Effect of Antimicrobial Agents on Inflammatory Cytokines in Acute Leptospirosis.

The aim of this study was to assess the inflammatory cytokine response and possible association with antimicrobial treatment with penicillin, ceftriaxone, and doxycycline in acute leptospirosis. In the early acute stage, interleukin-10 (IL-10) levels were higher in mild cases than in severe cases (P = 0.01). IL-6 and IL-8 levels were low in patients who received >5 antimicrobial doses (P < 0.01). IL-8 levels were negatively correlated with the number of ceftriaxone doses administered (r = -0.315; P = 0.031). Further studies are needed to evaluate the possible downregulation of proinflammatory cytokines by ceftriaxone in leptospirosis.

Early Course of Inflammatory Bowel Disease in a Population-Based Inception Cohort Study From 8 Countries in Asia and Australia.

BACKGROUND & AIMS: The incidence of inflammatory bowel disease (IBD) is increasing in Asia, but little is known about disease progression in this region. The Asia-Pacific Crohn's and Colitis Epidemiology Study was initiated in 2011, enrolling subjects from 8 countries in Asia (China, Hong Kong, Indonesia, Sri Lanka, Macau, Malaysia, Singapore, and Thailand) and Australia. We present data from this ongoing study. METHODS: We collected data on 413 patients diagnosed with IBD (222 with ulcerative colitis [UC], 181 with Crohn's disease [CD], 10 with IBD unclassified; median age, 37 y) from 2011 through 2013. We analyzed the disease course and severity and mortality. Risks for medical and surgical therapies were assessed using Kaplan-Meier analysis. RESULTS: The cumulative probability that CD would change from inflammatory to stricturing or penetrating disease was 19.6%. The cumulative probabilities for use of immunosuppressants or anti-tumor necrosis factor agents were 58.9% and 12.0% for patients with CD, and 12.7% and 0.9% for patients with UC, respectively. Perianal CD was associated with an increased risk of anti-tumor necrosis factor therapy within 1 year of its diagnosis (hazard ratio, 2.97; 95% confidence interval, 1.09-8.09). The cumulative probabilities for surgery 1 year after diagnosis were 9.1% for patients with CD and 0.9% for patients with UC. Patients with CD and penetrating disease had a 7-fold increase for risk of surgery, compared with patients with inflammatory disease (hazard ratio, 7.67; 95% confidence interval, 3.93-14.96). The overall mortality for patients with IBD was 0.7%. CONCLUSIONS: In a prospective population-based study, we found that the early course of disease in patients with IBD in Asia was comparable with that of the West. Patients with CD frequently progress to complicated disease and have accelerated use of immunosuppressants. Few patients with early stage UC undergo surgery in Asia. Increasing our understanding of IBD progression in different populations can help optimize therapy and improve outcomes.

Non-alcoholic fatty liver disease and its associations among adolescents in an urban, Sri Lankan community.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a common problem across the world. We aimed to determine the prevalence of NAFLD and its associations in Sri Lankan adolescents living in an urban Sri Lankan community. METHOD: The study population consisted of the birth cohort of the year 2000, residing in the Ragama Medical Officer of Health area. Socio-demographic and anthropometric data [anthropometric measurements, blood pressure and total body fat distribution] of these adolescents were collected by trained data collectors. Fasting blood sugar, serum insulin, fasting serum lipids and serum alanine aminotransferase (ALT) levels were measured and an abdominal ultrasound was performed. NAFLD was diagnosed on established ultrasound criteria for fatty liver and absent alcohol consumption. RESULTS: The study sample consisted of 499 adolescents [263 (51.8%) girls]. Forty two (8.4%) had NAFLD. NAFLD was significantly associated with being breast fed for less than 4 months (33.3% vs. 17.1 in controls, p = 0.02), higher waist circumference (prevalence risk ratio 83.3/20.3, 4.1, p < 0.0001), higher body mass index (prevalence risk ratio 40.5/4.8, 8.4, p < 0/0001),higher HOMA-IR (3.7 vs. 1.9, p < 0.0001) and high triglycerides (prevalence risk ratio 14.3/5.8, 2.5, p = 0.033). Adolescents with NAFLD also had a higher amount of total body fat (p < 0.001) and subcutaneous fat (p < 0.001) than those without NAFLD. The number of children with metabolic derangements was higher among adolescents with NAFLD than those without (85.8 vs 26.3 in controls, p < 0.0001), but a family history of hypertension, diabetes, myocardial infarction or dyslipidaemia were not. CONCLUSION: Prevalence of NAFLD was high in Sri Lankan adolescents, and was associated with metabolic derangements, especially obesity, insulin resistance and early cessation of breast feeding.

