Genome-Wide Association Study Identifies Two Novel Loci Associated with Female Stress and Urgency Urinary Incontinence.

PURPOSE: Genome-wide association studies have not identified replicable genetic risk loci for stress or urgency urinary incontinence. MATERIALS AND METHODS: We carried out a discovery stage, case control, genome-wide association study in 3 independent discovery cohorts of European women (8,979) for stress incontinence, urgency incontinence, and any incontinence phenotypes. We conducted replication in 6 additional studies of European ancestry (4,069). We collected bladder biopsies from women with incontinence (50) to further investigate bladder expression of implicated genes and pathways and used symptom questionnaires for phenotyping. We conducted meta-analyses using inverse variance fixed effects models and whole transcriptome analyses using Affymetrix® arrays with replication with TaqMan® polymerase chain reaction. RESULTS: In the discovery stage, we identified 16 single nucleotide polymorphisms genotyped or imputed at 5 loci that reached genome-wide significance (p <5×10-8). In replication, rs138724718 on chromosome 2 near the macrophage receptor with collagenous structure (MARCO) gene (replication p=0.003) was associated with stress incontinence. In addition, rs34998271 on chromosome 6 near the endothelin 1 (EDN1) gene (replication p=0.0008) was associated with urgency incontinence. In combined meta-analyses of discovery and replication cohorts, associations with genome-wide significance for these 2 single nucleotide polymorphisms were confirmed. Transcriptomics analyses showed differential expression of 7 of 19 genes in the endothelin pathway between stress and urgency incontinence (p <0.0001). CONCLUSIONS: We uncovered 2 new risk loci near the genes endothelin 1 (EDN1), associated with urgency incontinence, and macrophage receptor with collagenous structure (MARCO), associated with stress incontinence. These loci are biologically plausible given their roles in smooth muscle contraction and innate host defense, respectively.

Biochemical and histopathological changes in Wistar rats after consumption of boiled and un-boiled water from high and low disease prevalent areas for chronic kidney disease of unknown etiology (CKDu) in north Central Province (NCP) and its comparison with low disease prevalent Colombo, Sri Lanka.

BACKGROUND: Chronic Kidney Disease of unknown etiology (CKDu) is prevalent in North Central Province (NCP) of Sri Lanka. Consumption of un-boiled dug well water has been identified as one of the causative factors. This in-vivo study was performed to investigate some of the suspected factors associated with the pathogenesis of CKDu mediated via ground water. METHOD: Rats were given water, collected from high and low disease prevalent areas from the NCP of Sri Lanka and the results compared with those obtained from previously identified low disease prevalent area; Colombo. Blood Urea Nitrogen, creatinine, urinary microalbumin:creatinine ratio together with ALT and AST levels were analyzed and results were compared using one-way ANOVA and paired t-Test. Histopathology was analyzed using non-parametric method. RESULTS: Rats that ingested water from New Town Medirigiriya (NTM) from high disease prevalent NCP reported significantly elevated microalbumin:creatinine ratios compared to other water sources after 8 months, whilst boiled water from NTM had been able to significantly reduce it. Histopathological findings after the 14 months experimental period revealed significantly high tubular lesion index in rats that ingested water from NCP compared to Colombo. Rats that ingested water from high disease prevalent Divuldamana (DD) from NCP showed the highest kidney lesion index though the fluoride content was relatively low in this area compared to other water sources from high disease prevalent NCP. Rats that ingested boiled and un-boiled water from NTM also developed severe lesions whilst the group from Colombo reported the lowest. Low disease prevalent area from NCP, Huruluwewa (HW) also reported elevated liver enzymes and altered renal histopathology. Association of Na+:Ca2+ ratio in the disease progression was not reflected by the current study. Compared to Colombo, high fluoride, calcium and sodium contents were observed in water from high disease prevalent areas. All the water samples were negative for heavy metals. CONCLUSIONS: Though Fluoride is a known kidney toxic agent it cannot be the sole reason for CKDu in NCP, Sri Lanka. Various toxic elements present in NCP water may contribute to different grade of kidney and liver lesions in Wistar rats.

Genetic Evidence for Causal Relationships Between Maternal Obesity-Related Traits and Birth Weight.

