Mesothelioma among Motor Vehicle Mechanics: An Updated Review and Meta-analysis.
We published a meta-analysis of the association between work as a motor vehicle mechanic and mesothelioma in 2004. Since then, several relevant studies on this topic have been published. Thus, to update the state-of-the-science on this issue, we conducted a new systematic review and meta-analysis. A comprehensive PubMed literature search through May 2014 was conducted to identify studies that reported relative risk estimates for mesothelioma among motor vehicle mechanics (in general), and those who were engaged in brake repair (specifically). Studies were scored and classified based on study characteristics. Random-effects meta-analyses generated summary relative risk estimates (SRREs) and corresponding 95% confidence intervals (CI). Heterogeneity of results was examined by calculating Q-test P-values (P-H) and I (2) estimates. Sub-group and sensitivity analyses were conducted for relevant study characteristics and quality measures. Ten case-control studies, one cohort study, and five proportionate mortality ratio (PMR)/standardized mortality odds ratio (SMOR) studies were identified and included in the quantitative assessment. Most meta-analysis models produced SRREs below 1.0, and no statistically significant increases in mesothelioma were observed. The SRRE for all studies was 0.80 (95% CI: 0.61-1.05) with significant heterogeneity (P-H <0.001, I (2) = 62.90). A similar SRRE was observed among the five Tier 1 studies with the highest quality ratings (SRRE = 0.76, 95% CI: 0.46-1.25), with no heterogeneity among studies (P-H = 0.912, I (2) = 0.00). Meta-analysis of the Tier 2 (n = 5) and Tier 3 (n = 6) studies resulted in SRREs of 1.09 (95% CI: 0.76-1.58) and 0.73 (95% CI: 0.49-1.08), respectively. Restricting the analysis to Tiers 1 and 2 combined resulted in an SRRE of 0.92 (95% CI: 0.72-1.29). The SRRE specific to brake work (n = 4) was 0.64 (95% CI: 0.38-1.09). This meta-analysis of the epidemiologic studies provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma.


A perspective on structural and mechanistic aspects of protein O-fucosylation.
Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.


A calmodulin-related light chain from fission yeast that functions with myosin-I and PI 4-kinase.
Fission yeast myosin-I (Myo1p) not only associates with calmodulin, but also employs a second light chain called Cam2p. cam2Δ cells exhibit defects in cell polarity and growth consistent with a loss of Myo1p function. Loss of Cam2p leads to a reduction in Myo1p levels at endocytic patches and a 50% drop in the rates of Myo1p-driven actin filament motility. Thus, Cam2p plays a significant role in Myo1p function. However, further studies indicated the existence of an additional Cam2p-binding partner. Cam2p was still present at cortical patches in myo1Δ cells (or in myo1-IQ2 mutants, which lack an intact Cam2p-binding motif), whereas a cam2 null (cam2Δ) suppressed cytokinesis defects of an essential light chain (ELC) mutant known to be impaired in binding to PI 4-kinase (Pik1p). Binding studies revealed that Cam2p and the ELC compete for Pik1p. Cortical localization of Cam2p in the myo1Δ background relied on its association with Pik1p, whereas overexpression studies indicated that Cam2p, in turn, contributes to Pik1p function. The fact that the Myo1p-associated defects of a cam2Δ mutant are more potent than those of a myo1-IQ2 mutant suggests that myosin light chains can contribute to actomyosin function both directly and indirectly (via phospholipid synthesis at sites of polarized growth).


Genomic Characterization and Copy Number Variation of Bacillus anthracis Plasmids pXO1 and pXO2 in a Historical Collection of 412 Strains.
Bacillus anthracis plasmids pXO1 and pXO2 carry the main virulence factors responsible for anthrax. However, the extent of copy number variation within the species and how the plasmids are related to pXO1/pXO2-like plasmids in other species of the Bacillus cereus sensu lato group remain unclear. To gain new insights into these issues, we sequenced 412 B. anthracis strains representing the total phylogenetic and ecological diversity of the species. Our results revealed that B. anthracis genomes carried, on average, 3.86 and 2.29 copies of pXO1 and pXO2, respectively, and also revealed a positive linear correlation between the copy numbers of pXO1 and pXO2. No correlation between the plasmid copy number and the phylogenetic relatedness of the strains was observed. However, genomes of strains isolated from animal tissues generally maintained a higher plasmid copy number than genomes of strains from environmental sources (P < 0.05 [Welch two-sample t test]). Comparisons against B. cereus genomes carrying complete or partial pXO1-like and pXO2-like plasmids showed that the plasmid-based phylogeny recapitulated that of the main chromosome, indicating limited plasmid horizontal transfer between or within these species. Comparisons of gene content revealed a closed pXO1 and pXO2 pangenome; e.g., plasmids encode <8 unique genes, on average, and a single large fragment deletion of pXO1 in one B. anthracis strain (2000031682) was detected. Collectively, our results provide a more complete view of the genomic diversity of B. anthracis plasmids, their copy number variation, and the virulence potential of other Bacillus species carrying pXO1/pXO2-like plasmids. IMPORTANCE Bacillus anthracis microorganisms are of historical and epidemiological importance and are among the most homogenous bacterial groups known, even though the B. anthracis genome is rich in mobile elements. Mobile elements can trigger the diversification of lineages; therefore, characterizing the extent of genomic variation in a large collection of strains is critical for a complete understanding of the diversity and evolution of the species. Here, we sequenced a large collection of B. anthracis strains (>400) that were recovered from human, animal, and environmental sources around the world. Our results confirmed the remarkable stability of gene content and synteny of the anthrax plasmids and revealed no signal of plasmid exchange between B. anthracis and pathogenic B. cereus isolates but rather predominantly vertical descent. These findings advance our understanding of the biology and pathogenomic evolution of B. anthracis and its plasmids.


Inter-embodiment and the experience of genetic testing for familial hypercholesterolaemia.
In this article we explore the concept of inter-embodiment and its potential for advancing sociological research into illness biography and genetic identity. Inter-embodiment theory views embodied knowledge as produced through relations between bodies, as opposed to originating from within the body or as the product of relations between disembodied selves. Drawing on a qualitative study in which we interviewed 38 individuals about their experiences of discovering they had high cholesterol and undergoing genetic testing for familial hypercholesterolaemia (FH), we discuss how their narratives may be understood from an inter-embodiment perspective. The participants frequently talked at length about their family histories of high cholesterol and cardiovascular disease. Through these accounts, we develop the concept of the family corpus in order to highlight the role body networks play in shaping lay constructions of genetic identity and a familial disease biography. The notion of a family corpus, we argue, is useful in understanding why genetic testing for FH was experienced as either biographical re-enforcement or as biographical disruption. We conclude by discussing the implications of our findings for future sociological research into illness biography and genetic identity.


Windsor, Ontario Exposure Assessment Study: Design and Methods Validation of Personal, Indoor, and Outdoor Air Pollution Monitoring.
The Windsor, Ontario Exposure Assessment Study evaluated the contribution of ambient air pollutants to personal and indoor exposures of adults and asthmatic children living in Windsor, Ontario, Canada. In addition, the role of personal, indoor, and outdoor air pollution exposures upon asthmatic children's respiratory health was assessed. Several active and passive sampling methods were applied, or adapted, for personal, indoor, and outdoor residential monitoring of nitrogen dioxide, volatile organic compounds, particulate matter (PM; PM ≤ 2.5 μm [PM2.5] and ≤ 10 μm [PM10] in aerodynamic diameter),elemental carbon, ultrafine particles, ozone, air exchange rates, allergens in settled dust, and particulate-associated metals. Participants completed five consecutive days of monitoring during the winter and summer of 2005 and 2006. During 2006, in addition to undertaking the air pollution measurements, asthmatic children completed respiratory health measurements (including peak flow meter tests and exhaled breath condensate) and tracked respiratory symptoms in a diary. Extensive quality assurance and quality control steps were implemented, including the collocation of instruments at the National Air Pollution Surveillance site operated by Environment Canada and at the Michigan Department of Environmental Quality site in Allen Park, Detroit, MI. During field sampling, duplicate and blank samples were also completed and these data are reported. In total, 50 adults and 51 asthmatic children were recruited to participate, resulting in 922 participant days of data. When comparing the methods used in the study with standard reference methods, field blanks were low and bias was acceptable, with most methods being within 20% of reference methods. Duplicates were typically within less than 10% of each other, indicating that study results can be used with confidence. This paper covers study design, recruitment, methodology, time activity diary, surveys, and quality assurance and control results for the different methods used. [Box: see text].


Role of inosine triphosphate pyrophosphatase gene variant on fever incidence during zidovudine antiretroviral therapy.
Zidovudine, the antiretroviral drug used to treat HIV infection, commonly causes adverse effects, such as systemic fever and gastrointestinal alterations. In the present study, the potential role of inosine triphosphate pyrophosphatase (ITPA) gene variant on the incidence of adverse events during antiretroviral therapy (ART) of HIV with zidovudine was discussed. Individuals from Northeastern Brazil (N = 204) receiving treatment for HIV-1 infection were recruited. Zidovudine-related adverse effects developed during the treatment were registered. The rs1127354 polymorphism in the ITPA gene was genotyped using real-time PCR to assess whether this single nucleotide polymorphism was associated with the occurrence of zidovudine-related adverse effects. We observed a significant association between the ITPA variant genotype and the reported systemic fever (odds ratio = 7.17, 95% confidence interval = 1.19-43.15; P = 0.032). Zidovudine use could indirectly lead to an increase in the levels of inosine monophosphate in an antimetabolite-like manner, which is converted to inosine triphosphate (ITP). The rs1127354 variant caused a decrease in ITPA activity, thereby leading to ITP accumulation. This in turn resulted in cytotoxicity, which was manifested by neutropenia and fever. Therefore, we hypothesized a pharmacogenetic model involving the ITPA variant genotype in multifactorial components that act together to determine the onset of zidovudine-related adverse effects.


