Reference equations for evaluation of spirometry function tests in South Asia, and among South Asians living in other countries.

BACKGROUND: There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease. METHOD: We measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore. RESULTS: The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sd z-score: FEV1 -0.94±1.05, FVC -0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03±0.99, FVC 0.04±0.97, FEV1/FVC -0.03±0.99) and external validation (z-scores: FEV1 0.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia. CONCLUSION: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.

Chymase Level Is a Predictive Biomarker of Dengue Hemorrhagic Fever in Pediatric and Adult Patients.

Background: Most patients with dengue experience mild disease, dengue fever (DF), while few develop the life-threatening diseases dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS). No laboratory tests predict DHF or DSS. We evaluated whether the serum chymase level can predict DHF or DSS in adult and pediatric patients and the influence of preexisting conditions (PECs) on chymase levels. Methods: Serum chymase levels were measured in patients presenting with undifferentiated fever to hospitals in Colombo District, Sri Lanka. The value of serum the chymase concentration and clinical signs and symptoms as predictors of DHF and/or DSS was evaluated by multivariate analysis. We assessed the influence of age, PECs, and day after fever onset on the robustness of the chymase level as a biomarker for DHF and/or DSS. Results: An elevated chymase level in acute phase blood samples was highly indicative of later diagnosis of DHF or DSS for pediatric and adult patients with dengue. No recorded PECs prevented an increase in the chymase level during DHF. However, certain PECs (obesity and cardiac or lung-associated diseases) resulted in a concomitant increase in chymase levels among adult patients with DHF. Conclusions: These results show that patients with acute dengue who present with high levels of serum chymase consistently are at greater risk of DHF. The chymase level is a robust prognostic biomarker of severe dengue for adult and pediatric patients.

Markers of dengue severity: a systematic review of cytokines and chemokines.

The prognosis of dengue remains a challenge in the early, objective triage of patients with dengue fever of differing severity. Circulating immuno-modulating proteins have brought new possibilities as prognostic markers of severe dengue (SD). This systematic review is devoted to understanding the potential utility of blood-based cytokines and chemokines as prognostication markers of SD based on the current literature. PubMed and Embase were searched. Of 794 candidate articles, 685 abstracts were screened against our exclusion/inclusion criteria and 25 (3.6 %) studies met the quality assessments. A total of 18 studies were retrospective observational and 2 were prospective cohort studies. Elevated IL-10, up to day 7 of fever onset, stood out as a candidate prognostic marker for SD using the 1997 and 2009 World Health Organization (WHO) case definitions. IFNγ was another potential prognostic marker of SD (1997 WHO case definition), but its levels varied between studies. Significant heterogeneity in methodologies and patient cohorts prevent ready application of IL-10 and IFNγ as prognostic markers to other dengue populations. Our results suggest that the current non-randomized studies are delivering inconsistent messages and higher-quality studies, with consistent methodologies and validation in independent patient cohorts, are needed to delineate confounding variables. Major gaps identified were full accounting and transparency of sampling days, dengue virus type, infection status and age group.

Potential for international spread of wild poliovirus via travelers.

BACKGROUND: The endgame of polio eradication is hampered by the international spread of poliovirus via travelers. In response to ongoing importations of poliovirus into polio-free countries, on 5 May 2014, WHO's Director-General declared the international spread of wild poliovirus a public health emergency of international concern. Our objective was to develop a mathematical model to estimate the international spread of polio infections. METHODS: Our model took into account polio endemicity in polio-infected countries, population size, polio immunization coverage rates, infectious period, the asymptomatic-to-symptomatic ratio, and also the probability of a traveler being infectious at the time of travel. We applied our model to three scenarios: (1) number of exportations of both symptomatic and asymptomatic polio infections out of currently polio-infected countries, (2) the risk of spread of poliovirus to Saudi Arabia via Hajj pilgrims, and (3) the importation risk of poliovirus into India. RESULTS: Our model estimated 665 polio exportations (>99 % of which were asymptomatic) from nine polio-infected countries in 2014, of which 78.3 % originated from Pakistan. Our model also estimated 21 importations of poliovirus into Saudi Arabia via Hajj pilgrims and 20 poliovirus infections imported to India in the same year. CONCLUSION: The extent of importations of asymptomatic and symptomatic polio infections is substantial. For countries that are vulnerable to polio outbreaks due to poor national polio immunization coverage rates, our newly developed model may help guide policy-makers to decide whether imposing an entry requirement in terms of proof of vaccination against polio would be justified.

Serum chymase levels correlate with severe dengue warning signs and clinical fluid accumulation in hospitalized pediatric patients.