Adverse reactions to snake antivenom, and their prevention and treatment.

Antivenom is the mainstay of treatment of snakebite envenoming. However, adverse reactions to snake antivenom that is available are common in many parts of the world where snakebite is prevalent. Both acute (anaphylactic or pyrogenic) and delayed (serum sickness type) reactions occur. Acute reactions are usually mild but severe systemic anaphylaxis may develop, often within an hour or so of exposure to antivenom. Serum sickness after antivenom has a delayed onset between 5 and 14 days after its administration. Ultimately, the prevention reactions will depend mainly on improving the quality of antivenom. Until these overdue improvements take place, doctors will have to depend on pharmacological prophylaxis, where the search for the best prophylactic agent is still on-going, as well as careful observation of patients receiving antivenom in preparation for prompt management of acute as well as delayed reactions when they occur.

Asia Pacific Consensus Statements on Crohn's disease. Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific Crohn's Disease Consensus--Part 1).

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field.

Asia-Pacific consensus statements on Crohn's disease. Part 2: Management.

The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field.

Evaluation of two immunodiagnostic tests for early rapid diagnosis of leptospirosis in Sri Lanka: a preliminary study.

BACKGROUND: Leptospirosis is often treated based on clinical diagnosis. There is a need for rapid laboratory diagnosis for this condition. The aim of this study was to compare the diagnostic accuracy of two rapid IgM based immunodiagnostic assays with the microscopic agglutination test (MAT), in acute leptospirosis infection. METHODS: MAT, IgM based immunochromatographic test (Leptocheck-WB) and IgM ELISA were performed using acute sera of patients clinically suspected to have leptospirosis (n = 83). Bayesian latent class modeling was used to compare the accuracy of these tests. RESULTS: Percentage positivity for MAT, Leptocheck-WB, and IgM ELISA were 48.1, 55.3, and 45.7 % respectively. Bayesian latent class modeling showed a combined positivity rate of leptospirosis of 44.7 %. The sensitivity of MAT, Leptocheck-WB and IgM ELISA were 91.4, 95 and 81.1 %, and specificity were 86.7, 76.4 and 83.1 %, respectively. CONCLUSIONS: Leptocheck-WB has high sensitivity, and, because it is quick and easy to perform, would be a good screening test for acute leptospirosis infection. IgM ELISA has good specificity, and is comparable with MAT; given that it is easier to perform and more widely available than MAT, it would be a more appropriate confirmatory test for use in hospitals with limited access to a specialized laboratory.

Snake antivenom for snake venom induced consumption coagulopathy.

BACKGROUND: Snake venom induced consumption coagulopathy is a major systemic effect of envenoming. Observational studies suggest that antivenom improves outcomes for venom induced consumption coagulopathy in some snakebites and not others. However, the effectiveness of snake antivenom in all cases of venom induced consumption coagulopathy is controversial. OBJECTIVES: To assess the effect of snake antivenom as a treatment for venom induced consumption coagulopathy in people with snake bite. SEARCH METHODS: The search was done on 30 January 2015. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), three other sources, clinical trials registers, and we also screened reference lists. SELECTION CRITERIA: All completed, published or unpublished, randomised, controlled trials with a placebo or no treatment arm, where snake antivenom was administered for venom induced consumption coagulopathy in humans with snake bites. DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified trials and independently applied the selection criteria. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Randomised placebo-controlled trials are required to investigate the effectiveness of snake antivenom for clinically relevant outcomes in patients with venom induced consumption coagulopathy resulting from snake bite. Although ethically difficult, the routine administration of a treatment that has a significant risk of anaphylaxis cannot continue without strong evidence of benefit.

Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBD) are becoming more common in Asia, but epidemiologic data are lacking. The Asia-Pacific Crohn's and Colitis Epidemiology Study aimed to determine the incidence and phenotype of IBD in 8 countries across Asia and in Australia. METHODS: We performed a prospective, population-based study of IBD incidence in predefined catchment areas, collecting data for 1 year, starting on April 1, 2011. New cases were ascertained from multiple overlapping sources and entered into a Web-based database. Cases were confirmed using standard criteria. Local endoscopy, pathology, and pharmacy records were searched to ensure completeness of case capture. RESULTS: We identified 419 new cases of IBD (232 of ulcerative colitis [UC], 166 of Crohn's disease [CD], and 21 IBD-undetermined). The crude annual overall incidence values per 100,000 individuals were 1.37 for IBD in Asia (95% confidence interval: 1.25-1.51; 0.76 for UC, 0.54 for CD, and 0.07 for IBD-undetermined) and 23.67 in Australia (95% confidence interval: 18.46-29.85; 7.33 for UC, 14.00 for CD, and 2.33 for IBD-undetermined). China had the highest incidence of IBD in Asia (3.44 per 100,000 individuals). The ratios of UC to CD were 2.0 in Asia and 0.5 in Australia. Median time from symptom onset to diagnosis was 5.5 months (interquartile range, 1.4-15 months). Complicated CD (stricturing, penetrating, or perianal disease) was more common in Asia than Australia (52% vs 24%; P = .001), and a family history of IBD was less common in Asia (3% vs 17%; P < .001). CONCLUSIONS: We performed a large-scale population-based study and found that although the incidence of IBD varies throughout Asia, it is still lower than in the West. IBD can be as severe or more severe in Asia than in the West. The emergence of IBD in Asia will result in the need for specific health care resources, and offers a unique opportunity to study etiologic factors in developing nations.

Rickettsial infection among military personnel deployed in Northern Sri Lanka.

BACKGROUND: Military personnel deployed in field actvities report on frequent tick bites. Therefore they may run the risk of exposure to rickettsial organisms. METHODS: In order to assess the risk of exposure to rickettsial organisms, two groups of military personnel who were deployed in field activities of Nothern Sri Lanka were investigated. The first group was studied in order to assess the sero-prevalence of rickettsioses and consisted of soldiers who were admitted following injuries during field activities. The second group was studied to identify the incidence of acute rickettsioses during their acute febrile presentations. They were tested with IFA-IgG against spotted fever group rickettsioses (SFG), scrub typhus (ST) and murine typhus. RESULTS: In the first group, 48/57 (84%) military personnel had serological evidence of exposure to rickettsioses (in all, IFA-IgG titer ≥ 1:128): 33/50 (66%) to SFG rickettsioses, 1/50 (2%) to ST and 14/50 (28%) had mixed titers for both (in all, titers were higher for SFG). While all of them were in military uniform most of the time and frequently slept on scrub land, 35/57 (61.4%) had never used insect repellents and none were on doxycycline prophylaxis. 48/57 (84%) had experienced tick bites during field activity. In the second group, there were 49 who presented with acute febrile illness with a mean duration of 8.5 days (SD 3.2). 33/49 (67.3%) were serologically positive for acute rickettsioses (IgG ≥1:256); 26 (79%) due to ST and 7 (21%) due to SFG rickettsioses, CONCLUSIONS: Exposure to rickettsial disease was common among soldiers who were deployed in Northern Sri Lanka. Scrub typhus was the predominent species accounting for acute febrile illness. Further studies are needed to understand the reasons for very high sero-prevalence for SFG rickettsioses with no anticedent febrile illness. Use of preventive measures was not satisfactory. The high sero-prevelence of SFG rickettsioses is likely to interfere with serological diagnosis of acute SFG rickettsioses in this population.

Low serum total nitrite and nitrate levels in severe leptospirosis.

BACKGROUND: The relationship between inducible nitric oxide synthatase activity and disease severity in leptospirosis is unclear. Nitric oxide is converted to nitrites and nitrates, thus nitrite and nitrate levels (NOx) in serum are considered surrogate markers for nitric oxide. NOx are excreted through the kidneys, and elimination is diminished in renal impairment. We assessed the correlation of NOx with disease severity in patients with leptospirosis, compared with healthy controls and non-leptospirosis fever patients. METHODS: All patients admitted over a two-month period to the National Hospital, Colombo, Sri Lanka with a clinical picture suggestive of leptospirosis were included. Leptospirosis was confirmed by the microscopic agglutination test (titre ≥ 400). Severe leptospirosis was defined by the presence of two or more of the following criteria: jaundice (bilirubin> 51.3 µmol/l), oliguria (urine output < 400 ml/day), serum creatinine> 133 µmol/l or blood urea > 25.5 mmol/l, or the presence of organ dysfunction. Non-leptospirosis fever patients and healthy volunteers were used as control groups. NOx levels were measured using a modified Griess reaction. RESULTS: Forty patients were confirmed as having leptospirosis and 26 of them had severe disease. NOx levels were significantly higher in confirmed leptospirosis patients compared to healthy controls, MAT equivocal patients and non-leptospirosis fever patients (p<0.001). NOx concentrations were also significantly higher in patients with severe compared to mild leptospirosis (p<0.001). Once NOx levels were corrected for renal function, by using the ratio NOx/creatinine, NOx levels were actually significantly lower in patients with severe disease compared to other patients, and values were similar to those of healthy controls. CONCLUSIONS: We postulate that high NOx levels may be protective against severe leptospirosis, and that finding low NOx levels (when corrected for renal function) in patients with leptospirosis may predict the development of severe disease and organ dysfunction.

Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus.

BACKGROUND AND AIM: Non-alcoholic fatty liver disease (NAFLD) is linked to metabolic syndrome, and is known to be associated with impaired fasting glycemia and diabetes mellitus. This prospective community-based study was conducted to determine the association between NAFLD and incidence of diabetes mellitus in an urban adult population in Sri Lanka. METHODS: Participants of the Ragama Health Study cohort were assessed for NAFLD using established ultrasound criteria in 2007. Those who were free of diabetes at baseline were followed up for 3 years. Incidence rates of diabetes mellitus were compared between subjects with and without NAFLD at baseline. RESULTS: Out of 2984 subjects, 926 had NAFLD and 676 had diabetes in 2007. Of the 2276 subjects who were free of diabetes in 2007, 1914 were re-assessed in 2010. After 3 years, 104 out of 528 subjects with NAFLD and 138 out of 1314 subjects without NAFLD had developed diabetes mellitus de novo. Incidence rates of diabetes were respectively 64.2 and 34 per 1000 person-years of follow up for those with and without NAFLD. NAFLD was an independent predictor of developing diabetes mellitus. Other independent predictors were impaired fasting glycemia and dyslipidemia. CONCLUSIONS: Subjects with ultrasonically diagnosed NAFLD have an increased risk of developing diabetes mellitus. Intervention for NAFLD through lifestyle modification may prevent progression of the current diabetes epidemic.

Response of the airways and autonomic nervous system to acid perfusion of the esophagus in patients with asthma: a laboratory study.

BACKGROUND: Gastro-esophageal reflux disease (GERD) predisposes to airway disease through a vagally-mediated esophago-bronchial reflex. This study investigates this vagal response to esophageal acid perfusion. METHODS: 40 asthmatics with mild stable asthma participated. Each subject underwent spirometry and autonomic function testing (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) four times: a) before intubation, b) after intubation, and then immediately after perfusion with, in random order, c) concentrated lime juice solution (pH 2-3) and d) 0.9% saline. Subjects were blinded to the solution perfused. RESULTS: Asthmatics were of mean (SD) age 34.3 years (1.3), and 67.5% of them were females. pH monitoring demonstrated that 20 subjects had abnormal reflux and 20 did not. In each group 10 subjects had a positive GERD symptom score. Following perfusion with acid compared to saline, all subjects showed significant decreases in FEV1 and PEFR and significant increases in the mean valsalva ratio and heart rate difference on deep breathing from baseline values, but no changes in FVC or heart rate ratio on standing. There were no significant differences in any of the parameters between subjects with and without reflux. CONCLUSIONS: Acid stimulation of the distal esophagus results in increased parasympathetic activity and concomitant broncho-constriction in asthmatics irrespective of their reflux state. This strengthens the hypothesis that GER triggers asthma-like symptoms through a vagally mediated esophago-bronchial reflex and encourages a possible role for anti-cholinergic drugs in the treatment of reflux-associated asthma.

Mistakes in managing hepatocellular carcinoma and how to avoid them: a narrative review.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common liver-related cancer and the third leading cause of worldwide cancer-related mortality. AREAS COVERED: There have been many updated guidelines on the management of HCC in the past few years. Given the increasing burden of HCC in clinical practice, knowledge of evidence-based standards of care for these patients is essential for any practitioner managing patients with HCC. Early detection and judicious treatment based on the stage of the HCC can improve patient outcomes. We performed a PubMed (MEDLINE database) search for the latest guidelines related to the screening, detection, diagnosis, staging, and management of HCC. We aim to highlight some major considerations and common mistakes in managing HCC and attempt to provide evidence-based recommendations. EXPERT OPINION: The field of HCC management is expected to evolve in the coming years. Increased emphasis on personalized treatment and precision medicine with earlier detection methods, the development of noninvasive diagnostic tools, increased focus on combination therapies and a shift toward more targeted treatments will become more critical.

