on this occasion - I received the following error message; 'Error: an error has occurred. Check your logs or contact the app author for clarification'. I'm sure there will be a very simple fix, but I just wanted to flag this in case of a bug. Please feel free contact me if you would like me to share the specific datasets so that you can try to replicate the issue yourselves.\n\nIntroduction, paragraph 2: When describing the benefits of rmcorr in the Introduction, I wonder if it might be worth providing a more concrete example to highlight when this approach may be particularly useful - e.g., as a way to assess changes over time between two adjacent measures. A more concrete example might help to really drive home this point for interested readers. For example, researchers are often interested in examining to what extent changes over time in one measure (e.g., self-report) mirror changes over time in another measure (e.g., physiological). While data aggregation would collapse over (and thus ignore) this kind of association, rmcorr provides a powerful way to assess within-subject change between these paired measures.\n\nLimitations, line 4: I just had to re-read this sentence a few times. I wonder if changing this to 'if there are more than two outcome variables of interest' would help to clarify this point (instead of what is currently in brackets)?\n\nLimitations, line 4: I wonder if it would be helpful to clarify what you mean by 'data with more than two levels', with an example perhaps? I guess I'm just wondering if data collected at two separate time points constitutes two levels in this context (I'm guessing not, but I think it might just be useful to clarify).\n\nConclusions, lines 2-5: I found the first sentence of this paragraph ('we aim to increase analyses of patterns within-participants') a little tricky to parse. As a possible alternative that I hope does not misinterpret the point you are trying to make (if so, please feel free to ignore), how about something like: 'we aim to bolster the researcher’s toolbox by providing a simple but powerful tool for examining associations present at the within-subject level in a way that does not violate independence assumptions or require use of separate models or data aggregation'.\n\nConclusions, line 6: 'an' informative precursor.\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": "7348",
"date": "08 Nov 2021",
"name": "Laura Marusich",
"role": "Author Response",
"response": "I received the following error message; 'Error: an error has occurred. Check your logs or contact the app author for clarification'. I'm sure there will be a very simple fix, but I just wanted to flag this in case of a bug. Response: We contacted Dr. McGarrigle for more information and found the source of the bug. Spaces in variable names were causing errors in plotting. This has been fixed in the current version of the app, thanks. Introduction, paragraph 2: A more concrete example to highlight when this approach may be particularly useful - e.g., as a way to assess changes over time between two adjacent measures. A more concrete example might help to really drive home this point for interested readers. Response: We have attempted to draw more connections between the conceptual description of the repeated measures correlation technique and the use case showing analysis of data from Raz et al. (2005), to demonstrate that the within-individual patterns revealed by rmcorr may be different from between-individual patterns. Limitations, line 4 I wonder if changing this to 'if there are more than two outcome variables of interest' would help to clarify this point (instead of what is currently in brackets) I wonder if it would be helpful to clarify what you mean by 'data with more than two levels', with an example perhaps? Response: We agree this sentence is difficult to understand and have rewritten it. Conclusions, lines 2-5: I found the first sentence of this paragraph ('we aim to increase analyses of patterns within-participants') a little tricky to parse. As a possible alternative that I hope does not misinterpret the point you are trying to make (if so, please feel free to ignore), how about something like: 'we aim to bolster the researcher’s toolbox by providing a simple but powerful tool for examining associations present at the within-subject level in a way that does not violate independence assumptions or require use of separate models or data aggregation'. Response: Thanks! We switched to the suggested version above, it is much clearer than the original version. Conclusions, line 6: 'an' informative precursor Response: Fixed, thanks- good catch."
}
]
},
{
"id": "93337",
"date": "21 Sep 2021",
"name": "Emmeke Aarts",
"expertise": [
"Reviewer Expertise Methodology and statistics",
"multilevel modelling"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe authors present an online (and open source), user-friendly and very complete software tool within the R Shiny framework to infer the linear within-individual correlation for repeated observations within multiple individuals for two outcomes. The R shiny app is based on the previously developed R package rmcorr published on CRAN, making both analyses using rmcorr and data visualization accessible to an audience not comfortable with R. The manuscript provides a concise and clear rationalization for the development of the software tool, explaining why dependency due to repeated observations needs to be accommodated in the used analysis method. We especially enjoyed the clear and aesthetically pleasing graphs making use of ggplot2 provided with the app, and the numerous customization options for the graphs: from more basic matters like specifying the titles of the axes to even allowing the user to specify the color palette. Also, the code provided in the R Code tab is potentially very helpful and insightful to users wanting to become more acquainted with doing these analyses in R or wanting to slightly modify some steps of the analysis or visualization. The fact that multiple sample datasets are available within the tool is also a big plus. In conclusion, the app is a very nice resource valuable to a wide audience. It's a tool we will recommend to applied researchers analyzing dependent data and we look forward to use it for teaching purposes.\n\nWe have some minor suggestions that might help to further improve the tool and the utility for other researchers:\nIt is unclear what happens when the data includes missing observations. Will these cases be ignored using listwise deletion? It would be nice if the authors could provide a small comment on this in the manuscript.\n\nWe can imagine that for some users it might be very useful and insightful if the app includes a tab that provides (visual) information on whether the statistical assumptions of the analysis method are met. It would be a very nice addition to an already very complete app.\n\nWhen trying out the app, an error was produced on the max upload size (the app did work when using a different dataset of a smaller size), if there is a restriction on the maximum size for used datasets it would be nice if a mention of this could be included in 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": "7349",
"date": "01 Nov 2021",
"name": "Laura Marusich",
"role": "Author Response",
"response": "It is unclear what happens when the data includes missing observations. Will these cases be ignored using listwise deletion? It would be nice if the authors could provide a small comment on this in the manuscript. Response: That is correct, missing observations are ignored using listwise deletion. We added this key detail to the paper. We also discovered and fixed a bug with plotting data that had missing observations. We can imagine that for some users it might be very useful and insightful if the app includes a tab that provides (visual) information on whether the statistical assumptions of the analysis method are met. It would be a very nice addition to an already very complete app. Response: This is an excellent idea and desirable feature, but we think it will be very challenging to implement in Shiny. For now, we have added it as a wish-list item. In the paper, we added a sentence that the statistical assumptions for rmcorr are the same as ANCOVA, with the exception of independence, and again emphasized visualization of the data and model. The latter, to some extent, can be used to visually check assumptions such as homogeneity of variance and linearity. When trying out the app, an error was produced on the max upload size (the app did work when using a different dataset of a smaller size), if there is a restriction on the maximum size for used datasets it would be nice if a mention of this could be included in the manuscript. Response: Thanks for testing and finding this issue. We modified the web app to increase the maximum file size to 30 MB. Also, we noted this in the paper and added that a file exceeding 30 MB can be loaded by running the app locally."
}
]
}
] | 1
|
https://f1000research.com/articles/10-697
|
https://f1000research.com/articles/10-1127/v1
|
08 Nov 21
|
{
"type": "Opinion Article",
"title": "An active human role is essential in big data-led decisions and data-intensive science",
"authors": [
"Mohamed L. Seghier"
],
"abstract": "Big data is transforming many sectors, with far-reaching consequences to how decisions are made and how knowledge is produced and shared. In the current move toward more data-led decisions and data-intensive science, we aim here to examine three issues that are changing the way data are read and used. First, there is a shift toward paradigms that involve a large amount of data. In such paradigms, the creation of complex data-led models becomes tractable and appealing to generate predictions and explanations. This necessitates for instance a rethinking of Occam's razor principle in the context of knowledge discovery. Second, there is a growing erosion of the human role in decision making and knowledge discovery processes. Human users’ involvement is decreasing at an alarming rate, with no say on how to read, process, and summarize data. This makes legal responsibility and accountability hard to define. Third, thanks to its increasing popularity, big data is gaining a seductive allure, where volume and complexity of big data can de facto confer more persuasion and significance to knowledge or decisions that result from big-data-based processes. These issues call for an active human role by creating opportunities to incorporate, in the most unbiased way, human expertise and prior knowledge in decision making and knowledge production. This also requires putting in place robust monitoring and appraisal mechanisms to ensure that relevant data is answering the right questions. As the proliferation of data continues to grow, we need to rethink the way we interact with data to serve human needs.",
"keywords": [
"Knowledge creation",
"big data",
"analytics",
"complexity",
"data-based decisions"
],
"content": "Introduction\n\nBig data describes voluminous data that are measured at different pace, scale, size and type. Big data can be produced anytime, anywhere and can come in structured, semi-structured or unstructured formats. Figure 1 illustrates the main characteristics of big data (i.e. the 11 Vs) that make big data challenging and valuable at the same time,1,2 including volume, variety, velocity, visibility, variability, validity, veracity, value, volatility, vulnerability and versatility, though not all forms of big data possess all eleven characteristics.3 Many sectors have been transformed by the possibility to make accurate and useful decisions by harnessing big data through diverse effective strategies.4 For instance, in the health sector, sophisticated big data analytics can assist doctors to generate accurate and clinically useful individualized predictions for diagnostic or prognostic purposes, which ultimately translate into improved treatments, and more efficient and cost saving service delivery.5,6 In the education sector, the ability to process big data about students in real-time helps to understand and enhance learner’s behavior and performance and to integrate data into the curriculum.7,8 As many sectors are competing to take full advantage of the big data revolution, with the potential to generate data-driven ingenious solutions to hard questions, digitization pace is increasing at faster rates thanks to the internet revolution (Internet of Things, 5G) and the widespread adoption of wearable smart devices. Many experts and initiatives around the world consider big data availability as a key driver to transform health and education sectors in the next decades (e.g.9–13), with far-reaching consequences to how knowledge is produced and shared.\n\nFor data specialists and policy makers, big data can help tackle problems in a reliable, accurate, unbiased, fast, and comprehensive way. Big data is adding many features to knowledge creation and decision-making processes (Figure 2). This ‘added value’ is completely reshaping and expanding these processes with the ability to: (1) affect events and systems while they are still unfolding, thanks to the possibility to make fast decisions based on a continuous flow of data; (2) generate an exhaustive and fine-grained picture about every aspect of a student’s learning journey or a patient’s condition in order to create a holistic decision making process; (3) discover patterns and relationships without a priori knowledge or hypotheses, hence minimizing human bias and framing; (4) account for as many variables and features as possible to generate reliable and useful decisions; (5) combine data with different types and from multiple modalities, including unstructured data, to continuously improve the accuracy of decisions; (6) increase mobility where decision making processes can take place anywhere, in the cloud, and on any device; and (7) maximize data sharing and collaboration between different decision makers with the possibility to combine data across diverse sectors and domains to generate in-depth and wide-ranging insights about people and events. These abilities are some of the most frequent arguments listed by decision makers for relying on big data to address a variety of questions in different sectors.14,15\n\nAs the case for any technology, big data does not come free of challenges and limitations. Many challenges have been discussed extensively in the current literature regarding data capture, storage, searching, sharing, integration, transformation, analysis, visualization, consistency, completeness, scalability, timeliness, privacy, security, liability, accountability, governance and ownership.8,16,17 The aim of this article is to highlight another side of this big data revolution that warrants further discussion. This concerns the following issues: (1) the transformation of traditional research paradigms with emphasis on volume and quantity, (2) the erosion of the human role in decision making and knowledge discovery processes, and (3) the alluring nature of big data-based decisions. Below we discuss the implication of these issues on how big data is currently sought and treated.\n\n\nBig data and good data\n\nRapid development of processor power and computer parallelization has now made it possible to study huge amounts of data with relative ease. The push for more data is not new as classic models of knowledge discovery emphasize the need for high statistical power, a measure that is positively associated with data size.18 As current analytics and machine approaches require copious amounts of training data, the increase in size and complexity of models’ architecture will make the need for more data even bigger. Under the assumption that machines will be more accurate in extracting relevant and useful information with more and more data, quantity or volume is becoming the dominant feature in big data with sometimes little attention to data quality or relevance; for discussion see.19–21 Previous work has shown that data volume is not always a significant factor to drive innovation or improve performance.22,23 This is because the value of a data-driven decision cannot be better than the quality of data that is feeding the machines making that decision.24 Poor or inaccurate decisions can be due to lack of data and/or lack of good data.25 If a model or a process is fed poorly, data-driven features will be poor, and this will only yield poor decisions.26\n\nIn this context, as the increasingly attractive solution to understand complex phenomena is to acquire more and more data, traditional inquiry research methods with well-controlled designs and well-selected samples may lose their appeal to researchers, funding agencies and policy makers.27 It is important that collection of good data, even with a limited number of variables from samples that are not large, should not be deemed as a relic from the past. Many discoveries and breakthroughs made in the past, well before this era of big data, were the result of top-quality research with top-quality data that helped to generate accurate mechanistic accounts of many phenomena, mechanistic accounts that human users were able to comprehend, model and harness for diverse applications.28 However, what we learned from many solutions derived from big data is that the processes that yielded a solution remain opaque to human users as the solution itself is sometimes an intrinsic emerging property of big data. This gives very limited insights into the optimal mechanisms that human users can learn and follow to conquer similar problems. A new framework is needed to make sure that solutions derived from big data speak a similar language as solutions derived from prior knowledge by traditional ways of scientific inquiry.15,29\n\nAnother important point concerns the creation of useful models, whether in educational or clinical settings, which is an important endeavor in science. It is apparent that availability of big data will have major ramifications on how models are created and compared. For instance, the design of complex models becomes more appealing as data is getting bigger. Although simple useful models are conventionally preferred (i.e. Occam's razor principle), complex data-led models may shift the way we look for explanations and predictions. Big data can extend the model space to search and assess more complex models with more variables and more features. The aphorism ‘simple is beautiful’ is gradually being replaced by ‘complex is powerful’. Nevertheless, what we notice is that, while data is expanding in volume, this increase in model complexity is not necessarily translating into higher explicability or relevance, i.e. explained variation. Put another way, for a given phenomenon, the proportion of explained variance, as a proxy for the model’s ability to explain that phenomenon, is not growing dramatically with the increase in data volume. This calls for a different way of designing and comparing models given data, as big data are not only answering questions but also generating more.\n\n\nBig data with a human touch\n\nThe way big data is growing in its complexity, volume or type, makes it a product not crafted for human use or comprehension. How big data is typically created and collected illustrates that its purpose is mainly to feed sophisticated analytics, with little concern to how human users will read data.30 The human aspect is gradually left aside in the processing of big data and in the making of big data-driven decisions, hence reducing human contribution to merely conveying the output of data processing tools. What’s more concerning is that human users’ ability to interpret and make sense of such big data-driven decisions is continuously eroded, with sometimes no say on how such analytics should read, process, summarize and present big data. When big data is submitted to an AI-powered tool for instance, the way it is cleaned, reduced and processed bear no attempt to account for what is relevant for the human end-users. The education sector provides an interesting example about the implications of this issue. In this sector, there is a growing interest in using big data and analytics to predict students’ performance for diverse applications (for a recent systematic review, see31), with the ultimate goal to personalize learning and provide adequate and timely academic support.8,32 However, when students for instance are denied enrolment in a program or a track because an AI-powered warning system decided that they have an above-threshold risk of failing courses, this high-stake decision needs careful examination and opportunity for re-evaluation for a better protection of students’ rights.33 There is an even increasing risk that decision makers will hide behind the sophistication of such AI-powered tools, leaving no opportunity to challenge or question decisions because they have been made by intelligent machines on massive data, with the assumption that such decisions are, by design, error-free and unbiased. It is thus vital that opportunities for human involvement are encompassed in big data collection and processing. Processes that value the human input on top of big data-driven features should be supported.30,34 A proper dialogue needs to take place between policy makers and developers to create processes and tools that are accessible to all and that are in the service of the human decision makers.\n\nWe need big data with a human touch. Ongoing advances will increase big data’s dual potential to either empower or isolate human users from decision making and knowledge creation processes. It is thus vital to gradually build synergies that can bring big data to their utmost purpose which is to serve human needs. Policy makers should put in place safeguards and regulations to monitor how big data are collected and treated to address a given question. Transparency should be guaranteed at all levels, in particular regarding the exact purpose of collected data and how it is going to be manipulated and processed.35 When big data-driven decisions are made, the concept of legal responsibility and liability may become fuzzy. As analytics and machine learning algorithms are becoming increasingly impenetrable, decision makers are not always able to fully comprehend the breadth and consequences of a given data-driven decision. Hence, accountability needs to be clarified when wrong or inappropriate decisions or predictions are made with big data.36 It is important to be able to trace back all processes and stages involved in the making of a decision. There must be integrated tools that analyze and interrogate the making process of a decision in case of an inquiry or an appeal.37 Perhaps most importantly, the decision-making process must be freed from the opacity of big data and analysis methods, for example by scrutinizing the type of data selected or omitted in the process, the underlying assumptions behind the selected mathematical models, and the anticipated consequences of the decisions in the light of what is socially and legally acceptable.17,38,39\n\n\nThe seductive allure of big data\n\nWhen a presumably persuasive but irrelevant information is added to an argument, naïve or nonexpert users might be influenced by that information. For example, nonexperts may judge satisfying some bad explanations that are supported by irrelevant information that has a persuasive power such as a neuroscience evidence or brain images.40,41 What this suggests is that, when people are nonexperts or cannot comprehend a process, they tend to be influenced (seduced) by other irrelevant peripheral features42; for example, to be persuaded by peripheral aspects like an image of a brain, a complex equation, a massive number, or a photo of a famous person. Big data is no exception; nonexpert users and decision makers might be seduced by its size and complexity. Hence, there is a risk that decisions become more persuasive and significant just because the process used to generate them is based on big data. Decision makers might be tempted to give more authority (evidence) to decisions or information generated from big data. This might undermine appeals and grievance procedures if decisions and solutions are portrayed as the output of infallible machines on voluminous data.\n\nIt is thus important to dissociate core processes in big data-based decision making from peripheral aspects of that process. The way big data is visualized, presented and portrayed should not be made with the desire to obfuscate or complicate the information conveyed to users. When nonexperts are overwhelmed by the sheer complexity and the degree of details that result from a decision-making process on big data, they tend not to question such process. Data specialists should therefore devise user-friendly ways to make core processes as clear and as coherent as possible, such as how data is cleaned, reduced and what relevant features are selected. Additional data quality assurance processes must be put in place to ensure that big data is serving its main purpose in the most accurate and valid ways, using data sampling and profiling to minimize the risk for data quality degradation43 and systematic processes to ensure data validity for other purposes (i.e. repurposed data).44\n\nThis seductive nature of big data has implication on ethics. Results that emerge in a data-driven manner might not always be appropriate from an ethical point of view (e.g. results that stigmatize a group by gender, ethnicity or health condition), and participants from different groups might feel their data are being used or represented in ways they cannot fathom. This can create a divide between those who access and control big data and those who merely feature in them.45,46 Big data collection can be more invasive than necessary due to easy access,47 and it is not unusual to see big data used to answer different questions than the ones originally consented for by participants.48 Big data often contains much more information than is strictly necessary, hence guidelines and safeguards must be put in place to ensure fairness, equity and transparency. It is important that policy makers and ethics bodies uphold the same standards to big data given its longevity and intrusive nature. It is too easy to impress with big numbers, and it is a moral and legal obligation to communicate the right results with their very real limitations to society and policy makers.49\n\n\nConclusion\n\nBig data holds the potential for revolutionizing many sectors. We have seen the birth of many big data initiatives,50 for instance UN's Global Pulse initiative, Europe’s Data Saves Lives initiative, NIH’s All of Us program, China’s Cohort Consortium, and the UK Biobank. But big data is not the answer to all questions, regardless of how attractive and impressive big data is. As machines can process big data and discover new relationships between variables of any arbitrary shape, it is important to appraise the whole process by making sure that big data are answering the right questions. As we are moving toward a more data-intensive type of science, the objective must remain to understand than merely predict relationships. This necessitates a hybrid framework that incorporates insights from human experts in the data-led knowledge production. We are beholding how big data is gaining unprecedented authority in the decision making and knowledge production processes, while present standards (methodological, ethical and legal) are not able to keep pace with current growth in big data and their ramifications for many sectors. There is an urgent need for more critical reflection on how humans should interact with data and data-driven information.\n\n\nData availability\n\nNo data is associated with this article.",
"appendix": "References\n\nRistevski B, Chen M: Big Data Analytics in Medicine and Healthcare. J. Integr. Bioinform. 2018; 15(3).\n\nSun Z, Strang K, Li R: Big Data with Ten Big Characteristics. ICBDR 2018: Proceedings of the 2nd International Conference on Big Data Research. 2018; p. 56–61.\n\nKitchin R, McArdle J: What makes Big Data, Big Data? Exploring the ontological characteristics of 26 datasets. Big Data Soc. 2016; 3(1): 205395171663113. Publisher Full Text\n\nAl-Sai ZA, Abdullah R, Husin MH: Critical Success Factors for Big Data: A Systematic Literature Review. IEEE Access. 2020; 8: 118940–118956. Publisher Full Text\n\nWang Y, Kung L, Byrd TA: Big data analytics: Understanding its capabilities and potential benefits for healthcare organizations. Technol. Forecast. Soc. Chang. 2018; 126: 3–13. Publisher Full Text\n\nHulsen T, et al.: From Big Data to Precision Medicine. Front Med (Lausanne). 2019; 6: 34. 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Sci. 2021; 11: 237.\n\nKhan I, et al.: An artificial intelligence approach to monitor student performance and devise preventive measures. Smart Learnin Environments. 2021; 8: 17. Publisher Full Text\n\nBerendt B, Littlejohn A, Blakemore M: AI in education: learner choice and fundamental rights. Learn. Media Technol. 2020; 45(3): 312–324. Publisher Full Text\n\nHelzlsouer K, et al.: Humanizing Big Data: Recognizing the Human Aspect of Big Data. Front. Oncol. 2020; 10: 186. Publisher Full Text\n\nKantarcioglu M, Ferrari E: Research Challenges at the Intersection of Big Data, Security and Privacy. Front Big Data. 2019; 2: 1. Publisher Full Text\n\nKempeneer S: A big data state of mind: Epistemological challenges to accountability and transparency in data-driven regulation. Gov. Inf. Q. 2021; 38(3): 101578. Publisher Full Text\n\nUlbricht L, von Grafenstein M : Big data: big power shifts?. Internet Policy Review. 2016; 5(1). 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Publisher Full Text\n\nTaleb I, et al.: Big data quality framework: a holistic approach to continuous quality management. J Big Data. 2021; 8: 76. Publisher Full Text\n\nDiaz-Garelli JF, et al.: DataGauge: A Practical Process for Systematically Designing and Implementing Quality Assessments of Repurposed Clinical Data. EGEMS (Wash DC). 2019; 7(1): 32. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAndrejevic MB: The big data divide. Int. J. Commun. 2014; 8(1): 1673–1689.\n\nMetcalf J, Crawford K: Where are human subjects in Big Data research? The emerging ethics divide. Big Data Soc. 2016; 3(1): 205395171665021. Publisher Full Text\n\nSula CA: Research ethics in an age of big data. Bulletin of the Association for Information Science & Technology. 2016; 42(2): 17–21. Publisher Full Text\n\nXafis V, et al.: An Ethics Framework for Big Data in Health and Research. Asian Bioethics Review. 2019; 11: 227–254. PubMed Abstract | Publisher Full Text | Free Full Text\n\nHartung T: Making Big Sense From Big Data. Front Big Data. 2018; 1: 5. Publisher Full Text\n\nHulsen T: Sharing Is Caring-Data Sharing Initiatives in Healthcare. Int. J. Environ. Res. Public Health. 2020; 17(9) PubMed Abstract | Publisher Full Text | Free Full Text"
}
|
[
{
"id": "126888",
"date": "24 Mar 2022",
"name": "Marta Ewa Kuc-Czarnecka",
"expertise": [
"Reviewer Expertise ethics of quantification",
"big data and ethics",
"composite indicators",
"taxonomy",
"spatial statistics",
"GIS."