IMPORTANCE: Neonates born to overweight or obese women are larger and at higher risk of birth complications. Many maternal obesity-related traits are observationally associated with birth weight, but the causal nature of these associations is uncertain. OBJECTIVE: To test for genetic evidence of causal associations of maternal body mass index (BMI) and related traits with birth weight. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization to test whether maternal BMI and obesity-related traits are potentially causally related to offspring birth weight. Data from 30,487 women in 18 studies were analyzed. Participants were of European ancestry from population- or community-based studies in Europe, North America, or Australia and were part of the Early Growth Genetics Consortium. Live, term, singleton offspring born between 1929 and 2013 were included. EXPOSURES: Genetic scores for BMI, fasting glucose level, type 2 diabetes, systolic blood pressure (SBP), triglyceride level, high-density lipoprotein cholesterol (HDL-C) level, vitamin D status, and adiponectin level. MAIN OUTCOME AND MEASURE: Offspring birth weight from 18 studies. RESULTS: Among the 30,487 newborns the mean birth weight in the various cohorts ranged from 3325 g to 3679 g. The maternal genetic score for BMI was associated with a 2-g (95% CI, 0 to 3 g) higher offspring birth weight per maternal BMI-raising allele (P = .008). The maternal genetic scores for fasting glucose and SBP were also associated with birth weight with effect sizes of 8 g (95% CI, 6 to 10 g) per glucose-raising allele (P = 7 × 10(-14)) and -4 g (95% CI, -6 to -2 g) per SBP-raising allele (P = 1×10(-5)), respectively. A 1-SD ( ≈ 4 points) genetically higher maternal BMI was associated with a 55-g higher offspring birth weight (95% CI, 17 to 93 g). A 1-SD ( ≈ 7.2 mg/dL) genetically higher maternal fasting glucose concentration was associated with 114-g higher offspring birth weight (95% CI, 80 to 147 g). However, a 1-SD ( ≈ 10 mm Hg) genetically higher maternal SBP was associated with a 208-g lower offspring birth weight (95% CI, -394 to -21 g). For BMI and fasting glucose, genetic associations were consistent with the observational associations, but for systolic blood pressure, the genetic and observational associations were in opposite directions. CONCLUSIONS AND RELEVANCE: In this mendelian randomization study, genetically elevated maternal BMI and blood glucose levels were potentially causally associated with higher offspring birth weight, whereas genetically elevated maternal SBP was potentially causally related to lower birth weight. If replicated, these findings may have implications for counseling and managing pregnancies to avoid adverse weight-related birth outcomes.

Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model.

In our earlier studies, Semliki Forest virus vector VA7 completely eliminated type I interferon (IFN-I)-unresponsive human U87-luc glioma xenografts, whereas interferon-responsive mouse gliomas proved refractory. Here, we describe in two clones of CT26 murine colon carcinoma, opposed patterns of IFN-I responsiveness and sensitivity to VA7. Both CT26WT and CT26LacZ clones secreted biologically active interferon in vitro upon virus infection but only CT26WT cells were protected. Focal infection of CT26WT cultures was self-limiting but could be rescued using IFN-I pathway inhibitor Ruxolitinib or antibody against IFNß. Whole transcriptome sequencing (RNA-Seq) and protein expression analysis revealed that CT26WT cells constitutively expressed 56 different genes associated with pattern recognition and IFN-I signaling pathways, spanning two reported anti-RNA virus gene signatures and 22 genes with reported anti-alphaviral activity. Whereas CT26WT tumors were strictly virus-resistant in vivo, infection of CT26LacZ tumors resulted in complete tumor eradication in both immunocompetent and severe combined immune deficient mice. In double-flank transplantation experiments, CT26WT tumors grew despite successful eradication of CT26LacZ tumors from the contralateral flank. Tumor growth progressed uninhibited also when CT26LacZ inoculums contained only a small fraction of CT26WT cells, demonstrating dominance of IFN responsiveness when heterogeneous tumors are targeted with interferon-sensitive oncolytic viruses.

Pediatric intestinal transplant listing criteria - a call for a change in the new era of intestinal failure outcomes.