Esophageal motility, vagal function and gastroesophageal reflux in a cohort of adult asthmatics.

BACKGROUND: Asthmatics are known to have esophageal hypomotility. Vagal hypofunction and prolonged intra-esophageal acidification cause esophageal hypomotility. The contribution of gastroesophageal reflux (GER) and vagal function to esophageal motility in asthmatics is unclear. We studied the relationship between esophageal motility, GER and vagal function in a cohort of adult asthmatics. METHODS: Thirty mild, stable asthmatics (ATS criteria) and 30 healthy volunteers underwent 24-hour ambulatory esophageal monitoring, manometry, autonomic function testing and GER symptom assessment. 27 asthmatics underwent gastroscopy. A vagal function score calculated from 3 tests (valsalva maneuver, heart rate response to deep breathing and to standing from supine position) was correlated with esophageal function parameters. RESULTS: Asthmatics (mean age 34.8 (SD 8.4), 60% female) had more frequent GERD symptoms than controls (mean age 30.9 (SD 7.7), 50% female). 10/27 asthmatics had esophageal mucosal damage, 22 showed hypervagal response, none had a hyperadrenergic response. 14 asthmatics had ineffective esophageal motility. Higher GERD-score asthmatics had significantly fewer peristaltic and more simultaneous contractions than controls, and higher esophageal acid contact times than those with lower scores. All reflux parameters were significantly higher and acid clearance time prolonged in asthmatics than controls (p < 0.001, Mann-Whitney U test). There was no correlation between vagal function score and esophageal function parameters. CONCLUSIONS: A cohort of adult asthmatics was found to have peristaltic dysfunction and pathological GER, but otherwise normal esophageal motility. The peristaltic dysfunction seems to be associated with vagal hyperreactivity rather than vagal hypofunction.

A mechanistic model of snakebite as a zoonosis: Envenoming incidence is driven by snake ecology, socioeconomics and its impacts on snakes.

Snakebite is the only WHO-listed, not infectious neglected tropical disease (NTD), although its eco-epidemiology is similar to that of zoonotic infections: envenoming occurs after a vertebrate host contacts a human. Accordingly, snakebite risk represents the interaction between snake and human factors, but their quantification has been limited by data availability. Models of infectious disease transmission are instrumental for the mitigation of NTDs and zoonoses. Here, we represented snake-human interactions with disease transmission models to approximate geospatial estimates of snakebite incidence in Sri Lanka, a global hotspot. Snakebites and envenomings are described by the product of snake and human abundance, mirroring directly transmitted zoonoses. We found that human-snake contact rates vary according to land cover (surrogate of occupation and socioeconomic status), the impacts of humans and climate on snake abundance, and by snake species. Our findings show that modelling snakebite as zoonosis provides a mechanistic eco-epidemiological basis to understand snakebites, and the possible implications of global environmental and demographic change for the burden of snakebite.

Effects of probiotics combined with dietary and lifestyle modification on clinical, biochemical, and radiological parameters in obese children with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis: a randomized clinical trial.

BACKGROUND: Childhood obesity is a global problem associated with metabolic abnormalities. The gut-liver axis is thought to play a major role in its pathogenesis. Probiotics are known to alter the gut microbiota and, therefore, could be a therapeutic option in the management of childhood obesity-related complications. PURPOSE: This double-blind randomized placebo-controlled trial evaluated the effects of probiotics on metabolic derangement in obese children with nonalcoholic fatty liver disease/ nonalcoholic steatohepatitis (NAFLD/NASH). METHODS: Obese children with NAFLD/NASH treated at the nutrition clinic of the University Paediatric Unit at Lady Ridgeway Hospital, Colombo, were recruited. Anthropometry, body fat, metabolic derangement, and liver ultrasound scan (USS) results were evaluated at baseline and after 6 months. Transient elastography (FibroScan) was performed on a subsample of these patients. Eighty-four patients were recruited and randomized into the probiotics (n=43) and placebo (n= 41) groups. The mean age was 11.3±1.9 versus 12.1±1.5 years in the probiotic and placebo groups, respectively. Baseline parameters including liver disease stage on USS, body fat percentage, fasting blood sugar, lipid profile, liver function, and C-reactive protein showed no significant intergroup differences. RESULTS: In the probiotic group, a statistically significant reduction in body mass index was noted from the baseline value. However, the reduction was not significant compared with the placebo group. There was a significant reduction in triglycerides, aspartate transaminase (AST), alanine aminotransferase (ALT), AST/ALT ratio, and alkaline phosphatase in the placebo group over the treatment period. Although the liver disease stage on USS improved from stage II-III to stage I in a small number of patients in the probiotic-treated group, transient elastography performed in a subsample did not demonstrate significant improvement in either group. CONCLUSION: Our results indicate that probiotics have no advantage over lifestyle modification for improving obesityassociated metabolic derangement in children.

