Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin

A pragmatic, multicentre, randomised controlled trial comparing stapled haemorrhoidopexy to traditional excisional surgery for haemorrhoidal disease (eTHoS): study protocol for a randomised controlled trial

Background: Current interventions for haemorrhoidal disease include traditional haemorrhoidectomy (TH) and stapled haemorrhoidopexy (SH) surgery. However, uncertainty remains as to how they compare from a clinical, quality of life (QoL) and economic perspective. The study is therefore designed to determine whether SH is more effective and more cost-effective, compared with TH. Methods/Design: eTHoS (either Traditional Haemorrhoidectomy or Stapled Haemorrhoidopexy for Haemorrhoidal Disease) is a pragmatic, multicentre, randomised controlled trial. Currently, 29 secondary care centres are open to recruitment. Patients, aged 18 year or older, with circumferential haemorrhoids grade II to IV, are eligible to take part. The primary clinical and economic outcomes are QoL profile (area under the curve derived from the EuroQol Group’s 5 Dimension Health Status Questionnaire (EQ-5D) at all assessment points) and incremental cost per quality adjusted life year (QALY) based on the responses to the EQ-5D at 24 months. The secondary outcomes include a comparison of the SF-36 scores, pain and symptoms sub-domains, disease recurrence, complication rates and direct and indirect costs to the National Health Service (NHS). A sample size of n =338 per group has been calculated to provide 90% power to detect a difference in the mean area under the curve (AUC) of 0.25 standard deviations derived from EQ-5D score measurements, with a two-sided significance level of 5%. Allowing for non-response, 400 participants will be randomised per group. Randomisation will utilise a minimisation algorithm that incorporates centre, grade of haemorrhoidal disease, baseline EQ-5D score and gender. Blinding of participants and outcome assessors is not attempted. Discussion: This is one of the largest trials of its kind. In the United Kingdom alone, 29,000 operations for haemorrhoidal disease are done annually. The trial is therefore designed to give robust evidence on which clinicians and health service managers can base management decisions and, more importantly, patients can make informed choices. Trial registration: Current Controlled Trials ISRCTN80061723 (assigned 8 March 2010

Direct Type I IFN but Not MDA5/TLR3 Activation of Dendritic Cells Is Required for Maturation and Metabolic Shift to Glycolysis after Poly IC Stimulation

We thank the Rockefeller University Center for Clinical and Translational Science (UL1 TR000043 NCATS, NIH) for technical support

Global Burden of Double Malnutrition: Has Anyone Seen It?

Background. Low- to middle-income countries (LMICs) are believed to be characterized by the coexistence of underweight and overweight. It has also been posited that such coexistence is appearing among the low socioeconomic status (SES) groups. Methods. We conducted a cross-sectional analysis of nationally representative samples of 451321 women aged 20–49 years drawn from 57 Demographic and Health Surveys conducted between 1994 and 2008. Body Mass Index (BMI in $kg/m^2$), was used to define underweight and overweight following conventional cut-points. Covariates included age, household wealth, education, and residence. We estimated multinomial multilevel models to assess the extent to which underweight $(BMI<18.5 kg/m^2)$ and overweight $(BMI≥25.0 kg/m^2)$ correlate at the country-level, and at the neighborhood-level within each country. Results. In age-adjusted models, there was a strong negative correlation between likelihood of being underweight and overweight at country- (r = −0.79, p<0.001), and at the neighborhood-level within countries (r = −0.51, P<0.001). Negative correlations ranging from −0.11 to −0.90 were observed in 46 of the 57 countries at the neighborhood-level and 29/57 were statistically significant $(p\leq 0.05)$. Similar negative correlations were observed in analyses restricted to low SES groups. Finally, the negative correlations across countries, and within-countries, appeared to be stable over time in a sub-set of 36 countries. Conclusion. The explicitly negative correlations between prevalence of underweight and overweight at the country-level and at neighborhood-level suggest that the hypothesized coexistence of underweight and overweight has not yet occurred in a substantial manner in a majority of LMICs