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article addresses significant problems of the impact of visible numbers (scoring, rankings) and invisible numbers (algorithms) used due to the growing popularity of big data. Important aspects such as overinterpretation of data, blurring of messages, misleading the recipient (intentionally or not), lack of transparency, and too much confidence in the number at the decision-making stage were noted. I believe that reasonable and gentle voices pointing out the problematic issues are vital. Especially in the era of admiration for measuring everything and everywhere, as well as over-modelling and numerification of reality. Perhaps the authors could also devote a bit of space to the issue of big data and fake news - on the one hand, big data should help in capturing them, and on the other hand, they are often used in disinformation or propaganda. I also recommend the authors to read:\nSaltelli, A., Dankel, D., Di Fiore, M., Holland, N. & Pigeon, M. Science, the Endless Frontier of Regulatory Capture. https://papers.ssrn.com/abstract=3795058 (2021) doi:10.2139/ssrn.3795058.\n\nSaltelli, A. et al. Five ways to ensure that models serve society: a manifesto. Nature 582, 482–484 (2020).\n\nBruno, I., Didier, E. & Prévieux, J. Statactivisme. Comment lutter avec des nombres. (Zones, La Découverte, 2014).\n\nSaltelli, A. et al. Why ethics of quantification is needed now. UCL Institute for Innovation and Public Purpose, Working Paper Series (2021).\n\nCouldry, N. & Mejias, U. A. Data Colonialism: Rethinking Big Data’s Relation to the Contemporary Subject. Telev. New Media 20, 336–349 (2019).\nI have mentioned these articles because they refer to quantification in its broadest sense and its impact on decision-making, as well as the often questionable ethical use of numbers. Perhaps the author, on the basis of these works, will be able to expand the scope of his research in the future.\nI believe that the article in its current form meets the formal and substantive requirements, and therefore is suitable for indexing.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
},
{
"id": "238781",
"date": "28 Feb 2024",
"name": "Tariq Rahim Soomro",
"expertise": [
"Reviewer Expertise Big Data",
"IoT",
"GIS",
"IDNs",
"Cybersecurity",
"Quality Education"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe article discusses the transformative impact of big data on various sectors, highlighting its potential benefits and challenges. It focuses on three key issues: the transformation of traditional research paradigms, the diminishing human role in decision-making processes, and the seductive nature of big data.\n\nStrengths:\nThe article provides a comprehensive overview of the characteristics of big data, its applications across different sectors, and the challenges associated with its utilization.\n\nThe article critically examines the prevailing trend of emphasizing volume over data quality. It rightly emphasizes that the value of data-driven decisions is contingent on the quality of the data.\n\nThe discussion on the erosion of the human role in decision-making processes is thought-provoking. It underscores the importance of considering human interpretation and involvement in big data-driven decisions, especially in critical areas like education.\n\nThe article appropriately highlights ethical considerations associated with big data, emphasizing the potential biases and the need for transparency, accountability, and safeguards in data collection and processing.\n\nAreas for Improvement:\nThe article could benefit from clearer transitions between its main points. At times, the flow of arguments might be challenging to follow, affecting the overall coherence of the text.\n\nWhile the article mentions instances in healthcare and education where big data can be advantageous, providing more concrete examples and case studies could enhance the reader's understanding of these applications.\n\nWhile the article outlines challenges, it could provide a more balanced discussion by also highlighting successful implementations of big data and ways in which these challenges are being addressed in current practices.\n\nThe article references initiatives and programs up to November 2023, and considering the rapid evolution of technology and data-related fields, more recent references could strengthen the arguments.\n\nAuthor may avoid using the terms, such as \"we\", \"our\", etc.\n\nThe Author may consider the following relevant research articles: Naqvi et al. (20211); Tariq (20152).\n\nOverall: The article presents a valuable critique of the current trends in big data utilization, urging for a balanced approach that considers data quality, human involvement, and ethical considerations. Despite some areas for improvement, the article contributes to the ongoing discourse on responsible and effective big data practices.\n\nIs the topic of the opinion article discussed accurately in the context of the current literature? Yes\n\nAre all factual statements correct and adequately supported by citations? Yes\n\nAre arguments sufficiently supported by evidence from the published literature? Yes\n\nAre the conclusions drawn balanced and justified on the basis of the presented arguments? Yes",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1127
|
https://f1000research.com/articles/10-1125/v1
|
08 Nov 21
|
{
"type": "Software Tool Article",
"title": "PlotXpress, a webtool for normalization and visualization of reporter expression data",
"authors": [
"Elias Brandorff",
"Marc Galland",
"Joachim Goedhart"
],
"abstract": "In molecular cell biology, reporter assays are frequently used to investigate gene expression levels. Reporter assays employ a gene that encodes a light-emitting protein, of which the luminescence is quantified as a proxy of gene expression. Commercial parties provide reporter assay kits that include protocols and specialized detection machinery. However, downstream analysis of the output data and their presentation are not standardized. We have developed plotXpress to fill this gap, providing a free, open-source platform for the semi-automated analysis and standardized visualisation of experimental gene reporter data. Users can upload raw luminescence data acquired from a reporter gene assay with an internal control. In plotXpress, the data is corrected for sample variation with the internal control and the average for each condition is calculated. When a reference condition is selected the fold change is calculated for all other conditions, based on the selected reference. The results are shown as dot plots with a statistical summary, which can be adjusted to create publication-grade plots without requiring coding skills. Altogether, plotXpress is an open-source, low-threshold, web-based tool, that promotes a standardized and reproducible analysis while providing an appealing visualization of reporter data. The webtool can be accessed at: https://huygens.science.uva.nl/PlotXpress/",
"keywords": [
"Reporter assays",
"gene expression",
"luciferase",
"data visualization",
"webtool"
],
"content": "Introduction\n\nReporter gene assays are popular tools to investigate gene expression dynamics in cell biology (Barriscale et al., 2014; Liu et al., 2009; Schenborn and Groskreutz, 1999). In most systems, the reporter is a gene coding for a protein that emits light when it binds a substrate. An example is the firefly (Photinus pyralis) luciferase that emits light when it binds the substrate luciferin (Himes and Shannon, 2000). The luminescent light can be detected with dedicated equipment and reflects the expression of the reporter gene.\n\nThe expression level of the reporter gene is used as a proxy of the capacity of a DNA sequence to regulate gene expression under various experimental conditions. To this end, the DNA sequence of interest is cloned upstream of the reporter gene in a vector which is subsequently transfected into cells. Reporter gene activity can be compared between variations of a regulatory DNA sequence, for example by removing a transcription factor binding site or by modulating tandem repeat expansions in a promoter sequence (Rodriguez et al., 2020; Moparthi and Koch, 2020). Another option is to measure the effects on reporter activity of treatments such as pharmaceutical compounds or overexpression of transcription factors that interact with the sequence of interest (Asamitsu et al., 2021). In addition, reporter assays have been used to study the relation between microRNAs and cancer progression (Wang et al., 2021; Chengling et al., 2021). In the so-called “Dual-LuciferaseⓇ Reporter Assay System” (Promega), an internal control is used to correct for variations in cell density and transfection efficiency. This internal control is co-transfected and consists of a vector with a constitutively active promoter that drives expression of another luciferase. This second luciferase emits a different color of light and is, in our example, derived from Renilla reniformis (sea pansy). Transfection of the internal control is kept the same in each well and reflects transfection efficiency and cellular protein production.\n\nA given sequence of interest is cloned into a luciferase expressing plasmid in order to investigate its activity as a gene promoter. The transfection of an empty vector control, without this sequence, is an important reference condition and required to correct for unintended effects of the plasmid alone. For example, in some vectors, luciferase is expressed under control of an SV40 promoter element. A transcription factor binding site (TFBS), cloned upstream of this promoter will influence its activity and the expression of luciferase. The measured effect is a composite of promoter activity plus the TFBS. The empty vector control allows normalization for baseline promoter activity and isolation of the influence of the TFBS alone. Here, we will call the empty vector condition the reference condition.\n\nIn reporter assays with multiple reporter constructs, cell types, treatments and reference conditions, experiments may increase rapidly in size and complexity, leading to challenging downstream analyses. There is currently neither a standardized method nor a computational tool for the processing of reporter assay data and its visualization. PlotXpress was designed to simplify the analysis process of complex reporter assays (Figure 1) by providing an online tool with a standard for data processing and visualization. PlotXpress was built following the philosophy of transparent and state-of-the-art data visualization implemented in the data visualization app PlotsOfData (Postma and Goedhart, 2019). In addition to a streamlined analysis, plotXpress enables transparent communication of the data. Instead of only providing averaged data and error bars to summarize gene reporter data in bar graphs, plotXpress produces dot plots maintaining individual data points. Data in both wide and tidy format (Wickham, 2014) can be provided. As coding skills are not required, plotXpress is a readily available low entry-level application that democratizes the processing and visualization of dual reporter expression data.\n\nFirefly and renilla expressing plasmids are transfected into cells grown in 24-well plates. After incubation the cells are harvested and lysates pipetted into 96-wells optiplates. These are loaded into a plate reader where the luciferase substrates are added. Once the reactions are initiated, luminescence is detected, and readings are stored digitally.\n\n\nMethods\n\nThe plotXpress code is written in the R programming language using the following packages: ggplot2 (Wickham, 2016), tidyr, magrittr, readr, stringr, dplyr and readxl which are all part of the tidyverse suite of packages version 1.3.1 (Wickham et al., 2019), and Shiny and DT. This manuscript documents version 1.0.0 of the webtool which is archived (together with the example data) at Zenodo (Goedhart and Galland, 2021).\n\nBackground information, updates of the code and version releases will be published on GitHub: https://github.com/ScienceParkStudyGroup/PlotXpress. GitHub is the preferred channel for communication regarding issues and feature requests.\n\nAn example dataset with measurements and a dataset with conditions is automatically loaded when the plotXpress app launches. These files, ‘DualLuc_example_data.xlsx’ and ‘Tidy_design.csv’, are also available online (Goedhart and Galland, 2021).\n\nData upload\n\nUsers can upload their data in two different ways. The first option is for data acquired with the Promega GloMax plate reader. The alternative is a general-purpose option that accepts data in a tidy format.\n\nGloMax data upload\n\nThe output of the GloMax plate reader (Promega) is a spreadsheet XLSX format with two tables containing firefly and renilla luminescence signals stored in a 96-well lay-out. PlotXpress reads the cells with the firefly and renilla readings and provides a graphic overview of the experiment by showing a 96-well plate where signal intensity is colour coded (Figure 2).\n\nScreenshot of PlotXpress app showing a 96-well format with signal intensities represented by false colour.\n\nThe firefly and renilla reads from the GloMax data are converted into a tidy format and merged with experimental conditions that are taken from the uploaded design (Figure 3). The resulting tidy dataframe is used for data processing.\n\nPlotXpress allows uploading of GloMax spreadsheet input. An additional experimental design file in tidy format should be provided to connect the reads with the conditions. After supplying the design file, the GloMax data is converted to a table in tidy format, where each row contains a single observation and the experimental conditions. The table can be downloaded and used as input for plotXpress.\n\nA separate table in CSV format with the experimental conditions per well is required for the data processing. A template is available for download within the app or online (Goedhart and Galland, 2021).\n\nTidy data upload\n\nInstead of uploading a GloMax spreadsheet in 96-well format and an additional design file, users can choose to upload a single tidy dataset (.CSV) containing both experimental conditions and firefly and renilla signals. An example file is available online (Goedhart and Galland, 2021).\n\nAll the relevant data from one experiment (design and measurements) should be present in one tidy table. Users are free in the size of the experiment: any number of cell types, sequences of interest, or treatments may be added. The minimal information that is required is a column with wells (in the format A01, B01, ..), a column with intensity data and a column with the conditions. An additional column with reference data is optional and is used to normalize the data if supplied.\n\nData processing\n\nIn dual luciferase assays, each replicate consists of a firefly luciferase and renilla luciferase intensity reading. To normalize the reporter gene expression to the internal control, plotXpress calculates the ratio of firefly signal to renilla signal, resulting in the firefly/renilla ratio. An average firefly/renilla ratio is then calculated for each group of readings that share identical names in the “condition” column. Finally, the fold change is calculated by dividing the firefly/renilla ratio by the firefly/renilla ration of a selected reference condition:\n\nThe plotXpress web tool can be accessed at https://huygens.science.uva.nl/PlotXpress/ or https://goedhart.shinyapps.io/PlotXpress. The online web app runs on any computer platform with a browser and an internet connection. Instructions to run the app locally in R/Rstudio can be found in the README file on the Github page. Upon launching the app, the example data is loaded and the users can choose to visualize the example data by selecting the ‘Plot’ tab or to upload their own data (Figure 2).\n\nThe data upload accepts both GloMax xlsx files, as well as tidy data in CSV format. After data upload, PlotXpress offers flexibility in the selection of conditions to filter the data before plotting. Individual wells can be removed from the analysis or specific conditions can be filtered.\n\nThe combined data from an experiment can be downloaded as a CSV file in tidy format. This data format can be used for further processing, such as statistical testing and plotting. The tidy format is well handled by statistical software (R) and other web tools that we have developed (available online). For instance, when the data consists of a mix of technical and biological replicates, this can be visualized as a superplot (Lord et al., 2020) by uploading the data in the SuperPlotsOfData app (Goedhart, 2020).\n\nTo visualize the data, users can select the ‘Plot’ tab. First, a reference condition should be selected. This is generally a control condition, e.g. an empty vector in a reporter assay. Without selecting a reference, the firefly/renilla ratio is plotted on the y-axis. If a reference condition is selected, normalized firefly/renilla values from the other conditions are represented as fold-change relative to the reference (Figure 4A). As an optional feature, the reference can be shown or hidden, depending on user preference.\n\n(A) Standard output plot produced by PlotXpress after selecting a reference condition. The plots show the fold change in expression induced by gene A and gene B relative to a reference, for each of 8 different conditions. Individual datapoints are shown and the median of each condition is indicated with a horizontal line. (B) A 90° rotated panel for one of the conditions (drug1 in neurons) shown in panel A. Rotation of the panel improves readability of the fold change and allows for the display of a cartoon of the reporter gene next to it.\n\nSeveral options are available to optimize the data visualization. The size and transparency of the datapoints can be adjusted, gridlines can be removed, summary statistics can be selected, and the font size and plot size can be changed. The plots can be downloaded from PlotXpress in PNG or PDF format, the latter being ideal for downstream processing with vector-based graphic software.\n\nPlotXpress also produces a table with summary statistics that can be found under the ‘Data Summary’ tab. It can be downloaded in multiple formats such as CSV or PDF.\n\n\nUse cases\n\nThe plotXpress app automatically loads an experimental dataset from a GloMax dual-luciferase reporter assay. This set contains 96 measurements acquired from different conditions. The conditions differ in the vector that is transfected (control, geneA or geneB), in the drug treatment (no drug, drug1, drug2 or drug1&drug2) and the cell type (Hek or neuron). Three measurements were done for each unique condition. The ‘control’ is set as a reference condition and the ‘geneA’ and ‘geneB’ condition are compared to the reference and their levels are expressed as ‘Fold Change’ (Figure 4A). The resulting data visualization can be used to compare the effect of geneA and geneB relative to the empty vector control and under different conditions. The display of the actual datapoints contributes to the transparency in the communication of the results.\n\nWhen presenting reporter expression data, it can be useful to display a rotated plot. Diagrams of reporter constructs can be included to visually support the experimental set up and show the corresponding measurements in line (Figure 4B).\n\nA summary of the data is available under the ‘Data Summary’ tab (Figure 5) and this table can be included as supplemental data in publications.\n\nTable containing summary statistics of the data shown in Figure 4A.\n\n\nConclusion\n\nGene reporter assays are an invaluable tool for molecular biology, enabling the study of regulatory DNA sequences, transcription factors, pharmaceutical compounds, oligonucleotides and other factors that interact with DNA sequences. With each treatment or cellular context, the assay increases in complexity. PlotXpress simplifies the data analysis by bridging the gap between wet-lab standards (96-well format) and dry-lab conventions (tidy data format) that are typically used in downstream analysis of experimental biological data.\n\nThe current version of plotXpress was written to analyze expression data in tidy format as well as for GloMax output data. The import of data produced by plate readers from other manufacturers is not supported at this moment, but we welcome suggestions and example data to implement import functions for other data formats. Since plotXpress is open-source, users can modify the source code by making a fork to the GitHub repository and create a pull request to have their changes reviewed and possibly integrated. Although plotXpress was developed for the analysis and visualization of dual-luciferase experiments, it can be used for other types of data that require normalization or comparison with a reference condition, such as quantitative polymerase chain reaction data.\n\nThe open-source web tool is freely accessible online, democratizing the state-of-the art data visualization of reporter assay data. Moreover, the standardized data processing will contribute to transparent and reproducible science.\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: ScienceParkStudyGroup/PlotXpress: v1.0.1 https://doi.org/10.5281/zenodo.5554885 (Goedhart and Galland, 2021).\n\nThis project contains the following files:\n\n- DualLuc_example_data.xlsx. Example data file\n\n- Tidy_design.csv. Example conditions file\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\nSoftware available from: https://huygens.science.uva.nl/PlotXpress/\n\nAlso available from: https://goedhart.shinyapps.io/PlotXpress/\n\nSource code available from: https://github.com/ScienceParkStudyGroup/PlotXpress/tree/v1.0.0\n\nArchived source code at time of publication: https://doi.org/10.5281/zenodo.5554885 (Goedhart and Galland, 2021)\n\nLicense: Apache License v2.0\n\n\nAuthor contributions\n\nE.B. initiated the project, contributed experimental data, wrote code and wrote the manuscript. M.G. supervised the project, wrote code, reviewed code and edited the manuscript. J.G. wrote code and edited the manuscript.",
"appendix": "Acknowledgements\n\nWe thank our colleagues at the Swammerdam Institute for Life Sciences, University of Amsterdam, for their interest and support. We thank Dr. F.M.J. Jacobs for providing resources and accommodation for this project. An earlier version of this article can be found on bioRxiv (https://doi.org/10.1101/2021.07.08.451595).\n\n\nReferences\n\nAsamitsu S, Yabuki Y, Ikenoshita S, et al.: CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome. Sci. Adv. 2021; 7: eabd9440. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBarriscale KA, O’Sullivan SA, McCarthy TV: A single secreted luciferase-based gene reporter assay. Anal. Biochem. 2014; 453: 44–49. PubMed Abstract | Publisher Full Text\n\nChengling L, Yulin Z, Xiaoyu X, et al.: miR-325-3p, a novel regulator of osteoclastogenesis in osteolysis of colorectal cancer through targeting S100A4. Mol. Med. 2021; 27: 23. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGoedhart J: SuperPlotsOfData – a web app for the transparent display and quantitative comparison of continuous data from discrete conditions. bioRxiv. 2020. 2020.09.01.276881. Publisher Full Text\n\nGoedhart J, Galland M: ScienceParkStudyGroup/PlotXpress: v1.0.1 (v1.0.1). Zenodo. 2021. Publisher Full Text\n\nHimes SR, Shannon MF: Assays for transcriptional activity based on the luciferase reporter gene. Methods Mol. Biol. 2000; 130: 165–174. Publisher Full Text\n\nLiu AMF, New DC, Lo RKH, et al.: Reporter gene assays. Methods Mol. Biol. 2009; 486: 109–123. Publisher Full Text\n\nLord SJ, Velle KB, Mullins RD, et al.: SuperPlots: Communicating reproducibility and variability in cell biology. J. Cell Biol. 2020; 219. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMoparthi L, Koch S: A uniform expression library for the exploration of FOX transcription factor biology. Differentiation. 2020; 115: 30–36. PubMed Abstract | Publisher Full Text\n\nPostma M, Goedhart J: PlotsOfData—A web app for visualizing data together with their summaries. PLOS Biol. 2019; 17: e3000202. Publisher Full Text\n\nRodriguez CM, Wright SE, Kearse MG, et al.: A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nat. Neurosci. 2020; 23: 386–397. Publisher Full Text | PubMed Abstract | Free Full Text\n\nSchenborn E, Groskreutz D: Reporter gene vectors and assays. Mol. Biotechnol. 1999; 13: 29–44. PubMed Abstract | Publisher Full Text\n\nWang D, Feng M, Ma X, et al.: Transcription factor SP1-induced microRNA-146b-3p facilitates the progression and metastasis of colorectal cancer via regulating FAM107A. Life Sci. 2021; 277: 119398. PubMed Abstract | Publisher Full Text\n\nWickham H: Tidy Data. J. Stat. Soft. 2014; 59. Publisher Full Text\n\nWickham H: ggplot2: Elegant Graphics for Data Analysis. Cham: Springer International Publishing: Imprint: Springer; 2nd ed.2016; 1 pp. 2016. Publisher Full Text\n\nWickham H, Averick M, Bryan J, et al.: Welcome to the Tidyverse. JOSS. 2019; 4: 1686. Publisher Full Text"
}
|
[
{
"id": "99324",
"date": "24 Nov 2021",
"name": "Lorena Pantano Rubino",
"expertise": [
"Reviewer Expertise Bioinformatics",
"R",
"shiny",
"visualization",
"gene regulation"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nPlotXpress is well explained and documented. It has a clear rational about the need and the solution it brings. Authors have developed the application following best practices. It has a good explanation on installation and usage. I have only a few minor comments that should be easily addressed:\nAdding the possibility to make the plots interactive could be helpful to evaluate replicates. For instance, if there is a bad replicate, hovering over the dots should make easy to know which one is the issue or needs further discussion.\n\nAdding information on the README on how to contribute, authors can look at bigger projects to mimic the best practices for this.\n\nFix the install line code in the README to render in the proper way.\n\nNot sure why the README contains the gadgets from shiny package, I don't think they are needed here since they point to the test for the shiny app, not this package.\n\nIs the rsconnect folder necessary in the repository?\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": "7724",
"date": "18 Jan 2022",
"name": "Joachim Goedhart",
"role": "Author Response",
"response": "We thank the reviewer for the evaluation of our work and appreciate the suggestions for further development of the tool. We have amended the Github page to address issues 4 & 5."
