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Abstract A research protocol is a document that outlines the proposed research idea and is submitted to funding agencies, institutions, or journals for approval. Writing a research protocol represents a challenge, particularly for early-career researchers. In this guide, we aim to provide detailed guidance with the key components and offer practical tips for crafting a research protocol in line with the various study designs. Specifically, the structure of a research protocol should contain the following items: (1) a title that is specific, catchy, and impressive within the word limitation; (2) an abstract that briefs the critical points of the study; (3) an introduction highlighting the study context from broad to narrow and defining the knowledge gap; (4) a justification underlining the significance of the proposed study; (5) Specific, Measurable, Attainable, Relevant, and Time-bound (SMART) objective(s) and aim(s); (6) a methodology covering seven sub-items, including [i] study design and settings, [ii] study subjects, [iii] sample size calculation and sampling, [iv] participants recruitment and follow-up, [v] questionnaire development, [vi] potential variables and outcomes, and [vii] data analysis plan; (7) dissemination of the results; (8) ethics and conflict of interests; (9) budgets analysis/ funding disclosure; and (10) references. This guide will give an overview of these steps and provide clear and concise tips on how to successfully draft a scientific protocol. With careful planning and appropriate guidance, it is possible to develop a well-structured and compelling protocol to obtain approval for the conduction of the study or funding from agencies, institutions, or organizations.

Abstract Our study describes the reported rate of the Institutional Review Board (IRB) approval, declaration of Helsinki (DoH), and informed consent in the case reports and case series and investigates factors associated with the ethical approval report. We searched PubMed for case reports and case series from 2006 to 2017. Annually, we obtained the first 20 articles of a case report cluster from 20 distinct publications. This analysis initially contained at least 2400 papers, with 100 papers each study design and year. Only 26 (5.4%) of 480 included studies reported IRB approval, DoH approval, and participant informed consent; 58 (12.1%) reported two out of three ethical statements (DoH, informed consent, IRB); and 151 (31.5%) reported only one, leading to nearly 245 studies (51.0%) did not report any ethical approval item. Both clusters mentioned the DoH the least. Only years, ages, ethical item types, and cluster types were associated with ethical reporting practices. This study found the serious under‐reporting of ethical practices in both case reports and case series.

Abstract Backgrounds The success of direct‐acting antiviral (DAA) therapy provides a cure for patients chronically infected with hepatitis C virus (HCV); however, outcomes after hepatectomy for HCV‐associated hepatocellular carcinoma (HCC) before and after DAA introduction remain poorly studied. Methods Patients who underwent R0/R1 hepatectomy for HCV‐associated HCC were retrospectively analyzed. Two time periods were defined: Pre‐DAA (2007–2011, December 2013 was defined as the end of follow‐up) and Post‐DAA groups (2014–2018, December 2020 was defined as the end of follow‐up). Propensity score matching (PSM) analyses were performed to highlight the effect of DAA therapy. Results A total of 155 patients with HCV‐associated HCC were included in this study (Pre‐DAA group, n = 103 and post‐DAA group, n = 52). In the Post‐DAA group, DAA therapy was performed in 26 patients (50.0%), and all of these patients achieved sustained virologic response (SVR) (preoperative SVR, n = 7; postoperative SVR, n = 19). There was no significant difference between the two groups regarding surgical settings and tumor pathology. There was no significant difference in the 5‐year overall survival (OS) rate (61.1% and 64.8%, pre‐ and post‐DAA group, respectively, p = 0.441); meanwhile, the 5‐year recurrence‐free survival (RFS) rate in the post‐DAA group was better than the pre‐DAA group (21.1% and 40.2%, p = 0.073) with a trend toward significance. After PSM except for the postoperative SVR status, there were no significant differences in OS (p = 0.586) and RFS (p = 0.888). Conclusions This study showed that survival outcomes were not changed in hepatectomized cases of HCV‐associated HCC before and after the introduction of DAA therapy.