Identification of genetic effects underlying type 2 diabetes in South Asian and European populations.

South Asians are at high risk of developing type 2 diabetes (T2D). We carried out a genome-wide association meta-analysis with South Asian T2D cases (n = 16,677) and controls (n = 33,856), followed by combined analyses with Europeans (neff = 231,420). We identify 21 novel genetic loci for significant association with T2D (P = 4.7 × 10-8 to 5.2 × 10-12), to the best of our knowledge at the point of analysis. The loci are enriched for regulatory features, including DNA methylation and gene expression in relevant tissues, and highlight CHMP4B, PDHB, LRIG1 and other genes linked to adiposity and glucose metabolism. A polygenic risk score based on South Asian-derived summary statistics shows ~4-fold higher risk for T2D between the top and bottom quartile. Our results provide further insights into the genetic mechanisms underlying T2D, and highlight the opportunities for discovery from joint analysis of data from across ancestral populations.

Low-dose adrenaline, promethazine, and hydrocortisone in the prevention of acute adverse reactions to antivenom following snakebite: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Envenoming from snakebites is most effectively treated by antivenom. However, the antivenom available in South Asian countries commonly causes acute allergic reactions, anaphylactic reactions being particularly serious. We investigated whether adrenaline, promethazine, and hydrocortisone prevent such reactions in secondary referral hospitals in Sri Lanka by conducting a randomised, double-blind placebo-controlled trial. METHODS AND FINDINGS: In total, 1,007 patients were randomized, using a 2 × 2 × 2 factorial design, in a double-blind, placebo-controlled trial of adrenaline (0.25 ml of a 1∶1,000 solution subcutaneously), promethazine (25 mg intravenously), and hydrocortisone (200 mg intravenously), each alone and in all possible combinations. The interventions, or matching placebo, were given immediately before infusion of antivenom. Patients were monitored for mild, moderate, or severe adverse reactions for at least 96 h. The prespecified primary end point was the effect of the interventions on the incidence of severe reactions up to and including 48 h after antivenom administration. In total, 752 (75%) patients had acute reactions to antivenom: 9% mild, 48% moderate, and 43% severe; 89% of the reactions occurred within 1 h; and 40% of all patients were given rescue medication (adrenaline, promethazine, and hydrocortisone) during the first hour. Compared with placebo, adrenaline significantly reduced severe reactions to antivenom by 43% (95% CI 25-67) at 1 h and by 38% (95% CI 26-49) up to and including 48 h after antivenom administration; hydrocortisone and promethazine did not. Adding hydrocortisone negated the benefit of adrenaline. CONCLUSIONS: Pretreatment with low-dose adrenaline was safe and reduced the risk of acute severe reactions to snake antivenom. This may be of particular importance in countries where adverse reactions to antivenom are common, although the need to improve the quality of available antivenom cannot be overemphasized.

Iron overload in the Asian community.

Hereditary hemochromatosis is an iron overload disorder that can lead to the impairment of multiple organs and is caused by mutations in one or more different genes. Type 1 hemochromatosis is the most common form of the disease and results from mutations in the HFE gene. Juvenile hemochromatosis (JH) is the most severe form, usually caused by mutations in hemojuvelin (HJV) or hepcidin (HAMP). The autosomal dominant form of the disease, type 4, is due to mutations in the SLC40A1 gene, which encodes for ferroportin (FPN). Hereditary hemochromatosis is commonly found in populations of European origin. By contrast, hemochromatosis in Asia is rare and less well understood and can be masked by the presence of iron deficiency and secondary iron overload from thalassemia. Here, we provide a comprehensive report of hemochromatosis in a group of patients of Asian origin. We have identified novel mutations in HJV, HAMP, and SLC40A1 in countries not normally associated with hereditary hemochromatosis (Pakistan, Bangladesh, Sri Lanka, and Thailand). Our family studies show a high degree of consanguinity, highlighting the increased risk of iron overload in many countries of the developing world and in countries in which there are large immigrant populations from these regions.