}
]
},
{
"id": "99317",
"date": "29 Nov 2021",
"name": "Guillaume Jacquemet",
"expertise": [
"Reviewer Expertise Cell biology"
],
"suggestion": "Approved",
"report": "Approved\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nIn this article, Brandorff et al. describe a tool to visualize and display reporter expression data. PlotXpress is very easy to use and appears to be well documented. I particularly like the visualization of the dataset using the 96 well-plate layout, which is very intuitive and will prove very useful when analyzing HTS datasets. Below I outline several points the authors could consider when developing their tool further in the hope they find them helpful.\nThe authors describe PlotXpress as a tool to visualize luciferase-based reporter expression data. Why being so restrictive? I can easily imagine that this tool can also be used to visualize any time of dataset acquired in a 96 well-format (drug screening, Elisa binding assays, etc.). This could be easily reflected in the title and throughout the manuscript.\nWhile the tool is already very powerful, I think the most significant factor that will limit its adoption is the data format required to import the dataset. Tidy CSV formats are painful to create in the best of time. If possible to implement, it would be great to be able to import multiple CSV files (where each file is an individual repeat). It would be helpful to provide example input files on the PlotXpress website directly.\nRegarding the data visualization, it may be useful to allow the users to know control what is displayed in the color-coded 96-well plate. I am assuming that the average signal is currently displayed in the plot by default. But showing the standard variation (or other parameters) could be equally valuable to identify conditions with high variability.\n\nRegarding the normalization options, It could be helpful to provide the possibility to normalize the data to the overall detected signal in the plate for each repeat. This can sometimes be more beneficial than normalization to CTRL wells alone. It would also be beneficial for the quantifications to compute the Z-score, which is often used for HTS analyses.\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": "7723",
"date": "18 Jan 2022",
"name": "Joachim Goedhart",
"role": "Author Response",
"response": "We thank the reviewer for the evaluation of our work and appreciate the suggestions for further development of the tool."
}
]
},
{
"id": "99321",
"date": "14 Dec 2021",
"name": "Vincent J. Lynch",
"expertise": [
"Reviewer Expertise Evolutionary 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\nPlotXpress is well explained and documented, and has a very user friendly web application. I see no need for revisions for other changes to either the method or the manuscript describing the results. This will be extremely useful for those using Luciferase assays and other methods that use a plate.\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": "7722",
"date": "18 Jan 2022",
"name": "Joachim Goedhart",
"role": "Author Response",
"response": "We thank the reviewer for the evaluation of our work and appreciate the positive comments."
}
]
}
] | 1
|
https://f1000research.com/articles/10-1125
|
https://f1000research.com/articles/10-1123/v1
|
08 Nov 21
|
{
"type": "Research Article",
"title": "The impact of virtual learning on Multimedia University student performance: a cross-sectional study",
"authors": [
"Tai Hen Toong",
"Lim Liyen",
"Liew Yee Ping",
"Lim Liyen",
"Liew Yee Ping"
],
"abstract": "Background: The Covid-19 pandemic has imposed adaption to virtual learning for students and educators across all levels of education in the world. The effectiveness of virtual learning varies amongst age groups. It has been suggested that the adoption of virtual learning will continue to be implemented even after pandemic, particularly in higher education. Therefore, it is crucial to validate the effectiveness of a virtual learning approach among university students to ensure a smooth transition from a conventional education model to a hybrid education model. Thus, this study aims to evaluate the impact of virtual learning on students’ performance in a virtual classroom. Methods: We analysed survey data collected from undergraduate students at Multimedia University, Malaysia. Convenience sampling and self-administered online surveys were used to understand the impact of virtual learning. Multiple regression analysis was performed using SPSS software Results: A total of 210 first and second year degree and diploma students responded to the online surveys. Factors affecting virtual learning were segregated into three categories: virtual teaching techniques, technology issues, and environment distraction. Respondents stated that the critical factor that affect the effectiveness of virtual learning and impacts on students’ performance was the virtual teaching techniques employed by educators. Conclusions: This study concluded that virtual teaching techniques have significant impact on students’ performance whereas technology issues and environment distraction do not significantly influence students’ performance during virtual learning. Although this study is limited to students from Multimedia University, it lays the groundwork for future research to involve students from other universities or other countries. A future study can address more factors that affect virtual learning and students’ performance, such as students’ attitude and motivation.",
"keywords": [
"Virtual Learning",
"Student Performance",
"Covid-19 Pandemic"
],
"content": "F1000 Research Statement of Endorsement\n\nAssoc. Prof. Dr. Ong Thian Song 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. Assoc. Prof. Dr. Ong Thian Song declares they have no competing interests. Affiliation: Multimedia University.\n\n\nIntroduction\n\nThe Coronavirus disease-2019 (Covid-19) pandemic has affected many industries and sectors in terms of their operation and management worldwide. One of the greatly affected sectors is education. Since March 2020, 80% of the world’s leaners have been kept out of educational institutions due to the pandemic.1 Educators and learners across all levels of education globally have therefore had to adapt to virtual learning during the pandemic. Transition from physical face-to-face classes to virtual remote learning has become new norm practice in many universities since the Covid-19 outbreak in Malaysia. It was reported that there are a total of 111 universities and colleges in Malaysia that were impacted significantly by the rapid spread of the Covid-19 virus since 2020.2 Education institutions inclusive of schools and universities shifted towards the use of technologies and online learning during the pandemic period.3 In Malaysia, 36.9% of students lacked access to online learning during the lockdown.4 In most of the universities, academics were urged to implement virtual classroom with synchronous online teaching and learning in conjunction with closure of campus since the announcement of the Movement Control Order of 2020 to curb the spread of Covid-19. A synchronous learning environment is defined as “structured in the sense that students attend live lectures, there are real-time interactions between educators and learners, and there is a possibility of instant feedback”.5 With synchronous online learning in a virtual classroom, student performance needs to be taken into consideration.\n\nIt has been suggested that adoption of virtual learning will continue to be implemented even after the pandemic particularly in higher education. There is a huge impact on universities towards virtual learning due to the abrupt and rapid conversion from the traditional classroom to a virtual learning environment in terms of the sustainability of the education model.6 With regards to virtual learning, many universities also proposed hybrid learning when students are allowed to return to universities. Hybrid learning is referred to as “blended learning which lends itself to individualized learning, collaboration via online discussions, and several modes of interacting with course content for different learning styles”.7 It is much more flexible and easier to incorporate and facilitate hybrid learning in a virtual learning environment. It is crucial to validate the effectiveness of a virtual learning approach among university students, to ensure a smooth transition from a conventional education model to online or hybrid education models.\n\nThe effectiveness of virtual learning with regards to students’ performance has not been explored among university students at our university, Multimedia University, in Malaysia. A prior study in public higher education institution in Portugal found that the implementation of virtual learning environments had imposed its influence on universities students’ performance. The study revealed that the higher frequency of access to virtual learning environment, students were more likely to pass the course.8 Several studies have explored the differences between face-to-face classroom and online or hybrid learning, and the results revealed that students performed better in online or hybrid learning as compared to traditional education.9–11 Thus, this paper aims to evaluate the impact of virtual learning towards students’ performance in a virtual classroom during the Covid-19 pandemic at our university.\n\nShifting from a traditional learning mode to virtual learning is not simple. There are a lot of factors that would bring a different impact or learning experience to the students. Based on the studies by Schmidt12 and Kebritchi,13 students’ learning experience is strongly impacted by the educators’ teaching style and the selection of online learning tools in their learning environment. Another study14 shows that educators’ personality or attitude is one of the factors that would affect students’ learning motivation. The study revealed that the educator’s personalities such as being an extrovert, sensing, thinking, feeling and judging perspective do affect students’ learning motivation and it shows both positive and negative effects on the students’ learning experience. Another previous study15 also studied the impact of personality traits towards the students’ online learning perceptions. The result shows that different personality traits do bring different impacts on students’ online learning perceptions. Educators’ self-knowledge in managing online learning tools plays an important role as well. Dubey and Singh16 and Yu17 have studied various factors on online teaching and found that young educators manage online education more actively and this may be due to self-technical knowledge or familiarity with online learning tools. Besides personality traits and self-knowledge, the educators’ voice and pitch are also considered as techniques in handling virtual classrooms, as they can be used a teaching tool to attract students’ attention during online learning.18 A study by Bhowmik and Bhattacharya19 has shown that educators’ personal factors such as immediate feedback, use of e-learning tools or trained well to handle online delivery highly influence students’ learning.\n\nDuring the pandemic, virtual learning became the main tool of education. Moving away from the traditional way of teaching and learning to virtual learning does provide flexibility, but it can also influence the students’ learning perception. Implementing virtual learning uses a wide range of ICT and technology-based teaching tools in teaching and learning. Previous research20–22 has demonstrated the influence of learning with technology in the learning process. Another finding shows that there is correlation between the usage of Web 2.0 tools such as blogs, social networking sites and digital games with students in terms of learning engagement.23 There are several studies being carried out on the ICT components that might affect the students’ learning experience such as uploading videos after the class, social media platforms such as YouTube or Facebook and usage of e-learning tools.24–26 However, in some rural areas, issues, such as lack of devices and internet connection, can be found. According to Kulal and Nayak,27 the increasing use of technology in online learning brings a positive impact to the students but it also emphasizes that lack of computers or mobile devices and network connection for rural students. It seems that even though educators have strong technical skills in utilizing the teaching-based technology, unstable internet connection remains the main concern.28\n\nMost studies are related to personality traits, technologies, usage of learning tools or lack of devices for learning, but there is another factor that brings impact to the students’ online learning process, which is environment distraction. Research on this factor is very limited compared to other factors. Several studies have been done in identifying what kind of distractions would influence students’ concentration in the class and they found that the students are easily distracted by the use of mobile devices such as cell phones.29,30 Another study researched what makes students get distracted in the first place during the learning process, and found that it can be external factors (e.g. baby crying, people arguing in the same space) or internal factors (e.g. thinking of something, checking social networking sites).31 Findings by Chhetri32 and Coman et al33 showed that there are distractions from surroundings or family members, which means it is hard to focus on learning. Another study by Realyvásquez-Vargas et al34 also found that environmental conditions such as lighting, noise and temperature impact students’ learning performance.\n\nA lot of aspects may determine student performance in the virtual classroom. As shown by previous studies,35,36 students show positive response to virtual learning in terms of communicating with educators and certain e-learning and game-based tools that involve interaction. As compared to physical classrooms, students have obtained better performance and scored higher grades through online learning.37 In Ref. 38 study, the students prefer online learning when they are given the option and the result shows a higher rate of students scoring better through online learning. In the study by Paul and Jefferson,32 it was found that lecture recordings from virtual classrooms are able to help students, especially if there are technical issues such as internet connection or surrounding distraction. Furthermore, there are several factors that have been identified such as feedback and online course design that might influence students’ performance during the online learning process.39\n\n\nMethods\n\nThis paper’s framework shows the relationship among independent variables (virtual teaching techniques, technology, and environment distraction) and dependent variable (students’ performance during virtual classroom). Our hypotheses are provided below:\n\n– Virtual teaching techniques positively affect students’ performance during virtual classroom.\n\n– Technology positively affects students’ performance during virtual classroom.\n\n– Environment distraction positively affects students’ performance during virtual classroom.\n\nThese three elements of independent variables and dependent variables might be able to construct a significant study for the higher education profession industry in Malaysia (Figure 1).\n\nStudy setting and participants\n\nThe study population were IT students at Multimedia University. Convenience sampling was applied for respondent selection. Respondents were chosen from first year and second year students from the Degree and Diploma program, Faculty of Science and Technology at the university. Sample size comprises of 210 respondents.\n\nResearch Ethical Clearance was obtained from the Technology Transfer Office at our university (reference number: EA0242021). During data collection period, all participants were informed about the study and objectives. Participant consent was taken by incorporating the consent form within the questionnaire; respondents were asked to complete the consent part of the questionnaire before continuing. Questionnaires without the consent part filled in were not included in the analysis.\n\nThe online questionnaire was issued to the respondents in August 2020 for data collection. The questionnaire was comprised of three sections: Section A, four questions concerning respondent’s demographic profile (age, gender, first year students and programme enrolled) using closed-ended questions; Section B, three statements about the student’s perception on remote learning performance in virtual classrooms using Likert scales; Section C, five statements on the factors that affect their performance in the virtual classroom using Likert scales. A copy of the questionnaire can be found in the Extended data.46\n\nIBM SPSS Statistic version 26 was used for data analysis. Statistical tests were as follows: Cronbach Alpha test, Pearson Correlation test and t-test. The standard level of significance was 5%, or stated as 0.05 in the p-value.\n\n\nResults\n\nA total of 210 surveys were circulated in Multimedia University Malaysia among respondents aged between 20 to 30 years old. There was a 100% response rate. The biggest age group was <20 years old (n = 136, 64.8%), followed by 20-25 year olds (n = 73, 34.8%) and 25-30 year olds (n = 1, 0.5%). A total of 84.3% (n = 177) were male and 15.7% (n = 33) were female. The majority of the students who took part in the questionnaire are not from first year study in university. A total of 118 students (56%) were in their second or third year.\n\nInternal consistency reliability was assessed using Cronbach’s Alpha. The reliability is shown by a number that ranges from 0 to 1; values closer to 1 reveal higher reliability. All variables must achieve a critical value of greater than 0.75 to reflect a good internal reliability of the data.40 Cronbach’s Alpha value for this questionnaire was 0.759, which is acceptable.\n\nThe three independent variables were tested for their relationship with students’ performance during virtual classroom. It was identified that there is a positive relationship between two variables (virtual teaching technique and technology), and there is a negative yet weak relationship between one variable (environment distraction). However, according to the result derived from Pearson correlation test (Table 1) demonstrates that TE – Technology has a weak correlation with the impact of virtual learning towards students’ performance, which give a value of 0.234. Moreover, a weak negative/inverse relationship was been shown between EN – Environment Distraction with students’ performance during virtual classroom.\n\nTo prepare variable has a strong relationship among dependent variables and independent variables, in this research the r value has to be provided with a value more than 0.5 according to Pearson correlation test. The highest correlated variable was virtual teaching techniques (Pearson’s Correlation = 0.431; p = 0.000), followed by technology (Pearson’s = 0.234; p = 0.001). Environment distraction showed a result of −0.073, a weak negative correlation with the impact of VT towards students’ performance during virtual classroom (p = 0.405). In sum, Pearson correlation analysis has demonstrated two variables are positively correlated with students’ performance during virtual classroom.\n\nTable 2 demonstrates the multiple regression analysis used to test all the variables. It was found that virtual teaching techniques has a positive significance relationship with student performance during virtual classroom (p < 0.05).\n\nGenerally, a higher coefficient indicates a better fit of the model. The bigger the coefficient of Beta value, the stronger the determinant. Based on Table 2, the result demonstrates that the virtual teaching technique (B = 0.557) is the strongest predictor for the students’ performance during virtual classroom. As such, H1 is accepted. In contrast, technology and environment distraction showed insignificant and negative relationships with the students’ performance during virtual classroom, with B = −0.029 and −0.082, respectively. Moreover, the result demonstrated a P value of 0.784 and 0.145, respectively, which resulted in H2 and H3 both being rejected.\n\n\nDiscussion\n\nThe research revealed that virtual teaching techniques have a notable impact on students’ performance in virtual classroom. In this regard, the response shows that lecturers’ teaching style, which incorporates collaborative learning and personalised learning during virtual learning, has an impact on their performance. In addition, students also believed that teaching techniques used by their lecturers to deliver the course lesson during virtual classroom positively affects their performance in the course. A previous study showed that if the teaching techniques are not matched with students’ learning techniques, it would impact on students’ academic performance.41 Similarly, another study revealed that there is an impact of lecturers’ teaching styles towards the students’ academic performance.42\n\nHowever, the survey results showed insignificant and negative relationship between technology and its impact towards students’ performance in the virtual classroom. It showed that students do not recognize the significance of technological tools in relation to their performance. They do not perceive the importance of game-based learning or gamification learning with regards to their performance in the virtual classroom. According to previous studies, education environment with gamification resulted in poorer academic performance of university students.43,44 The results of this study also indicated that environment distraction is negatively associated with the impact towards students’ performance in the virtual classroom. It showed that all students never consider the significance of background noise, like bird chirping, dog barking, building construction, road traffic and other distractions with regards to their performance in the virtual classroom. According to a previous study, loud noise during virtual learning can negatively affect students’ academic performance in a virtual classroom.45\n\n\nConclusions\n\nBased on the analysis, this study concluded that IT students from our university believed that virtual teaching techniques significantly affect their performance in terms of online learning during a virtual classroom. Students appreciated the patience and sense of humour of lecturers during virtual classroom, which has significant impact on their performance. On the other hand, this study also concluded that technology and environment distraction do not show a significant impact on student performance of online learning during a virtual classroom. This could be due to IT students being already familiar with the usage of technological tools before the implementation of virtual learning and therefore the impact of technology applied during virtual classroom is not significant on their performance. Most of the IT students used a headset during the virtual classroom and that could be the reason that environment distraction does not significantly contribute to their performance of virtual learning. This study suggests that the lecturer applies an effective teaching style in virtual learning to improve students’ performance during the virtual classroom.\n\nThis study provides the groundwork for future research to involve students from other universities or other countries. Moreover, future study can address the impact of other factors which affect virtual learning and students’ performance such as students’ attitude and motivation. Future research can consider studying the significant difference between first year and non-first year students on factors affecting students’ performance in the virtual classroom.\n\n\nData availability\n\nFigshare: An Empirical Study on the Impact of Virtual Learning on Multimedia University Student Performance.csv, https://doi.org/10.6084/m9.figshare.14872782.v4.46\n\nFigshare: An Empirical Study on the Impact of Virtual Learning on Multimedia University Student Performance.csv, https://doi.org/10.6084/m9.figshare.14872782.v4.46\n\nData are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).",
