Linked dual-class HIV resistance mutations are associated with treatment failure.

We hypothesized that HIV-1 with dual-class but not single-class drug resistance mutations linked on the same viral genome, present in the virus population before initiation of antiretroviral therapy (ART), would be associated with failure of ART to suppress viremia. To test this hypothesis, we utilized an ultrasensitive single-genome sequencing assay that detects rare HIV-1 variants with linked drug resistance mutations (DRMs). A case (ART failure) control (nonfailure) study was designed to assess whether linkage of DRMs in pre-ART plasma samples was associated with treatment outcome in the nevirapine/tenofovir/emtricitabine arm of the AIDS Clinical Trials Group A5208/Optimal Combined Therapy After Nevirapine Exposure (OCTANE) Trial 1 among women who had received prior single-dose nevirapine.

Discrete Evaluative and Premotor Circuits Enable Vocal Learning in Songbirds.

Virtuosic motor performance requires the ability to evaluate and modify individual gestures within a complex motor sequence. Where and how the evaluative and premotor circuits operate within the brain to enable such temporally precise learning is poorly understood. Songbirds can learn to modify individual syllables within their complex vocal sequences, providing a system for elucidating the underlying evaluative and premotor circuits.

Divergent skeletal muscle mitochondrial phenotype between male and female patients with chronic heart failure.

Background: Previous studies in heart failure with reduced ejection fraction (HFrEF) suggest that skeletal muscle mitochondrial impairments are associated with exercise intolerance in men. However, the nature of this relationship in female patients remains to be elucidated. This study aimed to determine the relationship between skeletal muscle mitochondrial impairments and exercise intolerance in male and female patients with HFrEF.

Feedback of coastal marshes to climate change: Long-term phenological shifts.

Coastal marshes are important carbon sinks facing serious threats from climatic stressors. Current research reveals that the growth of individual marsh plants is susceptible to a changing climate, but the responses of different marsh systems at a landscape scale are less clear. Here, we document the multi-decadal changes in the phenology and the area of the extensive coastal marshes in Louisiana, USA, a representative of coastal ecosystems around the world that currently experiencing sea-level rise, temperature warming, and atmospheric CO increase.

HIV-1 in lymph nodes is maintained by cellular proliferation during antiretroviral therapy.

To investigate the possibility that HIV-1 replication in lymph nodes sustains the reservoir during ART, we looked for evidence of viral replication in 5 donors after up to 13 years of viral suppression. We characterized proviral populations in lymph nodes and peripheral blood before and during ART, evaluated the levels of viral RNA expression in single lymph node and blood cells, and characterized the proviral integration sites in paired lymph node and blood samples. Proviruses with identical sequences, identical integration sites, and similar levels of RNA expression were found in lymph nodes and blood samples collected during ART, and no single sequence with significant divergence from the pretherapy population was present in either blood or lymph nodes.

Forecasting species range dynamics with process-explicit models: matching methods to applications.

Knowing where species occur is fundamental to many ecological and environmental applications. Species distribution models (SDMs) are typically based on correlations between species occurrence data and environmental predictors, with ecological processes captured only implicitly. However, there is a growing interest in approaches that explicitly model processes such as physiology, dispersal, demography and biotic interactions.

microclimUS: hourly estimates of historical microclimates for the United States of America with example applications.

Microclimatic data are required for many problems in pure and applied ecology. This data includes aboveground convective and radiative conditions as well as soil temperature and moisture. In cold regions, the connection between above- and belowground microclimates via snow cover is also critically important.

Optimising pacemaker therapy and medical therapy in pacemaker patients for heart failure: protocol for the OPT-PACE randomised controlled trial.

Introduction: Permanent artificial pacemaker implantation is a safe and effective treatment for bradycardia and is associated with extended longevity and improved quality of life. However, the most common long-term complication of standard pacemaker therapy is pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to screen for heart failure to assess and optimise patient devices and medical therapy.

Clones of infected cells arise early in HIV-infected individuals.

In HIV-infected individuals on long-term antiretroviral therapy (ART), more than 40% of the infected cells are in clones. Although most HIV proviruses present in individuals on long-term ART are defective, including those in clonally expanded cells, there is increasing evidence that clones carrying replication-competent proviruses are common in patients on long-term ART and form part of the HIV reservoir that makes it impossible to cure HIV infection with current ART alone. Given the importance of clonal expansion in HIV persistence, we determined how soon after HIV acquisition infected clones can grow large enough to be detected (clones larger than ca.

Linking thermal adaptation and life-history theory explains latitudinal patterns of voltinism.

Insect life cycles are adapted to a seasonal climate by expressing alternative voltinism phenotypes-the number of generations in a year. Variation in voltinism phenotypes along latitudinal gradients may be generated by developmental traits at critical life stages, such as eggs. Both voltinism and egg development are thermally determined traits, yet independently derived models of voltinism and thermal adaptation refer to the evolution of dormancy and thermal sensitivity of development rate, respectively, as independent influences on life history.