Current listing indications used for intestinal transplantation (IT) were proposed in 2001. We undertook the present single center study to see if these criteria are still valid. The 2001 criteria (advanced cholestasis, loss of >50% central venous catheter (CVC) sites, ≥2 sepsis/year, ultrashort bowel) were compared in children with intestinal failure in old era-1998-2005 (N = 99) to current era-2006-2012 (N = 91) to predict the need for IT using sensitivity, specificity, NPV and PPV. Two 2001 criteria had poorer predictive value in the current era: Advanced cholestasis (PPV 64% old vs. 40% current era; sensitivity 84% vs. 65%, respectively) and ultrashort bowel (PPV 100% old vs. 9% current era; sensitivity 10% vs. 4%, respectively). Three newly proposed criteria had high predictive value: ≥2 ICU admissions (p = 0.0001, OR 23.6, 95% CI 2.7-209.8), persistent bilirubin >75 mmol/L despite lipid strategies (p = 0.0005, OR 24.0, 95% CI 3.2-177.4), and loss of ≥3 CVC sites (p = 0.0003, OR 33.3, 95% CI 18.8-54.0). There was 98% probability of needing IT when two of these new criteria were present. The 2001 IT criteria have limited predictive ability in the current era and should be revised. A multicenter study is required to validate the findings of this single center experience.

Genetics of common variable immunodeficiency: role of transmembrane activator and calcium modulator and cyclophilin ligand interactor.

Common variable immunodeficiency (CVID) is the most common clinically manifested primary immunodeficiency, which represents a heterogeneous group of hypogammaglobulinemias of largely unknown molecular defects. The hallmark of the disease is the elevated susceptibility to recurrent infections of respiratory and gastrointestinal tract, mainly due to encapsulated bacteria while a significant proportion of patients with CVID develop autoimmune and lymphoproliferative complications. The primary cause of CVID is still not known. However, a number of distinct genetic defects including in inducible co-stimulator (ICOS), B-cell-activating factor receptor (BAFFR) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) have been identified in a minority of patients with CVID. Mutations in tumour necrosis factor receptor superfamily (TNFRSF) member, TACI, are more frequently found to be associated to the disease in about 10% of patients with CVID, but may require additional immunologic defects for complete expression of the phenotype, as unaffected heterozygotes have also been described. Clinically, patients with TACI mutations could present with the complete spectrum of complications seen in CVID. Recent animal studies have provided substantial information on TACI signalling, yet it still offers an outstanding opportunity for further exploration of the aetiology, as a large part of it remains poorly understood. In this review, we aim at giving an insight into the genetics underlying the CVID and particularly at outlining the role of TACI and its relative contribution to the development of CVID-like phenotypes in human.

Prevalence of enterobiasis among primary school children in Ragama, Sri Lanka.

OBJECTIVES: To determine the prevalence of enterobiasis among school children in Ragama Medical Officer of Health (MOH) region and the association between clinical features, potential risk factors and infection status. DESIGN: Cross sectional study. SETTING: School based. Participants 260 school children aged 5-7 years, attending five state schools in the Ragama MOH region. MAIN OUTCOME MEASURES: Prevalence of Enterobius vermicularis infection as diagnosed using adhesive cellophane tapes on the perianal skin on 2 consecutive days. RESULTS: The overall prevalence of enterobiasis was 38%. The risk factors significant on a univariate analysis were male gender, maternal under-education, non-permanency of paternal employment, more household members, more siblings in a family, more persons sleeping with an index child and lack of recent deworming. On a multivariate model more household members, more children in a household, more persons sleeping with the index child, non-permanency of paternal employment and lack of recent deworming were significantly associated with infection. None of the clinical manifestations evaluated (peri-anal itching, insomnia, abdominal pain, and enuresis) showed a significant association with enterobiasis. CONCLUSIONS: Enterobiasis is highly prevalent among primary school children in Ragama.

Can probiotic gargles reduce post-tonsillectomy morbidity in adult patients? A pilot, triple-blind, randomised, controlled trial and feasibility study.

OBJECTIVE: This study aimed to determine the efficacy of probiotic gargles compared with placebo gargles on reducing post-tonsillectomy morbidity in adults. METHOD: This was a triple-blind, randomised, controlled trial and feasibility study. Thirty adults underwent elective tonsillectomy and were randomly assigned to receive either probiotic or placebo gargles for 14 days after surgery. Daily pain scores and requirement of analgesia were measured for 14 days post-operatively. Secondary outcomes assessed probiotic safety and tolerability and the feasibility of the trial. RESULTS: The probiotic group experienced less pain at rest on day 2. However, the amount of oxycodone (5 mg) tablets used was greater in the probiotic group compared with placebo. There were no statistically significant differences in the frequency of adverse effects between both groups. This trial was feasible. CONCLUSION: This pilot study suggested that probiotic gargles do not reduce post-tonsillectomy pain or bleeding, highlighting the importance of pilot and feasibility studies in clinical research.