"appendix": "References\n\nMcCarthy N: Covid-19’s Staggering Impact on Global Education. World Economic Forum; 2020. Reference Source\n\nStudy Malaysia: List of Universities in Malaysia. Study Malaysia.com.2020. Reference Source\n\nBridge S: Opinion: How Edtech Will Keep Our Students on Track During Covid-19. Arabian business.com.2020. Reference Source\n\nChan D, Karim KN, Yusof TA: Almost 40pct of Students Can’t Study at Home as They Lack Electronic Devices. New Straits Times. 2020. Reference Source\n\nDhawan S: Online Learning: A Panacea in the Time of Covid-19 Crisis. J. Educ. Technol. Syst. 2020; 49(1): 5–22. Publisher Full Text\n\nMartín CT, Acal C, Honrani ME, et al.: Impact on the virtual learning environment due to COVID-19. Sustainability. 2021; 13(2): 582. Publisher Full Text\n\nBuckle J: What Will Return to School Look Like This Fall? A Look Inside Hybrid Learning Plans.2020. Reference Source\n\nAlves P, Miranda L, Morais C: The Influence of Virtual Learning Environments in Students’ Performance. Univ. J. Educ. Res. 2017; 5(3): 517–527. Publisher Full Text\n\nLockman AS, Schirmer BR: Online instruction in higher education: Promising, research-based, and evidence-based practices. J. Educ. e-Learning Res. 2020; 7(2): 130–152. Publisher Full Text\n\nPei L, Wu H: Does online learning work better than offline learning in undergraduate medical education? A systematic review and meta-analysis. Med. Educ. Online. 2019; 24(1): 1666538. PubMed Abstract | Publisher Full Text | Free Full Text\n\nGonzález-Gómez D, Jeong JS, Rodríguez DA: Performance and perception in the flipped learning model: An initial approach to evaluate the effectiveness of a new teaching methodology in a general science classroom. J. Sci. Educ. Technol. 2016; 25(3): 450–459. Publisher Full Text\n\nSchmidt K: A Model to Integrate Online Teaching and Learning Tools into the Classroom. J. Technol. Stud. 2004; 30(2): 86–92. Publisher Full Text\n\nKebritchi M: Preferred teaching methods in online courses: Learners' views. J. Online Learn. Teach. 2014; 10(3): 468.\n\nSudarsi ET, Hamra A, Mahmud M: The Effects of Lecturers’ Personality on Students’ Learning Motivation. ELT Worldwide: Journal of English Language Teaching. 2016; 3(2): 188–203.\n\nBhagat KK, Wu LY, Chang CY: The impact of personality on students' perceptions towards online learning. Australas. J. Educ. Technol. 2019; 35(4). Publisher Full Text\n\nDubey DB, Singh DS: Perception of teachers on online teaching in higher education during covid-19 lockdown. Int. J. Creat. Res. Thoughts 2020; 8(5): 1017–1022.\n\nYu Z: The effects of gender, educational level, and personality on online learning outcomes during the COVID-19 pandemic. Int. J. Educ. Technol. High. Educ. 2021; 18(1): 1–17. Publisher Full Text\n\nMahmood S: Instructional strategies for online teaching in COVID-19 pandemic. Hum. Behav. Emerg. Technol. 2021; 3(1): 199–203. Publisher Full Text\n\nBhowmik S, Bhattacharya MD: Factors Influencing Online Learning in Higher Education in the Emergency Shifts of Covid 19. The Online Journal of Distance Education and e-Learning. 2021; 9(1).\n\nMashhadi VZ, Kargozari MR: Influences of digital classrooms on education. Procedia Comput. Sci. 2011; 3: 1178–1183. Publisher Full Text\n\nCarbonilla GV, Bhati SS: Students' perception on use of technology in the classroom at higher education institutions in Philippines. Asian Journal of Education and e-Learning. 2016; 4(3): 92–103.\n\nRaja R, Nagasubramani PC: Impact of modern technology in education. J. App. Adv. Res. 2018; 3(1): S33–S35. Publisher Full Text\n\nSchindler LA, Burkholder GJ, Morad OA, et al.: Computer-based technology and student engagement: a critical review of the literature. Int. J. Educ. Technol. High. Educ. 2017; 14(1): 1–28. Publisher Full Text\n\nComan C, Țîru LG, Meseșan-Schmitz L, et al.: Online Teaching and Learning in Higher Education during the Coronavirus Pandemic: Students’ Perspective. Sustainability. 2020; 12(24): 10367. Publisher Full Text\n\nVan Wart M, Ni A, Medina P, et al.: Integrating students’ perspectives about online learning: a hierarchy of factors. Int. J. Educ. Technol. High. Educ. 2020; 17(1): 1–22.\n\nMishra L, Gupta T, Shree A: Online teaching-learning in higher education during lockdown period of COVID-19 pandemic. Int. J. Educa. Res. Open. 2020; 1: 100012. Publisher Full Text\n\nKulal A, Nayak A: A study on perception of teachers and students toward online classes in Dakshina Kannada and Udupi District. Asian Assoc. Open. Univ. J. 2020; 15: 285–296. Publisher Full Text\n\nJunus K, Santoso HB, Putra POH, et al.: Lecturer Readiness for Online Classes during the Pandemic: A Survey Research. Educ. Sci. 2021; 11(3): 139. Publisher Full Text\n\nAttia NA, Baig L, Marzouk YI, et al.: The potential effect of technology and distractions on undergraduate students’ concentration. Pak. J. Med. Sci. 2017; 33(4): 860–865. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKay R, Benzimra D, Li J: Exploring factors that influence technology-based distractions in bring your own device classrooms. J. Educ. Comput. Res. 2017; 55(7): 974–995. Publisher Full Text\n\nSchmidt SJ: Distracted learning: Big problem and golden opportunity. Journal of Food Science Education. 2020; 19(4): 278–291. Publisher Full Text\n\nChhetri C: “I Lost Track of Things” Student Experiences of Remote Learning in the Covid-19 Pandemic. Proceedings of the 21st Annual Conference on Information Technology Education. 2020, October; 314–319.\n\nComan C, Țîru LG, Meseșan-Schmitz L, et al.: Online Teaching and Learning in Higher Education during the Coronavirus Pandemic: Students’ Perspective. Sustainability. 2020; 12(24): 10367. Publisher Full Text\n\nRealyvásquez-Vargas A, Maldonado-Macías AA, Arredondo-Soto KC, et al.: The impact of environmental factors on academic performance of university students taking online classes during the COVID-19 Pandemic in Mexico. Sustainability. 2020; 12(21): 9194. Publisher Full Text\n\nParker MA, Martin F: Synchronous virtual classrooms: Student perceptions from an online and blended education course. International Conference on Technology for Education. 2010; 93–100. Publisher Full Text\n\nFalloon G: Inside the virtual classroom: Student perspectives on affordances and limitations. Journal of Open Flexible and Distance Learning. 2012; 16(1): 108–126.\n\nBaig MA: A Critical Study of Effectiveness of Online Learning on Students' Achievement. J. Educ. Technol. 2011; 7(4): 28–34. Publisher Full Text\n\nPaul J, Jefferson F: A comparative analysis of student performance in an online vs. face-to-face environmental science course from 2009 to 2016. Front. Comp. Sci. 2019; 1: 7. Publisher Full Text\n\nGopal R, Singh V, Aggarwal A: Impact of online classes on the satisfaction and performance of students during the pandemic period of COVID 19. Educ. Inf. Technol. 2021; 1–25.\n\nSekaran U, Bougie R: Research Methods for Business: A Skill-Building Approach. New York: John Wiley and Sons Inc.; 5th ed2009.\n\nBaharudin AF, Sahabudin NA, Kamaludin A: Behavioral Tracking in E-Learning by Using Learning Styles Approach. Indonesian Journal of Electrical Engineering and Computer Science. 2017; 8(1): 17–26. Publisher Full Text\n\nChetty NDS, Handayani L, Sahabudin NA, et al.: Learning styles and teaching styles determine students’ academic performances. Int. J. Evalua. Res. Educ. 2019; 8(3): 610–615. Publisher Full Text\n\nDe-Marcos L, Domínguez A, Saenz-de-Navarrete J, et al.: An empirical study comparing gamification and social networking on e-learning. Comput. Educ. 2014; 75: 82–91. Publisher Full Text\n\nHanus MD, Fox J: Assessing the effects of gamification in the classroom: A longitudinal study on intrinsic motivation, social comparison, satisfaction, effort, and academic performance. Comput. Educ. 2015; 80: 152–161. Publisher Full Text\n\nZhong L, Yuan J, Fleck B: Indoor environmental quality evaluation of lecture classrooms in an institutional building in a cold climate. Sustainability. 2019; 11: 6591. Publisher Full Text\n\nTai HT, Liyen L, Ping LY: An Empirical Study on the Impact of Virtual Learning on Multimedia University Student Performance.csv. figshare. Dataset. 2021. Publisher Full Text"
}
|
[
{
"id": "101024",
"date": "05 Jan 2022",
"name": "Francis Chuah",
"expertise": [
"Reviewer Expertise Virtual learning",
"statistical 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 study examines the impact of the virtual learning approach on Multimedia University students’ performance. A total of 210 first- and second-year degree and diploma students participated in the survey. I would like to congratulate the authors for the accomplishment of the study as well as the submission of the manuscript for publication in the F1000Research journal. While the manuscript is well written, I would like the authors to consider the following suggestions:\nI would recommend including a few more descriptive statistics information into the manuscript, i.e. assessment of normality and measures of distribution, and measures of central tendency so readers will have a clear view of the nature of the data for each variable.\n\nBoth H2 and H3 show an insignificant relationship with the outcome variables, but in the discussion, the authors discuss the sign of the relationship as if the relationship is significant and negative. Why is that so? Statistically, it should be concluded that both technology and environmental distraction does not affect student performance in the classroom.\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": "122907",
"date": "22 Feb 2022",
"name": "Adrian A. Adascalitei",
"expertise": [
"Reviewer Expertise Blended Teaching and Learning (Virtual 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 Research Paper about the impact of virtual learning on Multimedia University student performance, is well realized. The paper evaluates the impact of virtual learning towards students’ performance in a virtual classroom.\nFactors affecting virtual learning were analysed and were segregated into three categories: virtual teaching techniques; technology issues; and environment distraction. Collaborative learning and personalised learning during virtual learning are essential. It is much more flexible and easier to incorporate and facilitate hybrid learning in a virtual learning environment.\nI congratulate the authors for the accomplishment of the study as well as the publication in the F1000Research journal.\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/10-1123
|
https://f1000research.com/articles/10-1122/v1
|
08 Nov 21
|
{
"type": "Research Article",
"title": "Driver perceptions of advanced driver assistance systems: A case study",
"authors": [
"Siti Fatimah Abdul Razak",
"Sumendra Yogarayan",
"Afizan Azman",
"Mohd Fikri Azli Abdullah",
"Anang Hudaya Muhamad Amin",
"Mazrah Salleh",
"Sumendra Yogarayan",
"Afizan Azman",
"Mohd Fikri Azli Abdullah",
"Anang Hudaya Muhamad Amin",
"Mazrah Salleh"
],
"abstract": "Background: Automobile manufacturers need to have an insight and understand how consumers, specifically drivers, respond to the advanced driver assistance systems (ADAS) technology in their manufactured vehicles. This study reveals drivers’ perceptions of Malaysia’s advanced driver assistance systems, which is currently lacking in the literature. So far, other studies have focused on countries that are unlike Malaysia’s multi-culture environment. Methods: A survey was designed and distributed using convenience sampling to obtain responses from licensed drivers. Questions included demographic and driving questions, the perceptions of benefits and obstacles relevant to ADAS use, vehicle decision-making, and technology use. Data were collected from 818 respondents who were licensed drivers in Malaysia. Results were then analysed using statistical approaches. Results: The findings indicated that 76.8% of drivers have a positive attitude towards ADAS technology, particularly safety applications when they are available. Regardless of the accuracy of these systems, acceptance of the technology may shift upon viewing or hearing messages of possible problems with ADAS. Conclusions: It can be concluded that the safety advantages of ADAS technology are less valued by drivers who do not have experience of road traffic accidents. Furthermore, acceptance of the technology could be undermined by assuming that the safety applications could be compromised.",
"keywords": [
"safety applications",
"road safety",
"collision avoidance",
"ADAS",
"driver perceptions",
"vehicle technology"
],
"content": "Introduction\n\nRoad safety is a collective responsibility involving public and private corporations and civil society1. In recent years, automobile manufacturers have provided in-vehicle or pre-installed Advanced Driver Assistance Systems (ADAS) and parking control2 to support three types of driving tasks: navigation, manoeuvring, and vehicle stabilisation. These systems were typically developed for the global market without considering cultural differentiation, influencing drivers’ attitudes and acceptance3. The perception of new technology will naturally vary depending on locality, and it is primarily dictated by individual-level factors such as age, experience and knowledge of the technology4. Hence, it is crucial to evaluate the response of individuals from specific cultural backgrounds5. To the best of our knowledge, a study to better understand Malaysian licensed driver’s general acceptance of ADAS technology has yet to be carried out. The technology currently being offered is vehicle-resident systems, and we believe the knowledge gap regarding these systems is worth filling.\n\nHence, this paper reports a survey to assess whether drivers are willing to adopt and use ADAS technology. Our specific objectives were to explore the perceived importance and benefits associated with the technology and the influence of driving behaviour on the willingness of drivers to adopt the technology.\n\n\nMethods\n\nIn this study, we invited 1000 individuals to participate as respondents using convenience sampling, a non-probability sampling often associated with this type of study. The authors of this survey, who met the eligibility criteria, were excluded as potential participants.\n\nThe survey was accessible to the respondent who received an email invitation. We contacted individuals with email addresses who might contribute to our survey. Participants and colleagues were encouraged to recommend additional potential survey participants. The survey was not promoted online.\n\nThe survey was administered by inviting respondents to fill out an online survey investigating their opinions about transportation and ADAS technology. A link to the Google Form survey was included in the invitation emails. Invitations were sent out for a duration of one month, starting 20th March 2020. Respondents were encouraged to provide feedback in a single session to avoid distractions. After three days, respondents who had not responded were sent a reminder email. A second reminder was sent if no response was received within seven days. If no response was received, the respondent was deemed disinterested. Responses could be modified before submission but respondents could not re-enter the form using the same email address after it was submitted. There were no incentives offered to respondents for completing the survey.\n\nThe survey instrument was adapted from 6 to tap factors affecting acceptance of ADAS technology. The survey instrument was designed to assess the acceptance rate of Malaysian licensed drivers towards ADAS technology.\n\nThe participants had to answer 20 closed-ended or rating-scale questions. The questions were divided into three sections: Section A, Section B, and Section C. First, respondents answered demographic and driving-related questions. Next, respondents were asked about their views of the advantages and challenges of utilising ADAS technology. Finally, respondents were queried on vehicle decision-making and technology use. To prevent distractions and higher turnover, they were also encouraged to keep survey sessions to 20 minutes or less. Respondents who rated three or higher for rating-based questions were classified as “ADAS accepters.”\n\nThis case study was not intended to make statistical inferences concerning the wider population. Respondents who were Malaysian licensed drivers had higher merit than others. The underlying data from this study is accessible from Abdul Razak et al.,7. We used descriptive statistics to analyse the ratings given by the respondents on each item. Microsoft Excel (Microsoft Excel, RRID: SCR_016137) was used for this purpose.\n\nThe Technology Transfer Office of the Multimedia University ethically approved this research. (Approval Number: EA0562021). In the invitation email, the survey participants were informed that (i) any information given was voluntary; (ii) the researchers were not accountable or responsible for any loss arising from the use of the information provided; (iii) the survey was expected to take 20 minutes; (iv) any identifying information acquired in connection with this survey would remain confidential; and (v) the findings may be submitted for publication, and the anonymised dataset would be made publicly available in a data repository. The original dataset was password-protected in a Google Drive folder.\n\nReporting Qualitative Research (SPQR)8 were adhered to to report the survey outcomes.\n\n\nResults\n\nOut of the invited 1000 individuals, 81.80% completed the survey. Out of these respondents, 92.42% were licensed drivers. The majority of respondents were 18 to 25 years old, including newly licenced drivers, students, and employees. For daily tasks or routines, these responders usually drove their own or a family member’s vehicle. The least represented group was those in the 55 years old and above range. About 45% of the respondents were adults in the 26 years and above age range. The distribution of male and female respondents was almost similar, marginally favouring males (Table 1). Over half of the respondents resided in urban and suburban areas.\n\nWe found that 10% of respondents had not driven since receiving their driving licence. Hence their driving behaviour was not analysed. Of those who drove, 50% resided in urban areas, 54.44% of respondents reported travelling less than 400 km daily for different reasons, while 44% claimed involvement in accidents previously (Table 2). However, of those involved in accidents, 58.49% were only involved in minor accidents.\n\nThe impact of the accident was further investigated. We asked if the accident caused major or minor damage to the vehicle involved and if the driver or passenger required medical attention. It could also have been a combination of any of these three factors. The respondents stated that 23.62% experienced major damage, which cost them more than RM1000 to repair their vehicles, whereas 53.27% were involved in minor accidents. Around 9% of the respondents were involved in more than one accident, which resulted in experiencing more than one of the factors mentioned earlier.\n\nRespondents were categorised as non-accepters, fence-sitters, and accepters based on their responses to a willingness to have in-vehicle systems providing driving assistance. Almost 82% of respondents were receptive to the technology (accepters), while 16.99% of respondents were non-receptive. Only 1.03% were fence-sitters. The accepters were younger drivers who were more receptive to new technology (see Table 3). Nevertheless, older drivers who had been involved in accidents previously were also receptive to the technology. Non-accepters required more information on the benefits of the technology and had a wait-and-see attitude before accepting the technology.\n\nAcc.=Yes: respondents who have experienced accidents\n\nAcc.=No: respondents who have never been in accidents\n\nRespondents were further requested to rate safety applications, which they perceived as crucial for their driving experience in terms of convenience, economy, and safety. This included self-driving systems, lane changing, automated braking, and collision avoidance, signal timing, or blind spot occupancy, as well as real-time information related to routes, congestion, and incidents as part of their driving experience. Figure 1 illustrates the importance, rated as extremely important, very important, moderately important, slightly important, and not important.\n\nOf the respondents, 82.7% favoured having Advanced Driver Assistance Systems, which can assist driving. Nevertheless, 48.9% of the respondents would like to wait until the technology has been thoroughly tested and checked before using Advanced Driver Assistance Systems. They would also be more confident about embracing the technology if they could see their associates, i.e., people they know using it. A total of 18.9% also tended to wait until the latest product excitement had subsided before the technology was purchased and used. However, almost a quarter (24.3%) of the respondents preferred to be the first to buy and try the new technology. About 7.8% of the respondents were not sure of their purchasing decision behaviour. This may be attributed to influence from family members, where 68.7% of the respondents indicated that family members influence their vehicle purchasing decision. However, 76.8% of the respondents would be willing to use the technology if it was pre-installed by the vehicle manufacturers. The remaining respondents would either ignore, disable, or remove the technology from the vehicle. About half of the respondents were willing to add Advanced Driver Assistance Systems to their vehicles if the cost was less than RM400.\n\nThe respondents’ concerns and perceived benefits relating to the implementation of ADAS technology in personal vehicles can be categorised into three groups: driver behaviour, security or safety, technology implementation.\n\nDriver behaviour relates to how the respondents react as drivers and how other drivers react. Of the respondents, 55% feared that over-reliance on technology or other diversions might make drivers less attentive. Drivers frequently depend on technology too much and don’t practice safe driving (e.g., maintain a safe distance from other vehicles). A total of 30% of respondents were worried about vehicle data security breaches allowing illegal activities and affecting their driving habits. Moreover, the electromagnetic activity of communication devices, such as those in the system, may endanger drivers’ health. Nevertheless, 15% of respondents were eager to adopt ADAS technology for a safer driving experience.\n\n\nDiscussion\n\nGenerally, consumer perceptions vary depending on age, experience, and technology knowledge4. Our results complement the findings of earlier studies where drivers acceptance of ADAS technology was the main focus but different populations and cultures were examined such as the Czech Republic9, Finland10 and Indonesia11. This research found that 76.8% of drivers favoured ADAS technology, especially safety applications. This is higher than a similar study among Czech drivers, which reported that ADAS technology was desired by at least 50 % of the respondents9. However, the majority were only ready to utilise the technology when it was available and free. Individual variables like experience may also affect drivers’ adoption of the technology. This is supported by our analysis that found that ADAS technology’s safety advantages are less valued by drivers who do not experience road traffic accidents. However, 44% of drivers who have never been in an accident could be the future technology acceptors.\n\nThe study that investigated Finnish drivers focused on drivers who drive regularly and have purchased new cars with adaptive cruise control (ACC) and lane keeping assist (LKA). Another study among Jakarta drivers focused on drivers acceptance of the forward collision warning and lane departure warning11. However, this research looked at drivers’ acceptance of ADAS technology in general, dividing them into three categories: acceptors, fence-sitters, and non-acceptors. Most drivers are unaware that the technology is available in recent vehicle models. Thus, their contribution is unaffected by their present technology usage.\n\nMoreover, to enhance the perceived self-risk and the importance of safety applications, communications with this group of drivers should discuss the prevalence of accidents. This group of drivers may respond to messages about the costs of even minor accidents. The advantages of using safety technology should be highlighted, including saving lives and avoiding serious injury. Regardless of the accuracy of these results, acceptance of the technology may shift upon viewing or hearing messages of possible problems with ADAS technology. Hence, the realistic goal for automotive manufacturers is to reach the majority of Malaysian drivers and thereby stimulate the development of ADAS technology to reduce the likelihood of road traffic accidents.\n\nCommunication strategies are often designed to overcome potential challenges. For instance, safety and security issues were reported by 33% percent of the respondents as very important. The respondents may think that the safety applications could be compromised, and related agencies should educate drivers about misconceptions with fact sheets, by using videos and exchanging expert opinions. Evidence and anecdotes from victims of traffic accidents or early technology users are also likely to be helpful.\n\nMost participants in the survey (76.8%) mentioned they would use the safety application system or ADAS technology in a purchased or leased vehicle. Presumably, if the systems were introduced in fleets such as taxis, e-hailing services, and rental cars, the systems would likely be more common, giving consumers a chance to embrace technology.\n\nTo summarise, the research investigated Malaysian drivers’ expectations concerning ADAS technology. Those who have never been in a road accident may be less interested in the ADAS technology’s safety benefits. It is feasible to anticipate the market’s future by analysing driver acceptance of ADAS technology, particularly in countries with comparable cultural variety to Malaysia. Thus, ADAS technology should be assessed often to determine which systems have the most potential to improve driver safety.\n\n\nConclusions\n\nThis paper aimed to fill a gap in the literature by examining drivers’ views of Advanced Driver Assistance Systems (ADAS) in Malaysia. Prior research has concentrated on countries that are not comparable to Malaysia’s multi-cultural context. Driver acceptance of ADAS technology is gradual because there are limited interactions or connectivity between systems functionalities and drivers via human-machine interface in the vehicle context. Thus, if ADAS technology aims to improve driver’s safety, much research remains to be done.\n\n\nData availability\n\nZenodo: Underlying data for ‘Driver perceptions on Advanced Driver Assistance Systems: A case study’, https://doi.org/10.5281/zenodo.55472227\n\nThis project contains the following underlying data:\n\ni. V2V safety technology survey (responses).xlsx\n\nii. V2V safety technology survey (processed).xlsx\n\niii. V2V safety technology survey_GoogleForm.pdf\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 participants’ details was obtained from the participants.",
"appendix": "Author contributions\n\n\n\nS.F.A.R., S.Y., A.A., M.F.A.A., A.H.M.A, and M.S. comprehended the idea and contributed to the research article. All authors contributed to the writing, editing, and consent of the final manuscript.\n\n\nAcknowledgements\n\nThe authors would like to thank everyone who has directly or indirectly contributed towards this research. We thank the anonymous reviewers for their constructive comments.\n\n\nReferences\n\nEusofe Z, Evdorides H: Assessment of road safety management at institutional level in Malaysia: A case study. IATSS research. 2017; 41(4): 172–181. Publisher Full Text\n\nHaboucha CJ, Ishaq R, Shiftan Y: User preferences regarding autonomous vehicles. Transport Res C-Emer. 2017; 78: 37–49. Publisher Full Text\n\nLarge DR, Burnett G, Mohd-Hasni Y: Capturing cultural differences between UK and Malaysian drivers to inform the design of in-vehicle navigation systems. Int J Auto Eng. 2017; 8(3): 112–119. Publisher Full Text\n\nMoody J, Bailey N, Zhao J: Public perceptions of autonomous vehicle safety: An international comparison. Safety Sci. 2020; 121: 634–650. Publisher Full Text\n\nKassim KA, Nasruddin MA, Jawi ZM: Assessing the Public Opinion on Autonomous Vehicles in Malaysia. J Soc Auto Malay. 2019; 3(2). Reference Source\n\nLevine E, Brennan E, Garfield K, et al.: Vehicle-to-Vehicle crash avoidance technology: public acceptance final report. (No. FHWA-JPO-17-491). 2015. Reference Source\n\nAbdul Razak SF, Yogarayan S, Azman A, et al.: Driver Perceptions on Advanced Drive Assistance Systems. [Data set]. Zenodo. 2021. http://www.doi.org/10.5281/zenodo.5547222\n\nO’Brien BC, Harris IB, Beckman TJ, et al.: Standards for reporting qualitative research. Acad Med. 2014; 89(9): 1245–51. Publisher Full Text\n\nViktorova L, Sucha M: Drivers’ acceptance of advanced driver assistance systems- what to consider? International Journal of Traffic and Transport Engineering. 2018; 8(3): 320–333. Publisher Full Text\n\nPentinnen M, Louma J: Acceptance and use of ADAS. Proceedings of TRA2020, the 8th Transport Research Arena. 2020; 1–10. Reference Source\n\nZaki A, Suzianti A, Ardi R: Assessing Driver Acceptance of Jakarta Community Towards FCW and LDW. 2019 4th International Conference on Intelligent Transportation Engineering (ICITE). 2019; 109–114. Publisher Full Text"
