Prognostic Factors of COVID-19: An Umbrella Review Endorsed by the International Society for Pharmacoepidemiology.

During the coronavirus disease 2019 (COVID-19) pandemic, the urgency for updated evidence to inform public health and clinical care placed systematic literature reviews (SLRs) at the cornerstone of research. We aimed to summarize evidence on prognostic factors for COVID-19 outcomes through published SLRs and to critically assess quality elements in the findings' interpretation. An umbrella review was conducted via electronic databases from January 2020 to April 2022. All SLRs (and meta-analyses) in English were considered. Data screening and extraction were conducted by two independent reviewers. AMSTAR 2 tool was used to assess SLR quality. The study was registered with PROSPERO (CRD4202232576). Out of 4,564 publications, 171 SLRs were included of which 3 were umbrella reviews. Our primary analysis included 35 SLRs published in 2022, which incorporated studies since the beginning of the pandemic. Consistent findings showed that, for adults, older age, obesity, heart disease, diabetes, and cancer were more strongly predictive of risk of hospitalization, intensive care unit admission, and mortality due to COVID-19. Male sex was associated with higher risk of short-term adverse outcomes, but female sex was associated with higher risk of long COVID. For children, socioeconomic determinants that may unravel COVID-19 disparities were rarely reported. This review highlights key prognostic factors of COVID-19, which can help clinicians and health officers identify high-risk groups for optimal care. Findings can also help optimize confounding adjustment and patient phenotyping in comparative effectiveness research. A living SLR approach may facilitate dissemination of new findings. This paper is endorsed by the International Society for Pharmacoepidemiology.

Do tax and subsidy on unhealthy food induce consumer consumption for healthy food? Evidence from experiment in Surabaya, Indonesia.

Background: This study investigates the impact of price changes on decision to buy particular foods among adults in Surabaya, East Java, Indonesia. Tax and subsidy were introduced for influencing decision buy particular foods, especially unhealthy foods that are predicted have consequences on health outcome. Unhealthy foods such as fast foods or junk foods, sugar sweetened beverages (SSB), salty, and fatty foods are reported as one of main causes of obesity incidence in most countries, such as Indonesia. Design and method: Computer laboratory experimental is designed for investigating the impacts of difference rates of taxes and subsidy on decision to buy foods. Taxes and subsidies rate are designed from low (5%), moderate (15%), and high rates (25%). Results: The findings are as follows. Firstly, participants do not respond immediately to price changes, that is, higher prices due to taxes and lower prices due to subsidies. Economic theory suggests that consumers demand for basic need such as foods is sensitive with change in price, they respond inversely to the price changes. However, the finding in this experimental study do not support this theory prediction. Secondly, 15% and subsidies are the threshold and the larger taxes and rate for changing consumer's choices on targeted foods. Conclusion: This study concludes that low rates of taxes and subsidies for unhealthy and healthy foods make these targeted foods affordable for majority of consumers. Besides introducing higher rates of taxes and subsidies, promoting and encouraging healthy life style such as consuming fresh and healthy foods is another alternative policy option.

Effectiveness of an Integrated Nutrition Rehabilitation on Growth and Development of Children under Five Post 2018 Earthquake in East Lombok, Indonesia.

BACKGROUND: In August 2018 Lombok Island in Indonesia was hit by a 7 Richter scale earthquake. This study aimed to assess the effectiveness of comprehensive nutrition disaster rehabilitation, based on the holistic integrated early child development concept, on the growth and development of children under five. METHODS: A community-based intervention was performed in the East Lombok district; four villages in two sub-districts were randomly allocated into intervention or control groups. Mothers of 6-49-month-old children in the intervention group (n = 240) attended parenting classes (twice weekly) and received shredded fish/liver/anchovy and optimized complementary feeding/food-based recommendations, developed using linear programming. Health staff from the public health center and teachers from early childhood education (ECE) centers delivered parenting sessions on health-nutrition and care-education. The control group (n = 240) received existing health services. Indicators measured at baseline and the end line point were weight, length/height, hemoglobin, feeding practices, psychosocial care (HOME) and maternal stress (SRQ). At the end line point, child development was assessed using BSID-III. RESULTS: At the end line point, maternal stress and child morbidity (cough) were lower and dietary diversity (+1) in 6-23-month-old children, and weight-for-age Z-score (+0.26) and social emotional score (+10 points) in ≥24-month-old children were higher in the intervention group. CONCLUSIONS: The nutrition rehabilitation intervention delivered through ECE centers has a positive effect on the growth and development of children under five in post-disaster conditions.