Dengue induces a spectrum of severity in humans from the milder dengue fever to severe disease, or dengue hemorrhagic fever (DHF). Chymase is a candidate biomarker that may aid dengue prognosis. This prospective study aimed to identify whether warning signs of severe dengue, including hypovolemia and fluid accumulation, were associated with elevated chymase. Serum chymase levels were quantified prospectively and longitudinally in hospitalized pediatric dengue patients in Sri Lanka. Warning signs were determined based on daily clinical assessments, laboratory tests and ultrasound findings. Chymase was significantly elevated during the acute phase of disease in DHF or Severe dengue, defined by either the 1997 or 2009 WHO diagnosis guidelines, and persisted longer in the most severe patients. Chymase levels were higher in patients with narrow pulse pressure and clinical warning signs such as severe leakage, fluid accumulation, pleural effusion, gall-bladder wall thickening and rapid haematocrit rise concurrent with thrombocytopenia. No association between chymase and liver enlargement was observed. This study confirms that serum chymase levels are associated with DHF/Severe dengue disease in hospitalized pediatric patients. Chymase levels correlate with warning signs of vascular dysfunction highlighting the possible functional role of chymase in vascular leakage during dengue.

Measles Resurgence in Europe: Migrants and Travellers are not the Main Drivers.

Measles is a highly transmissible viral infection that may lead to serious illness, lifelong complications, and death. As there is no animal reservoir for measles, measles resurgence is due to human movement of viremic persons. Therefore, some have blamed the enormous migration into Europe in the past 5 years for the measles resurgence in this region. We set out to determine the main driver for measles resurgence in Europe by assessing vaccine coverage rates and economic status in European countries, number of migrants, and travel volumes. Data on measles vaccine coverage rates with two vaccine doses of measles, mumps and rubella (MMR) [Measles Containing Vaccine (MCV)2] and total number of measles cases in 2017 for Europe, including Eastern European countries, were obtained, in addition to Gross Domestic Product (GDP), and number of migrants and tourist arrivals. The outcome measured, incidence of measles per 100,000, was log transformed and subsequently analyzed using multiple linear regression, along with predictor variables: number of international migrants, GDP per capita, tourist arrivals, and vaccine coverage. The final model was interpreted by exponentiating the regression coefficients. Incidence of measles was highest in Romania (46.1/100,000), followed by Ukraine (10.8/100,000) and Greece (8.7/100,000). MCV2 coverage in these countries is less than 84%, with lowest coverage rate (75%) reported in Romania. Only vaccine coverage appears to be the significant predictor in the model (p < 0.001) for incidence of measles even after adjusting for international migrants, international tourist arrivals, and GDP per capita. With one unit increase in vaccination coverage, the incidence of measles decreased by 18% [95% confidence interval (CI): 10-25]. Our results showed that number of migrants and international tourist arrivals into any of the European countries were not the drivers for increased measles cases. Countries with high vaccine coverage rates regardless of economic status did not experience a resurgence of measles, even if the number of migrants or incoming travellers was high. The statistically significant sole driver was vaccine coverage rates. These analyses reemphasize the importance of strategies to improve national measles vaccination to achieve coverage greater than 95%.

Zika in travellers 1947-2017: a systematic review.

Introduction: Travellers contributed substantially to the rapid spread of Zika virus (ZIKV). They act as sentinel and may unmask ongoing ZIKV transmission in countries where outbreaks have not yet been reported. Our objectives were to (i) describe the burden of ZIKV infections in international travellers over time; (ii) estimate the proportion of birth defects as a result of maternal ZIKV infection in travellers; (iii) track the extent of sexual transmission; (iv) summarize ZIKV infections in returning travellers as reported by the GeoSentinel network; and (v) identify countries without reports on local ZIKV transmission where travellers served as sentinel. Methods: We performed a systematic review from 1947 to April 2017 on travel-associated ZIKV infections. We also compared published reports on autochthonous ZIKV transmission in Asia with published reports on exportations from travellers in Asia. Results: Of 314 papers that fit the inclusion criteria, 61 were eligible for final analysis. There was an exponential increase in the number of reported ZIKV infected travellers from the years 2013 to 2016, which declined in 2017. Amongst pregnant women with ZIKV infection, (5%) resulted in a fetus or infant with ZIKV-associated birth defects. An estimated 1% of the total number of ZIKV cases reported in the USA and Europe were acquired through sexual transmission. Through the GeoSentinel network, five countries (Indonesia, Philippines, Thailand, Vietnam, Cameroon) were identified as sentinel markers where ZIKV was exported despite the absence of reported local transmission. Conclusions: Mobility patterns and travel volumes can help to identify the most likely origin of importation, and also in predicting further propagation. Studies on pregnant returning travellers have contributed to a better understanding of the risk estimates of congenital Zika syndrome/microcephaly as a result of maternal ZIKV infection, and the relative contribution of sexual transmisison.

Asymptomatic Prenatal Zika Virus Infection and Congenital Zika Syndrome.