Abstract Background Meta-analyses are on top of the evidence-based medicine pyramid, yet many of them are not completed after they are begun. Many factors impacting the publication of meta-analysis works have been discussed, and their association with publication likelihood has been investigated. These factors include the type of systematic review, journal metrics, h-index of the corresponding author, country of the corresponding author, funding sources, and duration of publication. In our current review, we aim to investigate these various factors and their impact on the likelihood of publication. A comprehensive review of 397 registered protocols retrieved from five databases was performed to investigate the different factors that might affect the likelihood of publication. These factors include the type of systematic review, journal metrics, h-index of the corresponding author, country of the corresponding author, funding sources, and duration of publication. Results We found that corresponding authors in developed countries and English-speaking countries had higher likelihoods of publication: 206/320 (p = 0.018) and 158/236 (p = 0.006), respectively. Factors affecting publications are the countries of corresponding author (p = 0.033), whether they are from developed countries (OR: 1.9, 95% CI: 1.2–3.1, p = 0.016), from English-speaking countries (OR: 1.8, 95% CI: 1.2–2.7, p = 0.005), update status of the protocol (OR: 1.6, 95% CI: 1.0–2.6, p = 0.033), and external funding (OR: 1.7, 95% CI: 1.1–2.7, p = 0.025). Multivariable regression retains three variables as significant predictors for the publication of a systematic review: whether it is the corresponding author from developed countries (p = 0.013), update status of the protocol (p = 0.014), and external funding (p = 0.047). Conclusion Being on top of the evidence hierarchy, systematic review and meta-analysis are the keys to informed clinical decision-making. Updating protocol status and external funding are significant influences on their publications. More attentions should be paid to the methodological quality of this type of publication.

From an ethyl acetate extract of the barks of Chukrasia tabularis, three compounds including one limonoid (tabularisin A), one flavonoid (quercetin), and one coumarin (scopoletin) were isolated by chromatographic methods. Their structures were comfirmed by analysis of spectroscopic data (ESI-MS, 1H-NMR, 13C-NMR, DEPT, HMBC, HSQC và COSY) and by comparison with the literature reports.

Background: The Japanese government advised mild or asymptomatic coronavirus disease-2019 (COVID-19) cases to self-isolate at home, while more severe individuals were treated at health posts. Poor compliance with self-isolation could be a potential reason for the new outbreak. Our study aimed to find out the correlation between the rising new cases of COVID-19 and home-based patients in Japan. Methods: A secondary data analysis study was conducted with the data from COVID-19- involved databases collected from Johns Hopkins University, Japanese Ministry of Health, Labour and Welfare, and Community Mobility Reports of Google. New community cases, stringency index, number of tests, and active cases were analyzed. Using a linear regression model, an independent variable was utilized for a given date to predict the future number of community cases. Results: Research results show that outpatient cases, the stringency, and Google Mobility Trend were all significantly associated with the number of COVID-19 community cases from the sixth day to the ninth day. The model predicting community cases on the eighth day (R2=0.8906) was the most appropriate showing outpatients, residential index, grocery and pharmacy index, retail and recreation index, and workplaces index were positively related (β1=24.2, 95% CI: 20.3– 26.3, P

Objectives: This study aimed to evaluate the efficacy and adverse events of favipiravir in patients with COVID-19. Methods: Our protocol was registered on PROSPERO (CRD42020206305). Fourteen databases were searched until February 8th, 2021. An update search for new RCTs was done on March 2nd, 2022. Meta-analysis was done for randomized controlled trials (RCTs) and non-RCTs. Results: Overall, 157 studies (24 RCTs, 1 non-RCT, 21 observational studies, 2 case series, and 106 case reports) were included. On hospitalized patients, in comparison to standard of care, favipiravir showed a higher rate of viral clearance at day 5 (RR = 1.60, p = 0.02), defervescence at day 3–4 (RR = 1.99, p