}
|
[
{
"id": "164618",
"date": "27 May 2024",
"name": "Elmer R. Magsino",
"expertise": [
"Reviewer Expertise Vehicular Communications",
"Machine Learning",
"Control Engineering"
],
"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 general, the submitted manuscript for journal publication is weak in content, presentation, analysis of data, and literature review, basically, all the major components of an accepted journal paper. They should have instead presented this in a conference and later on extend it with many and useful information. It would be better not to focus on Malaysians only even though here have been Czech and Finland papers already. ADAS technology is common and developed by car manufacturers around the world. This means that the respondents should have tried the available ADAS systems instead of just answering survey questions.\n\nIn your background, the focus is about the Malaysian driving attitude. It is true that literatures about the Malaysian perception is lacking and given this context, we can enumerate various and many countries that do not have studies related to this topic also. Thus, this should not be a background because this is too much specific and focused. Any findings cannot be incorporated to ADAS studies that do not include Malaysian people.\n\nIn the Results section, 76.8% have a positive attitude towards ADAS safety applications. However, in the Conclusions section, you mentioned that ADAS safety advantages are less valued by drivers who have not experienced accidents. Aren't these two contradicting or lacking in discussion?\n\nIn the introduction section, you focused on the study about Malaysian perception about ADAS. It would be better also as a background to study other papers focusing on a certain culture or nationality and compare their results with yours. In Malaysia, driving is on the left side with a right hand drive, right? You might want to compare your study to nations with at least the same condition.\n\nAlso, is the claim here using Malaysian-manufactured vehicles? It seems not, therefore, do you mean to say that the manufacturers will adjust their vehicles just to accommodate the results here? Does it also imply that there is an ADAS technology solely for Malaysians?\n\nThe introduction does not present the problem clearly. What are the behaviors of Malaysians compared to other nationalities? What are their styles? What vehicles with ADAS technology are already adopted in Malaysia? There are many questions that should have been presented and not simply focus that since your study is done in Malaysia. If so, then all localized studies should be considered novel already and must be applied to a localized ADAS technology. I find this inappropriate.\n\nAbout the 1000 individuals, why aren't there demographics about them? age? driving experience? vehicles driven? etc. I don't find your recruitment credible. There is Table 1 for the demographics but it does not sum to 1000. So, basically, is there a possibility that you chose an individual that should not be part of the study? This is confirmed that 92.42% were licensed drivers. This is not acceptable. Why are there participants who are not allowed to drive in the first place? I am looking for appropriate descriptions here.\n\nAlso, what part of ADAS technology has been presented to the participants? It seems that you just told the ADAS technology story. Would it be better to allow them to try driving a vehicle with the said ADAS technology?\n\nWhat does \"Driving Behaviour\" mean? How did you analyze it? It is only based on accidents? But, accidents can be categorized into many types. Why did you categorize it in terms of residential area? This implies that an urban accident is different from suburban accident even if both accidents were minor ones or major ones? I do not understand the location category.\n\nYou did not also discuss clearly what driving behaviour means.\n\nIn the acceptance section, you did not even mention what the participants are about to accept. What are in-vehicle systems, by the way?\n\nYour section titles are confusing and lack substance. You have to really do well in revising your work and presentation of ideas.\n\nThe references are too few. Also, these references are not Malaysian-based works. So, there is a contradiction in the presentation of the study and the use of such references.\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": []
}
] | 1
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https://f1000research.com/articles/10-1122
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https://f1000research.com/articles/9-623/v1
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17 Jun 20
|
{
"type": "Research Article",
"title": "Including a pen and/or cover letter, containing social incentive text, had no effect on questionnaire response rate: a factorial randomised controlled Study within a Trial",
"authors": [
"Sophie James",
"Adwoa Parker",
"Sarah Cockayne",
"Sara Rodgers",
"Caroline Fairhurst",
"David J. Torgerson",
"Sarah Rhodes",
"Sarah Cotterill",
"Adwoa Parker",
"Sarah Cockayne",
"Sara Rodgers",
"Caroline Fairhurst",
"David J. Torgerson",
"Sarah Rhodes",
"Sarah Cotterill"
],
"abstract": "Background: Postal questionnaires are frequently used in randomised controlled trials to collect outcome data on participants; however, poor response can introduce bias, affect generalisability and validity, and reduce statistical power. The objective of this study was to assess whether a pen and/or social incentive text cover letter sent with a postal follow-up questionnaire increased response rates in a trial. Method: A two-by-two factorial randomised controlled trial was embedded within the OTIS host trial. Participants due their 12-month (final) follow-up questionnaire were randomised to be sent: a pen; a social incentive text cover letter; both; or neither. The primary outcome measure was the proportion of participants in each group who returned the questionnaire. Secondary outcomes were: time to return, completeness of the questionnaire, necessity of a reminder letter, and the cost effectiveness. Results: The overall 12-month questionnaire response rate was 721 out of 755 (95.5%). Neither the pen nor social incentive cover letter had a statistically significant effect on response rate: pen 95.2% vs. no pen 95.8%, adjusted OR 0.90 (95% CI 0.45 to 1.80; p=0.77); social incentive cover letter 95.2% vs. no social incentive cover letter 95.8%, adjusted OR 0.84 (95% CI 0.42 to 1.69, p=0.63). No statistically significant differences were observed between either of the intervention groups on time to response, need for a reminder or completeness. Therefore, neither intervention was cost-effective. Conclusions: We found no evidence of a difference in response rates associated with the inclusion of a pen and/or social incentive cover letter with the final follow-up postal questionnaire of the host trial. However, when these results are combined with previous SWATs, the meta-analysis evidence remains that including a pen increases response rates. The social incentive cover letter warrants further investigation to determine effectiveness.\nTrial registration: ISRCTN22202133 (21st June 2020).",
"keywords": [
"Retention",
"pen",
"social incentive",
"cover letter",
"randomised controlled trial",
"embedded trial",
"SWAT",
"postal questionnaire",
"response rate"
],
"content": "Introduction\n\nRandomised controlled trials (RCTs) are the gold standard to assess effectiveness of treatment options and to inform care decisions1, yet only a few hundred studies exist to assess the effectiveness of different methods to improve retention or recruitment into RCTs2.\n\nTrial methodologists and funders have highlighted the need to evaluate participant recruitment and retention strategies in order to provide evidence on which to base decisions around the design and conduct of RCTs3.\n\nSeveral systematic reviews report on the topic of retention strategies, including improving response rates to questionnaires4–7. However, there remains a lack of definitive evidence regarding some commonly adopted practices such as sending a pen or using a cover letter with a questionnaire to encourage the participant to return it8–10. The results of a study within a trial (SWAT) evaluating these two strategies are reported here.\n\n\nMethods\n\nA two-by-two factorial RCT was embedded within the OTIS trial of occupational therapist-led home assessment and modification for the prevention of falls (ISRCTN22202133)11. OTIS recruited participants over the age of 65 years who were at risk of falling. Participants were randomised to receive an occupational therapist delivered visit or usual care. They were followed up for 12 months for falls data and were sent postal questionnaires at four, eight and 12 months. This SWAT was embedded at the 12-month time point. Ethical approval for this SWAT was received from the NHS West of Scotland Research Ethics Committee 3 (16/WS/0154) and Health Research Authority and Research Ethics approval in July 2018. Approvals were obtained from the University of York, Department of Health Sciences Research Governance Committee. Participants provided informed consent to be enrolled into the OTIS trial and to be sent study related information by post. Consent for the SWAT was therefore waived by the above-named ethics committee.\n\nA total of 779 participants due to receive their 12-month questionnaire between 16th October 2018 and 2nd August 2019 were randomised into the SWAT in a single tranche in September 2018. Participants who had withdrawn from the OTIS study prior to this were excluded from randomisation.\n\nThe participants were randomised in a single block in a 1:1:1:1 ratio. The allocation sequence was generated by the OTIS statistician, who was not involved with the sending of the questionnaires, using STATA v1512.\n\nTable 1 details the combination of interventions sent in the post with the 12-month questionnaire. We included an unconditional £5 note with the questionnaire for all participants.\n\nThe non-standard cover letter offered a mild level of social incentive, in the form of a personalised table that indicated whether or not a questionnaire had been received from the participant at the earlier (4 and 8-month) time points. This was intended to highlight to the participant that their questionnaire responses are noted and valued10.\n\n*Supplementary Files are available as Extended data14.\n\nParticipants were blind to their participation. Research administrators and research team members posting the questionnaire packs were not blind to the intervention; however, administrators who recorded the outcome data were blind to allocation.\n\nTo assess whether a pen and/or social incentive text cover letter sent with the 12-month questionnaire increased postal questionnaire response rates for participants in the OTIS trial.\n\nThe primary outcome was response rate, defined as the proportion of participants in each group who returned the 12-month questionnaire.\n\nTime to return 12-month questionnaire\n\nThe completeness of the 12-month questionnaire\n\nThe requirement for a reminder letter to be sent\n\nCost effectiveness\n\nThe data were analysed in SPSS v2513 using two-sided tests at the 5% significance level on an intention-to-treat basis. Participants who withdrew or died before the 12-month questionnaire was sent were excluded from the analysis. The primary outcome was compared using a logistic regression model adjusting for age (retention is generally higher in participants ˂75 years and older adults may respond differently to incentives15), gender (to control for potential differences in anticipation of social rewards between males and females16) and host trial treatment allocation. The presence of an interaction between the two interventions was tested by introducing the interaction term into the logisit model. Time to questionnaire return (calculated as days from questionnaire sent to return) was analysed using Cox Proportional Hazards regression, adjusting for the same covariates as in the primary analysis. The proportional hazards assumption was assessed using Schoenfeld residuals17. Completeness of response (defined as number of items completed) was analysed by linear regression model and adjusted as for the primary analysis.\n\nCost effectiveness was calculated for each group using the total cost of the pen/letter/postage/stationary and staff time.\n\nA fixed effect meta-analysis using the Mantel-Haenszel method was conducted using review manager v5.318 to pool the results of this study for enclosing a pen with the 12-month questionnaire with other RCT evidence. These were located utilising the Cochrane systematic review8 search strategy in MEDLINE and EMBASE, along with hand searching of previous systematic reviews references, published retention research reference lists, conference papers and co-author personal knowledge of studies. Pooled odds ratios and corresponding 95% CIs were calculated. Heterogeneity between trials was assessed using the Chi-squared and I2 statistics.\n\nA meta-analysis of the results of the social incentive intervention was not undertaken as the only previous study using this was conducted within a cohort study rather than an RCT10.\n\n\nResults\n\nFigure 1 depicts the recruitment and retention of participants in the embedded trial. Table 2 presents summary statistics for the baseline characteristics of the SWAT participants.\n\n#= How good or bad your healtd is today rated from 0 worst, 100 best.\n\nBetween randomisation into the SWAT and being sent their 12-month questionnaire, 24 randomised participants either died or withdrew from the host trial and so were not sent the questionnaire. A total of 721/755 (95.5%) returned the 12-month questionnaire. The response rate was identical in the pen only group (184/192, 95.8%), social incentive cover letter only group (181/189, 95.8%) and control group (182/190, 95.8%). However, it was marginally lower in the pen and social incentive cover letter group (174/184, 94.6%).\n\nNo evidence of a difference in response rates was found between participants with or without pens (pen: 358/376 [95.2%]; no pen: 363/379 [95.8%]; adjusted OR 0.90, 95% CI 0.45 to 1.80, p=0.77) nor with or without the social incentive cover letter (cover letter: 355/373 [95.2%]; no cover letter: 366/382 [95.8%]; adjusted OR 0.84, 95% CI 0.42 to 1.69, p=0.63) (Table 3).\n\nThe interaction between the interventions was found to be non-significant (interaction effect size estimate OR = 0.79 with corresponding 95% CI 0.2, 3.15 and p value = 0.74).\n\nTime to return. Median time to return the questionnaire was nine days, with a mean of 12.2 days. No statistically significant difference between the groups was found (Table 4).\n\nReminders sent. In total, 83/755 (11.0%) participants required a reminder letter. The pen and social incentive cover letter group required the least reminders (19/184 (10.3%)) and the control group required the most reminders (24/190 (12.6%)). No statistically significant evidence was found of a difference of participants requiring a reminder between the groups (Table 4).\n\nCompleteness of response. Overall average completeness of the questionnaires was 27.8/31 questions (89.6% complete) with no evidence of a difference in completeness of the questionnaire between pen received or not (Table 4).\n\nCost effectiveness. Due to the non-statistically significant effect of the interventions on response rates calculating overall associated costs provides evidence of potential cost savings not to send the social incentive cover letter and/or pen (Extended data: Supplementary File 914).\n\nA fixed effect meta-analysis of enclosing a pen with the 12-month questionnaire on response rate was conducted (Figure 2). We pooled these results with four previous SWATs8,9,19,20 investigating the same intervention, with the same dichotomous outcome of response to the questionnaire or not. This included a total of 13012 participants and gave a statistically significant pooled OR favouring the intervention (1.21, 95% CI 1.09, 1.34 p = 0.0004). Negligible heterogeneity was observed (chi-squared = 2.88 I2= 0%). The risk of bias was low, as indicated by the Cochrane’s risk of bias tool assessment undertaken21 (Extended data: Supplementary File 1014).\n\n\nDiscussion\n\nThis SWAT found no evidence that sending a pen and/or a social incentive cover letter with a postal, trial follow-up questionnaire improved response rate, time to return, requirement for a reminder, or questionnaire completeness.\n\nA limitation was the average age of the participants (79.9 years) giving a narrow age demographic thus restricting generalisability of results. Further investigation of the pen and social incentive cover letter in RCTs are required across more diverse populations.\n\nThe OTIS trial hosted three other methodological SWATs; therefore, there was a potential for contamination or interaction. It is preferable to plan all SWATs that will be undertaken in the early design stages22, to ensure they are planned accordingly to reduce the potential of this.\n\nThe overall response rate of the 12-month postal questionnaire for all SWAT participants was 95.7%. This high response rate is therefore difficult to improve upon, furthermore the incentives may not have been as effective with participants who are very committed to the behaviour10. The incentive required for committed participants may be different10,23. A learning point being that future SWATS testing these interventions should avoid doing so in trials with already high response rates.\n\n\nConclusion\n\nWhilst neither the pen nor the social incentive cover letter showed an effect on response rate, the meta-analysis evidence remains that including a pen increases response rates. This reinforces that for interventions where small effects are likely, it is important to undertake a number of trials and combine these to be confident of an intervention’s effectiveness. Further investigation of the social incentive cover letter in RCTs is required to determine effectiveness.\n\n\nData availability\n\nOpen Science Framework: Pen and Social Incentive Cover Letter Retention SWAT, https://doi.org/10.17605/OSF.IO/TYJDP14.\n\nOpen Science Framework: Pen and Social Incentive Cover Letter Retention SWAT, https://doi.org/10.17605/OSF.IO/TYJDP14.\n\nThis project contains the following extended data:\n\nFull study protocol\n\nSupplementary File 1- Cover letter for the Pen only group.\n\nSupplementary File 2 - Cover letter for the Social incentive cover letter only group.\n\nSupplementary File 3 - Cover letter for the Pen and social incentive cover letter group.\n\nSupplementary File 4 - Cover letter for the control group.\n\nSupplementary File 5 - Results table by intervention group\n\nSupplementary File 6 - Graph Survival curve of pen vs no pen and time taken to return 12-month questionnaire.\n\nSupplementary File 7 - Graph Survival curve of Social incentive cover letter vs no social incentive cover letter and time taken to return 12-month questionnaire.\n\nSupplementary File 8- Survival curve of host trial allocation and time taken to return 12-month questionnaire.\n\nSupplementary File 9 – Costings table\n\nSupplementary File 10 – Cochrane Risk of bias tool assessments for Bell et al., (2016), Sharp et al., (2006), Cunningham-Burley et al., (2020), Mitchell et al., (2020) and James et al., (2020).\n\nOpen Science Framework: CONSORT checklist for ‘Including a pen and/or cover letter, containing social incentive text, had no effect on questionnaire response rate: a factorial randomised controlled Study within a Trial’, https://doi.org/10.17605/OSF.IO/TYJDP14.\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 embedded trial participants who returned 12-month questionnaires.\n\nThis manuscript has been written by the authors on behalf of the OTIS Study Team. Sophie Boyes (York Teaching Hospital NHS Foundation Trust); Belen Corbacho (University of York); Shelley Crossland (Leicestershire Partnership NHS Trust); Avril Drummond (University of Nottingham); Simon Gilbody (University of York); Catherine Hewitt (University of York); Sarah E Lamb (University of Oxford); Katie Whiteside (University of York); Jennifer McCaffery (University of York); Alison Pighills (Mackay Base Hospital; Mackay Australia and James Cook University); Clare Relton (University of Sheffield).\n\nThe results from this project will contribute to the evidence towards trial methodology for improving retention of participants. This will study will be linked with a national research programme PROMETHEUS led by York Trials Unit (https://www.york.ac.uk/healthsciences/research/trials/research/swats/prometheus/) and findings will be combined with other studies in meta-analyses to detect small but cost effective differences. This will help future trials to be designed with effective interventions in place to maximise retention and avoid introduction of bias and reduced study power.\n\n\nReferences\n\nEble A, Boone P, Elbourne D: On minimizing the risk of bias in randomized controlled trials in economics. The World Bank. 2016. Reference Source\n\nClark L, Ronaldson S, Dyson L, et al.: Electronic prompts significantly increase response rates to postal questionnaires: a randomized trial within a randomized trial and meta-analysis. J Clin Epidemiol. 2015; 68(12): 1446–50. PubMed Abstract | Publisher Full Text\n\nEdwards P, Roberts I, Clarke M, et al.: Increasing response rates to postal questionnaires: systematic review. BMJ. 2002; 324(7347): 1183. PubMed Abstract | Publisher Full Text | Free Full Text\n\nNakash RA, Hutton JL, JØrstad-Stein EC, et al.: Maximising response to postal questionnaires - A systematic review of randomised trials in health research. BMC Med Res Methodol. 2006; 6: 5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nEdwards PJ, Roberts IG, Clarke MJ, et al.: Methods to increase response rates to postal questionnaires. Cochrane Database Syst Rev. 2007; (2): MR000008. PubMed Abstract | Publisher Full Text\n\nEdwards PJ, Roberts I, Clarke MJ, et al.: Methods to increase response to postal and electronic questionnaires. Cochrane Database Syst Rev. 2009; (3): MR000008. PubMed Abstract | Publisher Full Text\n\nBrueton VC, Tierney JF, Stenning S, et al.: Strategies to improve retention in randomised trials: a Cochrane systematic review and meta-analysis. BMJ Open. 2014; 4(2): e003821. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBell K, Clark L, Fairhurst C, et al.: Enclosing a pen reduced time to response to questionnaire mailings. J Clin Epidemiol. 2016; 74: 144–150. PubMed Abstract | Publisher Full Text\n\nSharp L, Cochran C, Cotton SC, et al.: Enclosing a pen with a postal questionnaire can significantly increase the response rate. J Clin Epidemiol. 2006; 59(7): 747–54. PubMed Abstract | Publisher Full Text\n\nCotterill S, Howells K, Rhodes S, et al.: The effect of using social pressure in cover letters to improve retention in a longitudinal health study: an embedded randomised controlled retention trial. Trials. 2017; 18(1): 341. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCockayne S, Pighills A, Adamson J: Can occupational therapist-led home environmental assessment prevent falls in older people? A modified cohort randomised controlled trial protocol. BMJ Open. 2018; 8(9): e022488. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStataCorp: Stata Statistical Software: Release 15. College Station, T.S.L. 2017. Reference Source\n\nCorp I: IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp. Released (2017). Reference Source\n\nJames S: Pen and Social Incentive Cover Letter Retention SWAT. 2020. http://www.doi.org/10.17605/OSF.IO/TYJDP\n\nChhatre S, Jefferson A, Cook R, et al.: Patient-centered recruitment and retention for a randomized controlled study. Trials. 2018; 19(1): 205. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSpreckelmeyer KN, Krach S, Kohls G, et al.: Anticipation of monetary and social reward differently activates mesolimbic brain structures in men and women. Soc Cogn Affect Neurosci. 2009; 4(2): 158–65. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSchoenfeld D: Partial residuals for the proportional hazards regression model. Biometrika. 1982; 69(1): 239–241. Publisher Full Text\n\nReview Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, T.C.C, 2014.\n\nCunningham-Burley R, Roche J, Fairhurst C, et al.: Enclosing a pen to improve response rate to postal questionnaire: an embedded randomised controlled trial [version 1; peer review: awaiting peer review]. F1000Res. 2020; 9: 577. Publisher Full Text\n\nMitchell A, Cook L, Dean A, et al.: An embedded randomised controlled retention trial of personalised text messages compared to non-personalised text messages in an orthopaedic setting [Version1; peer review: awaiting peer review]. F1000Res. 2020; In Press.\n\nHiggins JPT, Altman DG, Gøtzsche PC, et al.: The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBower P, Brueton V, Gamble C, et al.: Interventions to improve recruitment and retention in clinical trials: a survey and workshop to assess current practice and future priorities. Trials. 2014; 15: 399. PubMed Abstract | Publisher Full Text | Free Full Text\n\nO'Keefe DJ: Persuasion: Theory and Research. SAGE publishers, 2002. Reference Source"
}
|
[
{
"id": "66639",
"date": "21 Jul 2020",
"name": "Taylor Coffey",
"expertise": [
"Reviewer Expertise Health services research",
"design and evaluation of interventions to change behaviour",
"the application of behavioural theory to trial recruitment and retention."