Lymphatic filariases and soil-transmitted helminthiases in Sri Lanka: the challenge of eliminating residual pockets of transmission.

Sri Lanka has successfully met the challenge of controlling both lymphatic filariasis (LF) and soil-transmitted helminthiases (STH) as public health problems. The primary public health strategy for combatting both conditions has been preventive chemotherapy. The national programme for the elimination of LF implemented five annual rounds of mass chemotherapy in the endemic districts from 2002 to 2006 using a combination of diethylcarbamazine and albendazole. The overall microfilaria rate declined from 0.21% in 2001 before the mass chemotherapy, to 0.06% in 2016, at declaration of elimination of LF as a public health problem by the World Health Organization. Currently Sri Lanka is in the phase of post-validation surveillance. Achieving control of STH has been more difficult. Mass deworming programmes have been implemented for nearly a century, and national-level surveys reported prevalence rates declining from 6.9% in 2003 to 1% in 2017. However, neither of these infections has been completely eliminated. A situation analysis indicates continued transmission of both among high-risk communities. This paper explores the reasons for persistence of transmission of both LF and STH in residual pockets and the measures that are required to achieve long-term control, or perhaps even interrupt transmission in Sri Lanka. This article is part of the theme issue 'Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs'.

Evolutionarily labile dispersal behavior and discontinuous habitats enhance population differentiation in island versus continentally distributed swallows.

The causes of population divergence in vagile groups remain a paradox in evolutionary biology: dispersive species should be able to colonize new areas, a prerequisite for allopatric speciation, but dispersal also facilitates gene flow, which erodes population differentiation. Strong dispersal ability has been suggested to enhance divergence in patchy habitats and inhibit divergence in continuous landscapes, but empirical support for this hypothesis is lacking. Here we compared patterns of population divergence in a dispersive clade of swallows distributed across both patchy and continuous habitats. The Pacific Swallow (Hirundo tahitica) has an insular distribution throughout Southeast Asia and the Pacific, while its sister species, the Welcome Swallow (H. neoxena), has a continental distribution in Australia. We used whole-genome data to demonstrate strong genetic structure and limited introgression among insular populations, but not among continental populations. Demographic models show that historic changes in habitat connectivity have contributed to population structure within the clade. Swallows appear to exhibit evolutionarily labile dispersal behavior in which they reduce dispersal propensity after island colonization despite retaining strong flight ability. Our data support the hypothesis that fragmented habitats enhance population differentiation in vagile groups, and suggest that labile dispersal behavior is a key mechanism underlying this pattern.

A prospective cohort study on post COVID syndrome from a tertiary care centre in Sri Lanka.

There is a scarcity of follow-up data on post-COVID syndrome and its physical, psychological, and quality of life attributes, particularly from South Asian populations. This study was conducted to assess the prevalence, associations, and impact of the post-COVID syndrome among patients treated at a dedicated COVID-19 treatment unit. A prospective cohort study was conducted to follow-up patients with moderate to severe disease or mild disease with co-morbidities at 2 and 6 weeks, 3 and 6 months and 1 year from discharge. Clinical notes, an interviewer-administered questionnaire and six-item cognitive impairment, Montreal Cognitive Assessment, Fatigue (11-item Chalder) and EQ5D5L questionnaires were used for data collection. All patients had follow-up echocardiograms and symptomatic patients had biochemical and haematological investigations, chest x-rays, high-resolution computed tomography of chest and lung function tests. Among 153 patients {mean age 57.2 ± 16.3 years (83 (54.2% males)}, 92 (60.1%) got the severe disease. At least a single post-COVID symptom was reported by 119 (77.3%), 92 (60.1%), 54 (35.3%) and 25 (16.3%) at 6 weeks, 3 months, 6 months and 1 year respectively. Post-COVID symptoms were significantly associated with disease severity (p = 0.004). Fatigue was found in 139 (90.3%), 97 (63.4%) and 66 (43.1%) patients at 2, 6 and 12 weeks respectively. Dyspnoea {OR 1.136 (CI 95% 0.525-2.455)}, arthralgia {OR 1.83(CI 95% 0.96-3.503)} and unsteadiness {OR 1.34 (CI 95% 0.607-2.957)}were strongly associated with age above 60 years. Both genders were equally affected. In multivariable logistic regression, fatigue and anxiety/depression were associated with poor quality of life (QoL) (p = 0.014, p ≤ 0.001) in 6 weeks. In cardiac assessments, diastolic dysfunction (DD) was detected in 110 (72%) patients at 2 weeks and this number reduced to 64 (41.8%) at 12 weeks. The decline in diastolic dysfunction in elderly patients was significantly higher compared to young patients (p = 0.012). Most post-COVID symptoms, QoL and cognition improve during the first few months. The severity of the disease and older age are associated with post-COVID symptoms. Transient DD may contribute to cardiac symptoms of post-COVID syndrome, especially in elderly patients.

