The prevalence of Pfk13 polymorphism in malaria patients treated with artemisinin-based therapy: a systematic review and meta-analysis.

Artemisinin (ART) combination therapy is the main treatment for malaria. Pfk13 mutations (or K13 mutations, Kelch 13) are associated with ART resistance. This study aims to conduct a systematic review and meta-analysis of the prevalence of K13 mutations with ART resistance in malaria-endemic countries. An electronic search of studies in 2018 and a manual search in 2020 were performed to identify relevant studies. The risk of bias was assessed using the National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies. Data analysis was performed using R 4.1.0. Heterogeneity was estimated using the statistic I2 and Cochran Q test. A total of 170 studies were included in our review. Of these, 55 studies investigated the prevalence of K13 mutations in Southeast Asia. The meta-analysis showed that Southeast Asia had the highest prevalence of K13 mutations, whereas Africa, South America, Oceania, and other Asian countries outside Southeast Asia had a low prevalence of K13 mutations. The C580Y mutation was the most common in Southeast Asia with 35.5% (95%CI: 25.4-46.4%), whereas the dominant mutation in Africa was K189T (22.8%, 95%CI: 7.6-43.2%). This study revealed the emergence of ART resistance associated with K13 mutations in Southeast Asia. The diversity of each type of K13 mutation in other regions was also reported.

Anti-SARS-CoV-2 activity of various PET-bottled Japanese green teas and tea compounds in vitro.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a serious threat to global public health. The emergence of SARS-CoV-2 variants is a significant concern regarding the continued effectiveness of vaccines and antiviral therapeutics. Thus, natural products such as foods, drinks, and other compounds should be investigated for their potential to treat COVID-19. Here, we examined the in vitro antiviral activity against SARS-CoV-2 of various polyethylene terephthalate (PET)-bottled green Japanese teas and tea compounds. Six types of PET-bottled green tea were shown to inhibit SARS-CoV-2 at half-maximal inhibitory concentrations (IC50) of 121- to 323-fold dilution. Our study revealed for the first time that a variety of PET-bottled Japanese green tea drinks inhibit SARS-CoV-2 infection in a dilution-dependent manner. The tea compounds epigallocatechin gallate (EGCG) and epicatechin gallate showed virucidal activity against SARS-CoV-2, with IC50 values of 6.5 and 12.5 µM, respectively. The investigated teas and tea compounds inactivated SARS-CoV-2 in a dose-dependent manner, as demonstrated by the viral RNA levels and infectious titers. Furthermore, the green teas and EGCG showed significant inhibition at the entry and post-entry stages of the viral life cycle and inhibited the activity of the SARS-CoV-2 3CL-protease. These findings indicate that green tea drinks and tea compounds are potentially useful in prophylaxis and COVID-19 treatment.

Treatment for vestibular schwannoma: Systematic review and single arm meta-analysis.

OBJECTIVE: Vestibular schwannoma is a benign tumor in the schwannoma cells of the 8th cranial nerve. It causes symptoms like tinnitus, vertigo and end up with loss of hearing so the appropriate treatment is very important. There are many treatment techniques including conservative, surgery and radiosurgery. We aimed to systematically review and single arm meta-analysis the different treatment techniques of vestibular schwannoma. METHODS: A comprehensive literature search using thirteen databases including PubMed, Scopus, and Web of Science was performed. All clinical trials about treatment vestibular schwannoma were included and single arm meta-analyzed. We assessed the risk of bias using ROBIN-I's tool and scale of Council Australia's Cancer Guidelines Wiki. The protocol was registered in PROSPERO (CRD42018089784) and has been updated on 17 April 2019. RESULTS: A total of 35 clinical trials studies were included in the final analysis. The pooled proportion of stable hearing capability in patients receiving gamma knife radiosurgery (GKRS) was 64% (95% CI: 52%-74%). GKRS favored increased hearing capability 10% (95% CI: 7%-16%). Regarding tumor size, GKRS is the most protective method 53% (95% CI: 37%-69%). Complications occurred most commonly in single fractional linac stereotactic radiosurgery (SFSRT) 37% (95% CI: 12%-72%). CONCLUSION: Our analysis suggested gamma knife radiosurgery could be the most ideal treatment for vestibular schwannoma based on stabilizing hearing capability, increasing hearing capability, decreasing tumor size and complications.

