Adjunctive surgery improves treatment outcomes among patients with multidrug-resistant and extensively drug-resistant tuberculosis

SummaryObjectivesTo determine risk factors for poor outcomes among patients with pulmonary multidrug- or extensively drug-resistant (M/XDR) tuberculosis (TB) in Georgia.MethodsThis was a prospective, population-based observational cohort study.ResultsAmong 380M/XDR-TB patients (mean age 38 years), 179 (47%) had a poor outcome: 59 (16%) died, 37 (10%) failed, and 83 (22%) defaulted. Newly diagnosed M/XDR-TB cases were significantly more likely to have a favorable outcome than retreatment cases (odds ratio (OR) 4.26, 95% confidence interval (CI) 1.99–9.10, p<0.001). In the multivariable analysis, independent risk factors for a poor treatment outcome included previous treatment history (OR 2.92, 95% CI 1.29–6.58), bilateral disease (OR 1.90, 95% CI 1.20–3.01), body mass index (BMI, kg/m2) ≤18.5 (OR 1.91, 95% CI 1.11–3.29), and XDR-TB (OR 2.28, 95% CI 1.11–4.71). Patients who underwent surgical resection (OR 0.27, 95% CI 0.11–0.64) and had sputum culture conversion by 4 months (OR 0.33, 95% CI 0.21–0.52) were significantly less likely to have poor treatment outcomes.ConclusionsAdjunctive surgery appeared to be beneficial in treating patients with M/XDR-TB. Retreatment cases, XDR-TB, bilateral disease, and low BMI were associated with a poor outcome. Additional studies are needed to further define the apparent beneficial role of surgery in the treatment of M/XDR-TB

Transcriptomic-wide discovery of direct and indirect HuR RNA targets in activated CD4+ T cells

Due to poor correlation between steady state mRNA levels and protein product, purely transcriptomic profiling methods may miss genes posttranscriptionally regulated by RNA binding proteins (RBPs) and microRNAs (miRNAs). RNA immunoprecipitation (RIP) methods developed to identify in vivo targets of RBPs have greatly elucidated those mRNAs which may be regulated via transcript stability and translation. The RBP HuR (ELAVL1) and family members are major stabilizers of mRNA. Many labs have identified HuR mRNA targets; however, many of these analyses have been performed in cell lines and oftentimes are not independent biological replicates. Little is known about how HuR target mRNAs behave in conditional knock-out models. In the present work, we performed HuR RIP-Seq and RNA-Seq to investigate HuR direct and indirect targets using a novel conditional knock-out model of HuR genetic ablation during CD4+ T activation and Th2 differentiation. Using independent biological replicates, we generated a high coverage RIP-Seq data set (>160 million reads) that was analyzed using bioinformatics methods specifically designed to find direct mRNA targets in RIP-Seq data. Simultaneously, another set of independent biological replicates were sequenced by RNA-Seq (>425 million reads) to identify indirect HuR targets. These direct and indirect targets were combined to determine canonical pathways in CD4+ T cell activation and differentiation for which HuR plays an important role. We show that HuR may regulate genes in multiple canonical pathways involved in T cell activation especially the CD28 family signaling pathway. These data provide insights into potential HuR-regulated genes during T cell activation and immune mechanisms

Changing forests-changing streams: Riparian forest stand development and ecosystem function in temperate headwaters

Light availability influences temperature, primary production, nutrient dynamics, and secondary production in aquatic ecosystems. In forested freshwater ecosystems, shading by streamside (riparian) vegetation is a dominant control on light flux and represents an important interaction at the aquatic-terrestrial interface. Changes in forest structure over time, particularly tree mortality processes that gradually increase light penetration through maturing forest canopies, are likely to influence stream light fluxes and associated ecosystem functions. We provide a set of conceptual models describing how stream light dynamics change with the development of complex canopy structure and how changes in light availability are likely to affect stream ecosystem processes. Shortly after a stand-replacing event, light flux to the stream is high, but light fluxes decline as canopies reestablish and close. Tree density, the degree of understory growth, patterns of tree mortality, and small-scale disturbances interact as drivers of multiple pathways of forest structural development. Changes in canopy structure will, in turn, influence stream light, which is expected to impact primary production and stream nutrient dynamics as well as the amount of autochthonous carbon supporting aquatic food webs. Ultimately, these conceptual models stress the importance of recovery from historic forest disturbances as well as future forest change as important factors influencing the long-term trajectories of ecosystem processes in headwaters