Multiple genetic variants explain measurable variance in type 2 diabetes-related traits in Pakistanis.

AIMS/HYPOTHESIS: Multiple genetic variants are associated with type 2 diabetes-related traits in Europeans, but their role in South Asian populations needs further study. We hypothesised that genetic variants associated with diabetes-related traits in Europeans would explain a similar proportion of phenotypic variance in a Pakistani population and could be used in Mendelian randomisation analyses. METHODS: We used data from 2,131 individuals from the Control of Blood Pressure and Risk Attenuation Trial (COBRA) in Karachi, Pakistan. Individuals were aged 40 years or older. RESULTS: Combining information from multiple genetic variants showed that fasting glucose, BMI, triacylglycerol, and systolic and diastolic blood pressure variants explained 2.9%, 0.7%, 5.5%, 1.2% and 1.8% of the variance in those traits respectively. Genetic risk scores of fasting glucose, triacylglycerol, BMI, systolic blood pressure and diastolic blood pressure variants were associated with these traits, with per allele SD effects of 0.057 (95% CI 0.041, 0.074), p=3.44 × 10(-12), 0.130 (95% CI 0.105, 0.155), p=2.9 × 10(-21), 0.04 (95% CI 0.014, 0.072), p=0.004, 0.031 (95% CI 0.016, 0.047), p=7.9 × 10(-5), 0.028 (95% CI 0.015, 0.042), p = 5.5 × 10(-5), respectively. These effects are consistent with those observed in Europeans, except that the effect of triacylglycerol variants in South Asians was slightly lower. Mendelian randomisation provided evidence that genetically influenced, raised triacylglycerol levels do not causally affect type 2 diabetes risk to the extent predicted from observational data (p=0.0003 for difference between observed and instrumental variables correlations). CONCLUSIONS/INTERPRETATION: Genetic variants identified in Europeans are associated with type 2 diabetes-related traits in Pakistanis, with comparable effect sizes. Larger studies are needed to perform adequately powered Mendelian randomisation and help dissect the relationships between type 2 diabetes-related traits in diverse South Asian subgroups.

[Identification of restless legs syndrome in polysomnography studies and its association with other variables]. / Identificación del síndrome de piernas inquietas en estudios polisomnográficos y su asociación con otras variables.

INTRODUCTION: Restless legs syndrome (RLS) is a movement disorder characterized by an uncontrollable urge to move the legs in response to an unpleasant sensation. The coexistence of RLS and other sleep and mood disorders may require adjustment in the therapeutic strategy. The objective of this study was to determine the prevalence of RLS in adults studied with polysomnography and to evaluate its association with other sleep and mood disorders. PATIENTS AND METHODS: Descriptive cross-sectional study. We included adults studied with polysomnography between 2015 and 2021. We collected information on their medical history, polysomnographic data and mood and sleep disorders using a self-administered written questionnaire which is part of the routine evaluation of all patients referred to this sleep unit. These variables were compared between patients with and without RLS. RESULTS: We included 406 patients. The prevalence of RLS was 36.7% (n = 149). The presence of fatigue (45.3%), moderate to severe insomnia (38.9%) and depression (45.6%) was higher in subjects with RLS. We did not find differences regarding daytime sleepiness and anxiety symptoms. Periodic Limb Movements (PLM) was not associated with RLS (p = 0.26) and its prevalence was low. CONCLUSION: The prevalence of RLS in subjects studied with Polysomnography is high and it was associated with clinically significant fatigue, insomnia and depression. These symptoms should be identified in order to establish an adequate therapeutic strategy. The prevalence of periodic limb movements was low and was not linked with RLS. These findings contrast with previous publications. Therefore, it requires additional studies to clarify the cause of this variation.

