Association Between Chronic Hepatitis C Virus Infection and Myocardial Infarction Among People Living With HIV in the United States.

Hepatitis C virus (HCV) infection is common among people living with human immunodeficiency virus (PLWH). Extrahepatic manifestations of HCV, including myocardial infarction (MI), are a topic of active research. MI is classified into types, predominantly atheroembolic type 1 MI (T1MI) and supply-demand mismatch type 2 MI (T2MI). We examined the association between HCV and MI among patients in the Centers for AIDS Research (CFAR) Network of Integrated Clinical Systems, a US multicenter clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Third Universal Definition of Myocardial Infarction. We estimated the association between chronic HCV (RNA+) and time to MI while adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics, and history of injecting drug use. Among 23,407 PLWH aged ≥18 years, there were 336 T1MIs and 330 T2MIs during a median of 4.7 years of follow-up between 1998 and 2016. HCV was associated with a 46% greater risk of T2MI (adjusted hazard ratio (aHR) = 1.46, 95% confidence interval (CI): 1.09, 1.97) but not T1MI (aHR = 0.87, 95% CI: 0.58, 1.29). In an exploratory cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR = 2.01, 95% CI: 1.25, 3.24). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Cytotoxic activity of marine sponge extracts from the sub-Antarctic Islands and the Southern Ocean

publisher versionOver the past 50 years, marine invertebrates, especially sponges, have proven to be a valuable source of new and/or bioactive natural products that have the potential to be further developed as lead compounds for pharmaceutical applications. Although marine benthic invertebrate communities occurring off the coast of South Africa have been explored for their biomedicinal potential, the natural product investigation of marine sponges from the sub-Antarctic Islands in the Southern Ocean for the presence of bioactive secondary metabolites has been relatively unexplored thus far. We report here the results for the biological screening of both aqueous and organic extracts prepared from nine specimens of eight species of marine sponges, collected from around Marion Island and the Prince Edward Islands in the Southern Ocean, for their cytotoxic activity against three cancer cell lines. The results obtained through this multidisciplinary collaborative research effort by exclusively South African institutions has provided an exciting opportunity to discover cytotoxic compounds from sub-Antarctic sponges, whilst contributing to our understanding of the biodiversity and geographic distributions of these cold-water invertebrates. Therefore, we acknowledge here the various contributions of the diverse scientific disciplines that played a pivotal role in providing the necessary platform for the future natural products chemistry investigation of these marine sponges from the sub- Antarctic Islands and the Southern Ocean. Significance: This study will contribute to understanding the biodiversity and geographic distributions of sponges in the Southern Ocean. This multidisciplinary project has enabled the investigation of marine sponges for the presence of cytotoxic compounds. Further investigation will lead to the isolation and identification of cytotoxic compounds present in the active sponge extracts.University of Cape Town; South African Medical Research Council; National Research Foundation (South Africa); CANSA; Rhodes University; Department of Science and Technology; Department of Environmental Affairs; SANA

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

Homicide and geographic access to gun dealers in the United States

<p>Abstract</p> <p>Background</p> <p>Firearms are the most commonly used weapon to commit homicide in the U.S. Virtually all firearms enter the public marketplace through a federal firearms licensee (FFL): a store or individual licensed by the federal government to sell firearms. Whether FFLs contribute to gun-related homicide in areas where they are located, in which case FFLs may be a homicide risk factor that can be modified, is not known.</p> <p>Methods</p> <p>Annual county-level data (1993–1999) on gun homicide rates and rates of FFLs per capita were analyzed using negative binomial regression controlling for socio-demographic characteristics. Models were run to evaluate whether the relation between rates of FFLs and rates of gun homicide varied over the study period and across counties according to their level of urbanism (defined by four groupings, as below). Also, rates of FFLs were compared against FS/S – which is the proportion of suicides committed by firearm and is thought to be a good proxy for firearm availability in a region – to help evaluate how well the FFL variable is serving as a way to proxy firearm availability in each of the county types of interest.</p> <p>Results</p> <p>In major cities, gun homicide rates were higher where FFLs were more prevalent (rate ratio [RR] = 1.70, 95% CI 1.03–2.81). This association increased (p < 0.01) from 1993 (RR = 1.69) to 1999 (RR = 12.72), due likely to federal reforms that eliminated low-volume dealers, making FFL prevalence a more accurate exposure measure over time. No association was found in small towns. In other cities and in suburbs, gun homicide rates were significantly lower where FFLs were more prevalent, with associations that did not change over the years of the study period. FFL prevalence was correlated strongly (positively) with FS/S in major cities only, suggesting that the findings for how FFL prevalence relates to gun homicide may be valid for the findings pertaining to major cities but not to counties of other types.</p> <p>Conclusion</p> <p>Modification of FFLs through federal, state, and local regulation may be a feasible intervention to reduce gun homicide in major cities.</p

Population stratification may bias analysis of PGC-1α as a modifier of age at Huntington disease motor onset

Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by motor, cognitive and behavioral disturbances, caused by the expansion of a CAG trinucleotide repeat in the HD gene. The CAG allele size is the major determinant of age at onset (AO) of motor symptoms, although the remaining variance in AO is highly heritable. The rs7665116 SNP in PPARGC1A, encoding the mitochondrial regulator PGC-1α, has been reported to be a significant modifier of AO in three European HD cohorts, perhaps due to affected cases from Italy. We attempted to replicate these findings in a large collection of (1,727) HD patient DNA samples of European origin. In the entire cohort, rs7665116 showed a significant effect in the dominant model (p value = 0.008) and the additive model (p value = 0.009). However, when examined by origin, cases of Southern European origin had an increased rs7665116 minor allele frequency (MAF), consistent with this being an ancestry-tagging SNP. The Southern European cases, despite similar mean CAG allele size, had a significantly older mean AO (p < 0.001), suggesting population-dependent phenotype stratification. When the generalized estimating equations models were adjusted for ancestry, the effect of the rs7665116 genotype on AO decreased dramatically. Our results do not support rs7665116 as a modifier of AO of motor symptoms, as we found evidence for a dramatic effect of phenotypic (AO) and genotypic (MAF) stratification among European cohorts that was not considered in previously reported association studies. A significantly older AO in Southern Europe may reflect population differences in genetic or environmental factors that warrant further investigation

Development of a Kemp\u27s Ridley Sea Turtle Stock Assessment Model

We developed a Kemp’s ridley (Lepidochelys kempii) stock assessment model to evaluate the relative contributions of conservation efforts and other factors toward this critically endangered species’ recovery. The Kemp’s ridley demographic model developed by the Turtle Expert Working Group (TEWG) in 1998 and 2000 and updated for the binational recovery plan in 2011 was modified for use as our base model. The TEWG model uses indices of the annual reproductive population (number of nests) and hatchling recruitment to predict future annual numbers of nests on the basis of a series of assumptions regarding age and maturity, remigration interval, sex ratios, nests per female, juvenile mortality, and a putative ‘‘turtle excluder device effect’’ multiplier starting in 1990. This multiplier was necessary to fit the number of nests observed in 1990 and later. We added the effects of shrimping effort directly, modified by habitat weightings, as a proxy for all sources of anthropogenic mortality. Additional data included in our model were incremental growth of Kemp’s ridleys marked and recaptured in the Gulf of Mexico, and the length frequency of stranded Kemp’s ridleys. We also added a 2010 mortality factor that was necessary to fit the number of nests for 2010 and later (2011 and 2012). Last, we used an empirical basis for estimating natural mortality, on the basis of a Lorenzen mortality curve and growth estimates. Although our model generated reasonable estimates of annual total turtle deaths attributable to shrimp trawling, as well as additional deaths due to undetermined anthropogenic causes in 2010, we were unable to provide a clear explanation for the observed increase in the number of stranded Kemp’s ridleys in recent years, and subsequent disruption of the species’ exponential growth since the 2009 nesting season. Our consensus is that expanded data collection at the nesting beaches is needed and of high priority, and that 2015 be targeted for the next stock assessment to evaluate the 2010 event using more recent nesting and in-water data

HIV viral suppression trends over time among HIV-infected patients receiving care in the United States, 1997 to 2015 a cohort study

Background: Because HIV viral suppression is essential for optimal outcomes and prevention efforts, understanding trends and predictors is imperative to inform public health policy. Objective: To evaluate viral suppression trends in people living with HIV (PLWH), including the relationship of associated factors, such as demographic characteristics and integrase strand transfer inhibitor (ISTI) use. Design: Longitudinal observational cohort study. Setting: 8 HIV clinics across the United States. Participants: PLWH receiving clinical care. Measurements: To understand trends in viral suppression (≤400 copies/mL), annual viral suppression rates from 1997 to 2015 were determined. Analyses were repeated with tests limited to 1 random test per person per year and using inverse probability of censoring weights to address loss to follow-up. Joint longitudinal and survival models and linear mixed models of PLWH receiving antiretroviral therapy (ART) were used to examine associations between viral suppression or continuous viral load (VL) levels and demographic factors, substance use, adherence, and ISTI use. Results: Viral suppression increased from 32% in 1997 to 86% in 2015 on the basis of all tests among 31 930 PLWH. In adjusted analyses, being older (odds ratio [OR], 0.76 per decade [95% CI, 0.74 to 0.78]) and using an ISTI-based regimen (OR, 0.54 [CI, 0.51 to 0.57]) were associated with lower odds of having a detectable VL, and black race was associated with higher odds (OR, 1.68 [CI, 1.57 to 1.80]) (P < 0.001 for each). Similar patterns were seen with continuous VL levels; when analyses were limited to 2010 to 2015; and with adjustment for adherence, substance use, or depression. Limitation: Results are limited to PLWH receiving clinical care. Conclusion: HIV viral suppression rates have improved dramatically across the United States, which is likely partially attributable to improved ART, including ISTI-based regimens. However, disparities among younger and black PLWH merit attention

A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease

Objective: To test the hypothesis that chronic treatment of early-stage Huntington disease (HD) with high-dose coenzyme Q10 (CoQ) will slow the progressive functional decline of HD. Methods: We performed a multicenter randomized, double-blind, placebo-controlled trial. Patients with early-stage HD (n = 609) were enrolled at 48 sites in the United States, Canada, and Australia from 2008 to 2012. Patients were randomized to receive either CoQ 2,400 mg/d or matching placebo, then followed for 60 months. The primary outcome variable was the change from baseline to month 60 in Total Functional Capacity score (for patients who survived) combined with time to death (for patients who died) analyzed using a joint-rank analysis approach. Results: An interim analysis for futility revealed a conditional power of <5% for the primary analysis, prompting premature conclusion in July 2014. No statistically significant differences were seen between treatment groups for the primary or secondary outcome measures. CoQ was generally safe and well-tolerated throughout the study. Conclusions: These data do not justify use of CoQ as a treatment to slow functional decline in HD