Gene therapy for people with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma is the most common type of liver cancer, accounting for 70% to 85% of individuals with primary liver cancer. Gene therapy, which uses genes to treat or prevent diseases, holds potential for treatment, especially for tumours. Trials on the effects of gene therapy in people with hepatocellular carcinoma have been published or are ongoing. OBJECTIVES: To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation. SEARCH METHODS: We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023. SELECTION CRITERIA: We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported. DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up. MAIN RESULTS: We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials. AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.

Facilitators and barriers to engaging communities in health service research on dengue control in Indo-Pacific region: a systematic review.

BACKGROUND: Dengue is a public health problem in the Indo-Pacific countries. There are concerns over the facilitators and barriers to community engagement in health service research aimed at dengue control. The objective of his study was to identify and synthesize facilitators and barriers to community engagement in health service research aimed at dengue control. METHODOLOGY: The Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist was used to perform this review. Health-related databases including PubMed, Ovid, and Google Scholar were searched for relevant studies. A consolidated framework with five domains was developed after undertaking a six-phase reflective thematic assessment of the data. RESULTS: Thirteen studies were identified, spanning eight low-and middle-income countries of the Indo-Pacific region including Cambodia, India, Indonesia, Myanmar, Philippines, Sri Lanka, Thailand, and Vietnam. The studies in this review covered the period from 2002 to 2021. A broad range of study designs and objectives were revealed across these 13 studies. An array of communities such as the local government, project-related health staff, local health services staff, community leaders, local communities/residences/general public, heads of households, community health volunteers, school teachers, and schoolchildren participated in these dengue related studies. The five Consolidated Framework for Implementation Research (CFIR) domains of 'intervention characteristics', 'inner setting', 'outer setting',' individual characteristics', and 'program implementations' were used to identify and describe barriers and facilitators. CONCLUSIONS: The findings indicate a range of barriers and facilitators to community engagement in dengue control in the selected LMIC in the Indo-Pacific countries. Future health services research on dengue control approaches should be carefully planned, methodologically constructed, aligned with community engagement principles, and involve considerable community participation at all stages of the research.

Community engagement in health services research on elimination of lymphatic filariasis: A systematic review.

This study aimed to contextualize the extent, nature, and quality of community engagement in health services research on eliminating lymphatic filariasis in low-and middle-income countries of Southeast Asia and Pacific Region. We performed a systematic review, and the results were reported according to the PRISMA-S checklist. Relevant studies were searched in health-related electronic databases, and selected according to the inclusion criteria. Sixteen studies with various study designs were identified. The majority (68%) were conducted in India. Lay people, community leaders, and volunteers were the most common groups of community members (12/16,75%). Overall, the majority (13/16, 81%) were at the 'moderate level' of engagement in research context mainly by 'collaboration' in 'developing methodology' 'collaboration' in data collection and 'collaboration' for 'dissemination of findings. The common barriers to the community engagement were lack of involvement of participating bodies and technology-related issues. In conclusion, the insufficient description of the community engagement process in the studies limits a deeper understanding and analysis of the issue. Future well-designed prospective studies with attention to the description of mechanisms of engagement, facilitating the whole process and reporting the community level outcome are recommended.

Community engagement in health services research on soil-transmitted helminthiasis in Asia Pacific region: Systematic review.