Abstract Introduction Approximately 1000 children die each year due to preventable water and sanitation-related diarrheal diseases. Six in 10 people lacked access to safely managed sanitation facilities in 2015. Numerous community- and school-based approaches have been implemented to eradicate open defecation practices, promote latrine ownership, improve situation sanitation, and reduce waterborne disease. Objective Given that current evidence for sanitation interventions seem promising, the aim of this study was to systematically summarize existing research on the effectiveness of community- and school-based randomized controlled sanitation intervention in improving (1) free open defecation (safe feces disposal), (2) latrine usage, (3) latrine coverage or access, and (4) improved latrine coverage or access. Methods Eight electronic databases were searched: PubMed, Scopus, WHO Global Health Library (GHL), Virtual Health Library (VHL), POPLINE, Web of Science, Cochrane, and Google Scholar up to 26 April 2019. Original randomized clinical trials addressing community-based or school-based intervention that reported feces disposal and latrine coverage were deemed eligible. More than two researchers independently contributed to screening of papers, data extraction, and bias assessment. We conducted a meta-analysis by random-effects model. The risk of bias was assessed by the Cochrane risk of bias tool. Results Eighteen papers that matched all criteria and 16 studies were included in the final meta-analysis. Compared to the control, the sanitation intervention significantly increased safe feces disposal (OR 2.19, 95% CI 1.51–3.19, p < 0.05, I 2 = 97.28), latrine usage (OR 3.72, 95% CI 1.71–8.11, p < 0.05, I 2 = 91.52), latrine coverage or access (OR 3.95, 95% CI 2.08–7.50, p < 0.05, I 2 = 99.07), and improved latrine coverage or access (OR 3.68, 95% CI 1.52–8.91, p < 0.05, I 2 = 99.11). A combination of education and latrine construction was more effective compared to educational intervention alone. Conclusion Our study showed strong evidence for both community- and school-based sanitation interventions as effective for the safe disposal of human excreta. The finding suggests major implications for health policy and design of future intervention in developing countries.

Background: The diagnosis of osteomyelitis is invasive and expensive as the current standard technique is the bone biopsy. Our aim was to compare the degree of agreement and concordance between standard bone biopsy and other non-bone techniques. Methods: We performed an electronic search through 12 electronic databases to retrieve relevant studeis. Our criteria included any original article that reported the degree of agreement and/or the concordance between bone biopsy and other non-bone techniques in diagnosing osteomyelitis. We published our protocol in PROSPERO with a registration number, CRD42017080336. Results: There were 29 studies included in the qualitative analysis, of which 15 studies were included in the meta-analysis. Samples from sinus tract had the highest concordance with bone biopsy samples, while swab samples were the least concordant with bone biopsy samples. Additionally, Staphylococcus aureus was the most common bacteria isolated and the most concordant from samples, compared to other types of causative agents. Sinus tract had a significantly very high degree of agreement with bone samples. S. aureus had the highest degree of agreement in bone smaples. Conclusion: Diagnosis of osteomyelitis using sinus tract swab is close in results’ accuracy to bone biopsy. S. aureus was the most common extracted organism found in these samples and had the highest degree of agreement.

[This corrects the article DOI: 10.1371/journal.pntd.0009808.].

In recent years, histone deacetylases (HDACs) have emerged as promising targets in the treatment of cancer. The approach is to inhibit HDACs with drugs known as HDAC inhibitors (HDACis). Such HDACis are broadly classified according to their chemical structure, e.g., hydroxamic acids, benzamides, thiols, short-chain fatty acids, and cyclic peptides. Fluorination plays an important role in the medicinal–chemical design of new active representatives. As a result of the introduction of fluorine into the chemical structure, parameters such as potency or selectivity towards isoforms of HDACs can be increased. However, the impact of fluorination cannot always be clearly deduced. Nevertheless, a change in lipophilicity and, hence, solubility, as well as permeability, can influence the potency. The selectivity towards certain HDACs isoforms can be explained by special interactions of fluorinated compounds with the structure of the slightly different enzymes. Another aspect is that for a more detailed investigation of newly synthesized fluorine-containing active compounds, fluorination is often used for the purpose of labeling. Aside from the isotope 19F, which can be detected by nuclear magnetic resonance spectroscopy, the positron emission tomography of 18F plays a major role. However, to our best knowledge, a survey of the general effects of fluorination on HDACis development is lacking in the literature to date. Therefore, the aim of this review is to highlight the introduction of fluorine in the course of chemical synthesis and the impact on biological activity, using selected examples of recently developed fluorinated HDACis.