To investigate to what extent asymptomatic vs symptomatic prenatal Zika virus infections contribute to birth defects, we identified 3 prospective and 8 retrospective studies. The ratio varied greatly in the retrospective studies, most likely due to recruitment and recall bias. The prospective studies revealed a ratio of 1:1 for asymptomatic vs symptomatic maternal Zika infections resulting in adverse fetal outcomes.

The outcomes of Perthes' disease of the hip: a study protocol for the development of a core outcome set.

BACKGROUND: Perthes' disease is an idiopathic osteonecrosis of a developmental hip that is most frequent in Northern Europe. Currently, the absence of a common set of standardised outcomes makes comparisons between studies of different interventions challenging. This study aims to summarise the outcomes used in clinical research of interventions for Perthes' disease and define a set of core outcomes (COS) to ensure that the variables of primary importance are measured and reported in future research studies investigating Perthes' disease. METHODS: A systematic review of the current literature will be used to identify a list of outcomes reported in previous studies. Additional important outcomes will be sought by interviewing a group of children with Perthes' disease, adults who were treated with the disease in infancy and parents of children with the disease. This list will then be evaluated by experts in Perthes' disease using a Delphi survey divided into two rounds to ascertain the importance of each outcome. The final outcomes list obtained from the Delphi survey will be then discussed during a consensus meeting of representative key stakeholders in order to define the COS to be reported in future clinical trials related to Perthes' disease. DISCUSSION: The absence of high-quality research and clear guidelines concerning the management of Perthes' disease is, at least in part, due to the difficulties in the comparing the results from previous studies. The development of a COS seeks to standardise outcomes collected in future research studies to enable comparisons between studies to be made and to facilitate meta-analyses of results. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials Initiative (COMET), 1003 . Registered on 20 July 2017. Prospero International Prospective Register of Systematic Reviews, CRD 42017069742 . Registered on 10 July 2017.

Synthesis and Biological Evaluation of N-((1-(4-(Sulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide Inhibitors of Glycine Transporter-1.

We previously disclosed the discovery of rationally designed N-((1-(4-(propylsulfonyl)piperazin-1-yl)cycloalkyl)methyl)benzamide inhibitors of glycine transporter-1 (GlyT-1), represented by analogues 10 and 11. We describe herein further structure-activity relationship exploration of this series via an optimization strategy that primarily focused on the sulfonamide and benzamide appendages of the scaffold. These efforts led to the identification of advanced leads possessing a desirable balance of excellent in vitro GlyT-1 potency and selectivity, favorable ADME and in vitro pharmacological profiles, and suitable pharmacokinetic and safety characteristics. Representative analogue (+)-67 exhibited robust in vivo activity in the cerebral spinal fluid glycine biomarker model in both rodents and nonhuman primates. Furthermore, rodent microdialysis experiments also demonstrated that oral administration of (+)-67 significantly elevated extracellular glycine levels within the medial prefrontal cortex (mPFC).

Alcohol Use Disorder and Heavy Episodic Drinking in Rural Communities in Cambodia: Risk Factors and Community-Perceived Strategies.

Alcohol misuse is increasing in Southeast Asia. We investigated the extent of and risk factors for alcohol use disorder (AUD) and heavy episodic drinking (HED) in a rural community in Cambodia. We also attempted to explore the communities' perception of alcohol misuse and elicited potential community-based strategies to address the alcohol problem. A mixed-methods study design was used, combining a cross-sectional questionnaire survey with qualitative interviews (focus group discussions and key informant interviews). AUD and HED were measured using the AUDs Identification Test Alcohol Consumption questionnaire. The prevalence of AUD and HED was high: 25% and 31%, respectively. Male sex, younger age, and increasing income were significant risk factors. The communities were well aware of the harmful effects of alcohol, expressed the importance of implementing community-based measures, and proposed various community-led solutions. Evidence-based strategies that are culturally appropriate, accepted, and driven by communities are urgently needed.

A Rare Case of Simultaneous Acute Bilateral Quadriceps Tendon Rupture and Unilateral Achilles Tendon Rupture.

INTRODUCTION: There have been multiple reported cases of bilateral quadriceps tendon ruptures (QTR) in the literature. These injuries frequently associated with delayed diagnosis, which results in delayed surgical treatment. In very unusual cases, bilateral QTRs can be associated with other simultaneous tendon ruptures. CASE REPORT: We present a rare case of bilateral QTR with a simultaneous Achilles Tendon Rupture involving a 31 years old Caucasian man who is a semi-professional body builder taking anabolic steroids. To date bilateral QTR with additional TA rupture has only been reported once in the literature and to our knowledge this is the first reported case of bilateral QTR and simultaneous TA rupture in a young, fit and healthy individual. CONCLUSION: The diagnosis of bilateral QTR alone can sometimes be challenging and the possibility of even further tendon injuries should be carefully assessed. A delay in diagnosis could result in delay in treatment and potentially worse outcome for the patient.