The research question was what studies are available that have assessed community engagement in the health services research on soil-transmitted helminths? We aimed to synthesise evidence on how communities were engaged in health services research on soil-transmitted helminths in low-and-middle-income countries of the Asia-Pacific Region. We focused on this region because soil-transmitted helminths are endemic, and their burden is significant in this region. This review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) checklist. Relevant studies were searched in health-related databases including PubMed, Ovid, and Google Scholar. We selected studies based on the selection criteria set for this review. We collected textual information about the type of health services research, the degree of community engagement, the research phases involved, and the barriers/enablers affecting community engagement in research since they are pertinent to our review question and objective. Ten studies from seven countries in the Asia Pacific region were identified for this review. Albeit with variation in the extent of their involvement, various forms of communities/groups within communities were included such as Aboriginal communities, local communities, school children and their parents, school teachers and headmasters of schools, heads of villages, religious leaders, and so on. Overall, community engagement in health services research focused on of soil-transmitted helminths was limited. Six studies (60%) had collaboration at 'developing methodology', mainly through an explanation of the objectives of the study or study process to be conducted. Seven studies (70%) revealed community participation in soil-transmitted helminths at the "data collection" stage. Only one study (10%) documented that a community leader was involved as a co-author, reflecting an involvement in 'report writing' and further 'dissemination'. Findings suggest that there were various forms of community engagement in various aspects of the health services research context. Overall, there was moderate level of participation, but there was insufficient information on the partnership between various stakeholders, which prevented in-depth analysis of the engagement. Future health services research on soil-transmitted helminth interventions needs to be carefully planned, well designed, grounded in principles of community engagement, and designed methodologically to allow in-depth participation by communities in all stages of the research.

Loop-mediated isothermal amplification (LAMP) test in the detection of uncomplicated malaria in pregnancy: a meta-analysis of diagnostic accuracy.

BACKGROUND: Due to relatively low malaria parasitaemia in pregnancy, an appropriate field test that can adequately detect infections in pregnant women presenting with illness or for malaria screening during antenatal care is crucially important. The objective was to evaluate the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for the detection of uncomplicated malaria in pregnancy. METHODS: This was a meta-analysis of diagnostic accuracy. Relevant studies that assessed the diagnostic performance of LAMP for the detection of malaria in pregnancy were searched in health-related electronic databases including PubMed, Ovid, and Google Scholar. The methodological quality of the studies included was evaluated using the QUADAS-2 tool. RESULTS: Of the 372 studies identified, eight studies involving 2999 pregnant women in five endemic countries that assessed the accuracy of LAMP were identified. With three types of PCR as reference tests, the pooled sensitivity of LAMP was 91% (95%CI 67-98%) and pooled specificity was 99% (95%CI 83-100%, 4 studies), and the negative likelihood ratio was 9% (2-40%). Caution is needed in the interpretation as there was substantial between-study heterogeneity (I2: 80%), and a low probability that a person without infection is tested negative. With microscopy as a reference, the pooled sensitivity of LAMP was 95% (95%CI 26-100%) and pooled specificity was 100% (95%CI 94-100%, 4 studies). There was a wide range of sensitivity and substantial between-study heterogeneity (I2: 83.5-98.4%). To investigate the source of heterogeneity, a meta-regression analysis was performed with covariates. Of these potential confounding factors, reference test (p: 0.03) and study design (p:0.03) had affected the diagnostic accuracy of LAMP in malaria in pregnancy. Overall, there was a low certainty of the evidence in accuracy estimates. CONCLUSION: The findings suggest that LAMP is more sensitive than traditional tests used at facilities, but the utility of detecting and treating these low-density infections is not well understood. Due to the limited number of studies with bias in their methodological quality, variation in the study design, and different types of reference tests further research is likely to change the estimate. Well-conceived large prospective studies with blinding of the index test results are recommenced.

A comparison of neoadjuvant therapies for gastroesophageal and gastric cancer on tumour resection rate: A network meta-analysis.