Evolutionary Processes Acting on Candidate cis-Regulatory Regions in Humans Inferred from Patterns of Polymorphism and Divergence

Analysis of polymorphism and divergence in the non-coding portion of the human genome yields crucial information about factors driving the evolution of gene regulation. Candidate cis-regulatory regions spanning more than 15,000 genes in 15 African Americans and 20 European Americans were re-sequenced and aligned to the chimpanzee genome in order to identify potentially functional polymorphism and to characterize and quantify departures from neutral evolution. Distortions of the site frequency spectra suggest a general pattern of selective constraint on conserved non-coding sites in the flanking regions of genes (CNCs). Moreover, there is an excess of fixed differences that cannot be explained by a Gamma model of deleterious fitness effects, suggesting the presence of positive selection on CNCs. Extensions of the McDonald-Kreitman test identified candidate cis-regulatory regions with high probabilities of positive and negative selection near many known human genes, the biological characteristics of which exhibit genome-wide trends that differ from patterns observed in protein-coding regions. Notably, there is a higher probability of positive selection in candidate cis-regulatory regions near genes expressed in the fetal brain, suggesting that a larger portion of adaptive regulatory changes has occurred in genes expressed during brain development. Overall we find that natural selection has played an important role in the evolution of candidate cis-regulatory regions throughout hominid evolution

Normative Beliefs and Sexual Risk in China

We examined normative beliefs about multiple sexual partners and social status in China and their association with risky sexual behaviors and sexually transmitted infections (STIs). Self-reported and biological markers of sexual risk were examined among 3,716 market vendors from a city in eastern China. Men who were older or with less education believed having multiple sexual partners was linked to higher social status. Adjusting for demographic characteristics, normative beliefs were significantly associated with having multiple sexual partners, while having multiple sexual partners was significantly associated with STIs. Normative beliefs regarding sexual behaviors may play an important role in individual risk behaviors. Future HIV/STI interventions must address community beliefs about the positive meaning of sexual risks, particularly among men with traditional beliefs about gender roles

Impacts of Poultry House Environment on Poultry Litter Bacterial Community Composition

Viral and bacterial pathogens are a significant economic concern to the US broiler industry and the ecological epicenter for poultry pathogens is the mixture of bedding material, chicken excrement and feathers that comprises the litter of a poultry house. This study used high-throughput sequencing to assess the richness and diversity of poultry litter bacterial communities, and to look for connections between these communities and the environmental characteristics of a poultry house including its history of gangrenous dermatitis (GD). Cluster analysis of 16S rRNA gene sequences revealed differences in the distribution of bacterial phylotypes between Wet and Dry litter samples and between houses. Wet litter contained greater diversity with 90% of total bacterial abundance occurring within the top 214 OTU clusters. In contrast, only 50 clusters accounted for 90% of Dry litter bacterial abundance. The sixth largest OTU cluster across all samples classified as an Arcobacter sp., an emerging human pathogen, occurring in only the Wet litter samples of a house with a modern evaporative cooling system. Ironically, the primary pathogenic clostridial and staphylococcal species associated with GD were not found in any house; however, there were thirteen 16S rRNA gene phylotypes of mostly Gram-positive phyla that were unique to GD-affected houses and primarily occurred in Wet litter samples. Overall, the poultry house environment appeared to substantially impact the composition of litter bacterial communities and may play a key role in the emergence of food-borne pathogens

Body Composition, Symptoms, and Survival in Advanced Cancer Patients Referred to a Phase I Service

Background: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. Methods: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)$25 kg/m 2 was considered overweight. Sarcopenia, severe muscle depletion, was assessed using CT-based criteria. Results: Most patients were overweight (n = 65, 63$25 kg/m 2. Sarcopenic patients were older and less frequently African-American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71–358) (BMI,25 kg/m 2; sarcopenic), 271 (99–443) (BMI,25 kg/m 2; non-sarcopenic), 484 (286–681) (BMI$25 kg/m 2; sarcopenic); 501 d (309–693) (BMI$25 kg/m 2; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. Conclusions: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI$25 kg/m 2, independent o