BackgroundPredictive markers represent a solution for the proactive management of severe dengue. Despite the low mortality rate resulting from severe cases, dengue requires constant examination and round-the-clock nursing care due to the unpredictable progression of complications, posing a burden on clinical triage and material resources. Accordingly, identifying markers that allow for predicting disease prognosis from the initial diagnosis is needed. Given the improved pathogenesis understanding, myriad candidates have been proposed to be associated with severe dengue progression. Thus, we aim to review the relationship between the available biomarkers and severe dengue.MethodologyWe performed a systematic review and meta-analysis to compare the differences in host data collected within 72 hours of fever onset amongst the different disease severity levels. We searched nine bibliographic databases without restrictive criteria of language and publication date. We assessed risk of bias and graded robustness of evidence using NHLBI quality assessments and GRADE, respectively. This study protocol is registered in PROSPERO (CRD42018104495).Principal findingsOf 4000 records found, 40 studies for qualitative synthesis, 19 for meta-analysis. We identified 108 host and viral markers collected within 72 hours of fever onset from 6160 laboratory-confirmed dengue cases, including hematopoietic parameters, biochemical substances, clinical symptoms, immune mediators, viral particles, and host genes. Overall, inconsistent case classifications explained substantial heterogeneity, and meta-analyses lacked statistical power. Still, moderate-certainty evidence indicated significantly lower platelet counts (SMD -0.65, 95% CI -0.97 to -0.32) and higher AST levels (SMD 0.87, 95% CI 0.36 to 1.38) in severe cases when compared to non-severe dengue during this time window.ConclusionThe findings suggest that alterations of platelet count and AST level-in the first 72 hours of fever onset-are independent markers predicting the development of severe dengue.

Background: The outbreak of Coronavirus disease (COVID-19) caused by a novel coronavirus (named SARS-CoV-2) has gained attention globally and has been recognized as a Public Health Emergency of International Concern (PHEIC) by the World Health Organization (WHO) due to the rapidly increasing number of deaths and confirmed cases. Health care workers (HCWs) are vulnerable to this crisis as they are the first frontline to receive and manage COVID-19 patients. In this multicenter multinational survey, we aim to assess the level of awareness and preparedness of hospital staff regarding COVID-19 all over the world.Methods: From February to March 2020, the web-based or paper-based survey to gather information about the hospital staff's awareness and preparedness in the participants' countries will be carried out using a structured questionnaire based on the United States Centers for Disease Control and Prevention (CDC) checklist and delivered to participants by the local collaborators for each hospital. As of March 2020, we recruited 374 hospitals from 58 countries that could adhere to this protocol as approved by their Institutional Review Boards (IRB) or Ethics Committees (EC).Discussion: The awareness and preparedness of HCWs against COVID-19 are of utmost importance not only to protect themselves from infection, but also to control the virus transmission in healthcare facilities and to manage the disease, especially in the context of manpower lacking and hospital overload during the pandemic. The results of this survey can be used to inform hospitals about the awareness and preparedness of their health staff regarding COVID-19, so appropriate policies and practice guidelines can be implemented to improve their capabilities of facing this crisis and other future pandemic-prone diseases.

Vietnam has faced a high risk of transmission of COVID-19 during the pandemic. Despite the specific challenges that come with a low-resource country, the Vietnamese government has provided a sustainable response, demonstrating both great capacity and rapid decision-making to manage the entirety of the COVID-19 outbreak with lessons learned from the SARS and H1N1 epidemics in 2003 and 2009, respectively. A rapid response, specific epidemiological F0–F5 tracing system, and public education are some of the key measures that have helped Vietnam to control the outbreak. As of July 15, 2020, Vietnam has reported 373 accumulated confirmed cases and no deaths within the last 90 consecutive days of no new infections in the community. Vietnam can now consider declaring an end to the COVID-19 crisis on their part.

