Zanamivir susceptibility monitoring and characterization of influenza virus clinical isolates obtained during phase II clinical efficacy studies

Zanamivir is a highly selective neuraminidase (NA) inhibitor with demonstrated clinical efficacy against influenza A and B virus infections. In phase II clinical efficacy trials (NAIB2005 and NAIB2008), virological substudies showed mean reductions in virus shedding after 24 h of treatment of 1.5 to 2.0 log(10) 50% tissue culture infective doses compared to a placebo, with no reemergence of virus after the completion of therapy. Paired isolates (n = 41) obtained before and during therapy with zanamivir demonstrated no shifts in susceptibility to zanamivir when measured by NA assays, although for a few isolates NA activity was too low to evaluate. In plaque reduction assays in MDCK cells, the susceptibility of isolates to zanamivir was extremely variable even at baseline and did not correlate with the speed of resolution of virus shedding. Isolates with apparent limited susceptibility to zanamivir by plaque reduction proved highly susceptible in vivo in the ferret model. Further sequence analysis of paired isolates revealed no changes in the hemagglutinin and NA genes in the majority of isolates. The few changes observed were all natural variants. No amino acid changes that had previously been identified in vitro as being involved with reduced susceptibility to zanamivir were observed. These studies highlighted problems associated with monitoring susceptibility to NA inhibitors in the clinic, in that no reliable cell-based assay is available. At present the NA assay is the best available predictor of susceptibility to NA inhibitors in vivo, as measured in the validated ferret model of infection

The Latent Structure of Autistic Traits:A Taxometric, Latent Class and Latent Profile Analysis of the Adult Autism Spectrum Quotient

Autistic traits are widely thought to operate along a continuum. A taxometric analysis of Adult Autism Spectrum Quotient data was conducted to test this assumption, finding little support but identifying a high severity taxon. To understand this further, latent class and latent profile models were estimated that indicated the presence of six distinct subtypes: one with little probability of endorsing any autistic traits, one engaging in ‘systemising’ behaviours, three groups endorsing multiple components of Wing and Gould’s autistic triad, and a group similar in size and profile to the taxon previously identified. These analyses suggest the AQ (and potentially by extension autistic traits) have a categorical structure. These findings have important implications for the analysis and interpretation of AQ data

Prevalence and age of onset for drug use in seven international sites: Results from the international consortium of psychiatric epidemiology

This study compares lifetime prevalence and age of first use (onset) for alcohol, cannabis, and other drugs in six international sites. Data from seven epidemiologic field surveys that used compatible instruments and study designs were compiled for cross-site analyses by the International Consortium of Psychiatric Epidemiology (ICPE). The world health organization’s composite international diagnostic instrument (WHO-CIDI) and additional items were used to ascertain drug use in each site. Lifetime use rates were estimated for alcohol, cannabis, and other illicit drugs. Survival analyses were used to estimate age of onset. Study settings and main results: use of alcohol twelve or more times ranged in descending order from the Netherlands (86.3%), United States (71.7%), Ontario, Canada (71.6%); São Paulo, Brazil (66.1%), Munich, Germany (64.9%), Fresno, California (USA) (51.9%), to Mexico City (43.2%). Use of cannabis five or more times in a lifetime ranged from 28.8 in the United States to 1.7% in Mexico City, and other drugs ranged from United States (19.4%) to Mexico City (1.7%). Age of first use was similar across study sites. This study demonstrates the fundamental uniformity of onset patterns by age as contrasted with wide variations in lifetime prevalences across sites. Study findings suggest that drug use patterns may change among emigrating populations from low consumption nations as a consequence of international resettlement in nations with higher rates. Methodological limitations of the study along with recommendations for future international comparative research are discussed

Long-acting injectable Cabotegravir + Rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials

BACKGROUND: Long-acting (LA) injectable regimens are a potential therapeutic option in people living with HIV-1. SETTING: ATLAS (NCT02951052) and FLAIR (NCT02938520) were 2 randomized, open-label, multicenter, multinational phase 3 studies. METHODS: Adult participants with virologic suppression (plasma HIV-1 RNA <50 copies/mL) were randomized (1:1) to continue with their current antiretroviral regimen (CAR) or switch to the long-acting (LA) regimen of cabotegravir (CAB) and rilpivirine (RPV). In the LA arm, participants initially received oral CAB + RPV once-daily for 4 weeks to assess individual safety and tolerability, before starting monthly injectable therapy. The primary endpoint of this combined analysis was antiviral efficacy at week 48 (FDA Snapshot algorithm: noninferiority margin of 4% for HIV-1 RNA ≥50 copies/mL). Safety, tolerability, and confirmed virologic failure (2 consecutive plasma HIV-1 RNA ≥200 copies/mL) were secondary endpoints. RESULTS: The pooled intention-to-treat exposed population included 591 participants in each arm [28% women (sex at birth), 19% aged ≥50 years]. Noninferiority criteria at week 48 were met for the primary (HIV-1 RNA ≥50 copies/mL) and key secondary (HIV-1 RNA <50 copies/mL) efficacy endpoints. Seven individuals in each arm (1.2%) developed confirmed virologic failure; 6/7 (LA) and 3/7 (CAR) had resistance-associated mutations. Most LA recipients (83%) experienced injection site reactions, which decreased in incidence over time. Injection site reactions led to the withdrawal of 6 (1%) participants. The serious adverse event rate was 4% in each arm. CONCLUSION: This combined analysis demonstrates monthly injections of CAB + RPV LA were noninferior to daily oral CAR for maintaining HIV-1 suppression