Regulatory oversight on the use of experimental therapies during a pandemic: The case of early access to convalescent plasma therapy in three LMICs.

Clinicians, especially in low- and middle-income countries (LMICs), contend with limited economic and healthcare resources in deciding appropriate and feasible care for their patients. Some of the LMICs affected by COVID-19 implemented convalescent plasma therapy without sufficient regulatory guidance. Based on this experience, there are several requirements going forward, including: the need for an immediately accessible data gathering and processing system; the necessity of establishing regulatory pathways for early access to experimental treatment during emergency situations; and the accompanying reporting and monitoring requirements must be set. The different stakeholders must also be properly incorporated in the system that such a pathway will create, without neglecting to properly inform the public of the patient rights especially during an emergency situation.

Long working hours, poor sleep quality, and work-family conflict: determinant factors of fatigue among Indonesian tugboat crewmembers.

BACKGROUND: Tugboat crewmembers are susceptible to fatigue during their 24-h work shifts, despite the availability of rest time. The fatigue experienced by seafarers contributes to marine accidents and metabolic and cardiovascular diseases, which have long-term effects. This study aimed to analyse the association between working hours and fatigue and other possibly related factors in tugboat crewmembers. METHOD: This comparative cross-sectional study included 127 tugboat crew members from 15 randomly chosen tugboats in Samarinda Harbor, Indonesia. Their fatigue levels while at work were measured using a reaction timer and standardised questionnaire. Personal and occupational data of crewmembers, including age, marital status, rating (job ranking), duration on board, length of seafaring experience, watch system, smoking status, coffee and alcohol consumption, and working hours, were collected. Moreover, sleep quality and stress levels related to work-family conflict were measured and analysed using the Pittsburgh Sleep Quality Index (PSQI) and Work-Family Conflict Scale (WCFS), respectively. RESULTS: The study found that 40.2% of the subjects were classified as having fatigue. The determinant factors were long working hours (> 72 h/week), poor sleep quality, and work-family conflict [adj. OR = 13.32; 95%-CI (4.78-31.23)] and p < 0.001, [adj. OR = 4.49 (1.39-14.52)] and p = 0.012, [adj. OR = 2.87 (1.12-7.33)] and p = 0.028, respectively. However, personal and occupational factors, including age, marital status, duration on board, length of seafaring experience, smoking status, and coffee and alcohol consumption, were not significantly associated with crewmember fatigue. CONCLUSION: The incidence of fatigue among Indonesian tugboat crewmembers operating on the Mahakam River was considerably high. Working hours, sleep quality, and work-family conflict were strongly associated with fatigue in tugboat crewmembers; therefore, the working hours of tugboat crewmembers need to be improved. Crewmember lifestyle variables need to be studied further.

Development of a module for the prevention of nonsteroidal anti-inflammatory drugs-associated gastrointestinal adverse reactions in the elderly at a primary health center.

