Criteria for reducing unnecessary testing for herpes simplex virus, varicella-zoster virus, cytomegalovirus, and enterovirus in cerebrospinal fluid samples from adults

Excessive utilization of laboratory diagnostic testing leads to increased health care costs. We evaluated criteria to reduce unnecessary nucleic acid amplification testing (NAAT) for viral pathogens in cerebrospinal fluid (CSF) samples from adults. This is a single-center split retrospective observational study with a screening cohort from 2008 to 2012 and a validation cohort from 2013. Adults with available results for herpes simplex virus 1/2 (HSV-1/2), varicella-zoster virus (VZV), cytomegalovirus (CMV), or enterovirus (EV) NAAT with CSF samples between 2008 and 2013 were included (n = 10,917). During this study, 1.3% (n = 140) of viral NAAT studies yielded positive results. The acceptance criteria of >10 nucleated cells/μl in the CSF of immunocompetent subjects would have reduced HSV-1/2, VZV, CMV, and EV testing by 63%, 50%, 44%, and 51%, respectively, from 2008 to 2012. When these criteria were applied to the 2013 validation data set, 54% of HSV-1/2, 57% of VZV, 35% of CMV, and 56% of EV tests would have been cancelled. No clinically significant positive tests would have been cancelled in 2013 with this approach. The introduction of a computerized order entry set was associated with increased test requests, suggesting that computerized order sets may contribute to unnecessary testing. Acceptance criteria of >10 nucleated cells/μl in the CSF of immunocompetent adults for viral CSF NAAT assays would increase clinical specificity and preserve sensitivity, resulting in significant cost savings. Implementation of these acceptance criteria led to a 46% reduction in testing during a limited follow-up period

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study

The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study

Transkingdom Analysis of the Female Reproductive Tract Reveals Bacteriophages form Communities

The female reproductive tract (FRT) microbiome plays a vital role in maintaining vaginal health. Viruses are key regulators of other microbial ecosystems, but little is known about how the FRT viruses (virome), particularly bacteriophages that comprise the phageome, impact FRT health and dysbiosis. We hypothesize that bacterial vaginosis (BV) is associated with altered FRT phageome diversity, transkingdom interplay, and bacteriophage discriminate taxa. Here, we conducted a retrospective, longitudinal analysis of vaginal swabs collected from 54 BV-positive and 46 BV-negative South African women. Bacteriome analysis revealed samples clustered into five distinct bacterial community groups (CGs), and further, bacterial alpha diversity was significantly associated with BV. Virome analysis on a subset of baseline samples showed FRT bacteriophages clustering into novel viral state types (VSTs), a viral community clustering system based on virome composition and abundance. Distinct BV bacteriophage signatures included increased alpha diversity along with discriminant Bacillus, Burkholderia, and Escherichia bacteriophages. Bacteriophage-bacteria transkingdom associations were also identified between Bacillus and Burkholderia viruses and BV-associated bacteria, providing key insights for future studies elucidating the transkingdom interactions driving BV-associated microbiome perturbations. In this cohort, bacteriophage-bacterial associations suggest complex interactions, which may play a role in the establishment and maintenance of BV

Perspectives and Integration in SOLAS Science

Why a chapter on Perspectives and Integration in SOLAS Science in this book? SOLAS science by its nature deals with interactions that occur: across a wide spectrum of time and space scales, involve gases and particles, between the ocean and the atmosphere, across many disciplines including chemistry, biology, optics, physics, mathematics, computing, socio-economics and consequently interactions between many different scientists and across scientific generations. This chapter provides a guide through the remarkable diversity of cross-cutting approaches and tools in the gigantic puzzle of the SOLAS realm. Here we overview the existing prime components of atmospheric and oceanic observing systems, with the acquisition of ocean–atmosphere observables either from in situ or from satellites, the rich hierarchy of models to test our knowledge of Earth System functioning, and the tremendous efforts accomplished over the last decade within the COST Action 735 and SOLAS Integration project frameworks to understand, as best we can, the current physical and biogeochemical state of the atmosphere and ocean commons. A few SOLAS integrative studies illustrate the full meaning of interactions, paving the way for even tighter connections between thematic fields. Ultimately, SOLAS research will also develop with an enhanced consideration of societal demand while preserving fundamental research coherency. The exchange of energy, gases and particles across the air-sea interface is controlled by a variety of biological, chemical and physical processes that operate across broad spatial and temporal scales. These processes influence the composition, biogeochemical and chemical properties of both the oceanic and atmospheric boundary layers and ultimately shape the Earth system response to climate and environmental change, as detailed in the previous four chapters. In this cross-cutting chapter we present some of the SOLAS achievements over the last decade in terms of integration, upscaling observational information from process-oriented studies and expeditionary research with key tools such as remote sensing and modelling. Here we do not pretend to encompass the entire legacy of SOLAS efforts but rather offer a selective view of some of the major integrative SOLAS studies that combined available pieces of the immense jigsaw puzzle. These include, for instance, COST efforts to build up global climatologies of SOLAS relevant parameters such as dimethyl sulphide, interconnection between volcanic ash and ecosystem response in the eastern subarctic North Pacific, optimal strategy to derive basin-scale CO2 uptake with good precision, or significant reduction of the uncertainties in sea-salt aerosol source functions. Predicting the future trajectory of Earth’s climate and habitability is the main task ahead. Some possible routes for the SOLAS scientific community to reach this overarching goal conclude the chapter

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Activation of AMPK alpha2 is not required for mitochondrial FAT/CD36 accumulation during exercise

Exercise has been shown to induce the translocation of fatty acid translocase (FAT/CD36), a fatty acid transport protein, to both plasma and mitochondrial membranes. While previous studies have examined signals involved in the induction of FAT/CD36 translocation to sarcolemmal membranes, to date the signaling events responsible for FAT/CD36 accumulation on mitochondrial membranes have not been investigated. In the current study muscle contraction rapidly increased FAT/CD36 on plasma membranes (7.5 minutes), while in contrast, FAT/CD36 only increased on mitochondrial membranes after 22.5 minutes of muscle contraction, a response that was exercise-intensity dependent. Considering that previous research has shown that AMP activated protein kinase (AMPK) α2 is not required for FAT/CD36 translocation to the plasma membrane, we investigated whether AMPK α2 signaling is necessary for mitochondrial FAT/CD36 accumulation. Administration of 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) induced AMPK phosphorylation, and resulted in FAT/CD36 accumulation on SS mitochondria, suggesting AMPK signaling may mediate this response. However, SS mitochondrial FAT/CD36 increased following acute treadmill running in both wild-type (WT) and AMPKα 2 kinase dead (KD) mice. These data suggest that AMPK signaling is not required for SS mitochondrial FAT/CD36 accumulation. The current data also implicates alternative signaling pathways that are exercise-intensity dependent, as IMF mitochondrial FAT/CD36 content only occurred at a higher power output. Taken altogether the current data suggests that activation of AMPK signaling is sufficient but not required for exercise-induced accumulation in mitochondrial FAT/CD36

Representative Western blots on isolated subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria and assessment of mitochondrial respiratory coupling.

<p>Isolated mitochondria display an absence of MCT1, Cav1 and SERCA2, but the presence of COXIV, suggesting the preparation recovered mitochondria devoid of plasma membrane and sarcoplasmic reticulum contamination (A). Mitochondria were also utilized to assess coupling efficiencies as an index of mitochondrial damage. Specifically, the P/O ratios and RCR (reported in B) values suggest mitochondria were coupled, and therefore not damaged during the isolation procedure (B). Values are reported as the means ± SEM (n = 4).</p

Effects of acute treadmill running on FAT/CD36 mitochondrial content in WT and AMPKα2 KD mice.

<p>ACC Ser79 phosphorylation was examined in whole muscle (A), while subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria were isolated from WT (B) and AMPKα2 KD (C) mice run at 12m/min at a 5% grade for an hour or from sedentary controls. Mitochondria were utilized to determine FAT/CD36 protein content, while COXIV was utilized as a loading control. Values are reported as the means ± SEM (n = 4 for ACC Westerns, n = 8 for mitochondrial Westerns). *significantly (P<0.05) different from control.</p

Effects of AICAR and acute treadmill running on ERK1/2 phosphorylation.

<p>Treadmill running for 30 minutes increased ERK1/2 Thr202/Tyr204 phosphorylation in an intensity-dependent manner in WT mice (A). ERK1/2 Thr202/Tyr204 phosphorylation increased 30 minutes following an intraperitoneal injection of AICAR in the absence of alterations in total protein content in WT mice (B). Treadmill running for 30 minutes increased ERK1/2 Thr202/Tyr204 phosphorylation in AMPKα2 KD mice (C). Values are reported as the means ± SEM (n = 5). * significantly (P<0.05) different from control (saline or sedentary) and † significantly (P<0.05) different from low-intensity running.</p