Assembly of the Candida albicans genome into sixteen supercontigs aligned on the eight chromosomes

For Assembly 20 of the Candida albicans genome, the sequence of each of the eight chromosomes was determined, revealing new insights into gene family creation and dispersion, subtelomere organization, and chromosome evolution

Mental health outcomes from direct and indirect exposure to firearm violence: A cohort study of nonfatal shooting survivors and family members

Background: Firearm violence is a public health crisis in the US. Beyond the survivor, firearm violence also impacts family members and communities of firearm violence survivors. Despite the known health inequities that exist among nonfatal shooting survivors, little research has focused on the mental health needs of family members of nonfatal shootings survivors. Methods: Police and Medicaid claims data linked at the individual level between January 1, 2007 – December 31, 2016 in Indianapolis, Indiana. The Medicaid case number was used to identify nonfatal shooting survivors and family members. Differences in mental health prevalence and clinical care utilization were examined in the 12-months preceding and following an index nonfatal shooting for both survivors and family members. Results were stratified by age. Results: Mental health prevalence rates increased by nearly three percent for family members of nonfatal shooting survivors in the 12-months following a nonfatal shooting, compared to the preinjury period. Among youth with a new mental health diagnosis over half were family members and no differences were observed in mental health conditions between survivors and family members. Conclusions: Findings indicate a need for improved trauma informed services and connection to mental health care for both youth survivors and family members of nonfatal shootings.Dr. Magee was supported by the Indiana Clinical and Translational Science Award from the National Institutes of Health, National Center of Advancing Translational Sciences, Clinical and Translational Sciences Award (KL2TR002530,ULTR002529). This work was also supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health (F32HD101211), National Institute of Health (R01AI114435-01) and Agency for Healthcare Research and Quality (R01HS023318-01). The study sponsors had no role in the study design, data collection, analysis, interpretation of data, report writing, nor decision to submit for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health, Agency for Healthcare Research and Quality

Overexpression of the RNA-binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis [abstract]

Breast cancer is the second most common cancer in women and causes the death of 519,000 people worldwide. Many cancer genes are posttranscriptionally regulated by RNA-binding proteins (RBPs) and microRNAs. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, such as proto-oncogenes, stabilizing their mRNA and facilitating their translation into protein. HuR has been described to control genes in multiple areas of the acquired capabilities model of cancer and has been hypothesized to be a tumor maintenance gene, allowing for cancers to proliferate once they are established. We investigated the role of HuR in aggressive and difficult to treat triple-negative breast cancer

An empirical approach to modeling ion production rates in Titan’s ionosphere I: Ion production rates on the dayside and globally

Titan's ionosphere is created when solar photons, energetic magnetospheric electrons or ions, and cosmic rays ionize the neutral atmosphere. Electron densities generated by current theoretical models are much larger than densities measured by instruments on board the Cassini orbiter. This model density overabundance must result either from overproduction or from insufficient loss of ions. This is the first of two papers that examines ion production rates in Titan's ionosphere, for the dayside and nightside ionosphere, respectively. The first (current) paper focuses on dayside ion production rates which are computed using solar ionization sources (photoionization and electron impact ionization by photoelectrons) between 1000 and 1400 km. In addition to theoretical ion production rates, empirical ion production rates are derived from CH4, CH3+, and CH4+ densities measured by the INMS (Ion Neutral Mass Spectrometer) for many Titan passes. The modeled and empirical production rate profiles from measured densities of N2+ and CH4+ are found to be in good agreement (to within 20%) for solar zenith angles between 15 and 90°. This suggests that the overabundance of electrons in theoretical models of Titan's dayside ionosphere is not due to overproduction but to insufficient ion losses

Two-year prevalence rates of mental health and substance use disorder diagnoses among repeat arrestees