BACKGROUND: Gastric cancer is one of the most common malignancies around the world, and a variety of neoadjuvant chemotherapies with different drug combinations are available for the treatment. R0 resection refers to a microscopically negative margin on resection, where no gross or microscopic tumour remains in the primary tumour. We aimed to find evidence on the relative effectiveness of neoadjuvant therapies for patients with advanced gastroesophageal and gastric cancer on the R0 resection rate. METHODS: Relevant randomised controlled trials were searched using appropriate keywords in health-related databases. We performed network meta-analysis within a frequentist framework. The endpoint assessed was the R0 resection rate. We assessed consistency and transitivity assumptions that are necessary for network meta-analysis. This study only used data from published studies. The need for consent from participants was waived by the Ethics Review Committee of the International Medical University in Malaysia. RESULTS: Six randomised controlled trials involving 1700 patients were identified. A network plot was formed with five neoadjuvant regimens [DLX (pyrimidine analogue + platinum compounds + chemoradiotherapy), DELX (pyrimidine analogue + epipodophylllotoxins/etoposide + platinum compounds + chemoradiotherapy), ADL (anthracycline + pyrimidine analogue + platinum compounds), ADM (anthracycline+ pyrimidine analogue + anti-folate compounds) and LTX (platinum compounds + taxane + chemoradiotherapy)] and surgery alone for management of patients with advanced gastroesophageal and gastric cancer. Assumptions required for a network meta-analysis such as consistency ((global test: Chi2 (1): 3.71; p:0.054)), and the transitivity in accord to the characteristics of interventions considered in this review were not violated. In the network comparison, surgery alone has a lower R0 resection rate compared with LTX (OR 0.2, 95%CI:0.01, 0.38) or DLX (OR 0.48, 95%CI: 0.29, 0.79). LTX has higher resection rate compared with DLX (OR 2.47, 95%CI: 1.08 to 5.63), DELX (OR 106.0, 95%CI: 25.29 to 444.21), ADM (OR 5.41, 95%CI: 1.56 to 18.78) or ADL (OR 3.12, 95%CI: 1.27 to 7.67). There were wide or very wide CIs in many of these comparisons. Overall certainty of the evidence was low or very low. Further research in this field is very likely to have an important impact on our confidence in the R0 resection rates between LTX versus other neoadjuvant chemotherapy is likely to change the estimate. CONCLUSIONS: Findings suggest that overall quality of evidence on the relative effectiveness of neoadjuvant chemotherapies was low to very low level. Therefore, we are very uncertain about the true effect of neoadjuvant therapies in the R0 resection rate in patients with gastroesophageal and gastric cancer. Future well-designed large trials are needed. To recruit large samples in this field, multicountry trials are recommended. Future trials also need to assess treatment-related adverse events, and patients-centered outcomes such as health-related quality of life.

Detection of asymptomatic malaria in Asian countries: a meta-analysis of diagnostic accuracy.

BACKGROUND: Achieving malaria elimination requires the targeting of the human reservoir of infection, including those patients with asymptomatic infection. The objective was to synthesise evidence on the accuracy of the rapid-onsite diagnostic tests (RDTs) and microscopy for the detection of asymptomatic malaria as part of the surveillance activities in Asian countries. METHODS: This was a meta-analysis of diagnostic test accuracy. Relevant studies that evaluated the diagnostic performance of RDTs and microscopy for detection of asymptomatic malaria were searched in health-related electronic databases. The methodological quality of the studies included was assessed using the QUADAS-2 tool. RESULTS: Ten studies assessing RDT and/or microscopy were identified. The diagnostic accuracies in all these studies were verified by PCR. Overall, the pooled sensitivities of RDT, as well as microscopy for detection of any malaria parasites in asymptomatic participants, were low, while their pooled specificities were almost ideal. For the detection of Plasmodium falciparum, pooled sensitivity by RDT (59%, 95%CI:16-91%) or microscopy (55%, 95%CI: 25-82%) were almost comparable. For detection of Plasmodium vivax, pooled sensitivity of RDT (51%, 95% CI:7-94%) had also the comparable accuracy of microscopy (54%, 95%CI,11-92%). Of note are the wide range of sensitivity and specificity. CONCLUSION: The findings of this meta-analysis suggest that RDTs and microscopy have limited sensitivity and are inappropriate for the detection of asymptomatic Plasmodium infections. Other methods including a combination of PCR-based strategies, Loop-Mediated Isothermal Amplification (LAMP) technique must be considered to target these infections, in order to achieve malaria elimination. However, more data is needed for the wide acceptance and feasibility of these approaches. Studies to explore the role of asymptomatic and sub-patent infections in the transmission of malaria are of critical importance and are recommended.

Rapid diagnostic test (Leptocheck-WB) for detection of acute leptospirosis: a meta-analysis of diagnostic accuracy.

