The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

Genotype V Japanese Encephalitis Virus Is Emerging

Japanese encephalitis (JE) is a global public health issue that has spread widely to more than 20 countries in Asia and has extended its geographic range to the south Pacific region including Australia. JE has become the most important cause of viral encephalitis in the world. Japanese encephalitis viruses (JEV) are divided into five genotypes, based on the nucleotide sequence of the envelope (E) gene. The Muar strain, isolated from patient in Malaya in 1952, is the sole example of genotype V JEV. Here, the XZ0934 strain of JEV was isolated from Culex tritaeniorhynchus, collected in China. The complete nucleotide and amino acid sequence of XZ0934 strain have been determined. The nucleotide divergence ranged from 20.3% to 21.4% and amino acid divergence ranged from 8.4% to 10.0% when compared with the 62 known JEV isolates that belong to genotype I–IV. It reveals low similarity between XZ0934 and genotype I–IV JEVs. Phylogenetic analysis using both complete genome and structural gene nucleotide sequences demonstrates that XZ0934 belongs to genotype V. This, in turn, suggests that genotype V JEV is emerging in JEV endemic areas. Thus, increased surveillance and diagnosis of viral encephalitis caused by genotype V JEV is an issue of great concern to nations in which JEV is endemic

The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans

BACKGROUND: Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS: We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS: After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P=0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P=0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro–brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS: We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.

TNF-α promoter polymorphism: a factor contributing to the different immunological and clinical phenotypes in Japanese encephalitis

<p>Abstract</p> <p>Background</p> <p>More than three billion populations are living under the threat of Japanese encephalitis in South East Asian (SEA) countries including India. The pathogenesis of this disease is not clearly understood and is probably attributed to genomic variations in viral strains as well as the host genetic makeup. The present study is to determine the role of polymorphism of TNF-alpha promoter regions at positions -238G/A, -308G/A, -857C/T and -863C/A in the severity of Japanese encephalitis patients.</p> <p>Methods</p> <p>Total of 142 patients including 66 encephalitis case (IgM/RT-PCR positive), 16 fever cases (IgM positive) without encephalitis and 60 apparently healthy individuals (IgG positive) were included in the study. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) using site specific restriction enzymes were implemented for polymorphism study of TNF alpha promoter.</p> <p>Results</p> <p>Following the analysis of the digestion patterns of four polymorphic sites of the TNF- alpha promoter region, a significant association was observed between the allele -308A and -863C with the patients of Japanese encephalitis.</p> <p>Conclusions</p> <p>TNF- alpha 308 G/A has been shown to be associated with elevated TNF- alpha transcriptional activity. On the other hand, polymorphism at position -863C/A in the promoter region has been reported to be associated with reduced TNF- alpha promoter activity and lower plasma TNF levels. As per the literature search, this is the first study to identify the role of TNF- alpha promoter in JE infection. Our results show that subjects with - 308A and -863C alleles are more vulnerable to the severe form of JE infection.</p

Recombination and positive selection identified in complete genome sequences of Japanese encephalitis virus

The mosquito-borne Japanese encephalitis virus (JEV) causes encephalitis in man but not in pigs. Complete genomes of a human, mosquito and pig isolate from outbreaks in 1982 and 1985 in Thailand were sequenced with the aim of identifying determinants of virulence that may explain the differences in outcomes of JEV infection between pigs and man. Phylogenetic analysis revealed that five of these isolates belonged to genotype I, but the 1982 mosquito isolate belonged to genotype III. There was no evidence of recombination among the Thai isolates, but there were phylogenetic signals suggestive of recombination in a 1994 Korean isolate (K94P05). Two sites of the genome under positive selection were identified: codons 996 and 2296 (amino acids 175 of the non-structural protein NS1 and 24 of NS4B, respectively). A structurally significant substitution was seen at NS4B position 24 of the human isolate compared with the mosquito and pig isolates from the 1985 outbreak in Thailand. The potential importance of the two sites in the evolution and ecology of JEV merits further investigation

Identifying sources, pathways and risk drivers in ecosystems of Japanese Encephalitis in an epidemic-prone north Indian district

Japanese Encephalitis (JE) has caused repeated outbreaks in endemic pockets of India. This study was conducted in Kushinagar, a highly endemic district, to understand the human-animal-ecosystem interactions, and the drivers that influence disease transmission. Utilizing the ecosystems approach, a cross-sectional, descriptive study, employing mixed methods design was employed. Four villages (two with pig-rearing and two without) were randomly selected from a high, a medium and a low burden (based on case counts) block of Kushinagar. Children, pigs and vectors were sampled from these villages. A qualitative arm was incorporated to explain the findings from the quantitative surveys. All human serum samples were screened for JE-specific IgM using MAC ELISA and negative samples for JE RNA by rRT-PCR in peripheral blood mononuclear cells. In pigs, IgG ELISA and rRT-PCR for viral RNA were used. Of the 242 children tested, 24 tested positive by either rRT-PCR or MAC ELISA; in pigs, 38 out of the 51 pigs were positive. Of the known vectors, Culex vishnui was most commonly isolated across all biotopes. Analysis of 15 blood meals revealed human blood in 10 samples. Univariable analysis showed that gender, religion, lack of indoor residual spraying of insecticides in the past year, indoor vector density (all species), and not being vaccinated against JE in children were significantly associated with JE positivity. In multivariate analysis, only male gender remained as a significant risk factor. Based on previous estimates of symptomatic: asymptomatic cases of JE, we estimate that there should have been 618 cases from Kushinagar, although only 139 were reported. Vaccination of children and vector control measures emerged as major control activities; they had very poor coverage in the studied villages. In addition, lack of awareness about the cause of JE, lack of faith in the conventional medical healthcare system and multiple referral levels causing delay in diagnosis and treatment emerged as factors likely to result in adverse clinical outcomes