Background Individuals with mental illness and co-occurring substance use disorders often rapidly cycle through the justice system with multiple arrests. Therefore, is it imperative to examine the prevalence of mental health and substance use diagnoses among arrestees and repeat arrestees to identify opportunities for intervention. Methods We linked police arrest and clinical care data at the individual level to conduct a retrospective cohort study of all individuals arrested in 2016 in Indianapolis, Indiana. We classified arrestees into three levels: 1 arrest, 2 arrests, or 3 or more arrests. We included data on clinical diagnoses between January 1, 2014 and December 31, 2015 and classified mental health diagnoses and substance use disorder (SUD) based on DSM categories using ICD9/10 diagnoses codes. Results Of those arrested in 2016, 18,236 (79.5%) were arrested once, 3167 (13.8%) were arrested twice, and 1536 (6.7%) were arrested three or more times. In the 2 years before the arrest, nearly one-third (31.3%) of arrestees had a mental health diagnosis, and over a quarter (27.7%) of arrestees had an SUD diagnosis. Most of those with a mental health or SUD diagnosis had both (22.5% of all arrestees). Arrestees with multiple mental health (OR 2.68, 95% CI 2.23, 3.23), SUD diagnoses (OR 1.59, 95% CI 1.38, 1,82), or co-occurring conditions (1.72, 95% CI 1.48, 2.01) in the preceding 2 years had higher odds of repeat arrest. Conclusions Our findings show that linked clinical and criminal justice data systems identify individuals at risk of repeat arrest and inform opportunities for interventions aimed at low-level offenders with behavioral health needs

Inside the ‘imperfect mosaic’: Minority ethnic women’s qualitative experiences of race and ethnicity during pregnancy, childbirth, and maternity care in the United Kingdom

Background: Persistent, high rates of maternal mortality amongst ethnic minorities is one of the UK’s starkest examples of racial disparity. With greater risks of adverse outcomes during maternity care, ethnic minority women are subjected to embedded, structural and systemic discrimination throughout the healthcare service. Methods: Fourteen semi-structured interviews were undertaken with minority ethnic women who had recent experience of UK maternity care. Data pertaining to ethnicity and race were subject to iterative, inductive coding, and constant comparison through Grounded Theory Analysis to test a previously established theory: The ‘Imperfect Mosaic’. Analysis & findings: A related theory emerged, comprising four themes: ‘Stopping Short of Agentic Birth’; ‘Silenced and Stigmatised through Tick-Box Care’; ‘Anticipating Discrimination and the Need for Advocacy’; and ‘Navigating Cultural Differences’. The new theory: Inside the ‘Imperfect Mosaic’, demonstrates experiences of those who received maternity care which directly mirrors experiences of those who provide care, as seen in the previous theory we set-out to test. However, the current theory is based on more traditional and familiar notions of racial discrimination, rather than the nuanced, subtleties of socio-demographic-based micro-aggressions experienced by healthcare professionals. Conclusions: Our findings suggest the need for the following actions: Prioritisation of bodily autonomy and agency in perinatal physical and mental healthcare; expand awareness of social and cultural issues (i.e., moral injury; cultural safety) within the NHS; and undertake diversity training and support, and follow-up of translation of the training into practice, across (maternal) health services

MicroRNA profiling of the bovine alveolar macrophage response to Mycobacterium bovis infection suggests pathogen survival is enhanced by microRNA regulation of endocytosis and lysosome trafficking

peer-reviewedMycobacterium bovis, the causative agent of bovine tuberculosis, a major problem for global agriculture, spreads via an airborne route and is taken up by alveolar macrophages (AM) in the lung. Here, we describe the first next-generation sequencing (RNA-seq) approach to temporally profile miRNA expression in primary bovine AMs post-infection with M. bovis. One, six, and forty miRNAs were identified as significantly differentially expressed at 2, 24 and 48 h post-infection, respectively. The differential expression of three miRNAs (bta-miR-142-5p, bta-miR-146a, and bta-miR-423-3p) was confirmed by RT-qPCR. Pathway analysis of the predicted mRNA targets of differentially expressed miRNAs suggests that these miRNAs preferentially target several pathways that are functionally relevant for mycobacterial pathogenesis, including endocytosis and lysosome trafficking, IL-1 signalling and the TGF-β pathway. Over-expression studies using a bovine macrophage cell-line (Bomac) reveal the targeting of two key genes in the innate immune response to M. bovis, IL-1 receptor-associated kinase 1 (IRAK1) and TGF-β receptor 2 (TGFBR2), by miR-146. Taken together, our study suggests that miRNAs play a key role in tuning the complex interplay between M. bovis survival strategies and the host immune response