TITLE: Identificación del síndrome de piernas inquietas en estudios polisomnográficos y su asociación con otras variables.Introducción. El síndrome de piernas inquietas (SPI) es un trastorno del movimiento caracterizado por un impulso incontrolable de mover las piernas en respuesta a una sensación desagradable. La coexistencia de SPI junto con otros trastornos del sueño y del estado de ánimo puede modificar el enfoque terapéutico. El objetivo de este trabajo fue determinar la prevalencia de SPI en adultos estudiados con polisomnografía y evaluar su asociación con otros trastornos del sueño y del estado de ánimo. Pacientes y métodos. Estudio descriptivo transversal. Se incluyó a adultos estudiados con polisomnografía entre 2015 y 2021. Se recopiló información sobre sus antecedentes, datos polisomnográficos y trastornos del ánimo y del sueño mediante un cuestionario escrito autoadministrado que forma parte de la evaluación de todos los pacientes referidos a esta unidad de sueño. Se compararon estas variables en relación con la presencia de SPI. Resultados. Se incluyó a 406 pacientes. La prevalencia de SPI fue del 36,7% (n = 149). La presencia de fatiga (45,3%), insomnio moderado a grave (38,9%) y depresión (45,6%) fue mayor en sujetos con SPI. No se encontraron diferencias en relación con somnolencia diurna y síntomas de ansiedad. Los movimientos periódicos de las piernas no se asociaron con SPI (p = 0,26) y su prevalencia fue baja. Conclusión. La prevalencia de SPI en sujetos estudiados con polisomnografía fue elevada y se asoció a fatiga clínicamente significativa, insomnio y depresión. Estos síntomas deberían identificarse para establecer una estrategia terapéutica adecuada. La prevalencia de movimientos periódicos de las piernas fue baja y no se vinculó con SPI, hallazgo que contrasta con lo publicado previamente. Se requieren estudios adicionales para esclarecer la causa de esta asociación.

Selection of medical students in Sri Lanka: time to re-think criteria?

OBJECTIVE: To examine the validity of selected entry level characteristics in relation to the GCE A/L examination as independent predictors of performance of students in medical school. METHODS: A retrospective, analytical study was done at the Faculty of Medicine, University of Kelaniya. Student characteristics at entry were described by sex, the average z-score, General English grade and attempt at GCE A/L examination, and average mark obtained at the English placement test on registration to medical school. Average marks at three summative examinations were used as indicators of performance in medical school. Multivariate analysis using multiple linear regression was carried out using these three outcome measures in relation to four entry point variables as predictors of performance in medical school. Causal path diagrams were constructed using standardised regression coefficients for the whole group and for male and female students separately. RESULTS: The A/L z-score, A/L attempt and English placement test marks were all significant predictors of outcome at the First Examination. Of the variables relating to the A/L examination, the attempt had a much higher path coefficient with performance at the First Examination than the A/L z-score, as did the English marks. Separate path analyses for male and female students showed that while the significance of the relationships remained the same, the magnitude of the correlation was different. CONCLUSIONS: Students who gain admission on their 3rd attempt at the AL examination fare much worse than those admitted to medical school on their 1st attempt. Differences between sexes in examination performance are probably linked to both A/L attempt and English language proficiency.

Novel biological insights emerging from genetic studies of type 2 diabetes and related metabolic traits.