BACKGROUND: The prevention of nonsteroidal anti-inflammatory drugs (NSAIDs) adverse reactions should start from the primary health center (PHC), as the first gatekeeper in community health services. However, there is no specific module available for health care professionals (HCPs) in Indonesia for the prevention of adverse drug reactions (ADR) at PHCs. NSAID is commonly used for the elderly treated at PHC in Indonesia, even though the ADR risk is well-known. OBJECTIVE: We aimed to develop a module to be used in PHC for preventing NSAID-associated upper gastrointestinal (GI) ADRs in elderly patients treated for musculoskeletal diseases. METHODS: The module was developed based on inputs from focus group discussions (FGD) among government health officers, PHC representatives, clinical pharmacologists, internal medicine and community medicine clinicians, pharmacovigilance experts, and professional organizations. A pilot implementation was conducted to test its feasibility and its effect on the HCPs' knowledge. RESULTS: Capacity building of HCPs, development of intra-HCP cooperation, as well as standard operating procedure (SOP) for the prescription of NSAID constituted important components of the module. A pilot study of the module in two PHCs showed that it was applicable with some recommendations for improvement in duration, number of participants, room space, presentation, and use of credit points as compliments. The HCPs' knowledge was improved after following the module. CONCLUSIONS: Our study showed that the module is feasible in PHC in Indonesia and useful in improving knowledge of HPC.

Impact of Serum Human Chorionic Gonadotropin and Luteinizing Hormone Receptor Expression to Oocyte Maturation Rate: A Study of Controlled Ovarian Stimulation.

BACKGROUND: Few studies have assessed the impact of serum human chorionic gonadotropin (hCG) levels before oocyte retrieval and luteinizing hormone receptor (LHR) mRNA expression. AIMS: The objective was to assess the correlations between serum hCG levels at 12-h posttrigger granulosa cell LHR mRNA expression during the in vitro fertilization (IVF) cycle with oocyte maturation rate and to determine the cutoff level of serum hCG at 12-h posttrigger. SETTINGS AND DESIGN: A cross-sectional was conducted for this study at the IVF center of Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia. MATERIALS AND METHODS: Recombinant follicle-stimulating hormone was used on day 2 of the menstrual cycle with multiple doses of a gonadotropin-releasing hormone antagonist. Recombinant hCG was used to trigger ovulation. At 12-h posttrigger, hCG serum levels were measured using an enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS: Pearson's correlation coefficient was used to evaluate the correlation between oocyte maturation rates, serum hCG levels, and LHR mRNA levels. Cutoff values were determined using a receiver operating characteristic (ROC) curve. RESULTS: Serum hCG levels were positively correlated (r = 0.467;P < 0.01), and LHR mRNA expression was weakly correlated (r = 0.073; P = 0.701) with oocyte maturation. The cutoff of serum hCG for a high maturation rate was 77 mIU/mL, with an area under the ROC curve of 0.765 (95% confidence interval: 0.598-0.939) andP < 0.001. CONCLUSION: Oocyte maturation is correlated with serum hCG levels with 77 mIU/mL as the cutoff point for oocyte retrieval.

The implementation of community-based diabetes and hypertension management care program in Indonesia.

Since 2010, Indonesian government has initiated a chronic disease management program, Prolanis (Program Pengendalian Penyakit Kronis) targeted for diabetes and hypertension. The program is continued at the commencement of universal health coverage (UHC) in 2014. "This study aimed to report the utilization and cost of the implementation of Prolanis in Indonesia from 2014 to 2016, or two years since the commencement of Indonesian universal health coverage." Secondary data analysis was performed using publicly available data and data obtained from the national health insurance agency (BPJS); while data on disease prevalence were collected from basic national health survey. There was an increase trend of Prolanis participants, from around 11,000 participants in 2014 to more than 250,000 in 2016. More than 70% of participants were adults living in Java, however, the acceptance rate was very low in other area. Across different activities in Prolanis, physical activity was the most participated ones. In comparison to other regions, regions in Java were the most active area. The total expenditure for Prolanis program in 2016 increased almost triple from the annual cost in 2014. However, the cost per person was actually decreased more than 50%. Within two years of UHC implementation, there were increase covered participants and total costs, but cost per individual was decreased and there was significant difference in of cost between Java and outside Java. Further study and routine monitoring-evaluation process by health authority is needed to assess whether the cost difference would affect the service quality.

Mass screening vs lockdown vs combination of both to control COVID-19: A systematic review.