In situ human papillomavirus (HPV) genotyping of cervical intraepithelial neoplasia in South African and British patients: evidence for putative HPV integration in vivo.
In South Africa asymptomatic wart virus infection diagnosed by morphological criteria occurs in 16-20% of all ethnic groups; the incidence in black women is 66%. To identify human papillomavirus (HPV) types the prevalence of HPV in cervical intraepithelial neoplasia (CIN) in South African women (n = 72) with age matched British women (n = 73) was compared by non-isotopic in situ hybridisation (NISH) using digoxigenin labelled probes for HPV 6, 11, 16, 18, 31, 33 and 35 on archival biopsy specimens. A higher proportion of British biopsy specimens (68%) contained HPV than those from South Africa (50%) in CIN 2 and 3; this difference was due to HPV 16. Thirty six per cent of the positive biopsy specimens from South African women also contained HPV 33/35 compared with 16% in the United Kingdom. There was no difference in HPV detection with age in either group. These data indicate that HPV types vary geographically, with "minor" HPV types being more common in South Africa. Three qualitatively distinct NISH signals were observed; a diffuse (type 1) signal in superficial cells, mainly koilocytes; a punctate signal (type 2) in basal/"undifferentiated" cells in CIN 3; and combined type 1 and 2 signals in CIN with wart virus infection (type 3). The punctate signal may represent HPV integration.


Selling yourself: Titmuss's argument against a market in blood.
This article defends Richard Titmuss's argument, and Peter Singer's sympathetic support for it, against orthodox philosophical criticism. The article specifies the sense in which a market in blood is "dehumanising" as having to do with a loss of "imagined community" or social "integration," and not with a loss of valued or "deeper" liberty. It separates two "domino arguments"--the "contamination of meaning" argument and the "erosion of motivation" argument--which support, in different but interrelated ways, the claim that a market in blood is "imperialistic." Concentrating on the first domino argument the article considers the view that monetary and non-monetary meanings of the same good can co-exist given the robustness of certain kinds of relationship and joint undertakings within which gifts can figure. It argues that societal relationships are vulnerable or permeable to the effects of the market in a way that those constitutive of the personal sphere are not. General, more broadly political questions remain unanswered but the core of Titmuss's original and challenging argument remains and can be presented in a defensible form.


A mechanism-inspired UDP-N-acetylglucosamine pyrophosphorylase inhibitor.
UDP-N-acetylglucosamine pyrophosphorylase (UAP1) catalyses the last step in eukaryotic biosynthesis of uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc), converting UTP and GlcNAc-1P to the sugar nucleotide. Gene disruption studies have shown that this gene is essential in eukaryotes and a possible antifungal target, yet no inhibitors of fungal UAP1 have so far been reported. Here we describe the crystal structures of substrate/product complexes of UAP1 from Aspergillus fumigatus that together provide snapshots of catalysis. A structure with UDP-GlcNAc, pyrophosphate and Mg2+ provides the first Michaelis complex trapped for this class of enzyme, revealing the structural basis of the previously reported Mg2+ dependence and direct observation of pyrophosphorolysis. We also show that a highly conserved lysine mimics the role of a second metal observed in structures of bacterial orthologues. A mechanism-inspired UTP α,β-methylenebisphosphonate analogue (meUTP) was designed and synthesized and was shown to be a micromolar inhibitor of the enzyme. The mechanistic insights and inhibitor described here will facilitate future studies towards the discovery of small molecule inhibitors of this currently unexploited potential antifungal drug target.


Platelet membrane microviscosity in Sabra rats with early salt hypertension.
1. To investigate the possibility that arterial hypertension is associated with changes in the physicochemical properties of cell membranes, we have studied the effects of dietary salt loading on platelet membrane microviscosity in hypertension-prone and -resistant Sabra rats. 2. Sixteen hypertension-prone and 14 hypertension-resistant Sabra rats were submitted to either a low-salt (0.25% NaCl) or a high-salt (4% NaCl) diet for 3-4 weeks. Platelet membrane anisotropy was determined, in the presence and absence of extracellular Na+, using two fluorescent probes, diphenylhexatriene and trimethylamino-diphenylhexatriene, inserted in different areas of the cell membranes. 3. A decrease in diphenylhexatriene anisotropy was demonstrated when platelets of hypertension-prone (but not hypertension-resistant) Sabra rats were suspended in a Na(+)-free medium. This alteration in membrane dynamic properties is localized within the hydrophobic core of the platelet membranes and is independent of salt intake. It reflects an abnormal fluidizing effect of extracellular Na+ removal. 4. Platelets of hypertension-prone and hypertension-resistant Sabra rats did not differ significantly in trimethylamino-diphenylhexatriene fluorescence anisotropy, irrespective of the incubation media used. Extracellular Na+ removal caused an increase in trimethylamino-diphenylhexatriene fluorescence anisotropy in all groups, the change being greatest in salt-loaded rats. 5. This study indicates that platelet membrane microviscosity is specifically altered in the hypertension-prone Sabra rat irrespective of salt intake. This raises the question of the relation of this inherited defect with the susceptibility of this strain to dietary salt loading.


Physical activity after total knee arthroplasty: A critical review.
Total knee arthroplasty (TKA) is the most commonly performed elective surgery in the United States. TKA typically improves functional performance and reduces pain associated with knee osteoarthritis. Little is known about the influence of TKA on overall physical activity levels. Physical activity, defined as "any bodily movement produced by skeletal muscles that results in energy expenditure", confers many health benefits but typically decreases with endstage osteoarthritis. The purpose of this review is to describe the potential benefits (metabolic, functional, and orthopedic) of physical activity to patients undergoing TKA, present results from recent studies aimed to determine the effect of TKA on physical activity, and discuss potential sources of variability and conflicting results for physical activity outcomes. Several studies utilizing self-reported outcomes indicate that patients perceive themselves to be more physically active after TKA than they were before surgery. Accelerometry-based outcomes indicate that physical activity for patients after TKA remains at or below pre-surgical levels. Several different factors likely contributed to these variable results, including the use of different instruments, duration of follow-up, and characteristics of the subjects studied. Comparison to norms, however, suggests that daily physical activity for patients following TKA may fall short of healthy age-matched controls. We propose that further study of the relationship between TKA and physical activity needs to be performed using accelerometry-based outcome measures at multiple post-surgical time points.


Identifying the 'red flags' for unhealthy weight control among adolescents: findings from an item response theory analysis of a national survey.
Weight control behaviors are common among young people and are associated with poor health outcomes. Yet clinicians rarely ask young people about their weight control; this may be due to uncertainty about which questions to ask, specifically around whether certain weight loss strategies are healthier or unhealthy or about what weight loss behaviors are more likely to lead to adverse outcomes. Thus, the aims of the current study are: to confirm, using item response theory analysis, that the underlying latent constructs of healthy and unhealthy weight control exist; to determine the 'red flag' weight loss behaviors that may discriminate unhealthy from healthy weight loss; to determine the relationships between healthy and unhealthy weight loss and mental health; and to examine how weight control may vary among demographic groups. Data were collected as part of a national health and wellbeing survey of secondary school students in New Zealand (n = 9,107) in 2007. Item response theory analyses were conducted to determine the underlying constructs of weight control behaviors and the behaviors that discriminate unhealthy from healthy weight control. The current study confirms that there are two underlying constructs of weight loss behaviors which can be described as healthy and unhealthy weight control. Unhealthy weight control was positively correlated with depressive mood. Fasting and skipping meals for weight loss had the lowest item thresholds on the unhealthy weight control continuum, indicating that they act as 'red flags' and warrant further discussion in routine clinical assessments. Routine assessments of weight control strategies by clinicians are warranted, particularly for screening for meal skipping and fasting for weight loss as these behaviors appear to 'flag' behaviors that are associated with poor mental wellbeing.


Novel diagnosis for citrus stubborn disease by detection of a spiroplasma citri-secreted protein.
Citrus stubborn disease (CSD), first identified in California, is a widespread bacterial disease found in most arid citrus-producing regions in the United States and the Mediterranean Region. The disease is caused by Spiroplasma citri, an insect-transmitted and phloem-colonizing bacterium. CSD causes significant tree damage resulting in loss of fruit production and quality. Detection of CSD is challenging due to low and fluctuating titer and sporadic distribution of the pathogen in infected trees. In this study, we report the development of a novel diagnostic method for CSD using an S. citri-secreted protein as the detection marker. Microbial pathogens secrete a variety of proteins during infection that can potentially disperse systemically in infected plants with the vascular flow. Therefore, their distribution may not be restricted to the pathogen infection sites and could be used as a biological marker for infection. Using mass spectrometry analysis, we identified a unique secreted protein from S. citri that is highly expressed in the presence of citrus phloem extract. ScCCPP1, an antibody generated against this protein, was able to distinguish S. citri-infected citrus and periwinkle from healthy plants. In addition, the antiserum could be used to detect CSD using a simple direct tissue print assay without the need for sample processing or specialized lab equipment and may be suitable for field surveys. This study provides proof of a novel concept of using pathogen-secreted protein as a marker for diagnosis of a citrus bacterial disease and can probably be applied to other plant diseases.


Bone marrow stromal cells use TGF-beta to suppress allergic responses in a mouse model of ragweed-induced asthma.
Bone marrow stromal cells [BMSCs; also known as mesenchymal stem cells (MSCs)] effectively suppress inflammatory responses in acute graft-versus-host disease in humans and in a number of disease models in mice. Many of the studies concluded that BMSC-driven immunomodulation is mediated by the suppression of proinflammatory Th1 responses while rebalancing the Th1/Th2 ratio toward Th2. In this study, using a ragweed induced mouse asthma model, we studied if BMSCs could be beneficial in an allergic, Th2-dominant environment. When BMSCs were injected i.v. at the time of the antigen challenge, they protected the animals from the majority of asthma-specific pathological changes, including inhibition of eosinophil infiltration and excess mucus production in the lung, decreased levels of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage, and lowered serum levels of Th2 immunoglobulins (IgG1 and IgE). To explore the mechanism of the effect we used BMSCs isolated from a variety of knockout mice, performed in vivo blocking of cytokines and studied the effect of asthmatic serum and bronchoalveolar lavage from ragweed challenged animals on the BMSCs in vitro. Our results suggest that IL-4 and/or IL-13 activate the STAT6 pathway in the BMSCs resulting in an increase of their TGF-beta production, which seems to mediate the beneficial effect, either alone, or together with regulatory T cells, some of which might be recruited by the BMSCs. These data suggest that, in addition to focusing on graft-versus-host disease and autoimmune diseases, allergic conditions--specifically therapy resistant asthma--might also be a likely target of the recently discovered cellular therapy approach using BMSCs.