PURPOSE OF REVIEW: In the past 3 years, genome-wide association studies have identified many tens of common genetic variants associated with metabolic diseases and traits. Although much further research is needed to identify the target genes, the associations between gene variants and diseases are already providing biological insights. The purpose of this review is to update the reader with the most relevant findings, with a particular emphasis on type 2 diabetes (T2D) and glucose metabolism, and discuss some of the biological implications of the genetic findings. RECENT FINDINGS: Largely through recent genome-wide association studies, we now know of approximately 20 gene variants associated with T2D, 10 with body mass index (BMI) and obesity, four with fasting glucose levels in the normoglycaemic population and over 30 with lipid levels. These findings are stimulating many new important areas of research related to metabolic diseases. For T2D and glucose metabolism, we discuss a number of aspects and implications of the genetic findings, including the observations that T2D gene variants are not usually in or near obvious candidate genes, highlighting the poor prior knowledge of the biology of the disease; most T2D gene variants are associated with beta-cell function rather than insulin resistance; there is a difference between genes that influence variation in normal glucose levels compared with those influencing onset and progression of diabetes; and there is a genetic link between diabetes and foetal growth. SUMMARY: Genetic studies in the past 3 years have provided a greatly increased knowledge of the regions of the genome involved in adverse metabolic consequences. There are now over 100 common genetic variants reproducibly associated with metabolic traits, including reduced beta-cell function, obesity, increased lipid levels and increased glucose levels. These genetic findings are already altering perceptions of how these traits develop and interact to result in diseases such as T2D.

Molecular Characterization of a Reemergent Brugia malayi Parasite in Sri Lanka, Suggestive of a Novel Strain.

Sri Lanka achieved elimination status for lymphatic filariasis in 2016; still, the disease remains a potential public health issue. The present study is aimed at identifying a subperiodic Brugia sp. parasite which has reemerged in Sri Lanka after four decades via molecular-based analysis. Polymerase chain reaction performed with pan-filarial primers specific for the internal transcribed spacer region-2 (ITS-2) of the rDNA of Brugia filarial parasites isolated from human, canine, and feline blood samples yielded a 615 bp band establishing the species identity as Brugia malayi. Comparison of the ITS2 sequences of the reemerged B. malayi isolates with GenBank sequences revealed a higher sequence homology with B. pahangi than B. malayi with similar phylogenetic evidence. However, the mean interspecies Kimura-2-parameter pairwise divergence between the generated Brugia sequences with B. malayi and B. pahangi was less than 3%. During the analysis of parsimony sites of the new ITS2 sequences, substitutions at A36T, A296G, T373A, and G482A made the sequences different from both B. pahangi and B. malayi suggesting the possibility of a new genetic variant or a hybrid strain of B. malayi and B. pahangi. Mosquito dissections and xenomonitoring identified M. uniformis and M. annulifera as vectors of this novel strain of B. malayi circulating among cats, dogs, and humans in Sri Lanka.

Multi-site study of HPV type-specific prevalence in women with cervical cancer, intraepithelial neoplasia and normal cytology, in England.

BACKGROUND: Knowledge of the prevalence of type-specific human papillomavirus (HPV) infections is necessary to predict the expected, and to monitor the actual, impact of HPV immunisation and to design effective screening strategies for vaccinated populations. METHODS: Residual specimens of cervical cytology (N=4719), CIN3/CGIN and cervical cancer biopsies (N=1515) were obtained from sites throughout England, anonymised and tested for HPV DNA using the Linear Array typing system (Roche). RESULTS: The prevalence of HPV 16 and/or 18 (with or without another high-risk (HR) type) was 76% in squamous cell carcinomas, 82% in adeno/adenosquamous carcinomas and 63% and 91% in CIN3 and CGIN, respectively. Of all HR HPV-infected women undergoing cytology, non-vaccine HPV types only were found in over 60% of those with mild dyskaryosis or below, and in <20% of those with cancer. In women of all ages undergoing screening, HR HPV prevalence was 16% and HPV 16 and/or 18 prevalence was 5%. CONCLUSION: Pre-immunisation, high-grade cervical disease in England was predominantly associated with HPV 16 and/or 18, which promises a high impact from HPV immunisation in due course. Second-generation vaccines and screening strategies need to consider the best ways to detect and prevent disease due to the remaining HR HPV types.

Prevalence of childhood atopic diseases in the Western Province of Sri Lanka.

BACKGROUND: Atopic diseases in children are major public health problems around the world and the prevalence is increasing. Our objective was to assess the prevalence of atopic diseases in schoolchildren in the Western Province of Sri Lanka. METHODS: Children attending grade 5 in 17 schools in the Western Province of Sri Lanka were recruited to the study. Data were collected using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, which was filled by the parent/guardian of the selected children. RESULTS: A total of 640 schoolchildren were recruited. Their mean age was 10 years (SD +/- 0.5) and 55.9% of the study population was boys. Prevalence (95% CI) of asthma, rhinitis and eczema was 17% (13.7-20.3), 21.4% (17.8-25.1) and 5% (3.1-7.0) respectively, while 33.7% (29.6-37.9) had one or more diseases. Only the prevalence of allergic rhinitis showed a statistically significant difference between the two sexes, being more common in boys. Less than 30% of affected children's parents recognised that their child had either asthma or rhinitis, whereas a higher number of parents (54.2%) recognised that their child had eczema. Among children with asthma, 44.4% had rhinitis. CONCLUSIONS: The prevalence of atopic diseases in schoolchildren in grade 5 in the Western Province of Sri Lanka is as common as in other countries in the south Asian region. Parental recognition of these conditions was not satisfactory.