Coronavirus disease 2019 (COVID-19) is a global pandemic. Non-pharmacological interventions, such as lockdown and mass testing, remain as the mainstay of control measures for the outbreak. We aim to evaluate the effectiveness of mass testing, lockdown, or a combination of both to control COVID-19 pandemic. A systematic search on 11 major databases was conducted on June 8, 2020. This review is registered in Prospero (CRD420201 90546). We included primary studies written in English which investigate mass screening, lockdown, or a combination of both to control and/or mitigate the COVID-19 pandemic. There are four important outcomes as selected by WHO experts for their decision- making process: incident cases, onward transmission, mortality, and resource use. Among 623 studies, only 14 studies met our criteria. Four observational studies were rated as strong evidence and ten modelling studies were rated as moderate evidence. Based on one modelling study, mass testing reduced the total infected people compared to no mass testing. For lockdown, ten studies consistently showed that it successfully reduced the incidence, onward transmission, and mortality rate of COVID-19. A limited evidence showed that a combination of lockdown and mass screening resulted in a greater reduction of incidence and mortality rate compared to lockdown only. However, there is not enough evidence on the effectiveness of mass testing only.

Country Characteristics and Variation in Diabetes Prevalence among Asian Countries - an Ecological Study.

OBJECTIVES: To determine the variation in diabetes prevalence across Asian countries and its relationship with the quality of health system and socioeconomic characteristics of the country. METHODOLOGY: An ecological analysis was conducted using publicly available data from the World Bank, the World Health Organization and the International Diabetes Federation. Geographical variation in diabetes prevalence across countries was examined using control charts while the relationships between country-level determinants and diabetes prevalence were investigated using linear regression analysis. RESULTS: The control chart shows special-cause variation in diabetes prevalence in 21 (58%) of the Asian countries; nine countries were below the 99.8% control limits while twelve were above it.Fifteen (42%) countries suggest common-cause variation. Three country characteristics independently associated with diabetes prevalence were hypertension prevalence (OR 0.39, 95% CI 0.22 to 0.55; p-value<0.001), obesity prevalence (OR 0.15, 95% CI 0.13 to 0.18; p-value<0.001), and quality of health care governance (OR 0.18, 95% CI 0.04 to 0.34; p-value=0.02). CONCLUSIONS: There is a considerable geographical variation in diabetes prevalence across Asian countries. A substantial part of this variation could be explained by differences in the quality of health care governance, hypertension prevalence and obesity prevalence.

Adapting clinical guidelines in low-resources countries: a study on the guideline on the management and prevention of type 2 diabetes mellitus in Indonesia.

RATIONALE, AIMS AND OBJECTIVES: Most of the clinical guidelines in low-resource countries are adaptations from preexisting international guidelines. This adaptation can be problematic when those international guidelines are not based on current evidence or original evidence-based international guidelines are not followed. This study aims to evaluate the quality of an Indonesian type 2 diabetes mellitus guideline adapted from selected international guidelines. METHODS: The "Consensus on the Management and Prevention of type 2 Diabetes in Indonesia 2011" is a guideline by the Indonesian Society of Endocrinology (Perkeni). Four parent guidelines identified from its list of references were from the International Diabetes Federation (IDF), American Association of Clinical Endocrinologist (AACE), American Diabetes Association (ADA), and one jointly released by ADA and European Association for the Study of Diabetes (EASD). Two reviewers independently assessed its quality using the Appraisal of Guidelines, Research and Evaluation Collaboration (AGREE II) instrument. Six recommendations were compared: (1) screening for diabetes; (2) diagnosis; (3) control of hyperglycemia; (4) target blood glucose; (5) target blood pressure; and (6) treatment of dyslipidemia. RESULTS: Perkeni's guideline satisfied 55% of the AGREE II items, while its parent guidelines satisfied 59% to 74%. Perkeni's shows low score on "rigor of development" and "applicability" and the lowest score in the "scope and purpose" domain. Differences were found in 4 recommendations: the screening of diabetes, control of hyperglycemia, target blood glucose, and treatment of dyslipidemia. In 3 of 4, Perkeni followed the ADA's recommendation. CONCLUSION: Derivation of recommendations from parent guidelines and their adaptation to the context of Indonesian health care lacks transparency. When guidelines are either derived from other guidelines or adapted for use in different context, evidence-based practice principles should be followed and adhered to.