Treatment of erectile dysfunction following therapy for clinically localized prostate cancer: patient reported use and outcomes from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study.
Erectile dysfunction (ED) persists for years following curative therapies for clinically localized prostate cancer. We report use and treatment outcomes in a 5-year interval in a population based cohort from the Surveillance, Epidemiology, and End Results Prostate Cancer Outcomes Study. A sample of 1,977 men with localized prostate cancer who received external beam radiation therapy or radical prostatectomy in 1994 to 1995 were surveyed for 5 outcome measures of ED treatment, namely treatment, perceived helpfulness, erectile sufficiency, sexual activity frequency and erection maintenance. Subjects were surveyed 6, 12, 24 and 60 months after prostate cancer diagnosis. Overall 50.5% of men ever used ED treatment. The use of ED treatments increased during the study course. Subject age, regular sexual partner and baseline sexual activity were factors positively associated with ED treatments. While it was used uncommonly (1.9%), a penile prosthesis was perceived as the most helpful ED treatment (helped a lot in 52% of respondents). Sildenafil helped a lot in 12% of respondents. Erectile fullness, erection maintenance and sexual activity frequency were modestly improved in men using ED treatment compared with those in men not using ED treatment. Approximately half of the patients in this population based cohort of men used ED treatment during the 5 years following prostate cancer diagnosis. Men using ED treatments had modest improvement in sexual function compared with men that in who did not receive ED treatment at 60 months. More effective treatments for ED following local therapy for prostate cancer are needed.


Asian monsoons in a late Eocene greenhouse world.
The strong present-day Asian monsoons are thought to have originated between 25 and 22 million years (Myr) ago, driven by Tibetan-Himalayan uplift. However, the existence of older Asian monsoons and their response to enhanced greenhouse conditions such as those in the Eocene period (55-34 Myr ago) are unknown because of the paucity of well-dated records. Here we show late Eocene climate records revealing marked monsoon-like patterns in rainfall and wind south and north of the Tibetan-Himalayan orogen. This is indicated by low oxygen isotope values with strong seasonality in gastropod shells and mammal teeth from Myanmar, and by aeolian dust deposition in northwest China. Our climate simulations support modern-like Eocene monsoonal rainfall and show that a reinforced hydrological cycle responding to enhanced greenhouse conditions counterbalanced the negative effect of lower Tibetan relief on precipitation. These strong monsoons later weakened with the global shift to icehouse conditions 34 Myr ago.


Are some children genetically predisposed to poor sleep? A polygenic risk study in the general population.
Twin studies show moderate heritability of sleep traits: 40% for insomnia symptoms and 46% for sleep duration. Genome-wide association studies (GWAS) have identified genetic variants involved in insomnia and sleep duration in adults, but it is unknown whether these variants affect sleep during early development. We assessed whether polygenic risk scores for insomnia (PRS-I) and sleep duration (PRS-SD) affect sleep throughout early childhood to adolescence. We included 2,458 children of European ancestry (51% girls). Insomnia-related items of the Child Behavior Checklist were reported by mothers at child's age 1.5, 3, and 6 years. At 10-15 years, the Sleep Disturbance Scale for Children and actigraphy were assessed in a subsample (N = 975). Standardized PRS-I and PRS-SD (higher scores indicate genetic susceptibility for insomnia and longer sleep duration, respectively) were computed at multiple p-value thresholds based on largest GWAS to date. Children with higher PRS-I had more insomnia-related sleep problems between 1.5 and 15 years (BPRS-I < 0.001 = .09, 95% CI: 0.05; 0.14). PRS-SD was not associated with mother-reported sleep problems. A higher PRS-SD was in turn associated with longer actigraphically estimated sleep duration (BPRS-SD < 5e08 = .05, 95% CI: 0.001; 0.09) and more wake after sleep onset (BPRS-SD < 0.005 = .25, 95% CI: 0.04; 0.47) at 10-15 years, but these associations did not survive multiple testing correction. Children who are genetically predisposed to insomnia have more insomnia-like sleep problems, whereas those who are genetically predisposed to longer sleep have longer sleep duration, but are also more awake during the night in adolescence. This indicates that polygenic risk for sleep traits, based on GWAS in adults, affects sleep already in children.


Modelling the cumulative risk of a false-positive screening test.
The goal of a screening test is to reduce morbidity and mortality through the early detection of disease; but the benefits of screening must be weighed against potential harms, such as false-positive (FP) results, which may lead to increased healthcare costs, patient anxiety, and other adverse outcomes associated with diagnostic follow-up procedures. Accurate estimation of the cumulative risk of an FP test after multiple screening rounds is important for program evaluation and goal setting, as well as informing individuals undergoing screening what they should expect from testing over time. Estimation of the cumulative FP risk is complicated by the existence of censoring and possible dependence of the censoring time on the event history. Current statistical methods for estimating the cumulative FP risk from censored data follow two distinct approaches, either conditioning on the number of screening tests observed or marginalizing over this random variable. We review these current methods, identify their limitations and possibly unrealistic assumptions, and propose simple extensions to address some of these limitations. We discuss areas where additional extensions may be useful. We illustrate methods for estimating the cumulative FP recall risk of screening mammography and investigate the appropriateness of modelling assumptions using 13 years of data collected by the Breast Cancer Surveillance Consortium (BCSC). In the BCSC data we found evidence of violations of modelling assumptions of both classes of statistical methods. The estimated risk of an FP recall after 10 screening mammograms varied between 58% and 77% depending on the approach used, with an estimate of 63% based on what we feel are the most reasonable modelling assumptions.


TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user's guide.
More than seventy years after their initial characterisation, the aetiology of inflammatory bowel diseases remains elusive. A recent review evaluating the incidence trends of the last 25 years concluded that an increasing incidence has been observed almost worldwide. A north-south gradient is still found in Europe. Genetic associations are variably reproduced worldwide and indicate a strong impact of environmental factors. Tumour necrosis factor alpha (TNF-alpha) has been shown to play a critical role in the pathogenesis of inflammatory bowel disease (IBD). TNF-alpha blockers are biological agents that specifically target this key cytokine in the inflammatory process and have become a mainstay in the therapy of inflammatory bowel diseases. This paper reviews the necessary investigations before using such agents, the use of such agents in pregnancy and lactation, the role of co-immunosuppression, how to monitor efficacy and safety, dose-adaptation, and the decision as to when to switch to another TNF-alpha blocker. Finally it gives recommendations for special situations. Currently there are three TNF-alpha blockers available for clinical use in IBD in Switzerland: infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia). Infliximab is a chimeric monoclonal antibody composed of a human IgG1 constant region and a murine variable region and is administered intravenously. Adalimumab is a humanised monoclonal antibody, with both human IgG1 constant and variable regions. Certolizumab pegol is a pegylated, humanised monoclonal anti-TNF fragment antigen binding fragment. Both adalimumab and certolizumab pegol are administered by subcutaneous injection. The efficacy and safety of TNF-alpha blockers in Crohn's disease has been reviewed. The authors conclude that the three above-mentioned agents are effective in luminal Crohn's disease. In fistulizing Crohn's disease, TNF-alpha blockers other than infliximab require additional investigation.


NEK1 Facilitates Cohesin Removal during Mammalian Spermatogenesis.
Meiosis is a highly conserved process, which is stringently regulated in all organisms, from fungi through to humans. Two major events define meiosis in eukaryotes. The first is the pairing, or synapsis, of homologous chromosomes and the second is the exchange of genetic information in a process called meiotic recombination. Synapsis is mediated by the meiosis-specific synaptonemal complex structure in combination with the cohesins that tether sister chromatids together along chromosome arms through prophase I. Previously, we identified FKBP6 as a novel component of the mammalian synaptonemal complex. Further studies demonstrated an interaction between FKBP6 and the NIMA-related kinase-1, NEK1. To further investigate the role of NEK1 in mammalian meiosis, we have examined gametogenesis in the spontaneous mutant, Nek1kat2J. Homozygous mutant animals show decreased testis size, defects in testis morphology, and in cohesin removal at late prophase I of meiosis, causing complete male infertility. Cohesin protein SMC3 remains localized to the meiotic chromosome cores at diplonema in the Nek1 mutant, and also in the related Fkbp6 mutant, while in wild type cells SMC3 is removed from the cores at the end of prophase I and becomes more diffuse throughout the DAPI stained region of the nucleus. These data implicate NEK1 as a possible kinase involved in cohesin redistribution in murine spermatocytes.


A new method for sequencing DNA.
DNA can be sequenced by a chemical procedure that breaks a terminally labeled DNA molecule partially at each repetition of a base. The lengths of the labeled fragments then identify the positions of that base. We describe reactions that cleave DNA preferentially at guanines, at adenines, at cytosines and thymines equally, and at cytosines alone. When the products of these four reactions are resolved by size, by electrophoresis on a polyacrylamide gel, the DNA sequence can be read from the pattern of radioactive bands. The technique will permit sequencing of at least 100 bases from the point of labeling.