Dissolved noble gases and stable isotopes as tracers of preferential fluid flow along faults in the Lower Rhine Embayment, Germany

Groundwater in shallow unconsolidated sedimentary aquifers close to the Bornheim fault in the Lower Rhine Embayment (LRE), Germany, has relatively low δ2H and δ18O values in comparison to regional modern groundwater recharge, and 4He concentrations up to 1.7 × 10−4 cm3 (STP) g–1 ± 2.2 % which is approximately four orders of magnitude higher than expected due to solubility equilibrium with the atmosphere. Groundwater age dating based on estimated in situ production and terrigenic flux of helium provides a groundwater residence time of ∼107 years. Although fluid exchange between the deep basal aquifer system and the upper aquifer layers is generally impeded by confining clay layers and lignite, this study’s geochemical data suggest, for the first time, that deep circulating fluids penetrate shallow aquifers in the locality of fault zones, implying  that sub-vertical fluid flow occurs along faults in the LRE. However, large hydraulic-head gradients observed across many faults suggest that they act as barriers to lateral groundwater flow. Therefore, the geochemical data reported here also substantiate a conduit-barrier model of fault-zone hydrogeology in unconsolidated sedimentary deposits, as well as corroborating the concept that faults in unconsolidated aquifer systems can act as loci for hydraulic connectivity between deep and shallow aquifers. The implications of fluid flow along faults in sedimentary basins worldwide are far reaching and of particular concern for carbon capture and storage (CCS) programmes, impacts of deep shale gas recovery for shallow groundwater aquifers, and nuclear waste storage sites where fault zones could act as potential leakage pathways for hazardous fluids

GB virus-C – a virus without a disease: We cannot give it chronic fatigue syndrome

BACKGROUND: Chronic fatigue syndrome (CFS) is an illness in search of an infectious etiology. GB virus-C (GBV-C) virus is a flavivirus with cell tropism and host defense induction qualities compatible with a role in producing the syndrome. The GBV-C genome is detectable in 4% of the population and 12% of the population is seropositive. The present study evaluated the association between infection with GBV and CFS. METHODS: We used a commercial EIA to detect antibodies against the GBV-C E2 protein and a quantitative real-time RT-PCR assay to detect active GBV-C infection. Sera were from a case control study of CFS in Atlanta, Georgia. The Fisher's exact two-tailed test was used for statistical analysis. RESULTS: Two of 12 CFS patients and one of 21 controls were seropositive for prior GBV-C infection and one control had viral RNA detected, indicating active infection. The results are not statistically different. CONCLUSION: We found no evidence that active or past infection with GBV is associated with CFS

Eosinophilic pneumonia associated with daptomycin: a case report and a review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Although several studies did not demonstrate that daptomycin may cause significantly higher rates of pulmonary adverse effects when compared with vancomycin or penicillinase-resistant penicillins, there have been a few case reports of severe pulmonary complications associated with daptomycin administration.</p> <p>Case presentation</p> <p>A rare case of eosinophilic pneumonia occurring 10 days after daptomycin administration in a 78-year-old Caucasian man with possible infectious endocarditis is described. He developed new onset fever, up to 38.5°C, with bilateral pulmonary crackles on physical examination and with no signs of severe respiratory failure. A chest computed tomography-scan showed bilateral nodular consolidations with air bronchograms and pleural effusions. Immediate discontinuation of daptomycin was followed by vigorous improvement of clinical signs and symptoms with progressive resolution of pulmonary consolidations a month later.</p> <p>Conclusion</p> <p>Physicians should be aware of this rare but serious complication during daptomycin treatment, and prompt discontinuation of the offending agent, with or without additional supportive treatment, must occur immediately.</p

Phylogeography of Japanese encephalitis virus:genotype is associated with climate

The circulation of vector-borne zoonotic viruses is largely determined by the overlap in the geographical distributions of virus-competent vectors and reservoir hosts. What is less clear are the factors influencing the distribution of virus-specific lineages. Japanese encephalitis virus (JEV) is the most important etiologic agent of epidemic encephalitis worldwide, and is primarily maintained between vertebrate reservoir hosts (avian and swine) and culicine mosquitoes. There are five genotypes of JEV: GI-V. In recent years, GI has displaced GIII as the dominant JEV genotype and GV has re-emerged after almost 60 years of undetected virus circulation. JEV is found throughout most of Asia, extending from maritime Siberia in the north to Australia in the south, and as far as Pakistan to the west and Saipan to the east. Transmission of JEV in temperate zones is epidemic with the majority of cases occurring in summer months, while transmission in tropical zones is endemic and occurs year-round at lower rates. To test the hypothesis that viruses circulating in these two geographical zones are genetically distinct, we applied Bayesian phylogeographic, categorical data analysis and phylogeny-trait association test techniques to the largest JEV dataset compiled to date, representing the envelope (E) gene of 487 isolates collected from 12 countries over 75 years. We demonstrated that GIII and the recently emerged GI-b are temperate genotypes likely maintained year-round in northern latitudes, while GI-a and GII are tropical genotypes likely maintained primarily through mosquito-avian and mosquito-swine transmission cycles. This study represents a new paradigm directly linking viral molecular evolution and climate