Traceability is considered the most important requirement for shrimp products exported to global markets. However, implementing traceability in shrimp-exporting countries is challenging because of limited production at the local supply chain and lack of financial welfare awareness. This study aims to investigate the expected farm-gate price for traceability implementation using a double-bound dichotomous choice experiment. The censored regression model is used to estimate the factors influencing the anticipated farm-gate price of shrimp farmers. The survey was conducted in Ca Mau Province, Vietnam, by interviewing 71 Penaeus monodon Fabricius, 1798, and 43 Penaeus vannamei Boone, 1931, farmers. To implement traceability, P. monodon farmers estimated the farm-gate price at 10.17 USD.kg-1 , while P. vannamei farmers expected 6.18 USD.kg-1 . Application of international quality assurance certifications, willingness to implement traceability, land used, culture methods, shrimp species, current farm-gate price, and variable costs affected the expected farm-gate price. The attractive anticipated farm-gate price compensated for the negative influence of applying international quality assurance certifications, indicating that the farmers were willing to implement traceability. This suggests that the application of certifications increased the ability to implement traceability in the shrimp supply chain. The attractive farm-gate price for certified shrimp products would enhance their willingness to implement the traceability of shrimp products.

BackgroundIn response to the spread of the coronavirus disease 2019 (COVID-19), plenty of control measures were proposed. To assess the impact of current control measures on the number of new case indices 14 countries with the highest confirmed cases, highest mortality rate, and having a close relationship with the outbreak's origin; were selected and analyzed.MethodsIn the study, we analyzed the impact of five control measures, including centralized isolation of all confirmed cases, closure of schools, closure of public areas, closure of cities, and closure of borders of the 14 targeted countries according to their timing; by comparing its absolute effect average, its absolute effect cumulative, and its relative effect average.ResultsOur analysis determined that early centralized isolation of all confirmed cases was represented as a core intervention in significantly disrupting the pandemic's spread. This strategy helped in successfully controlling the early stage of the outbreak when the total number of cases were under 100, without the requirement of the closure of cities and public areas, which would impose a negative impact on the society and its economy. However, when the number of cases increased with the apparition of new clusters, coordination between centralized isolation and non-pharmaceutical interventions facilitated control of the crisis efficiently.ConclusionEarly centralized isolation of all confirmed cases should be implemented at the time of the first detected infectious case.

BackgroundSince the COVID-19 pandemic began, there have been concerns related to the preparedness of healthcare workers (HCWs). This study aimed to describe the level of awareness and preparedness of hospital HCWs at the time of the first wave.MethodsThis multinational, multicenter, cross-sectional survey was conducted among hospital HCWs from February to May 2020. We used a hierarchical logistic regression multivariate analysis to adjust the influence of variables based on awareness and preparedness. We then used association rule mining to identify relationships between HCW confidence in handling suspected COVID-19 patients and prior COVID-19 case-management training.ResultsWe surveyed 24,653 HCWs from 371 hospitals across 57 countries and received 17,302 responses from 70.2% HCWs overall. The median COVID-19 preparedness score was 11.0 (interquartile range [IQR] = 6.0-14.0) and the median awareness score was 29.6 (IQR = 26.6-32.6). HCWs at COVID-19 designated facilities with previous outbreak experience, or HCWs who were trained for dealing with the SARS-CoV-2 outbreak, had significantly higher levels of preparedness and awareness (pInterpretationThere was an unsurprising high level of awareness and preparedness among HCWs who participated in COVID-19 training courses. However, disparity existed along the lines of gender and type of HCW. It is unknown whether the difference in COVID-19 preparedness that we detected early in the pandemic may have translated into disproportionate SARS-CoV-2 burden of disease by gender or HCW type.