Risk factors for genital infections in people initiating SGLT2 inhibitors and their impact on discontinuation.
To identify risk factors, absolute risk, and impact on treatment discontinuation of genital infections with sodium-glucose co-transporter-2 inhibitors (SGLT2i). We assessed the relationship between baseline characteristics and genital infection in 21 004 people with type 2 diabetes initiating SGLT2i and 55 471 controls initiating dipeptidyl peptidase-4 inhibitors (DPP4i) in a UK primary care database. We assessed absolute risk of infection in those with key risk factors and the association between early genital infection and treatment discontinuation. Genital infection was substantially more common in those treated with SGLT2i (8.1% within 1 year) than DPP4i (1.8%). Key predictors of infection with SGLT2i were female sex (HR 3.64; 95% CI 3.23 to 4.11) and history of genital infection; <1 year before initiation (HR 4.38; 3.73 to 5.13), 1-5 years (HR 3.04; 2.64 to 3.51), and >5 years (HR 1.79; 1.55 to 2.07). Baseline HbA1c was not associated with infection risk for SGLT2i, in contrast to DPP4i where risk increased with higher HbA1c. One-year absolute risk of genital infection with SGLT2i was highest for those with a history of prior infection (females 23.7%, males 12.1%), compared with those without (females 10.8%, males 2.7%). Early genital infection was associated with a similar discontinuation risk for SGLT2i (HR 1.48; 1.21-1.80) and DPP4i (HR 1.58; 1.21-2.07). Female sex and history of prior infection are simple features that can identify subgroups at greatly increased risk of genital infections with SGLT2i therapy. These data can be used to risk-stratify patients. High HbA1c is not a risk factor for genital infections with SGLT2i.


Sensory design of foods for the elderly.
Elderly persons with dysphagia need food that requires little or no chewing, that is easy to swallow and has attractive sensory characteristics. The aim was to investigate how ingredients varied according to experimental designs influence the perceived sensory, chewing and swallowing characteristics of two types of texture-modified model foods. Meat- and carrot-based, texture-modified model foods were produced. The following parameters were varied: particle size, fat content, starch and egg composition. The samples were studied using sensory analyses, focus group discussions and consumer studies. The design parameters mainly had an impact on sensory texture attributes. The experts in the focus groups selected three products of each type which were regarded as being optimal for older persons. All the products contained a high proportion of egg yolk and a low amount of starch. Older consumers considered all the selected products to be easy to chew and swallow. The differences between older persons in nursing homes compared to those living in their own homes could be linked to health. Optimization of factors influencing food quality through the use of experimental designs in combination with sensory and consumer studies is required in order to meet the needs and demands of older people.


The natural history of radiographic knee osteoarthritis: a fourteen-year population-based cohort study.
To establish the natural history of radiographic knee osteoarthritis (OA) over 14 years in a community-based cohort. We examined women from the Chingford Women's Study, a community-based cohort followed up for more than 14 years. We selected women for whom bilateral radiographs of the knees (with the legs in full extension) were obtained at approximately 5-year intervals. Radiographs were scored for OA in a blinded manner, using Kellgren/Lawrence (K/L) grades. Descriptive statistics and odds ratios (ORs) were used to compare the incidence, worsening, and progression of radiographic knee OA. A complete radiography series was available for 561 of the original 1,003 subjects enrolled in the study. The median age of these subjects at baseline was 53 years (interquartile range 48-58 years). At baseline, 13.7% of the subjects had radiographic knee OA (K/L grade≥2) in at least one knee, and the prevalence increased to 47.8% by year 15. The annual cumulative incidence of radiographic knee OA was 2.3% between baseline and year 15. The annual rates of disease progression and worsening between baseline and year 15 were 2.8% and 3.0%, respectively. Subjects with a K/L grade of 1 at baseline were more likely to experience worsening by year 15 compared with subjects with a baseline grade of 0 (OR 4.5, 95% confidence interval 2.7-7.4). This is the longest natural history study of radiographic knee OA to date. The results showed relatively low rates for the incidence and progression of radiographic knee OA; more than half of all subjects had no radiographic evidence of knee OA over a 15-year period of time. Subjects with a baseline K/L grade of 1 were more likely than subjects with other baseline K/L grades to experience worsening of knee OA.


On-road traffic emissions of polycyclic aromatic hydrocarbons and their oxy- and nitro- derivative compounds measured in road tunnel environments.
Vehicular emissions are a key source of polycyclic aromatic compounds (PACs), including polycyclic aromatic hydrocarbons (PAHs) and their oxygenated (OPAH) and nitrated (NPAH) derivatives, in the urban environment. Road tunnels are a useful environment for the characterisation of on-road vehicular emissions, providing a realistic traffic fleet and a lack of direct sunlight, chemical reactivity and non-traffic sources. In the present investigation the concentrations of selected PAHs, OPAHs and NPAHs have been measured in the Parc des Princes Tunnel in Paris (PdPT, France), and at the Queensway Road Tunnel and an urban background site in Birmingham (QT, U.K). A higher proportion of semi-volatile (3-4 ring) PAH, OPAH and NPAH compounds are associated with the particulate phase compared with samples from the ambient environment. A large (~85%) decline in total PAH concentrations is observed between 1992 and 2012 measurements in QT. This is attributed primarily to the introduction of catalytic converters in the U.K as well as increasingly stringent EU vehicle emissions legislation. In contrast, NPAH concentrations measured in 2012 are similar to those measured in 1996. This observation, in addition to an increased proportion of (Phe+Flt+Pyr) in the observed PAH burden in the tunnel, is attributed to the increased number of diesel passenger vehicles in the U.K during this period. Except for OPAHs, comparable PAH and NPAH concentrations are observed in both investigated tunnels (QT and PdP). Significant differences are shown for specific substances between PAC chemical profiles in relation with the national traffic fleet differences (33% diesel passenger cars in U.K. vs 69% in France and up to 80% taking into account all vehicle categories). The dominating and sole contribution of 1-Nitropyrene observed in the PdPT NPAH profile strengthens the promising use of this compound as a diesel exhaust marker for PM source apportionment studies.


TRPV1 channels are involved in niacin-induced cutaneous vasodilation in mice.
Niacin is effective in treating dyslipidemias but causes cutaneous vasodilation or flushing, a side effect that limits its clinical use. Blocking prostaglandins in humans reduces but does not consistently eliminate flushing, indicating additional mechanisms may contribute to flushing. The transient receptor potential vanilloid 1 (TRPV1) channel, when activated, causes cutaneous vasodilation and undergoes tachyphylaxis similar to that seen with niacin. Using a murine model, early phase niacin-induced flushing was examined and TRPV1 channel involvement demonstrated using pharmacologic blockade, desensitization, and genetic knockouts (TRPV1 KO). The TRPV1 antagonist AMG9810 reduced the magnitude of the initial and secondary peaks and the rapidity of the vasodilatory response (slope). TRPV1 desensitization by chronic capsaicin reduced the initial peak and slope. TRPV1 KO mice had a lower initial peak, secondary peak, and slope compared with wild-type mice. Chronic niacin reduced the initial peak, secondary peak, and slope in wild-type mice but had no effect in knockout mice. Furthermore, chronic niacin diminished the response to capsaicin in wild-type mice. Overall, these data demonstrate an important role for TRPV1 channels in niacin-induced flushing, both in the acute response and with chronic administration. That niacin-induced flushing is a complex cascade of events, which should inform pharmacological intervention against this side effect.


Diabetes and cancer.
Diabetes and cancer are two heterogeneous, multifactorial, severe, and chronic diseases. Because of their frequency, reciprocal influences - even minor influences - may have a major impact. Epidemiological studies clearly indicate that the risk of several types of cancer (including pancreas, liver, breast, colorectal, urinary tract, and female reproductive organs) is increased in diabetic patients. Mortality is also moderately increased. Several confounding factors, having general or site-specific relevance, make it difficult to accurately assess cancer risk in diabetic patients. These factors include diabetes duration, varying levels of metabolic control, different drugs used for therapy, and the possible presence of chronic complications. Hyperinsulinemia most likely favors cancer in diabetic patients as insulin is a growth factor with pre-eminent metabolic but also mitogenic effects, and its action in malignant cells is favored by mechanisms acting at both the receptor and post-receptor level. Obesity, hyperglycemia, and increased oxidative stress may also contribute to increased cancer risk in diabetes. While anti-diabetic drugs have a minor influence on cancer risk (except perhaps the biguanide metformin that apparently reduces the risk), drugs used to treat cancer may either cause diabetes or worsen a pre-existing diabetes. In addition to the well-known diabetogenic effect of glucocorticoids and anti-androgens, an increasing number of targeted anti-cancer molecules may interfere with glucose metabolism acting at different levels on the signaling substrates shared by IGF-I and insulin receptors. In conclusion, diabetes and cancer have a complex relationship that requires more clinical attention and better-designed studies.


Photoinduced charge separation in a ferrocene-aluminum(III) porphyrin-fullerene supramolecular triad.
Light-induced electron transfer is investigated in a ferrocene-aluminum(III) porphyrin-fullerene supramolecular triad (FcAlPorC(60)) and the constituent dyads (AlPorC(60) and FcAlPorPh). The fullerene unit (C(60)) is bound axially to the aluminum(III) porphyrin (AlPor) via a benzoate spacer, and ferrocene (Fc) is attached via an amide linkage to one of the four phenyl groups in the meso positions of the porphyrin ring. The absorption spectra and voltammetry data of the complexes suggest that the ground state electronic structures of the Fc, AlPor, and C(60) entities are not significantly perturbed in the dyads and triad. Time-resolved optical and transient electron paramagnetic resonance (EPR) data show that photoexcitation of the AlPorC(60) dyad results in efficient electron transfer from the excited singlet state of the porphyrin to fullerene, producing the charge-separated state AlPor(•+)-C(60)(•-). The fluorescence and transient EPR data also suggest that some energy transfer from the porphyrin to fullerene may occur. The lifetime of the radical pair AlPor(•+)-C(60)(•-) measured by transient absorbance spectroscopy is found to be 39 ns in o-dichlorobenzene at room temperature. At 200 K, transient EPR experiments place a lower limit of 5 μs on the radical pair lifetime. In the triad, the data suggest that excitation of the porphyrin gives rise to the charge-separated state Fc(•+)-AlPor-C(60)(•-) in two electron transfer steps. Photocurrent measurements demonstrate that both dyads and the triad have good photovoltaic performance. However, when Fc is appended to AlPorC(60), the expected improvement of the radical pair lifetime and the photovoltaic characteristics is not observed.