Comparative effects of furosemide and other diuretics in the treatment of heart failure: a systematic review and combined meta-analysis of randomized controlled trials.

Diuretics have an essential role in the management of heart failure (HF). However, each drug has its own benefit and side effect. Side effects include fluid, electrolyte abnormalities, and acid-base disturbance. These adverse effects of diuretics predispose patients to serious cardiac arrhythmias and may increase the risk of arrhythmic mortality. Herein, we aim to summarize the relative efficacy and safety of all available diuretics used in the treatment of patients with HF. In June 2017, a systematic electronic database search was conducted in nine databases. All randomized controlled trials (RCTs) comparing the different diuretics used in HF were included for meta-analysis. The protocol was registered in Prospero with CRD42018084819. Among the included 54 studies (10,740 patients), 34 RCTs were eligible for quantitative network meta-analysis (NMA) and traditional meta-analysis while the other 20 studies were qualitatively analyzed. Our results showed that azosemide and torasemide caused a significant reduction in brain natriuretic peptide (BNP) level. Torasemide also caused a significant decrease in collagen volume fraction (CVF) and edema. No significant difference between the agents concerning glomerular filtration rate (GFR), water extraction, and sodium excretion was demonstrated. Regarding side effects, no significant difference among diuretics was observed in terms of hospital readmission and mortality rates. Diuretics are the main treatment of hypervolemia in HF patients. The choice of appropriate diuretic is essential for successful management and is mainly guided by patient clinical situations and the presence of other co-morbidities.

2D-quantitative structure-activity relationships model using PLS method for anti-malarial activities of anti-haemozoin compounds.

BACKGROUND: Emergence of cross-resistance to current anti-malarial drugs has led to an urgent need for identification of potential compounds with novel modes of action and anti-malarial activity against the resistant strains. One of the most promising therapeutic targets of anti-malarial agents related to food vacuole of malaria parasite is haemozoin, a product formed by the parasite through haemoglobin degradation. METHODS: With this in mind, this study developed two-dimensional-quantitative structure-activity relationships (QSAR) models of a series of 21 haemozoin inhibitors to explore the useful physicochemical parameters of the active compounds for estimation of anti-malarial activities. The 2D-QSAR model with good statistical quality using partial least square method was generated after removing the outliers. RESULTS: Five two-dimensional descriptors of the training set were selected: atom count (a_ICM); adjacency and distance matrix descriptor (GCUT_SLOGP_2: the third GCUT descriptor using atomic contribution to logP); average total charge sum (h_pavgQ) in pKa prediction (pH = 7); a very low negative partial charge, including aromatic carbons which have a heteroatom-substitution in "ortho" position (PEOE_VSA-0) and molecular descriptor (rsynth: estimating the synthesizability of molecules as the fraction of heavy atoms that can be traced back to starting material fragments resulting from retrosynthetic rules), respectively. The model suggests that the anti-malarial activity of haemozoin inhibitors increases with molecules that have higher average total charge sum in pKa prediction (pH = 7). QSAR model also highlights that the descriptor using atomic contribution to logP or the distance matrix descriptor (GCUT_SLOGP_2), and structural component of the molecules, including topological descriptors does make for better anti-malarial activity. CONCLUSIONS: The model is capable of predicting the anti-malarial activities of anti-haemozoin compounds. In addition, the selected molecular descriptors in this QSAR model are helpful in designing more efficient compounds against the P. falciparum 3D7A strain.

Quality assessment tools used in systematic reviews of in vitro studies: A systematic review.

BACKGROUND: Systematic reviews (SRs) and meta-analyses (MAs) are commonly conducted to evaluate and summarize medical literature. This is especially useful in assessing in vitro studies for consistency. Our study aims to systematically review all available quality assessment (QA) tools employed on in vitro SRs/MAs. METHOD: A search on four databases, including PubMed, Scopus, Virtual Health Library and Web of Science, was conducted from 2006 to 2020. The available SRs/MAs of in vitro studies were evaluated. DARE tool was applied to assess the risk of bias of included articles. Our protocol was developed and uploaded to ResearchGate in June 2016. RESULTS: Our findings reported an increasing trend in publication of in vitro SRs/MAs from 2007 to 2020. Among the 244 included SRs/MAs, 126 articles (51.6%) had conducted the QA procedure. Overall, 51 QA tools were identified; 26 of them (51%) were developed by the authors specifically, whereas 25 (49%) were pre-constructed tools. SRs/MAs in dentistry frequently had their own QA tool developed by the authors, while SRs/MAs in other topics applied various QA tools. Many pre-structured tools in these in vitro SRs/MAs were modified from QA tools of in vivo or clinical trials, therefore, they had various criteria. CONCLUSION: Many different QA tools currently exist in the literature; however, none cover all critical aspects of in vitro SRs/MAs. There is a need for a comprehensive guideline to ensure the quality of SR/MA due to their precise nature.