Body Mass Index and Employment-Based Health Insurance

<p>Abstract</p> <p>Background</p> <p>Obese workers incur greater health care costs than normal weight workers. Possibly viewed by employers as an increased financial risk, they may be at a disadvantage in procuring employment that provides health insurance. This study aims to evaluate the association between body mass index [BMI, weight in kilograms divided by the square of height in meters] of employees and their likelihood of holding jobs that include employment-based health insurance [EBHI].</p> <p>Methods</p> <p>We used the 2004 Household Components of the nationally representative Medical Expenditure Panel Survey. We utilized logistic regression models with provision of EBHI as the dependent variable in this descriptive analysis. The key independent variable was BMI, with adjustments for the domains of demographics, social-economic status, workplace/job characteristics, and health behavior/status. BMI was classified as normal weight (18.5–24.9), overweight (25.0–29.9), or obese (≥ 30.0). There were 11,833 eligible respondents in the analysis.</p> <p>Results</p> <p>Among employed adults, obese workers [adjusted probability (AP) = 0.62, (0.60, 0.65)] (<it>P </it>= 0.005) were more likely to be employed in jobs with EBHI than their normal weight counterparts [AP = 0.57, (0.55, 0.60)]. Overweight workers were also more likely to hold jobs with EBHI than normal weight workers, but the difference did not reach statistical significance [AP = 0.61 (0.58, 0.63)] (<it>P </it>= 0.052). There were no interaction effects between BMI and gender or age.</p> <p>Conclusion</p> <p>In this nationally representative sample, we detected an association between workers' increasing BMI and their likelihood of being employed in positions that include EBHI. These findings suggest that obese workers are more likely to have EBHI than other workers.</p

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings

Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.</p

Late 1920s film theory and criticism as a test-case for Benjamin’s generalizations on the experiential effects of editing

This article investigates Walter Benjamin’s influential generalization that the effects of cinema are akin to the hyper-stimulating experience of modernity. More specifically, I focus on his oft-cited 1935/36 claim that all editing elicits shock-like disruption. First, I propose a more detailed articulation of the experience of modernity understood as hyper-stimulation and call for distinguishing between at least two of its subsets: the experience of speed and dynamism, on the one hand, and the experience of shock/disruption, on the other. Then I turn to classical film theory of the late 1920s to demonstrate the existence of contemporary views on editing alternative to Benjamin’s. For instance, whereas classical Soviet and Weimar theorists relate the experience of speed and dynamism to both Soviet and classical Hollywood style editing, they reserve the experience of shock/disruption for Soviet montage. In order to resolve the conceptual disagreement between these theorists, on the one hand, and Benjamin, on the other, I turn to late 1920s Weimar film criticism. I demonstrate that, contrary to Benjamin’s generalizations about the disruptive and shock-like nature of all editing, and in line with other theorists’ accounts, different editing practices were regularly distinguished by comparison to at least two distinct hyper-stimulation subsets: speed and dynamism, and shock-like disruption. In other words, contemporaries regularly distinguished between Soviet montage and classical Hollywood editing patterns on the basis of experiential effects alone. On the basis of contemporary reviews of city symphonies, I conclude with a proposal for distinguishing a third subset – confusion. This is an original manuscript / preprint of an article published by Taylor & Francis in Early Popular Visual Culture on 02 Aug 2016 available online: https://doi.org/10.1080/17460654.2016.1199322

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.

This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.3448Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.We thank all participants of all the studies included for enabling this research by their participation in these studies. Computer resources for this project have been provided by the high-performance computing centers of the University of Michigan and the University of Regensburg. Group-specific acknowledgments can be found in the Supplementary Note. The Center for Inherited Diseases Research (CIDR) Program contract number is HHSN268201200008I. This and the main consortium work were predominantly funded by 1X01HG006934-01 to G.R.A. and R01 EY022310 to J.L.H

GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors

Objective: Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and crossvalidated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS metaanalysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures. Methods: This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses. Results: Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values &lt;5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors. Conclusions: This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.</p