Decay of Thermal Tolerance in Queensland Fruit Fly Eggs (Bactrocera tryoni, Diptera: Tephritidae) Following Non-Lethal Heat Hardening.

Quarantine disinfestation treatments for Queensland fruit fly (Bactrocera tryoni (Froggatt)) have been developed which use high temperatures to kill preimaginal life stages within fruit prior to export. However, thermal tolerance of individuals can be increased if they are exposed to elevated temperatures before disinfestation treatment. The rate that this thermal conditioning decays after exposure, and the effect of temperature on this decay process, were investigated. Eggs of B. tryoni were exposed to a nonlethal hot water treatment at 38°C for 15 min, 1 or 3 h, then held in air at 25°C for times ranging from 15 min to 12 h, before being exposed to hot water disinfestation at 46°C for various times. From each of these cohorts, the lethal time for 99% mortality (LT99) was calculated. The LT99 of B. tryoni eggs increased with longer conditioning times at 38°C. For each conditioning time, the LT99 decreased with longer delay periods at 25°C prior to disinfestation. The rate of decrease was greatest during the first hour of delay, after which the rate of decrease slowed and tended toward zero. This induction and decay was modeled using a double-exponential equation. These experiments show that thermal conditions prior to disinfestation, and the time delay before the procedure commences, both influence the response of the insect to the disinfestation treatment. These results have implications for the specification of postharvest quarantine treatments, which are usually expressed only in terms of a fruit-center target temperature.

Could vitamin D reduce obesity-associated inflammation? Observational and Mendelian randomization study.

BACKGROUND: Obesity is associated with inflammation but the role of vitamin D in this process is not clear. OBJECTIVES: We aimed to assess the associations between serum 25-hydroxyvitamin D [25(OH)D], BMI, and 16 inflammatory biomarkers, and to assess the role of vitamin D as a potential mediator in the association between higher BMI and inflammation. METHODS: Northern Finland Birth Cohort 1966 (NFBC1966) 31-y data on 3586 individuals were analyzed to examine the observational associations between BMI, 25(OH)D, and 16 inflammatory biomarkers. Multivariable regression analyses and 2-sample regression-based Mendelian randomization (MR) mediation analysis were performed to assess any role of vitamin D in mediating a causal effect of BMI on inflammatory biomarkers [soluble intercellular adhesion molecule 1 (sICAM-1), high sensitivity C-reactive protein (hs-CRP), and α1-acid glycoprotein (AGP)] for which observational associations were detected. For MR, genome-wide association study summary results ranging from 5163 to 806,834 individuals were used for biomarkers, 25(OH)D, and BMI. Findings were triangulated with a literature review of vitamin D supplementation trials. RESULTS: In NFBC1966, mean BMI (kg/m2) was 24.8 (95% CI: 24.7, 25.0) and mean 25(OH)D was 50.3 nmol/L (95% CI: 49.8, 50.7 nmol/L). Inflammatory biomarkers correlated as 4 independent clusters: interleukins, adhesion molecules, acute-phase proteins, and chemokines. BMI was positively associated with 9 inflammatory biomarkers and inversely with 25(OH)D (false discovery rate < 0.05). 25(OH)D was inversely associated with sICAM-1, hs-CRP, and AGP, which were positively associated with BMI. The MR analyses showed causal association of BMI on these 3 inflammatory biomarkers. There was no observational or MR evidence that circulating 25(OH)D concentrations mediated the association between BMI and these 3 inflammatory markers. Review of randomized controlled trials (RCTs) supported our findings showing no impact of vitamin D supplementation on inflammatory biomarkers. CONCLUSIONS: The findings from our observational study and causal MR analyses, together with data from RCTs, do not support a beneficial role of vitamin D supplementation on obesity-related inflammation.