Hips don't lie: Waist-to-hip ratio in trauma patients.
Obesity measured by body mass index (BMI) is known to be associated with worse outcomes in trauma patients. Recent studies have assessed the impact of distribution of body fat measured by waist-hip ratio (WHR) on outcomes in nontrauma patients. The aim of this study was to assess the impact of distribution of body fat (WHR) on outcomes in trauma patients. A 6-month (June to November 2013) prospective cohort analysis of all admitted trauma patients was performed at our Level 1 trauma center. WHR was measured in each patient on the first day of hospital admission. Patients were stratified into two groups: patients with WHR of 1 or greater and patients with WHR of less than 1. Outcome measures were complications and in-hospital mortality. Complications were defined as infectious, pulmonary, and renal complications. Regression and correlation analyses were performed. A total of 240 patients were enrolled, of which 28.8% patients (n = 69) had WHR of 1 or greater. WHR had a weak correlation with BMI (R = 0.231, R = 0.481). Eighteen percent (n = 43) of the patients developed complications, and the mortality rate was 10% (n = 24). Patients with a WHR of 1 or greater were more likely to develop in-hospital complications (32% vs. 13%, p = 0.001) and had a higher mortality rate (24% vs. 4%, p = 0.001) compared with the patients with a WHR of less than 1. In multivariate analysis, a WHR of 1 or greater was an independent predictor for the development of complications (odds ratio, 3.1; 95% confidence interval 1.08-9.2; p = 0.03) and mortality (odds ratio, 13.1; 95% confidence interval, 1.1-70; p = 0.04). Distribution of body fat as measured by WHR independently predicts mortality and complications in trauma patients. WHR is better than BMI in predicting adverse outcomes in trauma patients. Assessing the fat distribution pattern in trauma patients may help improve patient outcomes through focused targeted intervention. Prognostic study, level II.


Rapid response team activations within 24 hours of admission from the emergency department: an innovative approach for performance improvement.
Performance improvement programs in emergency medicine (EM) have evolved beyond peer reviews of referred cases and now encompass a large set of quality metrics that are measured proactively. However, peer review of cases continues to be an important element of performance improvement, and selection of cases tends to be driven by an ad hoc referral process based on concerns about problems with care in the emergency department (ED). In the past decade, there has been widespread hospital adoption of rapid response teams (RRTs) that respond to patients who decline clinically to reduce adverse outcomes. In an effort to cast a wider net, to take a more systematic approach, and to avoid "blind spots" from individual variability in criteria for referring cases, the institution instituted a new process for selecting cases for ED peer review based on RRT activations within 24 hours of admission from the ED. The hypothesis was that a formal process for review of these activation cases would increase the number of cases for peer review. This was a prospective, observational study conducted from July 1, 2012, to June 30, 2013, at an urban, academic medical center with an EM residency program. A new automated monthly report was created, capturing all RRT activations within 24 hours of admission from the ED. All events were reviewed by three physicians from the ED performance improvement committee to examine for systems issues, individual provider issues, or both, that might yield opportunities for improvement. Cases with potential opportunities were reviewed by the full ED performance improvement committee. Cases were classified according to the indication for response team activation using the system outlined by the U.S. Agency for Healthcare Research and Quality. During the study period 61,814 patients were treated in the ED, and 13,067 were admitted to inpatient status. Thirty-two RRT activations within 24 hours of admission from the ED occurred among these admitted patients, representing 0.24% of admissions (95% confidence interval [CI] = 0.16% to 0.33%). Of the 32 cases, only one was also referred independently for ED performance improvement review via the traditional ad hoc process. During the same period of time, 85 cases were referred to the ED performance improvement committee via the traditional ad hoc referral process. Thus, the RRT cases added an additional 31 cases, or 36.5%, to the 85 cases reviewed in ED performance improvement. Of the 32 cases, two were determined by the performance improvement committee to have individual provider factors in their ED care, which contributed to the clinical decline triggering the response teams; none had system factors. Most of the response team activations were for neurologic changes (n = 13) and respiratory status changes (n = 12). In two cases there was long-term morbidity or mortality related to the team activation event; in neither of these cases were ED system or individual provider factors judged to have contributed. The review of RRT activations within 24 hours of admission from the ED significantly supplemented the typical ad hoc referral system for peer review of cases, highlighting cases that likely would not have received attention within the ED. This novel and unique case review process revealed opportunities for education and performance improvement. This and other systematic approaches to case detection may be useful adjuncts to traditional case referrals for review.


Dynamics of self-propelled filaments pushing a load.
Worm-like filaments, which are propelled by a tangential homogeneous force along their contour, are studied as they push loads of different shapes and sizes. The resulting dynamics is investigated using Langevin dynamics simulations. The effects of size and shape of the load, propulsion strength, and thermal noise are systematically explored. The propulsive force and hydrodynamic friction of the load cause a compression in the filament that results in a buckling instability and versatile motion. Distinct regimes of elongated filaments, curved filaments, beating filaments, and filaments with alternating beating and circular motion are identified, and a phase diagram depending on the propulsion strength and the size of the load is constructed. Characteristic features of the different phases, such as beating frequencies and rotational velocities, are demonstrated to have a power-law dependence on the propulsive force.


Outcomes following penetrating neck injury during the Iraq and Afghanistan conflicts: A comparison of treatment at US and United Kingdom medical treatment facilities.
The United States and United Kingdom (UK) had differing approaches to the surgical skill mix within deployed medical treatment facilities (MTFs) in support of the military campaigns in Iraq and Afghanistan. The US and UK combat trauma registries were scrutinized for patients with penetrating neck injury (PNI) at deployed coalition MTF between March 2003 and October 2011. A multivariate mixed effects logistic regression model (threshold, p < 0.05) was used stratified by MTF location and year of injury. The dependent variable was fatality on leaving Role 3, and the independent variables were ISS on arrival, nationality, MTF nationality, and presence of head and neck surgeon. A total of 3,357 (4.9%) of 67,586 patients who arrived alive at deployed military MTF were recorded to have sustained neck injuries; of which 2,186 (83%) were PNIs and the remainder were blunt injuries. When service members killed in action were included, the incidence of neck injury rose from 4.9% to 10%. Seven hundred nine (32%) of 2,186 patients with PNI underwent neck exploration; 555 patients were recorded to have sustained cervical vascular injury, 230 (41%) of 555 underwent vascular ligation or repair. Where it was recorded, PNI directly contributed to death in 64 (28%) of 228 of patients. Fatality status was positively associated with ISS on arrival (odds ratio, 1.05; 95% confidence interval, 1.04-1.06; p < 0.001) and the casualty being a local national (odds ratio, 1.74; 95% confidence interval, 1.28-2.38; p < 0.001). Significant differences in the treatment and survival of casualties with PNI were identified between nations in this study; this may reflect differing cervical protection, management protocols, and surgical capability and is worthy of further study. In an era of increasing specialization within surgery, neck exploration remains a skill that must be retained by military surgeons deploying to Role 2 and Role 3 MTF. Retrospective cohort study, level III.


Recognition and treatment of depressive symptoms in Parkinson's disease: the NPF dataset.
Depression is a major determinant of Health Related Quality of Life in PD, but there is limited data on physician recognition of depression and treatment efficacy. We used data obtained from the QII dataset of the National Parkinson's Foundation database to determine whether there was an association between depressive symptoms and utilization of antidepressants and/or mental health services (MHS) in a large cohort of PD patients. We found that prevalence of depressive symptoms remained high in the PD population despite improved physician recognition and treatment initiation.


Measuring quality and outcomes of research collaborations: An integrative review.
Although the science of team science is no longer a new field, the measurement of team science and its standardization remain in relatively early stages of development. To describe the current state of team science assessment, we conducted an integrative review of measures of research collaboration quality and outcomes. Collaboration measures were identified using both a literature review based on specific keywords and an environmental scan. Raters abstracted details about the measures using a standard tool. Measures related to collaborations with clinical care, education, and program delivery were excluded from this review. We identified 44 measures of research collaboration quality, which included 35 measures with reliability and some form of statistical validity reported. Most scales focused on group dynamics. We identified 89 measures of research collaboration outcomes; 16 had reliability and 15 had a validity statistic. Outcome measures often only included simple counts of products; publications rarely defined how counts were delimited, obtained, or assessed for reliability. Most measures were tested in only one venue. Although models of collaboration have been developed, in general, strong, reliable, and valid measurements of such collaborations have not been conducted or accepted into practice. This limitation makes it difficult to compare the characteristics and impacts of research teams across studies or to identify the most important areas for intervention. To advance the science of team science, we provide recommendations regarding the development and psychometric testing of measures of collaboration quality and outcomes that can be replicated and broadly applied across studies.


Bradykinin-induced vasodilation is impaired at the atherosclerotic site but is preserved at the spastic site of human coronary arteries in vivo.
Bradykinin causes endothelium-dependent vasodilation of isolated human coronary arteries in vitro. However, the effect of bradykinin on vasomotion of human coronary arteries in vivo has not been studied. The aim of this study was to examine whether bradykinin-induced vasodilation is altered at the atherosclerotic or spastic site of human coronary arteries in vivo. The effect of bradykinin on vasomotion of epicardial coronary arteries was evaluated in 8 patients with normal coronary arteries (control group), 14 patients with organic coronary stenosis (coronary artery disease [CAD] group), and 8 patients with vasospastic angina (VSA group). Changes in the diameter of epicardial coronary artery were assessed by quantitative coronary arteriography. Intracoronary administration of bradykinin at graded doses (60, 200, and 600 ng) dilated epicardial coronary arteries without altering arterial pressure or heart rate in all patients of either group. In the control group, vasomotor responses of the site where acetylcholine caused dilation were compared with the responses of the site where acetylcholine caused constriction. The magnitudes of bradykinin-induced dilation at the site with acetylcholine-induced dilation (mean +/- SD: 6 +/- 6%, 11 +/- 9%, and 15 +/- 9%) were comparable to that (3 +/- 6%, 8 +/- 8%, and 13 +/- 9%) at the site with acetylcholine-induced constriction. In the CAD group, vasomotor responses of the stenotic site (% diameter stenosis, 15% to 50%) and nonstenotic site were examined. The bradykinin-induced dilation at the stenotic site (0 +/- 4%, 3 +/- 8%, and 5 +/- 9%) was significantly less (P < .01) than at the nonstenotic site (3 +/- 4%, 8 +/- 6%, and 16 +/- 11%) and in the control group. Coronary vasodilation with nitrate at the stenotic site (20 +/- 11%) was comparable to that at the nonstenotic site (22 +/- 16%) and in the control group (21 +/- 10%). In the VSA group, vasomotor responses of the site with acetylcholine-induced spasm and the site without spasm were examined. The bradykinin-induced vasodilation at the spastic site (5 +/- 5%, 16 +/- 15%, and 33 +/- 17%) was comparable to that at the nonspastic site (4 +/- 8%, 12 +/- 14%, and 21 +/- 9%). Nitrate-induced dilation was comparable at the spastic site (51 +/- 19%) and the nonspastic site (32 +/- 13%). The ratio of bradykinin-induced vasodilation to nitrate-induced vasodilation at the spastic site was comparable to the control group. These results suggest that bradykinin causes vasodilation of human epicardial coronary arteries in vivo and that bradykinin-induced endothelium-dependent vasodilation is impaired at the stenotic site but is preserved at the angiographically normal site where endothelium-dependent vasodilation by acetylcholine is impaired and at the spastic site.


Withdrawing an explicit request for euthanasia or physician-assisted suicide: a retrospective study on the influence of mental health status and other patient characteristics.
Mental health status may be closely related to an instability of intentions toward a premature death, but little is known about such instability following an explicit request for euthanasia or physician-assisted suicide (EAS) and patient characteristics associated with a change of mind. A questionnaire was sent to 6596 general practitioners in The Netherlands (response rate 60%). Of these, 1681 provided descriptions of the most recent explicit request for EAS they had received in the preceding 18 months. Symptoms of depression and anxiety were related to a change of mind, but no relationship was found with the total score of the NOSGER Mood Dimension. Multinomial regression analysis revealed that patients who changed their mind had more mental health problems and less mental clarity than those who died by EAS. They also had fewer general health problems, had less unbearable and pointless suffering (according to the physician), were less concerned about loss of dignity and alternative treatment options were more frequently available. A further analysis revealed that mental health problems were more prevalent among patients whose requests were refused than among those who changed their mind. The physicians' evaluations of the reasons why a patient requested EAS were similar to a more objective measure of the patient characteristics. These findings suggest that mental health status must be carefully assessed, and possible instability of desire must be taken into account in the course of a request for EAS. These results require replication, and future studies should adopt a prospective method.


Chemokine signaling controls endodermal migration during zebrafish gastrulation.
Directed cell movements during gastrulation establish the germ layers of the vertebrate embryo and coordinate their contributions to different tissues and organs. Anterior migration of the mesoderm and endoderm has largely been interpreted to result from epiboly and convergent-extension movements that drive body elongation. We show that the chemokine Cxcl12b and its receptor Cxcr4a restrict anterior migration of the endoderm during zebrafish gastrulation, thereby coordinating its movements with those of the mesoderm. Depletion of either gene product causes disruption of integrin-dependent cell adhesion, resulting in separation of the endoderm from the mesoderm; the endoderm then migrates farther anteriorly than it normally would, resulting in bilateral duplication of endodermal organs. This process may have relevance to human gastrointestinal bifurcations and other organ defects.


Changes in fish assemblages following the establishment of a network of no-take marine reserves and partially-protected areas.
Networks of no-take marine reserves and partially-protected areas (with limited fishing) are being increasingly promoted as a means of conserving biodiversity. We examined changes in fish assemblages across a network of marine reserves and two different types of partially-protected areas within a marine park over the first 5 years of its establishment. We used Baited Remote Underwater Video (BRUV) to quantify fish communities on rocky reefs at 20-40 m depth between 2008-2011. Each year, we sampled 12 sites in 6 no-take marine reserves and 12 sites in two types of partially-protected areas with contrasting levels of protection (n = 4 BRUV stations per site). Fish abundances were 38% greater across the network of marine reserves compared to the partially-protected areas, although not all individual reserves performed equally. Compliance actions were positively associated with marine reserve responses, while reserve size had no apparent relationship with reserve performance after 5 years. The richness and abundance of fishes did not consistently differ between the two types of partially-protected areas. There was, therefore, no evidence that the more regulated partially-protected areas had additional conservation benefits for reef fish assemblages. Overall, our results demonstrate conservation benefits to fish assemblages from a newly established network of temperate marine reserves. They also show that ecological monitoring can contribute to adaptive management of newly established marine reserve networks, but the extent of this contribution is limited by the rate of change in marine communities in response to protection.


Improving access to primary care for Aboriginal babies in Western Australia: study protocol for a randomized controlled trial.
Despite a decade of substantial investments in programs to improve access to primary care for Aboriginal mothers and infants, more than 50% of Western Australian Aboriginal babies are still not receiving primary and preventative care in the early months of life. Western Australian hospitals now input birth data into the Western Australian electronic clinical management system within 48 hours of birth. However, difficulties have arisen in ensuring that the appropriate primary care providers receive birth notification and clinical information by the time babies are discharged from the hospital. No consistent process exists to ensure that choices about primary care are discussed with Aboriginal families. We will undertake a population-based, stepped wedge, cluster randomized controlled trial of an enhanced model of early infant primary care. The intervention is targeted support and care coordination for Aboriginal families with new babies starting as soon as possible during the antenatal period or after birth. Dedicated health professionals and research staff will consult with families about the families' healthcare needs, provide information about healthcare in the first 3 months of life, offer assistance with birth and Medicare forms, consult with families about their choice for primary care provider, offer to notify the chosen primary care provider about the baby's health needs, and offer assistance with healthcare coordination at the time of discharge from the hospital. We will evaluate this model of care using a rigorous stepped wedge approach. Our primary outcome measure is a reduced hospitalization rate in infants younger than 3 months of age. Secondary outcome measures include completed Aboriginal and Torres Strait Islander child health screening assessments, immunization coverage, and satisfaction of the families about early infant primary care. We will also assess the cost effectiveness of the model of care. This study will be conducted over a 4-year period in partnership with birthing hospitals and primary care providers including Western Australian Aboriginal Community Controlled Health Services and the new Primary Health Networks. The results of our trial will be used to develop improved primary care models and to improve health outcomes for all Aboriginal infants. These are vital steps toward more equitable health service delivery for the Aboriginal and Torres Strait Islander children in Australia. Australian New Zealand Clinical Trials Registry Registration number: ACTRN12615000976583 Date registered: 17 September 2015.


Complicated Grief, Depression and Post-Traumatic Stress Symptoms Among Bereaved Parents following their Child's Death in the Pediatric Intensive Care Unit: A Follow-Up Study.
Parents often suffer reduced mental health after their child's death; however, the trajectory and risk factors are not well described. Describe the change in complicated grief, depression, and post-traumatic stress symptoms among parents between 6 and 13 months after their child's death in a pediatric intensive care unit (PICU), and factors associated with 13-month symptoms. Parents whose children died in 1 of 8 PICUs affiliated with the Collaborative Pediatric Critical Care Research Network completed surveys 6 and 13 months after their child's death. Surveys included the Inventory of Complicated Grief (ICG), the Patient Health Questionnaire-8 (PHQ-8) for depression, and the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT). Parents provided sociodemographics. Charts were reviewed for child characteristics. One-hundred and fifty seven parents of 104 deceased children completed surveys at both time points. Mental health symptoms declined over time (mean (SD)): ICG (33.8 (15.4) vs. 30.5 (15.2), p < 0.001), PHQ-8 (9.0 (6.4) vs. 7.3 (5.8), p < 0.001), and SPRINT (14.1 (8.3) vs. 12.0 (8.2), p < 0.001). After controlling for 6-month scores, higher 13-month ICG was independently associated with sudden unexpected death; higher PHQ-8 with Black race, insecure attachment style, and sudden unexpected death; and higher SPRINT with having a high school level of education (compared to college degree or higher). Mental health symptoms improve among parents during the first 13 months after their child's death; however, symptoms persist for many. Black parents and those whose children die suddenly may be high risk for poor adjustment during bereavement.


SU-E-T-13: Comparison of Dose Rates with and without Gold Backing of USC #9 Radioactive Eye Plaque Using MCNP5.
To show the effect of gold backing on dose rates for the USC #9 radioactive eye plaque. An I125 source (IsoAid model IAI-125A) and gold backing was modeled using MCNP5 Monte Carlo code. A single iodine seed was simulated with and without gold backing. Dose rates were calculated in two orthogonal planes. Dose calculation points were structured in two orthogonal planes that bisect the center of the source. A 2×2 cm matrix of spherical points of radius 0.2 mm was created in a water phantom of 10 cm radius. 0.2 billion particle histories were tracked. Dose differences with and without the gold backing were analyzed using Matlab. The gold backing produced a 3% increase in the dose rate near the source surface (<1mm) relative to that without the backing. This was presumably caused by fluorescent photons from the gold. At distances between 1 and 2 cm, the gold backing reduced the dose rate by up to 12%, which we attribute to a lack of scatter resulting from the attenuation from the gold. Dose differences were most pronounced in the radial direction near the source center but off axis. The dose decreased by 25%, 65% and 81% at 1, 2, and 3 mm off axis at a distance of 1 mm from the source surface. These effects were less pronounced in the perpendicular dimension near the source tip, where maximum dose decreases of 2% were noted. I 125 sources embedded directly into gold troughs display dose differences of 2 - 90%, relative to doses without the gold backing. This is relevant for certain types of plaques used in treatment of ocular melanoma. Large dose reductions can be observed and may have implications for scleral dose reduction.