],
"suggestion": "Approved With Reservations",
"report": "Approved With Reservations\n\ninfo_outline\nAlongside their report, reviewers assign a status to the article:\n\nApproved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested\n\nApproved with reservations\nA number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.\n\nNot approved Fundamental flaws in the paper seriously undermine the findings and conclusions\n\nThe present article by James et al. details a study within a trial (SWAT) of including a pen and/or cover letter with a postal questionnaire. A two-by-two factorial randomized control trial was conducted that assessed the effect of including a branded pen, a ‘social incentive’ cover letter, both a pen and ‘social incentive’ cover letter, or a standard cover letter as control. The primary outcome measure was the return of a postal questionnaire with secondary outcomes of time to return the questionnaire, completeness of the questionnaire, requirement for a reminder letter to be sent, and overall cost effectiveness. Overall, there was no effect of any intervention on return of questionnaires and no effect on secondary outcome measures. A meta-analysis was conducted with respect to including a pen with the questionnaire and its effect on response rate, with pooled results supporting the inclusion of pens.\nWe would firstly like to commend the authors for presenting the methods clearly and providing supplementary material which enhances replicability. Below we indicate points which could be addressed and identify areas of improvement to further enhance the quality of this article.\nMajor points to address: The peer review team would like to highlight the following areas for clarification.\nPotentially confounding incentives\nThe ‘social incentive’ intervention cover letter is described as including a “mild level of social incentive”. In referencing the supporting citation for the cover letter (Cotterill et al., 2017)1, the social incentive used is social pressure. Social pressure is described as conveying to participants that “information about their behavior will be noticed (Cotterill et al., 2017)1”. The present paper then describes the cover letter as “intended to highlight to the participant that their questionnaire responses are noted and valued”. It is apparent that reminder letters were also sent to some participants. A reminder letter could be argued to be another “mild level of social incentive” as it is similarly conveying to participants that their behaviour (i.e. not returning the questionnaire) is being noticed. Can the authors comment on the potential for the reminder letters to confound the results? The reminder is not included among the supplementary documents, but we would be interested in the authors’ thoughts on the potential for unintended social pressure cues or behaviour change techniques being delivered through the reminder letter.\n\nIn reviewing both the standard and social incentive cover letter, it is noted that they are identical apart from the personalized table indicating the participants’ previous responses. Similarly to the above point regarding unintended social pressure cues, we wonder if the phrases “We would be very grateful if you could return the completed questionnaire to us[…]” and “Your input to this trial is very important to us[…]”can be unintentionally introducing confounding social pressure by highlighting that their questionnaire responses are “noted and valued”. Can the authors reflect on how the addition of these phrases (and thereby the possibility that unintended ‘social incentives’ were applied within the control group) may have potentially affected results?\n\nUnder the section, “Interventions”, on page 3, it is mentioned that an unconditional £5 note was included with the questionnaire for all participants. Due to the financial incentive present, we would just like to clarify if the inclusion of the £5 note was controlled for in the analysis.\n\nIt is referenced in the “Discussion” section that the host trial included three other methodological SWATs that have a potential for contamination or interaction. If possible, it would be good to offer brief descriptions or links to other SWATS in the supplementary materials to better understand their potential to confound intervention effects.\nTheoretical foundation of cover letter\nApplying the Behaviour Change Techniques (BCT) taxonomy definitions to the intervention letter raises the possibility that the intervention being tested is more akin to “feedback on behaviour” (see Michie, 2013)2, given that the letter provides informative feedback on the frequency of questionnaire return, rather than the BCT taxonomy definition of ‘social incentive’ (i.e. “Inform that a verbal or nonverbal reward will be delivered if and only if there has been effort and/or progress in performing the behaviour\"). It is worth noting that some readers may interpret the meaning of 'social incentives' quite differently than how it is conceptualised here. Can the authors offer some clarification on this for the reader and on the theoretical underpinnings of the intervention? Adding citation(s) to clarify their conceptualisation of 'social incentive' would be helpful.\n\nIt is also unclear whether the authors regard the social incentive cover letter as a form of “social reward”: noted on page 4, the authors state that gender was controlled for within the logistic regression model to “control for potential differences in anticipation of social rewards…”. It does not appear that participants are presented with additional verbal or non-verbal reward above the standard letter with just the inclusion of the response table.\n\nIt is noted in Cotterill et al. (2017)1 that social pressure is “unlikely to be effective among those who are very committed to the behavior” which appears to be the case given that response rates across groups are >95%. Given that there are two prior postal response timepoints, was identifying if this group is highly committed to questionnaire response considered?\nMinor points to address:\n\nRegarding Table 2, are BMI, EQ-55D-5L score, and number of falls relevant to include? The table is already quite extensive and this data may detract the reader’s attention from other variables (e.g. age, sex) more pertinent to the study.\n\nThe pen is described as York Trials Unit branded. Was there branding specific to the host trial? It might be that participants would be quicker to recognize the trial versus the CTU. How might this affect the social incentive?\n\nCould it be mentioned briefly in the main body of the paper that the meta-analysis was undertaken as part of PROMETHEUS? We notice it is mentioned in the acknowledgments but one of the review team members was confused about the inclusion of the meta-analysis.\nOverall assessment: We would like to commend the authors on a concise and well-articulated presentation of the present study. The study is well designed and it is clearly presented with accompanying data and figures making it highly reproducible. We recognize the importance of each individual SWAT’s contribution to a larger body of evidence and the conclusions drawn and the recommendations for future work are appropriate. We have suggested potential limitations and concerns with the theoretical foundations of the social incentive cover letter and the presence of potential confounding incentives but our overall assessment is that the article meets its objectives and its strengths merit indexing.\n\nContribution to this peer review: This peer review was conducted by Taylor Coffey, Dr Louisa Lawrie and Dr Eilidh Duncan as part of TC and LL’s training. All reviewers contributed to writing the report.\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": "7168",
"date": "08 Nov 2021",
"name": "Sophie James",
"role": "Author Response",
"response": "Major points to address: The peer review team would like to highlight the following areas for clarification. Potentially confounding incentives The ‘social incentive’ intervention cover letter is described as including a “mild level of social incentive”. In referencing the supporting citation for the cover letter (Cotterill et al., 2017)1, the social incentive used is social pressure. Social pressure is described as conveying to participants that “information about their behavior will be noticed (Cotterill et al., 2017)1”. The present paper then describes the cover letter as “intended to highlight to the participant that their questionnaire responses are noted and valued”. It is apparent that reminder letters were also sent to some participants. A reminder letter could be argued to be another “mild level of social incentive” as it is similarly conveying to participants that their behaviour (i.e. not returning the questionnaire) is being noticed. Can the authors comment on the potential for the reminder letters to confound the results? The reminder is not included among the supplementary documents, but we would be interested in the authors’ thoughts on the potential for unintended social pressure cues or behaviour change techniques being delivered through the reminder letter. Thank you to the reviewers for their valued comments. For this paper the term ‘social incentive’ was used rather than ‘social pressure’ on the advice of two of the co-authors of this paper who were involved in the original Cotterill et al., (2017) embedded trial to test the social incentive cover letter intervention within a cohort study. They noted that following this paper the term ‘social pressure’ is not commonly used outside of politics literature. A copy of the reminder letter that was sent to 83 participants has been added to the OSF as supplementary document 12. Whilst it could be argued that the reminder letter provided another mild level of social incentive, it was not felt that it would provide additional social incentive as per the definition used for this study (discussed in relation to the next comment). Furthermore, the number of these sent out was evenly distributed across the randomised and analysed groups: 83 reminder letters sent were sent out of 755 and these were evenly distributed across the 4 groups (pen and social incentive cover letter group 19/184 (10.3%), control group 24/190 (12.6%), social incentive cover letter only group 20/189 (10.5%) and pen only group 20/192 (10.4%). So it would be unlikely that these additional reminder letters would confound the results. There was no statistically significant evidence of a difference in the likelihood of participants requiring a reminder between the groups (pen vs no pen: adjusted OR = 0.89 [95% CI 0.56, 1.42 p = 0.63]; social incentive cover letter vs no social incentive cover letter: adjusted OR = 0.92 [95% CI 0.58, 1.47 p = 0.74]. In reviewing both the standard and social incentive cover letter, it is noted that they are identical apart from the personalized table indicating the participants’ previous responses. Similarly to the above point regarding unintended social pressure cues, we wonder if the phrases “We would be very grateful if you could return the completed questionnaire to us[…]” and “Your input to this trial is very important to us[…]”can be unintentionally introducing confounding social pressure by highlighting that their questionnaire responses are “noted and valued”. Can the authors reflect on how the addition of these phrases (and thereby the possibility that unintended ‘social incentives’ were applied within the control group) may have potentially affected results? The standard text for this cover letter was the exact text used in the cover letters previously sent to participants with their 4 and 8 month questionnaires for the OTIS trial. The text of both the ‘control’ and ‘social incentive’ cover letters were identical the only difference was the addition of the table therefore it was not felt that this would affect the results. The example sentences noted could fall into some definitions for social incentive, but they would not meet ‘persuades people to behave in a certain way by the promise that their actions will be noticed or made public’ (Cotterill et al., 2017). Clarification of this definition has been added to the paper to help to clarify the comments around this. Under the section, “Interventions”, on page 3, it is mentioned that an unconditional £5 note was included with the questionnaire for all participants. Due to the financial incentive present, we would just like to clarify if the inclusion of the £5 note was controlled for in the analysis. Since all participants received the £5 it was neither necessary nor appropriate to control for this in the analysis. It is referenced in the “Discussion” section that the host trial included three other methodological SWATs that have a potential for contamination or interaction. If possible, it would be good to offer brief descriptions or links to other SWATS in the supplementary materials to better understand their potential to confound intervention effects. A supplementary file 11 has been added to OSF outlining the other SWATs that were undertaken within the OTIS Trial. Theoretical foundation of cover letter Applying the Behaviour Change Techniques (BCT) taxonomy definitions to the intervention letter raises the possibility that the intervention being tested is more akin to “feedback on behaviour” (see Michie, 2013)2, given that the letter provides informative feedback on the frequency of questionnaire return, rather than the BCT taxonomy definition of ‘social incentive’ (i.e. “Inform that a verbal or nonverbal reward will be delivered if and only if there has been effort and/or progress in performing the behaviour\"). It is worth noting that some readers may interpret the meaning of 'social incentives' quite differently than how it is conceptualised here. Can the authors offer some clarification on this for the reader and on the theoretical underpinnings of the intervention? Adding citation(s) to clarify their conceptualisation of 'social incentive' would be helpful. Although recent work has pointed towards the importance of using behaviour change theory to support and influence behavioural actions required by participants in RCTs (Gilles et al., 2018), behaviour change theory and associated research is such a vast area that this is a valid point that different concepts can be defined in different ways by different theories/authors. To help to clarify this in the paper sentences have been added to provide further detail and detail how the concept of social incentive was interpreted in relation to this study. [added to paper v2: ‘The concept of social incentive that underpinned the intervention for this study was that a social incentive is something that persuades people to behave in a certain way by the promise that their actions will be noticed or made public [10].’ It is also unclear whether the authors regard the social incentive cover letter as a form of “social reward”: noted on page 4, the authors state that gender was controlled for within the logistic regression model to “control for potential differences in anticipation of social rewards…”. It does not appear that participants are presented with additional verbal or non-verbal reward above the standard letter with just the inclusion of the response table. Error in terminology of the paper, social reward was used interchangeably with social incentive in error. Social reward removed from this sentence and replaced with social incentive with a further reference added. [changed paper v2 to read: ‘gender, to control for potential difference in the effect of social incentives between males and females] It is noted in Cotterill et al. (2017)1 that social pressure is “unlikely to be effective among those who are very committed to the behavior” which appears to be the case given that response rates across groups are >95%. Given that there are two prior postal response timepoints, was identifying if this group is highly committed to questionnaire response considered? Thank you, this is a valid point. At the time this SWAT was designed and added to the OTIS trial the high response rates of the previous time points were not known. This is currently noted in the paper as a consideration for future research to consider when using this type of social incentive cover letter. Minor points to address: Regarding Table 2, are BMI, EQ-55D-5L score, and number of falls relevant to include? The table is already quite extensive and this data may detract the reader’s attention from other variables (e.g. age, sex) more pertinent to the study. These variables have been removed from Table 2 as suggested. The pen is described as York Trials Unit branded. Was there branding specific to the host trial? It might be that participants would be quicker to recognize the trial versus the CTU. How might this affect the social incentive? The pen had the logo of York Trials Unit and was not specific to the OTIS trial. This would be an interesting follow on question for future work, whether the branding of the pen sent with a questionnaire had any effect on response rate. The pen was not considered to provide a social incentive for this SWAT, only the cover letter. Could it be mentioned briefly in the main body of the paper that the meta-analysis was undertaken as part of PROMETHEUS? We notice it is mentioned in the acknowledgments but one of the review team members was confused about the inclusion of the meta-analysis. [Added to paper v2: ‘Due to SWATs typically being under-powered to show small effects, it is essential that the results are seen within the context of the wider literature (added to methods section under statistical analysis) The results of this study were pooled with four previous SWATs [8,9,22,23] investigating the same intervention, with the same dichotomous outcome of response to the questionnaire or not. Pooled odds ratios and corresponding 95% CIs were calculated. Heterogeneity between trials was assessed using the Chi-squared and I 2 statistics. The meta-analysis was facilitated by the PROMoting THE USE of SWATs (PROMETHEUS) programme, which supports host trial teams to conducted SWATs and for data obtained to be collated and meta-analysed.’(Summary details for the studies included in the meta-analysis are provided in Supplementary file 13)]"
}
]
},
{
"id": "91091",
"date": "16 Aug 2021",
"name": "Susanne Grylka-Baeschlin",
"expertise": [
"Reviewer Expertise Midwifery",
"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\nThank you very much for giving me the opportunity to review this article. Studies Within A Trial (SWAT) are important and a good opportunity to make optimal use of resources. Despite their disadvantage that the original trial has not been designed for the purpose of the SWAT, they provide important indications for further studies. In this sense, the results of this SWAT are important for further research.\nGeneral impression: This SWAT was planned at the same time as the original trial. The methods are described in detail and are the strongest part of the article. Nevertheless, there are some important concerns. Participants were rewarded with a 5-pound note. This is in itself also an intervention to increase response rates. As the authors themselves note, the response rate is generally very high. Possibly the additional reward and together with the high response rate made it impossible to show an effect of the two tested interventions.\n\nAbstract:\nBackground: Is it still true that postal questionnaires are used frequently in randomized controlled trials? One could imagine that a swift towards online surveys can be observed.\n\nBackground:\nThis very short background is the weakest part of the manuscript.\n\nThe rational for the SWAT differs between the abstract and the main text. The general problem of low response rate for the generalizability of results seems important also for the article, not only for the abstract.\n\nMethods:\nThis is the strongest part of the article and mostly very clear.\n\nIt was a good idea to combine the results of this SWAT with results of other studies in a meta-analysis. However, it could be meaningful to provide further details about the literature research for the articles, which were included. There is not enough information to decide if the research was really systematic or not. Especially the comment that co-author personal knowledge of studies was considered for finding studies raises some questions. Did the included articles test the same interventions?\n\nResults:\nResults are presented in a clear way with nice tables. Especially Figure 1 which gives very good overviews about the study process.\n\nAre differences between the study groups described in Table 2 significant or not?\n\nDiscussion:\nThe enclosed 5-pound note represents a further limitation and should be mentioned.\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": "7169",
"date": "08 Nov 2021",
"name": "Sophie James",
"role": "Author Response",