The majority of leptospirosis is subclinical or mild self-limiting systemic illness. A rapid and accurate diagnostic test for the detection of leptospirosis is essential to prevent disease progression from acute non-severe illness to potentially fatal infection. Rapid diagnostic tests (RDTs) recognized as point-of-care (PoC) tests may support clinical decision-making in resource-poor settings. We aimed to assess the accuracy of PoC (Leptocheck-WB) for the detection of acute leptospirosis by meta-analysis of data from eligible studies. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guideline. The pooling of data was done only when there were two or more studies that used a particular type of reference test. A total of ten studies (n = 5369) were identified. The majority (70%) were from the Asian region. Using microscopic agglutination test (MAT) as reference test, the pooled sensitivity (0.75, 95% CI: 0.64 to 0.84, 10 studies, I2: 85.9%) and specificity (0.87, 95% CI: 0.77 to 0.94, 10 studies, I2: 97.37%) of Leptocheck-WB in the detection of leptospirosis were moderate. With the use of enzyme-linked immunosorbent assay (ELISA) reference test, the pooled sensitivity 0.85 (95% CI: 0.79 to 0.9, 4 studies, I2: 27.49%) and specificity 0.79 (95% CI: 0.71 to 0.85, 4 studies, I2: 58.9%) of Leptocheck-WB were also moderate. Diagnostic odds ratio of Leptocheck-WB with MAT (21, 95% CI: 10-44) or with ELISA as reference test (21, 95% CI: 9-46) showed an acceptable level of accuracy. Meta-regression analysis showed methodological quality of studies (p: 0.06) and study design (p: 0.09) were potential factors that affected the accuracy of Leptocheck-WB test. Findings suggest that Leptocheck-WB has a moderate level of acceptance for detection of acute leptospirosis. Further confirmation with large-sampled, prospectively designed studies using the same samples for evaluating test accuracy is recommended.

Loop-mediated isothermal amplification (LAMP) test for diagnosis of uncomplicated malaria in endemic areas: a meta-analysis of diagnostic test accuracy.

BACKGROUND: The global malaria decline has stalled and only a few countries are pushing towards pre-elimination. The aim of the malaria elimination phase is interruption of local transmission of a specified malaria parasite in a defined geographical area. New and improved screening tools and strategies are required for detection and management of very low-density parasitaemia in the field. The objective of this study was to synthesize evidence on the diagnostic accuracy of loop-mediated isothermal amplification (LAMP) test for the detection of malaria parasites among people living in endemic areas. METHODS: This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Diagnostic Test Accuracy (PRISMA-DTA) guideline. Relevant studies in the health-related electronic databases were searched. According to the criteria set for this study, eligible studies were identified. The quality of included studies was evaluated with the use of a quality assessment checklist. A summary performance estimates such as pooled sensitivity and specificity were stratified by type of LAMP. Bivariate model for data analyses was applied. Summary receiver operating characteristics plots were created to display the results of individual studies in a receiver operating characteristics space. Meta-regression analysis was performed to investigate the sources of heterogeneity among individual studies. RESULTS: Twenty-seven studies across 17 endemic countries were identified. The vast majority of studies were with unclear risk of bias in the selection of index test. Overall, the pooled test performances were high for Pan LAMP (sensitivity: 0.95, 95% CI 0.91 to 0.97; specificity: 0.98, 95% CI 0.95 to 0.99), Plasmodium falciparum (Pf) LAMP (sensitivity: 0.96, 95% CI 0.94 to 0.98; specificity: 0.99, 95% CI 0.96 to 1.00) or for Plasmodium vivax (Pv) LAMP from 6 studies (sensitivity: 0.98, 95% CI 0.92 to 0.99; specificity: 0.99, 95% CI 0.72 to 1.00). The area under the curve for Pan LAMP (0.99, 95% CI 0.98-1.00), Pf LAMP (0.99, 95% CI 0.97-0.99) and Pv LAMP was (1.00, 95% CI 0.98-1.00) indicated that the diagnostic performance of these tests were within the excellent accuracy range. Meta-regression analysis showed that sample size had the greatest impact on test performance, among other factors. CONCLUSIONS: The current findings suggest that LAMP-based assays are appropriate for detecting low-level malaria parasite infections in the field and would become valuable tools for malaria control and elimination programmes. Future well-designed larger sample studies on LAMP assessment in passive and active malaria surveillances that use PCR as the reference standard and provide sufficient data to construct 2 × 2 diagnostic table are needed.

Efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region: A network meta-analysis.

BACKGROUND: The WHO recommends artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated falciparum malaria. Hence, monitoring the efficacy of antimalarial drugs is a key component of malaria control and elimination. The published randomized trials that assessed comparisons of ACTs for treating uncomplicated falciparum malaria reported conflicting results in treatment efficacy. A network meta-analysis is an extension of pairwise meta-analysis that can synthesize evidence simultaneously from both direct and indirect treatment comparisons. The objective was to synthesize evidence on the comparative efficacy of antimalarial drugs for treatment of uncomplicated falciparum malaria in Asian region. METHODS: Relevant randomized trials that assessed efficacy of antimalarial drugs for patients having uncomplicated falciparum malaria in Asian region were searched in health-related databases. We evaluated the methodological quality of the included studies with the Cochrane risk of bias tool. Main outcome was treatment success at day 28 as determined by the absence of parasiteamia. We performed network meta-analysis of the interventions in the trials, and assessed the overall quality of evidence using the GRADE approach. RESULTS: Seventeen randomized trials (n = 5043) were included in this network meta-analysis study. A network geometry was formed with 14 antimalarial treatment options such as artemether-lumefantrine (AL), artemisinin-piperaquine, artesunate-amodiaquine, artesunate-mefloquine (ASMQ), artesunate-chloroquine, artesunate-mefloquine home treatment, artesunate-mefloquine 2-day course, artesunate plus sulfadoxine-pyrimethamine, chloroquine, dihydroartemisinin-piperaquine (DHP), dihydroartemisinin-piperaquine home treatment, dihydroartemisinin-piperaquine 4-day course, dihydroartemisinin-piperaquine and added artesunate, sulfadoxine-pyrimethamine. A maximum number of trials included was DHP compared to ASMQ (n = 5). In general, DHP had better efficacy than AL at day 28 (DHP vs AL: OR 2.5, 95%CI:1.08-5.8). There is low certainty evidence due to limited number of studies and small trials. DISCUSSION/ CONCLUSIONS: The findings suggest the superiority of DHP (3-day course) to AL and other comparator ACTs are with the overall low/very low quality of evidence judgements. Moreover, one drug regimen is better than another is only if current drug-resistance patterns are at play. For example, the AL might be better than DHP in areas where both artemisinin and piperaquine resistance patterns are prevalent. For substantiation, well-designed larger trials from endemic countries are needed. In the light of benefit versus harm concept, future analysis with safety information is recommended.

Risk factors for human leptospirosis following flooding: A meta-analysis of observational studies.

Leptospirosis is probably the most widespread zoonotic disease in the world especially in tropical countries. There has been an increase in individual studies, which assessed the frequency of leptospirosis in flood conditions. Some studies showed contact with floods was significantly associated with the occurrence of leptospirosis while other studies reported differently. The objective of this meta-analysis was to synthesize the evidence on the risk factors which are associated with human leptospirosis following flooding. We set up the inclusion criteria and searched for the original studies, addressing leptospirosis in human with related to flood in health-related electronic databases including PubMed, Embase, Ovid Medline, google scholar and Scopus sources. We used the terms 'leptospirosis', 'flood', 'risk factor' and terms from the categories were connected with "OR" within each category and by "AND" between categories. The initial search yielded 557 citations. After the title and abstract screening, 49 full-text papers were reviewed and a final of 18 observational studies met the pre-specified inclusion criteria. Overall, the pooled estimates of 14 studies showed that the contact with flooding was a significant factor for the occurrence of leptospirosis (pooled OR: 2.19, 95%CI: 1.48-3.24, I2:86%). On stratification, the strength of association was greater in the case-control studies (pooled OR: 4.01, 95%CI: 1.26-12.72, I2:82%) than other designs (pooled OR:1.77,95%CI:1.18-2.65, I2:87%). Three factors such as 'being male'(pooled OR:2.06, 95%CI:1.29-2.83), the exposure to livestock animals (pooled OR: 1.95, 95%CI:1.26-2.64), the lacerated wound (pooled OR:4.35, 95%CI:3.07-5.64) were the risk factors significantly associated with the incidence of leptospirosis following flooding in the absence of within-study heterogeneity (I2: 0%). We acknowledge study limitations such as publication bias and type 2 statistical errors. We recommended flood control and other environmental modifications that are expected to reduce the risk of leptospiral infection, and a multi-sectoral effort to this aspect would have long-term benefits.