Budget impact model of avelumab in patients with metastatic merkel cell carcinoma in the US.

To estimate the budget impact of avelumab as a treatment option for patients with treatment-naïve first-line (1L) and previously treated second-line or later (2L+) metastatic Merkel cell carcinoma (mMCC) in the US. A budget impact model was developed to evaluate the addition of avelumab for the treatment of mMCC patients using a hypothetical 30 million-member US health plan over a 3-year time horizon (2019-2021). The comparator treatments included in the analysis were pembrolizumab and nivolumab (other immuno-oncology agents); and the chemotherapies routinely used in the eligible mMCC population.

Influence of primary care antibiotic prescribing on incidence rates of multidrug-resistant Gram-negative bacteria in hospitalised patients.

Purpose: Use of antibiotics can give rise to the selection of resistant bacteria. It remains unclear whether antibiotic use in primary care can influence bacterial resistance incidence in patients when hospitalised. The aim of this study is to explore the impact of prior community antibiotic usage on hospital-detected multidrug-resistant Gram-negative (MRGN) incidence rate.

Integrating mechanistic and correlative niche models to unravel range-limiting processes in a temperate amphibian.

Insights into the causal mechanisms that limit species distributions are likely to improve our ability to anticipate species range shifts in response to climate change. For species with complex life histories, a mechanistic understanding of how climate affects different lifecycle stages may be crucial for making accurate forecasts. Here, we use mechanistic niche modeling (NicheMapR) to derive "proximate" (mechanistic) variables for tadpole, juvenile, and adult Rana temporaria.

The CSS-12: Development and Validation of a Short-Form Version of the Cyberchondria Severity Scale.

Cyberchondria is defined as an increase in anxiety about one's health status as a result of excessive online searches. McElroy and Shevlin (2014) developed the first multidimensional, self-report measure of this construct-the Cyberchondria Severity Scale (CSS). The CSS consists of 33 items which can be summed to form a total score, and/or 5 subscale scores.

Meta-analysis of Calibration, Discrimination, and Stratum-Specific Likelihood Ratios for the CRB-65 Score.

Background: The CRB-65 score is recommended as a decision support tool to help identify patients with community-acquired pneumonia (CAP) who can safely be treated as outpatients.

Objective: To perform an updated meta-analysis of the accuracy, discrimination, and calibration of the CRB-65 score using a novel approach to calculation of stratum-specific likelihood ratios.

Design: Meta-analysis of accuracy, discrimination, and calibration.

Phylogenetic inference for the study of within-host HIV-1 dynamics and persistence on antiretroviral therapy.

Although antiretroviral therapy (ART) is highly effective at inhibiting HIV-1 replication and preventing AIDS, it cannot eradicate the infection. Many studies have used viral genetic information from single-genome and deep sequencing of blood and tissue samples to investigate the mechanisms that sustain the HIV-1 reservoir. Sequence data are analysed by use of measurements of population diversity and divergence and by exploration of phylogenetic associations.

How economic inequality shapes mobility expectations and behaviour in disadvantaged youth.

Economic inequality can have a range of negative consequences for those in younger generations, particularly for those from lower-socioeconomic status (SES) backgrounds. Economists and psychologists, among other social scientists, have addressed this issue, but have proceeded largely in parallel. This Perspective outlines how these disciplines have proposed and provided empirical support for complementary theoretical models.

Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer.

Histologic transformation to small cell neuroendocrine prostate cancer occurs in a subset of patients with advanced prostate cancer as a mechanism of treatment resistance. Rovalpituzumab tesirine (SC16LD6.5) is an antibody-drug conjugate that targets delta-like protein 3 (DLL3) and was initially developed for small cell lung cancer.

The origin and maintenance of metabolic allometry in animals.

Organisms vary widely in size, from microbes weighing 0.1 pg to trees weighing thousands of megagrams - a 10-fold range similar to the difference in mass between an elephant and the Earth. Mass has a pervasive influence on biological processes, but the effect is usually non-proportional; for example, a tenfold increase in mass is typically accompanied by just a four- to sevenfold increase in metabolic rate.

Review: HIV-1 phylogeny during suppressive antiretroviral therapy.

Purpose Of Review: Studies of HIV-1 genetic diversity can provide clues on the effect of antiretroviral therapy (ART) on viral replication, the mechanisms for viral persistence, and the efficacy of new interventions. This article reviews methods for interrogating intrahost HIV-1 diversity, addresses the ongoing debate regarding HIV-1 compartmentalization and replication during ART, and summarizes recent findings on the effects of curative strategies on HIV-1 populations.

Recent Findings: HIV-1 replication in the blood is virtually halted upon the initiation of ART.