The association between dengue viremia kinetics and dengue severity: A systemic review and meta-analysis.

In this study, we aim to assess the association of dengue viremia with dengue severity. The study protocol was developed and registered in PROSPERO (CRD42016039864). We searched nine databases to find potential papers. Studies meeting the inclusion criteria were included. We, based our analysis on three outcomes which are disease severity, dengue serotype and disease infection type. Thirty studies with 3316 patients were included. Our analysis revealed that viremia is significantly higher in dengue hemorrhagic fever patients than dengue fever in days 5 to 6. Regarding the serotype of dengue, the maximum viremia titre of serotype 1 was significantly higher than serotype 3 and the viremia in dengue serotype 2 was significantly higher than serotype 4 in days 2 to 4. However, comparison of the daily viremia level between the primary and secondary dengue infection revealed that secondary infection was significantly higher than the primary infection on seventh day and on the eighth day. Viremia is strongly associated with disease severity and type of infection which gave viremia a high indicative power to be used as a clinical predictor. Dengue serotype is also associated with viral load with higher viremia in DENV-2/1.

Mast cell mediators in relation to dengue severity: A systematic review and meta-analysis.

BACKGROUND: Degranulation of mast cells (MCs) releases several mediators such as vascular endothelial growth factor (VEGF), chymase, tryptase, histamine, and cytokines, which all have important roles in the severity of dengue infection. We aimed to investigate the role of MCs in severity of dengue. METHODS: We searched for relevant studies in 10 databases on 15 August 2016. Meta-analysis (MA) was conducted by R version 3.5.0. RESULTS: We included 24 studies. in vivo and in vitro studies showed higher MC products released from infected mice/cells with dengue virus. In addition, when administering MC stabilizers or antihistaminic drugs, there was a decrease in vascular/capillary permeability. In human and at early stages, studies revealed an insignificant difference in VEGF levels in dengue fever (DF) versus dengue hemorrhagic fever (DHF) (standardized mean difference [SMD] 0.145; 95% confidence interval [CI], -0.348-0.638). Meanwhile, at acute stages and compared with healthy controls, high heterogeneity with an inconclusive difference in VEGF levels were noted in DF and DHF. However, pooled serum and plasma levels of VEGF were increased significantly in dengue shock syndrome (DSS) versus healthy controls (SMD 0.65; 95% CI, 0.3-0.95). There were also significantly higher chymase levels in DHF patients compared with DF during the acute phase (MD -6.531; 95% CI, -12.2 to -0.9). CONCLUSION: VEGF and chymase levels are mediators in dengue pathogenesis. However, limited data were available to support their role in severe dengue cases. Further studies are needed to evaluate the function of other mediators in dengue severity.

Prevalence and burden of dengue infection in Europe: A systematic review and meta-analysis.

Imported dengue cases are thought to be important source for transmission of autochthonous dengue in Europe. We aimed to investigate the prevalence of dengue in Europe, its severity, and factors associated with it. Out of 5287 reports resulting from the search of nine electronic search engines, we included 174 reports. Meta-analysis was performed by pooling the event rate and 95% confidence interval (CI). Subgroup meta-analyses were performed to test the effect of the covariates. Among 20 284 reported cases, 130 autochthonous dengue cases were reported in eight countries with the highest number of cases reported in Israel (n = 41). The highest number of imported dengue cases was in Germany (n = 6638) then France (n = 6610). Most cases were imported from Southeast Asia (n = 2533) especially Thailand. Dengue infection cases increased with time, with 4157 cases reported in 2010. Second dengue infection and dengue serotype 2 were positively associated with dengue severity. The proportion of autochthonous dengue infection increased with time to reach 14.8% (95% CI, 7.6-26.9) in 2015. The pooled proportion of severe dengue was 6.18% (95% CI, 2.7-13.3). The United Kingdom and France had the highest rate of severe dengue (25%; 95% CI, 6.3-62.3, and 21.4%; 95% CI, 24.5-18.7, respectively). This change may be due to the surveillance efforts instead of true biological phenomenon; thus, the lack of surveillance is an obvious limitation. In conclusion, imported and autochthonous dengue has been increasing in Europe. Severe dengue began to increase recently in Europe. European health authorities should pay more attention for the diagnosis and control of dengue infection among returning travelers, especially the travelers with fever of unknown origin.

Survey of knowledge, attitude and practice of healthcare professionals on dengue transmission, diagnosis and clinical classification.

BACKGROUND: To investigate the knowledge, attitudes, and practices of the healthcare professionals (HCPs) including physicians and nurses regarding dengue transmission, diagnosis and clinical classification using the warning signs of World Health Organization (WHO) 2009 classification. RESULTS: Out of 471 respondents from three countries, 80.9% of physicians and 74% of nurses did not receive previous training regarding the dengue infection. The majority of respondents could identify the primary dengue vector (86%), while only a third of HCPs knew the biting time of dengue mosquitoes. Only half of our respondents knew about immunity induced by serotypes; Moreover, half of our participants could determine the diagnostic tests. On the other hand, about 90% of the respondents took responsibility for talking to the patients about preventive measures. Our respondents also showed wide variations in definition of warning signs listed in the WHO 2009 classification. Multivariate analysis linked the impact of different cofactors including prior training on dengue infection, type of profession, frequency of taking care of dengue patients and country on how HCPs defined these warning signs. CONCLUSIONS: This study could declare the variation in employing the warning signs listed in the WHO 2009 classification. We have figured that most of the HCPs did not take prior training on the dengue viral infection; Also, we found gaps in the knowledge regarding various topics in dengue fever. This paper recommends the gathering of efforts to establish the proper knowledge of dengue infection and the warning signs listed by the WHO.

Anti-malarial activity of traditional Kampo medicine Coptis rhizome extract and its major active compounds.

BACKGROUND: Herbal medicine has been a rich source of new drugs exemplified by quinine and artemisinin. In this study, a variety of Japanese traditional herbal medicine ('Kampo') were examined for their potential anti-malarial activities. METHODS: A comprehensive screening methods were designed to identify novel anti-malarial drugs from a library of Kampo herbal extracts (n = 120) and related compounds (n = 96). The anti-malarial activity was initially evaluated in vitro against chloroquine/mefloquine-sensitive (3D7) and-resistant (Dd2) strains of Plasmodium falciparum. The cytotoxicity was also evaluated using primary adult mouse brain cells. After being selected through the first in vitro assay, positive extracts and compounds were examined for possible in vivo anti-malarial activity. RESULTS: Out of 120 herbal extracts, Coptis rhizome showed the highest anti-malarial activity (IC50 1.9 µg/mL of 3D7 and 4.85 µg/mL of Dd2) with a high selectivity index (SI) > 263 (3D7) and > 103 (Dd2). Three major chlorinated compounds (coptisine, berberine, and palmatine) related to Coptis rhizome also showed anti-malarial activities with IC50 1.1, 2.6, and 6.0 µM (against 3D7) and 3.1, 6.3, and 11.8 µM (against Dd2), respectively. Among them, coptisine chloride exhibited the highest anti-malarial activity (IC50 1.1 µM against 3D7 and 3.1 µM against Dd2) with SI of 37.8 and 13.2, respectively. Finally, the herbal extract of Coptis rhizome and its major active compound coptisine chloride exhibited significant anti-malarial activity in mice infected with Plasmodium yoelii 17X strain with respect to its activity on parasite suppression consistently from day 3 to day 7 post-challenge. The effect ranged from 50.38 to 72.13% (P < 0.05) for Coptis rhizome and from 81 to 89% (P < 0.01) for coptisine chloride. CONCLUSION: Coptis rhizome and its major active compound coptisine chloride showed promising anti-malarial activity against chloroquine-sensitive (3D7) and -resistant (Dd2) strains in vitro as well as in vivo mouse malaria model. Thus, Kampo herbal medicine is a potential natural resource for novel anti-malarial agents.

Correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds.

BACKGROUND: Despite noticeable improvement in anti-malarial treatment, rapid growth of resistant malaria strains points out the need for continuous development of novel anti-malarials to fight the disastrous infection. Haemozoin is considered as a novel inhibitory pathway for new anti-malarial drugs, therefore, this study aimed to systematically review all articles investigating the correlation between anti-malarial and anti-haemozoin activities of anti-malarial compounds. METHODS: A literature search was conducted on 22 October 2017 in eight databases for relevant in vitro articles reporting the correlation between anti-malarial and anti-haemozoin of anti-malarial compounds, based on the constructed search terms and inclusion criteria. ToxRtool was used to assess quality of each study. RESULTS: A total of ten articles were included in the review. In vitro anti-malarial and anti-haemozoin activity had a good correlation for quinolines for sensitive strains (R2 ranging from 0.66 to 0.95) and xanthones (Spearman ρ = 0.886). However, these correlations were reached after removing some compounds which had non-detectable anti-malarial or anti-haemozoin effects. Other structures (acridines, pyrolidines) showed negligible correlation with Spearman ρ ranging from 0.095 to 0.381 for acridines, and r varying from 0.54 to 0.62 for pyrolidines. Some good correlations were only shown in a logarithmic manner or when the anti-malarial activity was normalized. CONCLUSION: The results raised a relative relationship between anti-haemozoin and in vitro anti-malarial activities. Some studies reported compounds that were effective in the inhibition of haemozoin formation, but failed to inhibit the parasite survival and vice versa. The correlation results in these studies were calculated after these compounds were removed from their analysis. The ability of anti-malarial compounds to accumulate inside the reaction site might strengthen their anti-malarial activity.

Plasmodium falciparum multidrug resistance gene-1 polymorphisms in Northern Nigeria: implications for the continued use of artemether-lumefantrine in the region.

BACKGROUND: The analysis of single nucleotide polymorphism (SNPs) in drug-resistance associated genes is a commonly used strategy for the surveillance of anti-malarial drug resistance in populations of parasites. The present study was designed and performed to provide genetic epidemiological data of the prevalence of N86Y-Y184F-D1246Y SNPs in Plasmodium falciparum multidrug resistance 1 (pfmdr1) in the malaria hotspot of Northern Nigeria. METHODS: Plasmodium falciparum-positive blood samples on Whatman-3MM filter papers were collected from 750 symptomatic patients from four states (Kano, Kaduna, Yobe and Adamawa) in Northern Nigeria, and genotyped via BigDye (v3.1) terminator cycle sequencing for the presence of three SNPs in pfmdr1. SNPs in pfmdr1 were used to construct NYD, NYY, NFY, NFD, YYY, YYD, YFD and YFY haplotypes, and all data were analysed using Pearson Chi square and Fisher's exact (FE) tests. RESULTS: The prevalence of the pfmdr1 86Y allele was highest in Kaduna (12.50%, 2 = 10.50, P = 0.02), whilst the 184F allele was highest in Kano (73.10%, 2 = 13.20, P = 0.00), and the pfmdr1 1246Y allele was highest in Yobe (5.26%, 2 = 9.20, P = 0.03). The NFD haplotype had the highest prevalence of 69.81% in Kano (2 = 36.10, P = 0.00), followed by NYD with a prevalence of 49.00% in Adamawa, then YFD with prevalence of 11.46% in Kaduna. The YYY haplotype was not observed in any of the studied states. CONCLUSION: The present study suggests that strains of P. falciparum with reduced sensitivity to the lumefantrine component of AL exist in Northern Nigeria and predominate in the North-West region.

Exploring association between MBL2 gene polymorphisms and the occurrence of clinical blackwater fever through a case-control study in Congolese children.