Developing alerting thresholds for prospective drug safety monitoring.

BACKGROUND: Current methods for prospective drug safety monitoring focus on determining whether and when to generate safety alerts indicating that a new drug may be less safe than a comparator. Approaches are needed to develop safety thresholds that can be used to define whether a new drug is no less than or equally safe as the comparator. OBJECTIVES: Our aim is to develop a framework for determining which safety statements can be made about a new drug and when they can be made during prospective monitoring. METHODS: We developed a two-pronged approach to establish safety thresholds for active monitoring. First, we adapted concepts from setting margins in non-inferiority (NI) trials ("NI approach"). Second, we summarized NI margins used in published randomized trials and reviewed publicly available data from the US FDA's website to identify the type and magnitude of evidence used in regulatory decisions involving withdrawals and black box warnings between 2009 and 2013 ("benchmark approach"). We applied the framework to a case study of dabigatran versus warfarin and major bleed. RESULTS: We provide formulas on both risk ratio and risk difference scales for the NI approach that are analogous to threshold setting in NI trials but based on point estimates and using a maximum tolerable increase rather than a preservation factor. Using this approach, we established a safety threshold for the dabigatran case study that was within range of the findings from the benchmark approach (1.18 to 7.30). Comparing the safety threshold with post-approval studies of dabigatran versus warfarin indicated that no safety statement can be made. CONCLUSIONS: The proposed framework expands the safety statements that can be made in current prospective drug safety monitoring systems. Copyright © 2015 John Wiley & Sons, Ltd.

Indonesian prostate cancer risk calculator (IPCRC): an application for predicting prostate cancer risk (a multicenter study).

AIM: to develop a prediction risk model of prostate cancer based on Indonesia population. METHODS: we included all benign prostate hyperthrophy (BPH) and PCa patients who had prostate biopsy and prostatectomy between January 2009 and December 2013 from 5 urology centers in Indonesia. The relationship between the possibility of PCa with the following variables including: age; PSA level, prostate volume (by transabdominal ultrasound or transrectal ultrasound) and digital rectal examination (DRE) finding. We calculated a predictive scoring equation to predict the possibility of PCa using chi-square analysis, Kolmogorov-Smirnov test, multiple logistic regression and ROC curve. Then, we designed an application for predicting prostate cancer risk called Indonesian Prostate Cancer Risk Calculator (IPCRC). RESULTS: there were 784 PCa and 1173 BPH patients were used for developing the risk calculator in our study. The mean ages, PSA and prostate volume are 66.9±8.1 years old; 72.4±248.9 ng/ml and 49.6±28.2 ml, respectively. Abnormal DRE was found in 637 PCa and 56 BPH. We included age, PSA level, abnormal DRE finding (all showed significant p<0.05 in univariate model). Additionally, although not significant, we included prostate volume (p=0.157) due to its clinical importance. The corrected ROC analysis showed AUC 0.935, sensitivity of 90.1% and specificity 80% in predicting the prostate cancer in our population. CONCLUSION: we have developed the Indonesian Prostate Cancer Risk Calculator which includes age, PSA, DRE, and prostate volume as its variables. Future prospective study to validate the risk calculator is needed.

Quality and reporting of publications by Indonesian researchers: a literature survey.