Extraction, Enrichment, and in situ Electrochemical Detection on Lab-on-a-Disc: Monitoring the Production of a Bacterial Secondary Metabolite.
Development of microsystems, which enable "sample-to-answer" detection from real samples, is often challenging. We present the first integration of supported liquid membrane extraction combined with electrochemical detection on a centrifugal fluidic platform. The developed lab-on-a-disc (LoD) system enabled the separation, enrichment, and subsequent electrochemical detection of the target analyte from a complex sample mixture. As a case study, we quantified the amount of a dietary supplement and pharmaceutical precursor, p-coumaric acid, from bacterial growth media at different time points during production. The assay, extraction, and detection, performed on the LoD device, proved to be a low cost and environmentally friendly approach, requiring only a few tens of microliters of organic solvent and enabled detection in a 3 μL volume. In addition, the data obtained from the centrifugal platform showed a good correlation with data obtained from the high performance liquid chromatography analysis.


The impact of perioperative red blood cell transfusions on postoperative outcomes in vascular surgery patients.
Red blood cell (RBC) transfusions are common in vascular surgery and aim to reduce tissue ischemia. However, the evidence that transfusions are beneficial is contradictory. This study evaluates the impact of perioperative transfusion (transfusion within 3 days of surgery) on 30-day postoperative outcomes in elective vascular surgery patients. This observational cohort included 1,041 vascular surgery patients between 2002 and 2011 in a tertiary referral center for whom hemoglobin levels were retrospectively available. Patients who received transfusions after 3 days postoperatively were excluded. A propensity score was developed for the likelihood of receiving perioperative transfusion. The study end points were 30-day cardiovascular (CV) events (myocardial infarction, heart failure, arrhythmias, stroke, asymptomatic troponin-T release, and CV death) and all-cause mortality. Multivariable logistic regression analyses, adjusting for relevant confounders and transfusion propensity, were used to determine the associations between perioperative transfusion and the study end points. The final study sample comprised 992 patients; 265 (27%) patients received perioperative transfusions. During the 30-day follow-up, a total of 190 (19%) patients suffered from a 30-day postoperative CV event, of which 116 (44%) occurred in patients who received perioperative RBC transfusions compared with 74 (10%) patients without transfusions (P < 0.01). The end point all-cause mortality was reached in 36 (4%) patients-26 (10%) patients with perioperative RBC transfusion compared with 10 (1%) patients without transfusion (P < 0.01). Perioperative transfusion was associated with an independently increased risk of 30-day CV events (odds ratio 5.0; 95% confidence interval 3.1-8.2) and all-cause mortality (odds ratio 4.4; 95% confidence interval 1.6-12.1). Perioperative transfusion is associated with a strongly increased risk of both 30-day CV events and mortality in elective vascular surgery patients.


Seroprevalence of Herpes Simplex Virus Type 1 and 2 in Taiwan and Risk Factor Analysis, 2007.
Herpes simplex virus type 1 (HSV-1) and 2 (HSV-2) are common human pathogens and might cause severe illness. Following primary infection, the viruses establish lifelong latent infection and are transmitted by close contact, both sexual and nonsexual. However, the information about the seroprevalence of HSV-1 and HSV-2 across all age groups is limited. Residual sera collected during the nationwide serosurvey in 2007 in Taiwan were selected for the study. The enzyme-linked immunosorbent assay was used to detect anti-HSV-1 and anti-HSV-2 type-specific glycoprotein IgG. Demographics and personal health data were used for risk analysis. A total of 1411 and 1072 serum samples were included for anti-HSV-1 and anti-HSV-2 seroprevalence analysis, respectively. The weighted overall seroprevalence was 63.2% for HSV-1, and 7.7% for HSV-2, respectively. The HSV-1 seropositive rate was 19.2% for those less than 5 years old, increased to 46.4% for those aged 5-13 years, 60.9% for those aged 14-29 years, and reached as much as 95.0% for those aged over 30 years. In contrast, the HSV-2 seropositve rate was 1.6% for those less than 30 years old, rose to 10.1% for those age 30-39 years, and was up to 31.2% for those aged over 60 years. A significantly higher HSV-2 seropositive rate was noted in females than males aged over 40 years (26.3% v.s. 16.8%), and the overall HSV-2 seropositive rate was almost twice higher in females than males. Smoking history, drinking habit, and educational level were associated with the HSV-1 seropositivity. Female gender and rural residence were independent factors for the HSV-2 seropositivity. An obvious increase of primary HSV-1 infection occurred in late adolescents and young adults, joined by the rise of HSV-2 infection in middle-aged adults, especially females. The acquistion and transmission of HSV warrant further studies in the susceptible population.


The effect of female body size on male mounting behaviour in Dermacentor variabilis and D. andersoni.
This study was undertaken to determine if body size of female ticks was an important factor in eliciting the mating behaviour of Dermacentor variabilis and D. andersoni males. Dummy female ticks (DFTs) representing varying sizes of feeding females were prepared from plastic beads. Size of DFT was shown to be important in determining both the time spent by males in contact with DFTs and the extent of male mating response released. Dermacentor variabilis males preferred the smaller-sized DFT, whereas D.andersoni males preferred the larger sizes. Males of both species were able to discriminate between size of DFT only when mounting sex pheromone (MSP) was present. Size of the DFT was more important than the composition of the MSP extract in determining the time males spent in contact with DFTs. Males of both species were sensitive to variations in concentration of extract, and spent 2-6 times longer in contact with DFTs when the concentration was optimal than when it was not. No significant difference in the male's mating response was seen in response to variation in concentration of heterospecific extract. Male mating response, i.e. the behaviour of the male as it progresses through the initial contact, climbing onto the dorsal surface and turning onto the venter, was shown not to be dependent upon how long the male spent in contact with the DFT. Male D. andersoni had a much lower mating response to DFTs than D. variabilis males, suggesting that some further stimulus may be required.


Liver-specific Prkn knockout mice are more susceptible to diet-induced hepatic steatosis and insulin resistance.
PARKIN is an E3 ubiquitin ligase that regulates mitochondrial quality control through a process called mitophagy. Recent human and rodent studies suggest that loss of hepatic mitophagy may occur during the pathogenesis of obesity-associated fatty liver and contribute to changes in mitochondrial metabolism associated with this disease. Whole-body Prkn knockout mice are paradoxically protected against diet-induced hepatic steatosis; however, liver-specific effects of Prkn deficiency cannot be discerned in this model due to pleotropic effects of germline Prkn deletion on energy balance and subsequent protection against diet-induced obesity. We therefore generated the first liver-specific Prkn knockout mouse strain (LKO) to directly address the role of hepatic Prkn. Littermate control (WT) and LKO mice were fed regular chow (RC) or high-fat diet (HFD) and changes in body weight and composition were measured over time. Liver mitochondrial content was assessed using multiple, complementary techniques, and mitochondrial respiratory capacity was assessed using Oroboros O2K platform. Liver fat was measured biochemically and assessed histologically, while global changes in hepatic gene expression were measured by RNA-seq. Whole-body and tissue-specific insulin resistance were assessed by hyperinsulinemic-euglycemic clamp with isotopic tracers. Liver-specific deletion of Prkn had no effect on body weight or adiposity during RC or HFD feeding; however, hepatic steatosis was increased by 45% in HFD-fed LKO compared with WT mice (P < 0.05). While there were no differences in mitochondrial content between genotypes on either diet, mitochondrial respiratory capacity and efficiency in the liver were significantly reduced in LKO mice. Gene enrichment analyses from liver RNA-seq results suggested significant changes in pathways related to lipid metabolism and fibrosis in HFD-fed Prkn knockout mice. Finally, whole-body insulin sensitivity was reduced by 35% in HFD-fed LKO mice (P < 0.05), which was primarily due to increased hepatic insulin resistance (60% of whole-body effect; P = 0.11). These data demonstrate that PARKIN contributes to mitochondrial homeostasis in the liver and plays a protective role against the pathogenesis of hepatic steatosis and insulin resistance.


Thermodynamic efficiency of solar concentrators.
The optical thermodynamic efficiency is a comprehensive metric that takes into account all loss mechanisms associated with transferring flux from the source to the target phase space, which may include losses due to inadequate design, non-ideal materials, fabrication errors, and less than maximal concentration. We discuss consequences of Fermat's principle of geometrical optics and review étendue dilution and optical loss mechanisms associated with nonimaging concentrators. We develop an expression for the optical thermodynamic efficiency which combines the first and second laws of thermodynamics. As such, this metric is a gold standard for evaluating the performance of nonimaging concentrators. We provide examples illustrating the use of this new metric for concentrating photovoltaic systems for solar power applications, and in particular show how skewness mismatch limits the attainable optical thermodynamic efficiency.


Beliefs of women's risk as research subjects: a four-city study examining differences by sex and by race/ethnicity.
Given the history of vulnerability of women of childbearing age to medical treatments that have caused injury, for example, diethylstilbestrol (DES) and thalidomide, it is surprising that, to date, little research has directly examined attitudes of the general public regarding the vulnerability of women when they participate in biomedical research studies. We asked three questions about beliefs of women as biomedical research subjects of 623 white, 353 black, and 157 Hispanic people in four U.S. cities: (1) Do you believe that women are more likely to be "taken advantage of" when they become subjects in a medical research project as compared to men? (2) Do you believe that women of childbearing age (15-45-year-olds) should become study participants in medical research projects? and, if the response was no or don't know/not sure, (3) Would you still say no or don't know/not sure to question 2 even if it meant that we would not know anything about the health and medical treatments for women aged 15-45 years? Overall, women were 60% more likely than men to state that women were more likely than men to be "taken advantage of," even when controlling for potential confounders, and both black and Hispanic participants were much more likely than white participants to state that this was the case. The majority of respondents (57.4%) said that women of childbearing age should not be research subjects; among women, both black and Hispanic people were less likely than white people to change their minds when prompted that this might mean that "nothing would be known about the health and medical treatments for women aged 15-45 years." A substantial proportion of the participants reported knowledge of historical events, and this knowledge was related, particularly in black participants, to attitudes toward vulnerability of women as biomedical research subjects.