Association of tumour necrosis factor-α (TNF-α) gene polymorphisms (-308 G>A and -238 G>A) and the risk of severe dengue: A meta-analysis and trial sequential analysis.

Individual studies have assessed the association between TNF-α-308G>A and TNF-α-238 G>A polymorphisms and severity of dengue infection. However, the results are inconclusive and most studies had small sample sizes. The objective of this study was to summarize the evidence of association between TNF-α-308 G>A and TNF-α-238 G>A and severity of dengue infection. This study follows the preferred reporting items for systematic reviews and meta- analyses of genetic association studies, recommended by PLOS One. We calculated pooled odds ratio and its 95% confidence interval (CI) to estimate the association between TNF-α-308 G>A or TNF-α-238 G>A and the risk of severe dengue infections. To determine the information size required for this meta-analysis study, a trial sequential analysis (TSA) was done. Eight studies (640 cases and 1275 controls), which assessed the association of TNF-α-308 G>A or TNF-α-238 G>A and the risk of DHF were included. Overall, we found no significant association between TNF-α-308 G>A and the DHF risk in the allelic model (OR, 0.91; 95% CI, 0.51-1.63), the recessive model (OR,1.32;95%CI,0.73-2.37), the dominant model (OR,0.93;95%CI:0.59-1.47) or the additive model (OR,1.43,95;95%CI:0.79-2.59). There was also no significant association between TNF-α-238 G>A and DHF risk under the allele contrast model (OR:1.51;95%CI:0.88-2.58), the recessive model (OR,1.48,95% CI:0.33-6.58), the dominant model (OR,1.48;95%CI:0.56-3.92), or the additive model (OR:1.5;95%CI:0.34-6.69). On subgroup analysis, neither the Asian population nor the non-Asian population showed significant association between TNF-α-308 G>A/TNF-α-238 G>A and the DHF risk under any genetic models. Leave-one-out meta-analysis showed stability of the results. TSA plots suggested that the sample size in this meta-analysis study was below the required information size. The findings suggest an inclusive evidence of the association between TNF-α-308/ TNF-α-238 G>A and the risk of developing severe dengue infection. Large studies with evidence of Hardy-Weinberg equilibrium, assessing gene-gene interactions are recommended.

An association between IL-10 promoter polymorphisms and diabetic nephropathy: a meta-analysis of case-control studies.

BACKGROUND: This study aimed to synthesize evidence on the association between IL-10 gene (-819 C/T, -1082 A/G, -592 A/C) polymorphisms and the risk of developing diabetic nephropathy. METHODS: A systematic literature search was done in health-related electronic databases. The search was limited to studies published in English until September 2017. We also checked the references of retrieved articles and relevant reviews for any additional studies. The methodological quality of the studies included in this review was assessed using the 'Scales for Quality Assessment'. The I 2 test was used to quantify between-study heterogeneity. A value of I 2 > 50% indicated substantial heterogeneity. For the pooled analysis, summary odds ratio (OR) and its 95% confidence interval (CI) in random effect model were used. RESULTS: Eight case-control studies (1192 cases with diabetic nephropathy and 2399 controls) met the inclusion criteria. Three groups of people namely Africans, Asians and Caucasians were included in this review. There were significant protective effects of SNP -819 C/T in overall population (OR 0.32, 95% CI 0.26-0.4) and - 1082 A/G SNP in the Asian population (OR 0.64, 95% CI 0.47-0.86) on diabetic nephropathy in the recessive model. There was no significant effect of -592 A/C on diabetic nephropathy. CONCLUSION: The findings suggest the protective effects of -1082A/G and -819G/A polymorphisms on the risk of developing diabetic nephropathy in type 2 diabetes mellitus, especially in the Asian population. Well- designed, prospective studies with sufficient number of participants are recommended to substantiate these findings.