BACKGROUND: Blackwater fever (BWF), one of the most severe and life-threatening forms of falciparum malaria, is characterized by acute massive intravascular haemolysis, often leading to acute renal failure. Thus far, the genetics of the underlying susceptibility to develop BWF is not fully elucidated. Deficiency in the MBL protein, an important component of the innate immune system, has previously been suggested to be a susceptibility factor for the development of severe malaria. This study aimed to evaluate the association between MBL2 gene polymorphisms, known to affect the MBL protein level/activity, and the occurrence of BWF among Congolese children. METHODS: This is a case-control study. Cases were patients with BWF, whereas controls, matched for gender and age, had uncomplicated malaria (UM). Dried blood spot was collected for genotyping. RESULTS: A total of 129 children were screened, including 43 BWF and 86 UM. The common allele in BWF and UM was A, with a frequency of 76.7 and 61.0%, respectively (OR: 2.67 (0.87-829) and p = 0.079). The frequency of the C allele was 18.6 and 29.1% in BWF and UM groups, respectively, with p = 0.858. Not a single D allele was encountered. Genotype AA was at higher risk for BWF whereas genotypes A0 (AB and AC) were over-represented in UM group (OR: 0.21 (0.06-0.78)) with p = 0.019. Nine haplotypes were observed in this study: 3 high MBL expression haplotypes and 6 low MBL expression haplotype. One new haplotype HYPC was observed in this study. None of these haplotypes was significantly associated with BWF. CONCLUSION: This pilot study is a preliminary research on MBL2 gene and infectious diseases in DRC. The study results show a higher risk for BWF in AA. This suggests that future studies on BWF should further investigate the contribution of a strong immune response to the occurrence of BWF.

Systematic review of spontaneous splenic rupture in dengue-infected patients.

Dengue infection varies from a mild febrile form to more severe disease with plasma leakage, shock, and multiorgan failure. Several serious complications such as cardiomyopathy, encephalopathy, encephalitis, hepatic damage, and neural manifestations cause organ damage in dengue infection. Splenic rupture, a less well known but life-threatening complication, can occur in dengue. The mechanism of splenic rupture in dengue is still unclear. Optimal therapeutic management is required to save the lives of patients with this complication. The objective of this study was to conduct a systematic review of studies documenting the development of spontaneous nontraumatic splenic rupture in patients with dengue infection. In March 2018, a search was conducted systematically in nine electronic databases, in addition to hand- searching. A total of 127 references were exported to Endnote; 47 references remained after removing duplicates. Finally, 16 reports met the inclusion criteria and represented 17 cases. All articles were evaluated and data extracted according to predefined criteria: number of cases, age, sex, severity of dengue disease, days of illness before admission, methods of definitive diagnosis, timing of the event, and management and outcome. A total of 17 individual patients including 13 males and four females were found. Most of the patients were young adults (ranging from 20 to 52 years) and diagnosed with computed tomography scan and managed with splenectomy. Four cases were fatal. Pathological splenic rupture in dengue is a rare, life-threatening condition where timely management can achieve a favorable outcome.

Primary lymph node sites in Hodgkin lymphoma and the risk of second primary cancers: a population-based study.

Aim: Little is known about the association between specific primary lymph node (LN) sites and the risk of developing second primary cancers in Hodgkin lymphoma (HL) patients. Materials & methods: To fill this knowledge gap, we used the multiple primary standardized incidence ratio function of the SEER*stat program to explore such an association for multiple latency periods. Results: Several SPCs occurred at various time points following different primary LN presentations of HL. Conclusion: HL survivors may benefit from a tailored primary LN site-specific follow-up screening.

Methodological steps used by authors of systematic reviews and meta-analyses of clinical trials: a cross-sectional study.

BACKGROUND: The quality of systematic reviews and meta-analyses (SR/MAs) depends on the extent of the methods used. We investigated the methodological steps used by authors of SR/MAs of clinical trials via an author survey. METHODS: We conducted an email-based cross-sectional study by contacting corresponding authors of SR/MAs that were published in 2015 and 2016 and retrieved through the PubMed database. The 27-item questionnaire was developed to study the methodological steps used by authors when conducting a SR/MA and the demographic characteristics of the respondent. Besides the demographic characteristics, methodological questions regarding the source, extraction and synthesis of data were included. RESULTS: From 10,292 emails sent, 384 authors responded and were included in the final analysis. Manual searches were carried out by 69.2% of authors, while 87.3% do updated searches, 49.2% search grey literature, 74.9% use the Cochrane tool for risk of bias assessment, 69.8% assign more than two reviewers for data extraction, 20.5% use digital software to extract data from graphs, 57.9% use raw data in the meta-analysis, and 43.8% meta-analyze both adjusted and non-adjusted data. There was a positive correlation of years of experience in conducting of SR/MAs with both searching grey literature (P = 0.0003) and use of adjusted and non-adjusted data (P = 0.006). CONCLUSIONS: Many authors still do not carry out many of the vital methodological steps to be taken when performing any SR/MA. The experience of the authors in SR/MAs is highly correlated with use of the recommended tips for SR/MA conduct. The optimal methodological approach for researchers conducting a SR/MA should be standardized.