Bayesian Causal Mediation Analysis for Group Randomized Designs with Homogeneous and Heterogeneous Effects: Simulation and Case Study.
A fully Bayesian approach to causal mediation analysis for group-randomized designs is presented. A unique contribution of this article is the combination of Bayesian inferential methods with G-computation to address the problem of heterogeneous treatment or mediator effects. A detailed simulation study shows that this approach has excellent frequentist properties, particularly in the case of small sample sizes with accurate informative priors. The simulation study also demonstrates that the proposed approach can take into account heterogeneous treatment or mediator effects without bias. A case study using data from a school-based randomized intervention designed to increase parent social capital leading to improved behavioral and academic outcomes in children is offered to illustrate the Bayesian approach to causal mediation in group-randomized designs.


Long-term temporal and spatial trends in eutrophication status of the Baltic Sea.
Much of the Baltic Sea is currently classified as 'affected by eutrophication'. The causes for this are twofold. First, current levels of nutrient inputs (nitrogen and phosphorus) from human activities exceed the natural processing capacity with an accumulation of nutrients in the Baltic Sea over the last 50-100 years. Secondly, the Baltic Sea is naturally susceptible to nutrient enrichment due to a combination of long retention times and stratification restricting ventilation of deep waters. Here, based on a unique data set collated from research activities and long-term monitoring programs, we report on the temporal and spatial trends of eutrophication status for the open Baltic Sea over a 112-year period using the HELCOM Eutrophication Assessment Tool (HEAT 3.0). Further, we analyse variation in the confidence of the eutrophication status assessment based on a systematic quantitative approach using coefficients of variation in the observations. The classifications in our assessment indicate that the first signs of eutrophication emerged in the mid-1950s and the central parts of the Baltic Sea changed from being unaffected by eutrophication to being affected. We document improvements in eutrophication status that are direct consequences of long-term efforts to reduce the inputs of nutrients. The reductions in both nitrogen and phosphorus loads have led to large-scale alleviation of eutrophication and to a healthier Baltic Sea. Reduced confidence in our assessment is seen more recently due to reductions in the scope of monitoring programs. Our study sets a baseline for implementation of the ecosystem-based management strategies and policies currently in place including the EU Marine Strategy Framework Directives and the HELCOM Baltic Sea Action Plan.


Comorbidities in lung cancer: prevalence, severity and links with socioeconomic status and treatment.
Survival from lung cancer remains poor in Scotland, UK. Although the presence of comorbidities is known to influence outcomes, detailed quantification of comorbidities is not available in routinely collected audit or cancer registry data. The aim of the present study was to assess the prevalence and severity of comorbidities in patients with newly diagnosed lung cancer across four centres throughout Scotland using validated criteria. Between 2005 and 2008, all patients with newly diagnosed lung cancer coming through the multidisciplinary teams in four Scottish centres were included in the study. Patient demographics, WHO/Eastern Cooperative Oncology Group performance status, clinicopathological features and primary treatment modality were recorded. Details of 882 patients were collected prospectively. The majority of patients (87.3%) had at least one comorbidity, the most common being weight loss (53%), chronic obstructive pulmonary disease (43%), renal impairment (28%) and ischaemic heart disease (27%). A composite score was produced that included both number and severity of comorbidities. One in seven patients (15.3%) had severe comorbidity scores. There were statistically significant variations in comorbidity scores between treatment centres and between non-small cell lung carcinoma treatment groups. Disease stage was not associated with comorbidity score. There is a high prevalence of multiple, severe comorbidities in Scottish patients with lung cancer, and these vary by site and treatment group. Further research is needed to determine the relationship between comorbidity scores and survival in these patients.


Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial.
Integrase strand transfer inhibitors (INSTIs) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors (NRTIs) are recommended as first-line treatment for HIV, and coformulated fixed-dose combinations are preferred to facilitate adherence. We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir-a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinically relevant drug interactions-coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide. In this randomised, double-blind, multicentre, placebo-controlled, non-inferiority trial, HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia, Europe, Latin America, and North America. Participants were previously untreated adults (HIV-1 RNA ≥500 copies per mL) with estimated glomerular filtration rate of at least 30 mL/min. Chronic hepatitis B virus or hepatitis C co-infection was allowed. We randomly assigned participants (1:1) to receive oral fixed-dose combination bictegravir 50 mg, emtricitabine 200 mg, and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg, with matching placebo, once a day for 144 weeks. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. All participants who received at least one dose of study drug were included in primary efficacy and safety analyses. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of -12%. This study is registered with ClinicalTrials.gov, number NCT02607956. Between Nov 11, 2015, and July 15, 2016, 742 participants were screened for eligibility, of whom 657 were randomly assigned to treatment (327 with bictegravir, emtricitabine, and tenofovir alafenamide fixed-dose combination [bictegravir group] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [dolutegravir group]). 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses. At week 48, HIV-1 RNA <50 copies per mL was achieved in 286 (89%) of 320 participants in the bictegravir group and 302 (93%) of 325 in the dolutegravir group (difference -3·5%, 95·002% CI -7·9 to 1·0, p=0·12), showing non-inferiority of the bictegravir regimen to the dolutegravir regimen. No treatment-emergent resistance to any study drug was observed. Incidence and severity of adverse events were similar between groups, and few participants discontinued treatment due to adverse events (5 [2%] of 320 in the bictegravir group and 1 [<1%] 325 in the dolutegravir group). Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group (57 [18%] of 320 vs 83 [26%] of 325, p=0·022). At 48 weeks, virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults. There was no emergent resistance to either regimen. The fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen. Gilead Sciences Inc.


A systematic literature review of cysteamine bitartrate in the treatment of nephropathic cystinosis.
To summarize available clinical evidence for cysteamine bitartrate preparations in the treatment of nephropathic cystinosis as identified through a systematic literature review (SLR). We searched MEDLINE, MEDLINE In-Process and Embase using Ovid with a predefined search strategy through 19 January 2016. All publicly available clinical reports on the use of delayed-release (DR) cysteamine bitartrate (Procysbi 1 ) or immediate-release (IR) cysteamine bitartrate (Cystagon 2 ) in patients with cystinosis were included. We identified a total of 103 publications and 10 trial records. Of these, 9 studies describe DR cysteamine bitartrate (n = 267 patients), 42 describe IR cysteamine bitartrate (n = 1,427 patients) and in 53 studies the exact preparation was not specified (n = 906 patients). The vast majority of the studies used a non-randomized study design, with randomized clinical trials (RCTs) being scarce (1 study comparing DR and IR formulation) and case reports (n = 49) being the most common study design representing 47% of the total. A substantial evidence base for cysteamine bitartrate in the treatment of nephropathic cystinosis was identified. However, the majority of the evidence was of relatively low quality, with evidence levels of 3 or 4.


Auditory midbrain laminar structure appears adapted to f0 extraction: further evidence and implications of the double critical bandwidth.
The psychoacoustic 'critical bandwidth' (CB), e.g. approximately 2.6 semitones (= 0.22 octave) at 1.5-3 kHz, is known from many spectral integration phenomena. Cat data suggest that it is represented in the inferior colliculus (IC) (Ehret and Merzenich, 1985, Science 227, 1245-1247), where it is consistently related to the fibrodendritic laminae (Schreiner and Langner, 1997, Nature 388, 383-386). The recent discovery of the CB and the double CB (2CB) in the statistics of frequency spacing of spontaneous otoacoustic emissions (Braun, 1997. Hear. Res. 114, 197-203) has initiated further investigations of the novel phenomenon of 2CB. Meta-analysis of psychoacoustic valuation studies of pure-tone intervals again revealed the effects of CB and 2CB. Valuations showed a significant stepwise change with interval size: <CB unpleasant, CB-2CB pleasant, >2CB indifferent. Scrutiny of cat and human data indicated that for both species, at least in the midspectrum (1-3 kHz in humans), the tonotopic ranges within single IC laminae and the tonotopic distances between neighboring laminae may equal 1 CB (distances to second next laminae being 2CB). This unique architecture would provide the most economical neural convergence of period information from pairs of adjacent harmonic partials 3-6 of complex sound. The resulting summed postsynaptic potentials would thus contain a beat frequency equaling f0 of sound input and being detectable by the known neural behavior of characteristic periodicity response.


Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes.
Multiwalled carbon nanotubes (MWCNTs) are nanomaterials composed of multiple layers of graphene cylinders with unique properties that make them valuable for a number of industries. However, rising global production has led to concerns regarding potential occupational exposures to them as raw materials during handling. This is especially true for long MWCNT fibers, whose aspect ratio has been posited to initiate pathology similar to that of asbestos. Matrix metalloproteinases (MMPs) are a class of extracellular endopeptidases that control various processes related to tissue repair, inflammation, and more. Stromelysin-2 (MMP-10) has roles in modulating macrophage activation and function, and hence, we used an MMP-10 null (Mmp10-/-) mouse model to assess its role in controlling lung responses to inhaled long MWCNTs. Oropharyngeal aspiration of long MWCNTs (80 µg/mouse) by wild-type mice induced expression of Mmp10 mRNA, which was accompanied by a robust inflammatory response characterized by elevated expression of Tnfa, Il6, and Il1b. In Mmp10-/- mice, we found that absence of MMP-10 led to impaired pulmonary clearance of MWCNTs and reduced macrophage cell survival. Exposure of wild-type bone marrow-derived macrophages (BMDMs) and alveolar macrophages to MWCNTs caused a rapid, dose-dependent upregulation of Mmp10 mRNA expression, which was accompanied by expression of pro-inflammatory products (Il6 and Il1b). These products were further enhanced in Mmp10-/- macrophages, resulting in increased caspase-3-dependent cell death compared with wild-type cells. These findings indicate that MMP-10 facilitates the clearance of MWCNTs and moderates the pro-inflammatory response of exposed alveolar and infiltrated macrophages.