"response": "We thank the reviewer for the helpful comments and points raised. We hope that our responses are satisfactory and the article has been updated in response to the points raised from both reviewers (v2). General impression: This SWAT was planned at the same time as the original trial. The methods are described in detail and are the strongest part of the article. Nevertheless, there are some important concerns. Participants were rewarded with a 5-pound note. This is in itself also an intervention to increase response rates. As the authors themselves note, the response rate is generally very high. Possibly the additional reward and together with the high response rate made it impossible to show an effect of the two tested interventions. Response: Thank you, these are valid points. Brueton et al., (2013) report that the addition of a monetary incentive was more effective than no incentive (RR 1.31; 95% CI 1.11 to 1.55, p=0.002) so the £5 monetary reward was included as standard in the OTIS trial at the 12 month time point. All participants received the £5 so this was not felt to be a limitation in assessing the effectiveness of the 2 interventions investigated by this SWAT, but it may have added to the high response rate and this is now noted in the discussion. At the time this SWAT was designed and added to the OTIS trial the high response rates were not known. The high response rate is mentioned in the discussion of the paper with a learning point for future SWATs, as we acknowledge that this limits the scope for the interventions to have a large benefit. Abstract: Background: Is it still true that postal questionnaires are used frequently in randomized controlled trials? One could imagine that a swift towards online surveys can be observed. Response: We believe it is still true, indeed most of the trials we conduct in York Trial Unit still use postal questionnaires; however, we agree that the use of online data collection has increased since this SWAT was designed 4 years ago. With RCTs in this demographic/population and for participants in RCTs who do not have internet provision, in order to ensure inclusivity, there is likely to remain a need for future RCTs to still have a postal paper questionnaire option available and so keeps this relevant. Background: This very short background is the weakest part of the manuscript. The rational for the SWAT differs between the abstract and the main text. The general problem of low response rate for the generalizability of results seems important also for the article, not only for the abstract. Response: Thank you for this, we have updated the paper v2 to include this information from the abstract into the introduction to ensure consistency. We were limited by the word count of the article to be able to provide any further detail in this section. Methods: This is the strongest part of the article and mostly very clear. It was a good idea to combine the results of this SWAT with results of other studies in a meta-analysis. However, it could be meaningful to provide further details about the literature research for the articles, which were included. There is not enough information to decide if the research was really systematic or not. Especially the comment that co-author personal knowledge of studies was considered for finding studies raises some questions. Did the included articles test the same interventions? Response: All the studies included in the meta-analysis are now published and peer reviewed with the references provided so that these can be located and a summary of the key information of the studies included in the meta analysis is now provided in Supplementary file 13. [Added to paper v2: The Cochrane systematic review search strategy (supplementary file 14) was used to search MEDLINE and EMBASE. Additionally previous systematic reviews references were hand searched, along with published retention research reference lists, conference papers and co-author personal knowledge of studies.] Results: Results are presented in a clear way with nice tables. Especially Figure 1 which gives very good overviews about the study process. Are differences between the study groups described in Table 2 significant or not? Response: Table 2 presents summary statistics for the baseline characteristics of the SWAT participants. According to the CONSORT statement, significance testing of baseline differences in randomized controlled trials should not be performed. Indeed, this practice has been discouraged by numerous authors. (Reference for the above information = Michiel R de Boer, Wilma E Waterlander, Lothar DJ Kuijper, Ingrid HM Steenhuis, andJos WR Twisk(2015) Testing for baseline differences in randomized controlled trials: an unhealthy research behavior that is hard to eradicate. Int J Behav Nutr Phys Act. 2015; 12: 4.Published online 2015 Jan 24. doi: 10.1186/s12966-015-0162-z) Discussion: The enclosed 5-pound note represents a further limitation and should be mentioned. Now mentioned in the discussion"
}
]
}
] | 1
|
https://f1000research.com/articles/9-623
|
https://f1000research.com/articles/10-1115/v1
|
04 Nov 21
|
{
"type": "Case Report",
"title": "Case Report: Acute abdomen presentation revealing a metastatic invasive mole with uterine rupture",
"authors": [
"Fatma Dhieb",
"Miriam Boumediene",
"Armi Saoussem",
"Garci Mariem",
"Mathlouthi Nabil",
"Linda Bel Haj Kacem",
"Meriem Ksentini",
"Miriam Jrad",
"Miriam Boumediene",
"Armi Saoussem",
"Garci Mariem",
"Mathlouthi Nabil",
"Linda Bel Haj Kacem",
"Meriem Ksentini",
"Miriam Jrad"
],
"abstract": "Gestational trophoblastic neoplasia refers to the aggressive subset of gestational trophoblastic disease, including invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor. These tumors may have atypical clinical presentations that can mislead the diagnosis. The reported case is a 48-year-old woman in perimenopause, without any history of vaginal bleedings nor molar pregnancy, who presented to the Emergency Department with acute abdominal pain. Serum beta human chorionic gonadotropin (β-HCG) was highly elevated at 261 675.23 mIU/ml. A complicated invasive mole was suspected, and an abdominal computed tomography was performed, showing a moderate hemoperitoneum associated to complex cystic and solid uterine mass, with a common left iliac adenomegaly and multiple pulmonary nodules. MRI showed a multiloculated cystic uterine mass with zones of hemorrhage recalling an invasive mole with perforation of the posterior uterus wall, associated to a high abundance hemoperitoneum. The diagnosis of a metastatic invasive mole complicated of uterine rupture and hemoperitoneum was retained. A surgical intervention was decided immediately and a subtotal hysterectomy with bilateral annexectomy was done. Pathologic examination of the specimen was positive for an invasive mole. The patient was proposed for chemotherapy. This case study will increase awareness of unusual clinical presentations of gestational trophoblastic neoplasia We believe that our case will contribute to the literature not only because of the rarity of this entity in perimenopausal period, but also due the atypical clinical presentation as acute abdomen without vaginal bleeding nor history of molar pregnancy evacuation",
"keywords": [
"Invasive mole – Hemoperitoneum – MRI – CT-scan"
],
"content": "Introduction\n\nInvasive mole, a rare subgroup of gestational trophoblastic desease, are much more common in women of productive age, and rarer in perimenopausal years.1 It usually occurs after molar pregnancy, and rarer, they can arise after any gestation even abortions.2\n\nThis disease is rarely documented in emergency medicine literature.3 It may present with a wide variety of symptoms depending on the extent of invasive growth and on the presence or not of metastases. The most common presentation is uterine bleeding,4 however, this abnormal bleeding may be masked by irregular menstrual cycles, commonly seen during perimenopausal period.\n\nWe are presenting the case of an unusual presentation of invasive mole in a perimenopause age woman, without history of molar pregnancy, complicated by a uterine rupture and hemoperitoneum, and occurring as acute abdominal pain.\n\n\nCase presentation\n\nA 48-year-old woman in perimenopause, G12A9P3 (gravida, abortion and living), without any past medical history, presented to the emergency department of Charles Nicolle Hospital Tunis, Tunisia in May 2021 with a two-day history of general abdominal pain, nausea and vomiting. The pain was dull and continuous with progressive worsening, resistant to analgesics. She had experienced amenorrhea for 8 weeks without any vaginal bleeding.\n\nPhysical examination revealed normal vital signs and no fever. The abdominal palpation showed a distended abdomen with generalized tenderness.\n\nLaboratory results showed a highly elevated serum at 261 675.23 mIU/ml [normal range: <5 mIU/ml], normochromic normocytic anemia with Hemoglobin at 10.8g/dL [normal range: 12.3-15.3 g/dL], without biological inflammatory syndrome.\n\nThe patient was referred to the Gynecology Department where she was hospitalized. The examination by speculum and bimanual palpation revealed congested cervix with vaginal bleeding.\n\nA complicated invasive mole was suspected and an abdominal Computed Tomography was performed.\n\nThe CT-scan demonstrated a moderately abundant hemoperitoneum associated to a complex solid and cystic uterine mass of 13 cm. This mass was the seat of intense enhancement after injection of contrast, with thrombosis of the left ovarian vein (Figure 1). CT also showed a common left iliac adenomegaly.\n\nA pelvic MRI was performed and it showed a globular uterus, with a multiloculated cystic endocavitary mass occupying the fundal region, deeply thinning the myometrium. This mass was with high T2 and low T1 signal. Few areas of high T1 signal were present related to hemorrhage (Figure 2). A large zone of perforation in the posterior fundal uterine wall was noted (Figure 3), associated to a high abundance hemoperitoneum. Ovaries were normal.\n\nIntervention was decided immediately. Intra-operatively, one liter of hemoperitoneum was found. The uterus was globular, with perforation in its posterior wall, bringing chorionic villus (Figure 4). No macroscopic invasion of bilateral uterine parameters was noted.\n\nA subtotal hysterectomy with bilateral annexectomy was done without any intra or postoperative incident.\n\nA thoracic computed tomography with a cerebral MRI were done as an assessment of extension showing multiple pulmonary ground glass and solid nodules with a metastatic aspect (Figure 5), and no cerebral lesion.\n\nThe pathologic examination of the specimen was positive for an invasive mole without parametrial invasion (Figure 6).\n\nThe patient was classified as high risk with a FIGO 2000 prognosis score to 15 [age >40 years (1 point); previous gestation: abortion (1 point); interval from index pregnancy more than 12 months (4 points); pretreatment hCG > 105 (4 points) ; largest tumor size >5 cm (2 points); site of metastases: lung (2 points); number of metastases identified between 5 and 8 (2 points); no previous failed chemotherapy (0 points)].5\n\nMedical oncology consultation was obtained postoperatively, and the patient was proposed for adjuvant polychemotherapy including EMA-CO (Etoposide, Methotrexate, and Dactinomycin with Cyclophosphamide and Vincristine). The serum β-HCG level rapidly decreased after one cycle chemotherapy and dropped to normal values after the second cycle. Three additional courses of chemotherapy were given. Actually, four months after surgery, the patient is under periodic follow-up evaluations of serum β-HCG level which remained negative.\n\n\nDiscussion\n\nGestational trophoblastic neoplasia refers to the aggressive subset of gestational trophoblastic disease (GTD) that has a capability for independent growth and metastases.6\n\nIt is a very rare group including invasive mole, choriocarcinoma, placental site trophoblastic tumor, and epithelioid trophoblastic tumor.7,8\n\nHydatidiform mole, accounts for 80% of all GTD, estimated to occur in 0.6 to 1.1 per 1000 pregnancies in North America.9 Invasive mole, by elsewhere is rarer and constitutes 5 to 8% of trophoblastic diseases.10 It may arise from any pregnancy event, although in most cases it is diagnosed after molar pregnancy.\n\nThe usual clinical presentation is vaginal bleedings, pelvic pain, abdominal distension due to enlargement of the uterus. Sometimes it can be accompanied with altered general state condition or pre-eclampsia.11,12\n\nAcute abdomen without any past history of vaginal bleedings nor molar pregnancy is an unusual presentation that may mislead the diagnosis to an abdominal cause. Some authors such as Aminimoghadam et al. in 2017 and Bruner et al. in 2014 reported few cases of invasive mole presenting as acute hemoperitoneum.3,13\n\nDevelopment of trophoblastic tissue in uterine stroma and the invasion of myometrium by molar structures may lead to uterine perforation.14 In our case, this perforation was responsible for a heavy intraperitoneal hemorrhage.\n\nImaging aspects of gestational trophoblastic neoplasms reveal a great polymorphism. Distinction between invasive mole and choriocarcinoma is highly difficult in imaging.15\n\nUltrasound examination shows a heterogenous echogenic uterine structure due to zones of hemorrhage and necrosis. Infiltration of different tunics of the uterus with disorganization of their structure and irregularities is in favor of an aggressive tumor. Hypervascularization is usually seen in color doppler.16\n\nPelvic MRI is indicated essentially to check for local extension. It shows a poorly limited complex cystic mass, with high heterogenous enhancement after gadolinium. In fact, it shows the hyper vascularized character of these tumors and the dilation of adjacent myometrial vessels. MRI is performed for the study of mural uterine invasion and parametrial extension. Distinction between invasive mole and choriocarcinoma is not obvious in MRI despite a possible difference in enhancement which is peripheral in choriocarcinoma with large zones of central necrosis, and essentially central in invasive mole. These features are not always seen, and histological confirmation is necessary to confirm the precise diagnosis.15\n\nThese tumors have hematogenous dissemination, with pulmonary, hepatic, and cerebral metastatic sites. For extension assessment, a thoraco-abdominal Computed tomography is requested, completed eventually by cerebral MRI or CT scan. In our case an internal iliac adenomegaly with pulmonary nodules was discovered which is very rare in invasive mole unlike choriocarcinoma.\n\nIn summary, we reported a special case of an invasive mole, arising as a complication of hemoperitoneum and acute abdomen. This atypical presentation mislead the diagnosis initially. Imaging features and elevated rate of serum β-HCG permitted the proper diagnosis thereafter.\n\nThe absence of periodic follow-up after multiple abortions caused the delay in diagnosis, the degeneration and the distant extension of her molar pathology.\n\nMoreover, the request for beta human chorionic gonadotropin (β-HCG) in case of acute abdomen presentation made it possible to quickly rectify the diagnosis and to take charge of the patient before the deterioration of her dynamic state.\n\n\nConsent\n\nWritten informed consent for publication of clinical details and 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\nOzalp SS, Telli E, Oge T, et al.: Multicenter analysis of gestational trophoblastic neoplasia in Turkey. Asian Pac. J. Cancer Prev. 2014; 15(8): 3625–8. PubMed Abstract | Publisher Full Text\n\nAkyol A, Şimşek M, Üçer Ö: Giant invasive mole presenting as a cause of abdominopelvic mass in a perimenopausal woman: An unusual presentation of a rare pathology. Obstet Gynecol Sci. 2016; 59(6): 548–53. PubMed Abstract | Publisher Full Text | Free Full Text\n\nBruner D, Pritchard A, Clarke J: Uterine Rupture Due to Invasive Metastatic Gestational Trophoblastic Neoplasm. WestJEM. 2013 Sep 17; 14(5): 444–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLurain JR: Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am. J. Obstet. Gynecol. 2010 Dec; 203(6): 531–9. PubMed Abstract | Publisher Full Text\n\nGestational Trophoblastic Disease - Stage and Risk Grouping: Cancer. Net. 2012 [cited 2021 Sep 29].Reference Source\n\nHui P, Martel M, Parkash V: Gestational Trophoblastic Diseases: Recent Advances in Histopathologic Diagnosis and Related Genetic Aspects. Adv. Anat. Pathol. 2005 May; 12(3): 116–25. PubMed Abstract | Publisher Full Text\n\nGestational Trophoblastic Disease:[cited 2021 Sep 29].Reference Source\n\nCheung AN-Y: Pathology of gestational trophoblastic diseases. Best Pract. Res. Clin. Obstet. Gynaecol. 2003 Dec; 17(6): 849–68. PubMed Abstract | Publisher Full Text\n\nMangili G, Lorusso D, Brown J, et al.: Trophoblastic disease review for diagnosis and management: a joint report from the International Society for the Study of Trophoblastic Disease, European Organisation for the Treatment of Trophoblastic Disease, and the Gynecologic Cancer InterGroup. Int. J. Gynecol. Cancer. 2014 Nov; 24(9 Suppl 3): S109–16. Publisher Full Text\n\nSudha CP, Sahana M: Chemoresistant Gestational Trophoblastic Neoplasia: A Case Report. J. Clin. Diagn. Res. 2014 Jul; 8(7): OD12–3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nMamouni N, Boumhaoued S, Erraghay S, et al.: Tumeurs trophoblastiques gestationnelles: aspects cliniques et radiologiques. Pan Afr. Med. J. 2017 Nov 14 [cited 2021 Sep 16]; 28(228). Publisher Full Text Reference Source\n\nKanter D, Lindheimer MD, Wang E, et al.: Angiogenic dysfunction in molar pregnancy. Am. J. Obstet. Gynecol. 2010 Feb; 202(2): 184.e1–5. PubMed Abstract | Publisher Full Text | Free Full Text\n\nAminimoghaddam S, Maghsoudnia A: Unusual Presentation of Invasive Mole: A Case Report. J Reprod Infertil. 2017 Mar; 18(1): 205–9. PubMed Abstract | Free Full Text\n\nKumar S, Nellore V, Mittal S: Invasive Mole Presenting as Acute Haemoperitoneum. JK Science: J. Med. Educ. Res. 2004 Jul; 1: 6.\n\nImagerie des maladies trophoblastiques gestationnelles - EM consulte:[cited 2021 Sep 16].Reference Source\n\nAspects échographiques du choriocarcinome gestationnel: Résultats préliminaires à propos 13 cas - ScienceDirect:[cited 2021 Sep 29].Reference Source"
}
|
[
{
"id": "99194",
"date": "25 May 2024",
"name": "Vorapong Phupong",
"expertise": [
"Reviewer Expertise placental related diseases",
"maternal fetal 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\nThe authors presented a case of invasive mole with uterine perforation presenting as acute abdominal pain. There are some points to add:\nCase presentation\nDid the patient notice that she had a pregnancy after amenorrhea for 8 weeks?\n\nWhen was the patient’s last pregnancy?\n\nThe authors stated that “Laboratory results showed a highly elevated serum at 261 675.23 mIU/ml [normal range:<5 mIU/ml]” What was the test?\n\nWhy was beta hCG sent at the first time at emergency department?\n\nWas a transvaginal ultrasonogram performed?\n\nFor each figure, please add arrow signs to demonstrate the described finding.\n\nFigures 4 & 5 were incorrectly mentioned in the text.\n\nWhat was the preoperative diagnosis?\n\nThe authors stated that “No macroscopic invasion of bilateral uterine parameters was noted.” What do the uterine parameters mean?\n\nWhy was a subtotal hysterectomy with bilateral annexectomy was done?\n\nWhy did the authors not perform total hysterectomy with bilateral annexectomy?\n\nWas the lung metastasis improved after treatment with chemotherapy?\nDiscussion\nPlease discuss which imaging can be used to diagnose invasive moles and differentiate from choriocarcinoma.\n\nPlease add to the discussion regarding the management of invasive mole with or without uterine perforation.\n\nIs the background of the case’s history and progression described in sufficient detail? Partly\n\nAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes? Partly\n\nIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment? Partly\n\nIs the case presented with sufficient detail to be useful for other practitioners? Partly",
"responses": []
}
] | 1
|
https://f1000research.com/articles/10-1115
|
https://f1000research.com/articles/9-1382/v1
|
30 Nov 20
|
{
"type": "Case Report",
"title": "Case Report: Neuroleptic malignant syndrome in a HIV-positive patient",
"authors": [
"Sibi Joseph",
"Jerry George",
"Mongezi Tau",
"Lourdes de Fatima Ibanez-Valdes",
"Thozama Dubula",
"Humberto Foyaca-Sibat",
"Sibi Joseph",
"Jerry George",
"Mongezi Tau",
"Lourdes de Fatima Ibanez-Valdes",
"Thozama Dubula"
],
"abstract": "We report a 29-year-old, HIV-positive woman being treated with antipsychotic medication for psychosis (Clopixol 200mg intramuscularly monthly, Risperidone 2mg orally daily Haloperidol 2.5mg twice a day), who presented with neuroleptic malignant syndrome. She was also receiving lorazepam and sodium valproate. The patient was referred to our department as she had developed involuntary upper limb movements and simple permanent focal seizure on the lower part of the left hemiface. Clinically the patient had altered consciousness, autonomic dysfunction, and rigidity. Her blood tests showed elevated creatine kinase (1467U/L) but no leucocytosis. We did a thorough workup for other causes of such a presentation. A comprehensive history was taken from the family to exclude other medications used. Her cerebrospinal fluid results were average. Blood tests did not show evidence of infection or other abnormalities. Computed tomography brain was normal. The patient died a few days after the beginning of the attack, which we have also observed in other HIV-female patients. As far as we know, it is the first report about this comorbidity reported in the medical literature.",
"keywords": [
"Neuroleptic Malignant Syndrome",
"HIV",
"permanent focal simple motor seizure",
"elevated creatine kinase",
"neuroleptic side effects."