Dengue hemophagocytic syndrome: A systematic review and meta-analysis on epidemiology, clinical signs, outcomes, and risk factors.

We systematically searched and meta-analyzed the epidemiological characteristics, frequency of clinical signs, and outcomes of dengue-associated hemophagocytic lymphohistiocytosis. Ten electronic databases were searched systematically plus manual search of reference lists to identify relevant articles published until May 2017. The highest number of reported cases were from South-East Asia region (62 cases), followed by Western Pacific region (20 cases), and America (31 cases). The term "dengue hemorrhagic fever" predominated in studies that used the World Health Organization 1997 definition (59.7%), whereas "severe dengue" predominated in studies using the World Health Organization 2009 definition (76.8%). Among 122 cases, fever, splenomegaly, hepatomegaly, anemia, thrombocytopenia, and serum ferritin ≥500 µg/L were likely to report by articles representing by large sample size. The pooled proportion of these findings were as follows: fever 97.2%, hepatomegaly 70.2%, splenomegaly 78.4%, thrombocytopenia 90.1%, anemia 76.0%, and serum ferritin ≥500 µg/L 97.1%. This study highlighted a high case fatality rate (14.6%) and co-infection among dengue hemophagocytic lymphohistiocytosis patients. We suggest that long fever duration, persistent thrombocytopenia, elevated serum ferritin, and lactate dehydrogenase levels could be good diagnostic indicators for dengue-associated hemophagocytic syndrome. Bone marrow aspiration could be used as one criterion for diagnosis but is not obligatory. Further research is needed to examine the possible risk difference for development of hemophagocytic syndrome and to explore potential relationships between specific dengue classifications and dengue-associated hemophagocytic syndrome.

Definitions for warning signs and signs of severe dengue according to the WHO 2009 classification: Systematic review of literature.

Since warning signs and signs of severe dengue are defined differently between studies, we conducted a systematic review on how researchers defined these signs. We conducted an electronic search in Scopus to identify relevant articles, using key words including dengue, "warning signs," "severe dengue," and "classification." A total of 491 articles were identified through this search strategy and were subsequently screened by 2 independent reviewers for definitions of any of the warning or severe signs in the 2009 WHO dengue classification. We included all original articles published in English after 2009, classifying dengue by the 2009 WHO classification or providing the additional definition or criterion of warning signs and severity (besides the information of 2009 WHO). Analysis of the extracted data from 44 articles showed wide variations among definitions and cutoff values used by physicians to classify patients diagnosed with dengue infection. The establishment of clear definitions for warning signs and severity is essential to prevent unnecessary hospitalization and harmonizing the interpretation and comparability of epidemiological studies dedicated to dengue infection.

Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta-analysis.

Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus. Because of lack of vaccination, various studies investigated the therapeutic efficacy of antiviral drugs and supportive remedies. A systematic literature search from 10 databases was conducted and screened for relevant articles. Studies reporting information about the treatment of MERS coronavirus infection were extracted and analyzed. Despite receiving treatment with ribavirin plus IFN, the case fatality rate was as high as 71% in the IFN-treatment group and exactly the same in patients who received supportive treatment only. Having chronic renal disease, diabetes mellitus and hypertension increased the risk of mortality (P < .05), and chronic renal disease is the best parameter to predict the mortality. The mean of survival days from onset of illness to death was 46.6 (95% CI, 30.5-62.6) for the IFN group compared with 18.8 (95% CI, 10.3-27.4) for the supportive-only group (P = .001). Delay in starting treatment, older age group, and preexisting comorbidities are associated with worse outcomes. In conclusion, there is no difference between IFN treatment and supportive treatment for MERS patients in terms of mortality. However, ribavirin and IFN combination might have efficacious effects with timely administration and monitoring of adverse events. Large-scale prospective randomized studies are required to assess the role of antiviral drugs for the treatment of this high mortality infection.