OBJECTIVES: To evaluate the quality of reporting of the risk of bias of the Indonesian medical research. METHODS: Publications from PubMed and non-PubMed indexed Indonesian medical journals between January 2008 to December 2010 were assessed for risk of bias based on criterion combination from Hedges-criteria and the Oxford Center for Evidence-Based Medicine. We assessed whether the publications addressed the risk of bias adequately (quality of reporting) and whether the risk of bias criterion was fulfilled (quality of methods). The quality (both of reporting and of methods) of a study was classified as "high" if, for at least two-thirds of the criteria were adequately reported and fulfilled. It was classified as "low" when only one-third of the criteria were reported and or fulfilled. RESULTS: Of the 1753 publications, 29% (n = 507) were original medical research. For 21% (109/507) the quality of reporting was high; for 15% (77/507) the quality of methods was high. The proportion of high quality was significantly higher among PubMed than non-PubMed, with difference between proportions: (95%CI of difference: 3 to 23). CONCLUSION: A small proportion of Indonesian studies have high quality of reporting or methods. When international reporting guidelines are endorsed and followed, the quality of future studies may improve.

Regulatory scientific advice on non-inferiority drug trials.

The active-controlled trial with a non-inferiority design has gained popularity in recent years. However, non-inferiority trials present some methodological challenges, especially in determining the non-inferiority margin. Regulatory guidelines provide some general statements on how a non-inferiority trial should be conducted. Moreover, in a scientific advice procedure, regulators give companies the opportunity to discuss critical trial issues prior to the start of the trial. The aim of this study was to identify potential issues that may benefit from more explicit guidance by regulators. To achieve this, we collected and analyzed questions about non-inferiority trials posed by applicants for scientific advice in Europe in 2008 and 2009, as well as the responses given by the European Medicines Agency (EMA). In our analysis we included 156 final letters of advice from 2008 and 2009, addressed to 94 different applicants (manufacturers). Our analysis yielded two major findings: (1) applicants frequently asked questions 'whether' and 'how' to conduct a non-inferiority trial, 26% and 74%, respectively, and (2) the EMA regulators seem mainly concerned about the choice of the non-inferiority margin in non-inferiority trials (36% of total regulatory answers). In 40% of the answers, the EMA recommended using a stricter margin, and in 10% of the answers regarding non-inferiority margins, the EMA questioned the justification of the proposed non-inferiority margin. We conclude that there are still difficulties in selecting the appropriate methodology for non-inferiority trials. Straightforward and harmonized guidance regarding non-inferiority trials is required, for example on whether it is necessary to conduct such a trial and how the non-inferiority margin is determined. It is unlikely that regulatory guidelines can cover all therapeutic areas; therefore, in some cases regulatory scientific advice may be used as an opportunity for tailored advice.

Phase IV non-inferiority trials and additional claims of benefit.

BACKGROUND: Non-inferiority (NI) trials in drug research are used to demonstrate that a new treatment is not less effective than an active comparator. Since phase IV trials typically aim at informing a clinical decision, the value of a phase IV non-inferiority trial hinges also on its clinical relevance. In such trials, clinical relevance would refer to the added benefit claims of a specific drug, apart from efficacy, relative to its comparator drug in the trial. METHODS: In this study, we reviewed 41 phase IV trials and extracted information on whether the authors mentioned any additional benefit beyond the NI (efficacy) claim of the drug and whether the additional benefit was proven in the trial. We checked whether the additional claim was based on descriptions only or on formal statistical analyses. RESULTS: Our results showed that 22 out of the 41 NI trials mentioned additional benefit of the test drug and most of these claims were related to the safety profile. Of all the post-authorization NI trials that claimed additional benefit, 10 out of 22 NI trials used formal statistical analyses to show additional benefit, and only one included a sample size calculation for the additional benefit prior to the trial. CONCLUSION: We conclude that there is room for improvement in terms of designing phase IV NI trials with added benefit claims and in proving these additional claims.

Should non-inferiority drug trials be banned altogether?

Non-inferiority (NI) trials can be used in a situation when a new drug is expected to have a similar efficacy to its comparator but can offer other advantages over the existing drug, such as a more convenient method of administration or fewer side effects. Here, we discuss the advantages and disadvantages of NI trials from an ethical, methodological and regulatory perspective. We suggest that such trials should be designed to address simultaneously the objective of showing NI with regard to drug efficacy and the objective of establishing superiority of the additional advantages of a drug over its active comparator.