],
"content": "Introduction\n\nMost authors define neuroleptic malignant syndrome (NMS) as a rare, yet life-threatening, idiosyncratic reaction to medications, mostly but not limited to neuroleptic drugs (dopamine receptor antagonists)1–3. Though fatal, it is potentially a treatable condition4.\n\nNMS was initially described by Delay and colleagues in 1960, who noticed it in patients treated with high-potency antipsychotics5,6. Though rare, every clinician must bear in mind that this is a significant differential to consider and that it is also a diagnosis of exclusion. One study conducted in 1986 discovered about 500 patients who were on neuroleptics, and about 1.4% clinically had NMS, while one case was fatal since it was not found in time1.\n\nHere we present the case of a young HIV-positive woman whose history was not evident to us initially and had permanent focal seizures on the lower part of the left hemiface and features meeting Leveson’s and Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV criteria for NMS. The patient passed away on the third day of admission. To the best of our knowledge, a case such as this has not been reported in the literature before.\n\n\nCase presentation\n\nA 29-year old woman with a past medical history of chronic psychosis and agitated behaviour presented to the Neurology Outpatient Department of Nelson Mandela Academic Central Hospital in Mthatha, South Africa in June 2020. For the past three months, the patient has been an inpatient at the Level I regional hospital because she presented with a sudden onset of confusion and restless behaviour, including jumping fences and foul language, palpitations, delusions of persecution, and anxiety. She also complained of tachycardia, diaphoresis, and urinary disturbances. The patient received Clopixol (200 mg IM monthly), Risperidone (2 mg PO nocte), Lorazepam (2.5 mg PO nocte), Valproic acid (600 mg PO twice), and (Haloperidol 2.5 mg twice a day) during this hospitalization. Laboratory tests revealed the following: haemoglobin, 11 g/Dl (normal range, 12–15 g/dL); erythrocyte sedimentation rate, 42mm/hr (0–10 mm/hr); creatine kinase, 3049 U/L (20–180 U/L); creatinine, 96 µmol/L (49–90 µmol/l); and alanine transaminase, 47 U/L (7–45 U/L). Cerebrospinal fluid (CSF) was normal.\n\nThe patient was admitted to the Neurology Outpatient Department due to altered mental status, permanent partial simple myoclonic seizure on the left lower hemiface, and involuntary upper limb movement. On examination, her blood pressure was labile (ranging from 129/79mmHg to –158/112 mm Hg), and she had tachycardia (119 beats/minute) and mild dehydration. The patient was fully conscious but disorientated to place and time with generalized muscle rigidity characterized by bilateral cogwheel signs at the wrist level and lead pipe signs on both elbows and knees. Bilateral resting tremors of the upper limbs with focal simple myoclonic seizures on the left lower face were observed. She had decreased muscle strength of all four limbs, which was more remarkable on the lower limbs (3/5), normal deep tendon reflexes, and generalized myalgias on palpation.\n\nOn the second day of admission, when were unaware of her previous treatments (especially the neuroleptics), the patient presented a temperature of 40.5°C. Based on her clinical picture and follow-up with the family by social workers on her previous medications, the diagnosis of NMS was made. The patient was started on Orphenadrine (50mg PO 8 hourly), L-dopa and Carbidopa (125 mg orally eight hourly), and Bromocriptine (5 mg loading dose then 2.5 mg three times daily).\n\nHaematological investigations were as follows: white cell count, 7.59 × 109/L (normal range, 3.90–12.60 ×109/L); ELISA test for HIV, positive; creatine phosphokinase, 1,467 U/L (20–180 U/L); Vitamin B12, 579 pmol/L (145–569 pmol/L); Toxoplasmosis ELISA, negative; VDRL, non-reactive; ferritin, 2136 ug/L (13–150 ug/L); iron, 2.2 µmol/L (9–30.4 µmol/L); transferrin, 1.32 g/L (2.5–3.8 g/L), percentage saturation, 10%; (15–50%) blood sugar, regular; hepatitis B surface Ag, negative; urea, 8.6 mmol/L (2.1–7.1 mmol/L); creatinine 112 µmol/L (49–90 µmol/L); alkaline COVID-19 test by PCR, negative; and CSF, average. Other blood test results (including CD4 and viral load) did not arrive during admission time. Computer tomography (CT) scan of the head was entirely normal.\n\nThere were no changes noted in her clinical condition during the period of her admission and on the third day of hospitalization, the patient died. No post-mortem examination was conducted due to wishes of the family.\n\n\nDiscussion\n\nThree previous studies have collected epidemiological data on NMS. One showed an incidence of 1.4% in 500 patients with one fatality recorded7. This study reported that a delay in diagnosis often occurs. Another study recorded an incidence of 1.4/1000 over three years4, the mortality rate was 14.28%, with 28% of patients developing NMS after antipsychotic medication. The third study conducted in Turkey from 1985 to 2005 reported on 36 patients, 22% of whom developed NMS after antipsychotic drug use8.\n\nIt has been shown that age and sex of patients do not have much of a role in NMS development. No specific neuropsychiatric conditions can predispose one to NMS; however, more catatonia cases have shown a propensity to progress to NMS. Other systemic factors include agitation, restraint, and exhaustion. Metabolic factors such as dehydration and low serum iron have been shown to predispose to NMS. Drugs like dopamine antagonists and high potency antipsychotics have a higher risk associated than low potency and atypical anti psychotics9,10.\n\nThe primary trigger causing NMS is dopamine receptor blockade, and the causative agent is an antipsychotic drug. The sudden cessation/reduction in the dosage of dopaminergic medications may also precipitate NMS11. Other drugs that are not neuroleptic, but have antidopaminergic activity, have also been implicated in NMS's causality (Table 1).\n\nClinical presentation of NMS usually has four so-called cardinal features, i.e. hyperthermia, muscular rigidity, autonomic instability, and altered consciousness level. However, many authors have reported more atypical presentations to this syndrome.\n\nHyperthermia of >38°C associated with profound diaphoresis is present in almost all cases reported and seems to be one of the most unifying factors in the different diagnostic criteria (discussed below)12. Fever can be of late-onset and may increase fatality, as a diagnosis of NMS may not be made to the lack of fever. Rigidity is commonly present as lead pipe/cogwheel signs13. However, it is also often associated with other neurological symptoms like tremors, sialorrhea, akinesia, dystonia, and dysphagia. Laboratory findings can help rule out other causes such as substance abuse and other systemic neurological or psychiatric conditions. Despite the following list being the most expected clinical presentation, as presented by the literature, none are specific to NMS11,13: elevated white cell count (leucocytosis); metabolic acidosis as shown by arterial blood gas and urea/electrolytes; elevated creatine kinase (CK); elevated serum muscle enzymes, e.g. lactic acid dehydrogenase and transaminases; elevated serum catecholamines, e.g. aldolase; and decreased serum iron levels. These presentations could lead to myoglobinuria and subsequent renal failure. CSF analysis in NMS patients is reported as normal in 95% of patients1. Similarly, imaging, e.g. CT of the brain and magnetic resonance imaging, show unremarkable findings1. Electroencephalogram shows features akin to those of metabolic encephalopathy1.\n\nReaching NMS diagnosis is not easy, as much of the disease mimics many other conditions. However, the American Psychiatric Association Diagnostic and Statistics Manual of Mental Disorders (DSM-IV; Table 2)13, the World Health Organisation International Classification of Diseases 10th revision (ICD-10), and the Caroff-Mann criteria from 1993 provide guidance. The most widely accepted diagnostic criteria is Levenson’s criteria, proposed in 1985, which has major and minor criteria for diagnosis; major criteria: fever, rigidity and elevated CK; minor criteria: labile blood pressure, tachypnoea, altered consciousness, and leucocytosis. All three of the major, or two major and four minor criteria must be met to diagnose NMS14.\n\nAccording to ICD-10, NMS is a fatal disease associated mainly with neuroleptic agents accompanied by dopaminergic receptor blockade in the lentiform nucleus, thalamus, head of caudate nucleus hypothalamus with autonomic dysregulation.\n\nCaroff and Mann present the following criteria for NMS diagnosis15: hyperthermia; muscle rigidity; use of neuroleptics within the last seven days; any five of altered mental status, tachypnoea, hypertension, tachycardia, hypotension, incontinence, diaphoresis, sialorrhea, elevated CK, myoglobinuria, or leucocytosis; absence of any other drug-induced, systemic, or neuropsychiatric disorder.\n\nThough many authors and clinicians have often not found common ground in the diagnostic criteria, Gurrera et al.16 showed that agreement was best between International Expert Consensus (IEC) criteria with a cut-off score of 74 and modified DSM-IV-TR criteria (sensitivity 69.6%, specificity 90.7%); this cut-off score demonstrated the highest agreement in all comparisons.\n\nThe sequelae of the condition usually happen after the initiation of neuroleptic drugs (or dopaminergic drugs). In about 16% of patients, NMS symptoms show within 24 hours; in another two thirds, symptoms show within one week; and almost all cases show symptoms at one month. Beyond a month, it is unlikely for the symptoms to start showing unless there has been an increase in the drugs' current dose1.\n\nDifferential diagnosis can be broadly separated into four systemic causes: environmental, endocrine or infections, toxic/pharmaceutical agents, and psychiatric/neurological causes1,11. We discuss examples and distinguishing features in Table 3.\n\nThe actual pathophysiology of NMS is still not elucidated, but one hypothesis is that an antipsychotic-induced dopamine blockade does play a key role in triggering NMS17. This is evidenced by the presentation of symptoms when initiating antipsychotics or stopping dopaminergic medications. Also, all reported drugs that have precipitated NMS have been dopamine receptor blocker medications. The decreased levels of homovanillic acid, a CSF metabolite of dopamine, also supports this theory18. Other hypotheses are that sympathoadrenal dysfunction has a contributory role in NMS19, or a low serum iron concentration can be a contributory factor in decreasing the number of dopaminergic receptors, thereby leaving patients susceptible to developing NMS. This is supported by the finding of low serum iron in patients with NMS20. A final theory is that multiple neuroendocrine and neurochemical dysregulation cascade can lead to this NMS1. Gurrera provides an excellent composite aggregation of the many postulated theories17.\n\nNMS should be considered an emergency by all managing physicians, and attending doctors should apply urgent treatment, even if the diagnosis is in doubt11. There have been no systemic trials or studies conducted towards the best management protocol for the condition, mostly due to its rarity. As always, and as with any medical condition, the treatment is tailored to the clinical setting and the patient, but based on the many case reports, the following seem to be the most effective.\n\nPrimarily, cessation of the causative neuroleptic medication or if it is suspected that NMS is because of the withdrawal of a particular dopaminergic drug, then restart it as soon as possible. Supportive therapy, such as aggressive rehydration, management of hyperthermia and management of any complications (e.g. cardiopulmonary failure, seizures or arrhythmias) should be then initiated. Finally, as the severity of the condition worsens, empirical medication should be used1,11, as follows:\n\nBromocriptine mesylate: a dopamine agonist, is used to reverse hypodopaminergic. The starting dose of 2.5mg per os is eight to 12 hours and quantity is increased by 2.5mg every 24 hours to a maximum amount of 45mg/day. This should be used for at least ten days when the NMS has been caused by oral neuroleptics and about 2–3 weeks where depot preparations denote the cause.\n\nDantrolene sodium: a muscle relaxant that inhibits calcium release from the sarcoplasmic reticulum. Starting dosage is 1–2.5mg/kg iv bolus, then followed by 1mg/kg every 6 hours, to a maximum dose of 10mg/kg/day. Oral dantrolene (50–200mg/day) can be used in other less severe cases or when tapering down from the intravenous form. Dantrolene should be discontinued as soon as symptoms start to improve, as it is associated with a high risk of hepatic toxicity.\n\nOther dopaminergic agents: the following have been reported in previous studies – amantadine hydrochloride21, levodopa22, and apomorphine23.\n\nBenzodiazepines: these have been used by clinicians to control agitation24.\n\nElectro convulsant therapy: a second-line treatment proposed for those patients not responding to empirical treatment25.\n\nThere is always a challenge when restarting neuroleptic medications for patients that need continuous treatment, especially regarding NMS recurrence. The literature consensus is that the drug should be reinitiated at the lowest possible dose, with reasonable precautions taken and close monitoring after approx. two weeks of recovery from an NMS episode in oral neuroleptics and about six weeks for depot preparations. However, many authors opine the use of different neuroleptic medication; we must bear in mind that this is an idiosyncratic disease11.\n\nAn algorithm adapted from Woodbury and Woodbury, which appears to be an invaluable tool in NMS management1,26.\n\nThere have been medical reports of cases where NMS has had atypical presentations and unexpected comorbidities12. In one large study comprising of 1346 patients from 2002 to 2011, the authors report the commonest complication to be rhabdomyolysis (30.1%), acute kidney injury (17.7%), acute respiratory failure (16.1%), and sepsis (6.2%). Mortality rate was 5.6%27. Hypoxemia and haemoconcentration that follow NMS predispose patients to cerebral infarction28. The use of neuroleptics in trauma centers for burn victims has precipitated NMS29. Complications can include dehydration, electrolyte imbalances, cardiac arrhythmias, aspiration pneumonia, myocardial infarction, deep venous thrombosis, and disseminated intravascular coagulation. Therefore, it is especially important to have close monitoring of patients.\n\nA morphometric study of cardiac patients previously conducted reports neuroleptic cardiomyopathy (NCMP) and patients who died from NMS. The authors of this study described the damage in those patients’ myocardium due to an acute process that involved disturbances in microcirculation, interstitial edema, and dystrophic degenerative changes of cardiomyocytes30. The severity of the myocardium damage in NMS is directly dependent on the NCMP, NMS, and HIV.\n\nThe incidence of NMS is high in HIV patients; the consensus is that it is so because of the changes that occur to the brain structure either from opportunistic infections secondary to HIV or to HIV itself. These patients have an increased possibility of developing NMS31. However, it has not been easy to get a thorough picture of the epidemiology since many NMS symptoms also fall under symptomatology caused by other opportunistic infections32. Nausea, vomiting, psychotic symptoms and agitation are all commonly seen in patients with HIV, and usually, many clinicians use neuroleptics to treat these symptoms33.\n\nHaloperidol is the most frequently associated medication with NMS. The main clinical signs are hyperthermia, rigidity, altered consciousness level, and autonomic disturbances. Hernández et al. present an algorithm adapted to manage patients with NMS (especially with extrapyramidal reactions) and HIV33.\n\nThere are scant publications about the presence of NMS and coronavirus disease 2019 (COVID-19). However, Soh et al.34 have reported that two of their patients on the ventilator due to the COVID-19 developed delirium when they received benzodiazepine and neuroleptics. The patients subsequently developed NMS, which was managed and resolved. Kajani et al.35 also reported a COVID-10 case with developed NMS, but the only causative agent they found was haloperidol given three weeks before onset. An autopsy showed a hyperaemic and oedematous brain. Therefore, it is unclear if COVID-19 itself can bring about changes that would lead to NMS due to changes it causes to the brain.\n\nOur patient meets the criteria by Levenson and the DSM-IV criteria for NMS36. She developed NMS most likely due to the administration of antipsychotic medication and secondary to an idiosyncratic reaction. This occurred a few weeks after initiation, but it can occur even if the patient has been taking the drug for months to years37. In our patient’s case, she had been on oral risperidone and haloperidol and the depot preparation of Clopixol for about eight weeks.\n\nOur patient’s risk factors for developing NMS were the fact that she was on three different antipsychotic medications, she was HIV positive (new diagnosis, previously unknown), and had low serum iron levels in the blood, such a case has been reported by other authors38. We want to highlight that our patient presented typical signs and symptoms for NMS and had elevated CK.\n\nThis case presented to us as we were dealing with the COVID-19 pandemic; and we were not aware of the psychiatric history at the time of admission, therefore a NMS diagnosis was made one day after admission. Social workers were recruited to track family members for a thorough history and medication details. The delay was not intentional, but the patient had what seemed like an atypical presentation. The atypical presentation of NMS was not evident immediately, as she presented with symptoms highly suggestive of COVID-19. Regarding other complications, our patient had a mild pre-renal injury, but blood results did not show the development of the other complications associated with NMS, as discussed above.\n\nThe recommendations for treatment of NMS currently are based on case reports and clinical experience as there is no published clinical trial to date. Therefore, NMS treatment of our patient followed the recommendations as discussed earlier: (1) stop causative agents; (2) aggressive supportive care (rehydration, treat hyperthermia, and other complications); and (3) specific medical therapy.\n\nIn our medical practice, we have treated a small group of HIV-positive women (N=5) with low CD4 count levels presenting with permanent focal simple motor seizures affecting the lower part of the face for a few days duration without other comorbidities followed by an unexpected death. We do not know the cause of death of these previously non-reported patients, but we believe that, to the best of our knowledge, it is the first time that NMS and this type of seizure in HIV patients has occurred in our region.\n\n\nConclusions\n\nWe report a young HIV-positive female patient who died due to NMS preceded by the intake of typical/atypical neuroleptics. Apart from her altered consciousness, autonomic disturbances, extrapyramidal signs, and high fever, she also with presented permanent focal simple motor seizures on the lower hemiface. After reviewing the available medical literature, we found no similar case reported in the medical literature.\n\n\nConsent\n\nWritten informed consent for publication of this case report, along with any associated images, was obtained from the mother of 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": "Acknowledgments\n\nWe extend our thanks to our patient’s family and relatives for granting us permission for the publication and the support received during her management.\n\n\nReferences\n\nStrawn JR, Keck PE Jr, Caroff SN: Neuroleptic malignant syndrome. Am J Psychiatry. 2007; 164(6): 870–6. PubMed Abstract | Publisher Full Text\n\nLaughon SL, Sowa NA, Gala GJ: Case Reports Complexities of Diagnosing Neuroleptic Malignant Syndrome in a Patient with Burn Injury: Could Stimulant Abuse be a Risk Factor? [cited 2020 Jun 23]. Reference Source\n\nRodnitzky R: Treatment of the neuroleptic malignant syndrome. In: Current Clinical Neurology. Humana Press Inc.; 2019 [cited 2020 Jun 24]; 305–7. Publisher Full Text\n\nPanagariya A, Sharma B, Singh R, et al.: The neuroleptic malignant syndrome: A report of 14 cases from North India. Neurol India. 2007 [cited 2020 Jun 23]; 55(2): 166–8. PubMed Abstract | Publisher Full Text\n\nKhaldi S, Kornreich C, Choubani Z, et al.: Neuroleptic malignant syndrome and atypical antipsychotics: A brief review. Encephale. Elsevier Masson SAS. 2008 [cited 2020 Jun 23]; 34(6): 618–24. PubMed Abstract | Publisher Full Text\n\nPelonero AL, Levenson JL, Pandurangi AK: Neuroleptic malignant syndrome: a review. Psychiatr Serv. 1998 [cited 2020 Jun 23]; 49(9): 1163–72. PubMed Abstract | Publisher Full Text\n\nKeck PE Jr, Pope HG Jr, Cohen BM, et al.: Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. 1989 [cited 2020 Jun 24]; 46(10): 914–8. PubMed Abstract | Publisher Full Text\n\nTural Ü, Önder E: Clinical and pharmacologic risk factors for neuroleptic malignant syndrome and their association with death. Psychiatry Clin Neurosci. 2010 [cited 2020 Jun 23]; 64(1): 79–87. PubMed Abstract | Publisher Full Text\n\nAnanth J, Parameswaran S, Gunatilake S, et al.: Neuroleptic malignant syndrome and atypical antipsychotic drugs. J Clin Psychiatry. 2004 [cited 2020 Jun 26]; 65(4): 464–70. PubMed Abstract | Publisher Full Text\n\nKeck PE Jr, Pope HG Jr, Cohen BM, et al.: Risk factors for neuroleptic malignant syndrome. A case-control study. Arch Gen Psychiatry. 1989 [cited 2020 Jun 26]; 46(10): 914–8. PubMed Abstract | Publisher Full Text\n\nBerman B: Neuroleptic Malignant Syndrome: A Review for Neurohospitalists. Neurohospitalist. 2011 [cited 2020 Jun 26]; 1(1): 41–7. PubMed Abstract | Publisher Full Text | Free Full Text\n\nCollins A, Davies D, Menon S: Atypical neuroleptic malignant syndrome. BMJ Case Rep. 2016; 2016: bcr2016214901. PubMed Abstract | Publisher Full Text | Free Full Text\n\nStrawn JR, Keck PE Jr, Caroff SN: Neuroleptic malignant syndrome. Am J Psychiatry. 2007; 164(6): 870–6. PubMed Abstract | Publisher Full Text\n\nLevenson JL: Neuroleptic malignant syndrome. Am J Psychiatry. 1985 [cited 2020 Jun 24]; 142(10): 1137–45. PubMed Abstract | Publisher Full Text\n\nCaroff SN, Mann SC, Keck PE Jr: Specific treatment of the neuroleptic malignant syndrome. Biol Psychiatry. 1998; 44(6): 378–81. PubMed Abstract | Publisher Full Text\n\nGurrera R, Mortillaro G, Velamoor V, et al.: A Comparison of DSM-IV and international expert consensus diagnostic criteria for NMS. Eur Psychiatry. 2017; 41(S1): S754. Publisher Full Text\n\nGurrera RJ: Sympathoadrenal hyperactivity and the etiology of neuroleptic malignant syndrome. Am J Psychiatry. 1999 [cited 2020 Jun 26]; 156(2): 169–80. PubMed Abstract\n\nNishijima K, Ishiguro T: Cerebrospinal fluid levels of monoamine metabolites and gamma-aminobutyric acid in neuroleptic malignant syndrome. J Psychiatr Res. 1995 [cited 2020 Jun 26]; 29(3): 233–44. PubMed Abstract | Publisher Full Text\n\nFeibel JH, Schiffer RB: Sympathoadrenomedullary hyperactivity in the neuroleptic malignant syndrome: a case report. Am J Psych. 1981 [cited 2020 Jun 26]; 138(8): 1115–6. PubMed Abstract | Publisher Full Text\n\nPatil BS, Singh S, Subramanyam A, et al.: Low serum iron as a possible risk factor for neuroleptic malignant syndrome. Int J Appl Basic Med Res. 2014 [cited 2020 Jun 23]; 4(2): 117–8. PubMed Abstract | Publisher Full Text | Free Full Text\n\nPirovino M, Meier J, Meyer M, et al.: [Malignant neuroleptics syndrome]. Dtsch Med Wochenschr. 1984 [cited 2020 Jun 29]; 109(10): 378–81. PubMed Abstract | Publisher Full Text\n\nHenderson VW, Wooten GF: Neuroleptic malignant syndrome: A pathogenetic role for dopamine receptor blockade? Neurology. 1981; 31(2): 132–7. PubMed Abstract | Publisher Full Text\n\nColosimo C, Merello M, Albanese A: Clinical usefulness of apomorphine in movement disorders. 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PubMed Abstract | Publisher Full Text\n\nPullicino P, Galizia AC, Azzopardi C: Cerebral infarction in neuroleptic malignant syndrome. J Neuropsychiatry Clin Neurosci. 1991 [cited 2020 Jun 23]; 3(1): 75–7. PubMed Abstract | Publisher Full Text\n\nGragnani A, Cezillo MVB, Oliveira AF, et al.: Neuroleptic malignant syndrome in trauma patients. Burns. Elsevier Ltd; 2015 [cited 2020 Jun 23]; 41(6): 1147–51. PubMed Abstract | Publisher Full Text\n\nVolkov VP: [Pathomorphology of the myocardium in the neuroleptic malignant syndrome]. Zh Nevrol Psikhiatr Im S S Korsakova. 2012 [cited 2020 Jun 23]; 112(4): 60–3. PubMed Abstract\n\nBreitbart W, Marotta RF, Call P: AIDS AND NEUROLEPTIC MALIGNANT SYNDROME. Lancet. 1988 [cited 2020 Jun 26]; 2(8626–8627): 1488–9. PubMed Abstract | Publisher Full Text\n\nPerry WW, Perry MD: 1990; 696–710.\n\nHernández JL, Palacios-Araus L, Echevarria S, et al.: Neuroleptic malignant syndrome associate to acquired immunodeficiency syndrome. Postgrad Med J. 1997 [cited 2020 Jun 26]; 73(866): 779–84. PubMed Abstract | Publisher Full Text | Free Full Text\n\nSoh M, Hifumi T, Isokawa S, et al.: Neuroleptic malignant syndrome in patients with COVID-19. Am J Emerg Med. 2020 [cited 2020 Jul 1]; 38(10): 2243.e1–2243.e3. PubMed Abstract | Publisher Full Text | Free Full Text\n\nKajani R, Apramian A, Vega A, et al.: Neuroleptic malignant syndrome in a COVID-19 patient. Brain Behav Immun. 2020 [cited 2020 Jul 1]; 88: 28–29. PubMed Abstract | Publisher Full Text | Free Full Text\n\nLevenson JL: Neuroleptic malignant syndrome. Am J Psychiatry. 1985; 142(10): 1137–1145. PubMed Abstract | Publisher Full Text\n\nPope HG Jr, Aizley HG, Keck PE Jr, et al.: Neuroleptic malignant syndrome: long-term follow-up of 20 cases. J Clin Psychiatry. 1991; 52(5): 208–12. PubMed Abstract\n\nBreitbart W, Marotta RF, Call P: AIDS and Neuroleptic Malignant Syndrome. Lancet. 1988; 332(8626–8627): 1488–1489. Publisher Full Text"
}
|
[
{
"id": "75587",
"date": "07 Dec 2020",
"name": "Ravindra Kumar Garg",
"expertise": [
"Reviewer Expertise CNS infections"
],
"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 nicely written case report. Though association of neuroleptic malignant syndrome (NMS) with HIV infection is not unique but topic has been adequately reviewed. Another point I want to make that possibly EEG was not done. I agree that many cases of neuroleptic malignant syndrome in COVID-19 has been described and authors have reviewed them as well.\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": "6173",
"date": "09 Dec 2020",
"name": "Humberto Foyaca-Sibat",
"role": "Author Response",
"response": "Dear Prof Ravindra Kumar Garg Thanks a lot for your revision; we highly appreciate your recommendations. It has been a great sense of delight to receive your very nice and professional comments. Kindest regards Prof. Foyaca MD. Ph.D"
}
]
}
] | 1
|
https://f1000research.com/articles/9-1382
|
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