Background We systematically reviewed the evidence on how primary healthcare workers obtain information during consultations to support decision-making for prescribing in low and lower middle-income countries.Methods We searched electronic databases, consulted the Healthcare Information For All network, hand searched reference lists, ran citation searches of included studies and emailed authors of identified papers. Two reviewers extracted data and appraised quality with relevant tools.Results Of 60 497 records found, 23 studies met our inclusion criteria. Fourteen studies were observational and nine were interventional. Frequently mentioned sources of information were books, leaflets, guidelines, aids and the internet. These sources were sometimes out of date and health workers reported being confused which to use. Internet access varied and even when it was available, use was limited by technical issues. Of the five electronic tools that were assessed, four had positive outcomes. Tools assisted prescribers with medicine selection and dosage calculations, which increased prescribing accuracy. The quality of reporting varied but was overall low.Discussion Studies indicated a lack of up-to-date and relevant medicine information in low and lower middle-income settings. Internet-based sources appeared to be useful when it is possible to download content for offline use and to update when there is internet access. Electronic tools showed promise, but their accuracy needs to be validated and they should focus on giving actionable advice to guide prescribers.PROSPERO registration number CRD42018091088.

BackgroundNodding syndrome (NS), is an unexplained form of epilepsy which leads to stunted growth, cognitive decline, and a characteristic nodding of the head. Current data about its impact on households in Uganda is scarce. Therefore, this study aims to assess the economic burden of the persistent morbidity of NS on caregivers in affected households in Northern Uganda.MethodsA cross-sectional cost-of-care study was conducted from January 2019 to February 2019 in Lakwela village-Northern Uganda in 14 households, who are members of a community-based organization (CBO) established in the village with the support of a Japanese research team, (Uganda-Japan Nodding Syndrome Network). Data was collected through questionnaires. Both direct (medical and non-medical) and indirect (informal care) costs of caregiving were assessed. Indirect costs were valued using the human-capital method as loss of production.ResultsDirect costs constituted a higher proportion of costs for NS households, accounting for on average 7.7% of household expenditure. The annual weighted mean cost per NS patient was estimated at 27.6 USD (26.4 USD direct costs, 96.2% and 1.2 USD indirect cost, 3.8%). Average time spent on informal caregiving was 4.4 ±1.7 (standard deviation) hours/week with an estimated annual informal caregiving cost of 24.85 USD and gross domestic product (GDP) loss of 412.40 USD.ConclusionDirect costs due to NS are still high among households in this study. More studies are needed to investigate measures that could help bring down these costs and equally reduce the day-to-day disruption of caregiver's activities; consequently, improving the lives of these affected households and communities.

A series of 14 new (-)-gossypol Schiff bases and hydrazones have been synthesized via an in situ procedure in high yields. Structural data showed that all target compounds exist as the enamine tautomer. Bioassays showed that several compounds exhibited cytotoxic effects against three human cancer cell lines. Compound 8a showed the greatest cytotoxic effect against hepatocellular carcinoma (HepG2), lung carcinoma (LU-1), and breast cancer (MCF-7) cell lines with IC50 values of 20.93, 13.58, and 9.40 μM, respectively. However, in an antibacterial test, compounds 8a and 8b inhibited Staphylococcus aureus and Bacillus cereus and compound 8e inhibited only Staphylococcus aureus at the same MIC values of 1024 μg/ml.

Twelve melatonin amide prodrugs aiming at prolonging the action of melatonin in vivo by improving its half-life were designed and synthesized. Using an 80% human plasma model, it was found that the aliphatic amide derivatives were relatively stable and melatonin release from these compounds was not sufficient with melatonin release percentage. After 4-hour incubation with 80% human plasma, the melatonin release percentage achieved only approximately less than 20%. In contrast, the -succinyl and -glutaroylmelatonin derivatives (compounds 11 and 12, resp.) were found to release melatonin in much higher rates. After 3-hour incubation in 80% human plasma, the melatonin release rates from 11 and 12 were found to be 67.3 and 75.6%, respectively. From these results, the -succinyl and -glutaroylmelatonin derivatives (compounds 11 and 12) could be promising as sustained release prodrugs of melatonin.

This study uses a quantile-on-quantile regression framework to establish a link between investor sentiment proxied by market turnover and stock returns in G7 countries. The QQ analysis results reveal that the impact of investor sentiment on future stock returns is asymmetric and varies across quantiles of stock returns and sentiment. Overall, a significantly negative relationship is observed for all G7 countries. Interestingly, when the market is very bullish, and investors are pessimistic, investor sentiment positively influences future returns, except for Japan. [ABSTRACT FROM AUTHOR]