Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine

Quantifying the Spatial Dimension of Dengue Virus Epidemic Spread within a Tropical Urban Environment

Global trends in population growth and human redistribution and movement have reshaped the map of dengue transmission risk, exposing a significant proportion of the world's population to the threat of dengue epidemics. Knowledge on the relative contribution of vector and human movement to the widespread and explosive nature of dengue epidemic spread within an urban environment is limited. By analyzing a very detailed dataset of a dengue epidemic that affected the Australian city of Cairns we performed a comprehensive quantification of the spatio-temporal dimensions of dengue virus epidemic transmission and propagation within a complex urban environment. Space and space-time analysis and models allowed derivation of detailed information on the pattern of introduction and epidemic spread of dengue infection within the urban space. We foresee that some of the results and recommendations derived from our study may also be applicable to many other areas currently affected or potentially subject to dengue epidemics

Glucose variability measures and their effect on mortality: a systematic review

Objective: To systematically review the medical literature on the association between glucose variability measures and mortality in critically ill patients. Methods: Studies assessing the association between a measure of glucose variability and mortality that reported original data from a clinical trial or observational study on critically ill adult patients were searched in Ovid MEDLINE (R) and Ovid EMBASE (R). Data on patient populations, study designs, glucose regulations, statistical approaches, outcome measures, and glucose variability indicators (their definition and applicability) were extracted. Result: Twelve studies met the inclusion criteria; 13 different indicators were used to measure glucose variability. Standard deviation and the presence of both hypo-and hyperglycemia were the most common indicators. All studies reported a statistically significant association between mortality and at least one glucose variability indicator. In four studies both blood glucose levels and severity of illness were considered as confounders, but only one of them checked model assumptions to assert inference validity. Conclusions: Glucose variability has been quantified in many different ways, and in each study at least one of them appeared to be associated with mortality. Because of methodological limitations and the possibility of reporting bias, it is still unsettled whether and in which quantification this association is independent of other confounders. Future research will benefit from using an indicator reference subset for glucose variability, metrics that are linked more directly to negative physiological effects, more methodological rigor, and/or better reportin

Phenotypic insights into ADCY5-associated disease

BACKGROUND: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations. METHODS: In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing. RESULTS: Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement. CONCLUSION: We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Greenland ice sheet surface mass loss: recent developments in observation and modeling

Surface processes currently dominate Greenland ice sheet (GrIS) mass loss. We review recent developments in the observation and modelling of GrIS surface mass balance (SMB), published after the July 2012 deadline for the Fifth Assessment Report of the Intergovernmental Panel on Climate Change (IPCC AR5). Since IPCC AR5 our understanding of GrIS SMB has further improved, but new observational and model studies have also revealed that temporal and spatial variability of many processes are still poorly quantified and understood, e.g. bio-albedo, the formation of ice lenses and their impact on lateral meltwater transport, heterogeneous vertical meltwater transport (‘piping’), the impact of atmospheric circulation changes and mixed-phase clouds on the surface energy balance and the magnitude of turbulent heat exchange over rough ice surfaces. As a result, these processes are only schematically or not at all included in models that are currently used to assess and predict future GrIS surface mass loss

Best Practices in Dengue Surveillance: A Report from the Asia-Pacific and Americas Dengue Prevention Boards

The Pediatric Dengue Vaccine Initiative organized Dengue Prevention Boards in the Asia-Pacific and the Americas regions consisting of dengue experts from endemic countries. Both Boards convened meetings to review issues in surveillance. Through presentations, facilitated discussions, and surveys, the Boards identified best practices in dengue surveillance including: (1) Dengue should be a notifiable disease in endemic countries; (2) World Health Organization regional case definitions should be consistently applied; (3) electronic reporting systems should be developed and used broadly to speed delivery of data to stakeholders; (4) minimum reporting should include incidence rates of dengue fever, dengue hemorrhagic fever, dengue shock syndrome, and dengue deaths, and hospitalization and mortality rates should be reported by age group; (5) periodic additional studies (e.g., capture/recapture) should be conducted to assess under-detection, under-reporting, and the quality of surveillance; (6) laboratory methods and protocols should be standardized; (7) national authorities should encourage laboratories to develop networks to share expertise and data; and (8) RT-PCR and virus isolation (and possibly detection of the NS1 protein) are the recommended methods for confirmation of an acute dengue infection, but are recommended only for the four days after onset of fever—after day 4, IgM-capture enzyme-linked immunosorbent assay is recommended

Subsequent chemotherapy reverses acquired tyrosine kinase inhibitor resistance and restores response to tyrosine kinase inhibitor in advanced non-small-cell lung cancer

<p>Abstract</p> <p>Background</p> <p>Patients with advanced or metastatic non-small cell lung cancer (NSCLC) can develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Here, we report the successful treatment with alternating chemotherapy and TKIs of two cases of advanced NSCLC who developed resistance to TKI.</p> <p>Case presentation</p> <p>Two patients with advanced or metastatic NSCLC were treated with palliative chemotherapy followed by erlotinib/gefitinib. When TKI therapy failed, two cycles of chemotherapy were provided, which were followed by re-challenge with erlotinib or gefitinib.</p> <p>Conclusion</p> <p>NSCLC patients with acquired TKI resistance should be managed aggressively whenever possible. Subsequent chemotherapy and target treatment is one of the reasonable choices for those with an initial dramatic clinical response with erlotinib/gefitinib treatment. Further studies are warranted to substantiate the association of erlotinib /gefitinib treatment with the efficacy of NSCLC patients with acquired TKI failure.</p

Implementing glucose control in intensive care: a multicenter trial using statistical process control

Glucose control (GC) with insulin decreases morbidity and mortality of critically ill patients. In this study we investigated GC performance over time during implementation of GC strategies within three intensive care units (ICUs) and in routine clinical practice. All adult critically ill patients who stayed for >24 h between 1999 and 2007 were included. Effects of implementing local GC guidelines and guideline revisions on effectiveness/efficiency-related indicators, safety-related indicators, and protocol-related indicators were measured. Data of 17,111 patient admissions were evaluated, with 714,141 available blood glucose levels (BGL) measurements. Mean BGL, time to reach target, hyperglycemia index, sampling frequency, percentage of hyperglycemia events, and in-range measurements statistically changed after introducing GC in all ICUs. The introduction of simple rules on GC had the largest effect. Subsequent changes in the protocol had a smaller effect than the introduction of the protocol itself. As soon as the protocol was introduced, in all ICUs the percentage of hypoglycemia events increased. Various revisions were implemented to reduce hypoglycemia events, but levels never returned to those from pre-implementation. More intensive implementation strategies including the use of a decision support system resulted in better control of the process. There are various strategies to achieve GC in routine clinical practice but with variable success. All of them were associated with an increase in hypoglycemia events, but GC was never stopped. Instead, these events have been accepted and managed. Statistical process control is a useful tool for monitoring phenomena over time and captures within-institution change

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD