Defining the Pulmonary Disease and Disability from Lung Dysfunction in Cutis Laxa

Cutis laxa is a heterogeneous group of disorders characterized by loose, lax, and inelastic skin. Other complications include lung, cardiovascular, musculoskeletal, gastrointestinal, and genitourinary disease. Cutis laxa (CL) can be congenital or acquired, with the congenital forms resulting from mutations in numerous genes. Chronic obstructive pulmonary disease (COPD) is a major contributor to morbidity and mortality in CL, making it a subject of public health importance. This purpose of this analysis is to determine quantitative differences between CL onset, congenital and acquired, and CL diagnosis, CL versus CL carrier in regard to pulmonary function and disability that results from lung dysfunction. An odds ratio determined that the cutis population has an increased risk for COPD and t-test analysis determined that COPD severity was the same between congenital and acquired subjects, but significantly different between CL and CL carriers. Multiple people with a previous asthma diagnosis were determined to actually have COPD. Additionally, the SGRQ total score was found to be highly correlated with FEV1/FVC and CT visual emphysema score. Further studies are warranted to more clearly determine genotype-phenotype correlations and assess longitudinal changes

Whose Business is Your Pancreas?: Potential Privacy Problems in New York City\u27s Mandatory Diabetes Registry (with N. Gingo et al.)

New York City authorities in 2006 formulated a policy requiring that medical data from all diabetics in the City be stored in a centralized registry. This diabetic registry is the first in the nation to require collection of personal testing data for the purpose of monitoring treatments for a noninfectious disease. The registry represents an important step on the path toward better understanding and managing of the disease. Nonetheless, establishment of the registry threatens privacy in a number of ways. Many individuals are open about their diabetes, but others prefer to keep that information to themselves, whether because of concerns for discrimination in the workplace or for ramifications in custody disputes. Although New York City’s regulation includes a confidentiality provision, privately identifiable information may be divulged through the notification process set up by the City, under which both physicians and patients are notified when their hemoglobin tests are dangerously high; through subpoenas in criminal and family court actions, and through use of the information by public health researchers to conduct epidemiological research. Regulators have already indicated that, despite the confidentiality provision, they intend to use the registry to conduct public health research that can only be attained by combining registry information with other statistics about the individuals covered. Moreover, there is no confidentiality provision at all for physicians, and operation of the registry may intrude upon the sanctity of the physician/patient relationship by providing physicians with troubling incentives either to circumvent the reporting requirements or to ensure that their patients appear healthier than they are. After considering the ways in which implementation of the registry potentially compromises privacy, the article concludes with a list of specific recommendations for both the NYC and future registries targeted at noninfectious diseases. In short, we recommend making the confidentiality provision more explicit, limiting secondary uses of the information obtained, protecting diabetics from adverse insurance consequences due to operation of the registry, and protecting the privacy of physicians

Whose Business is Your Pancreas?: Potential Privacy Problems in New York City\u27s Mandatory Diabetes Registry (with N. Gingo et al.)

New York City authorities in 2006 formulated a policy requiring that medical data from all diabetics in the City be stored in a centralized registry. This diabetic registry is the first in the nation to require collection of personal testing data for the purpose of monitoring treatments for a noninfectious disease. The registry represents an important step on the path toward better understanding and managing of the disease. Nonetheless, establishment of the registry threatens privacy in a number of ways. Many individuals are open about their diabetes, but others prefer to keep that information to themselves, whether because of concerns for discrimination in the workplace or for ramifications in custody disputes. Although New York City’s regulation includes a confidentiality provision, privately identifiable information may be divulged through the notification process set up by the City, under which both physicians and patients are notified when their hemoglobin tests are dangerously high; through subpoenas in criminal and family court actions, and through use of the information by public health researchers to conduct epidemiological research. Regulators have already indicated that, despite the confidentiality provision, they intend to use the registry to conduct public health research that can only be attained by combining registry information with other statistics about the individuals covered. Moreover, there is no confidentiality provision at all for physicians, and operation of the registry may intrude upon the sanctity of the physician/patient relationship by providing physicians with troubling incentives either to circumvent the reporting requirements or to ensure that their patients appear healthier than they are. After considering the ways in which implementation of the registry potentially compromises privacy, the article concludes with a list of specific recommendations for both the NYC and future registries targeted at noninfectious diseases. In short, we recommend making the confidentiality provision more explicit, limiting secondary uses of the information obtained, protecting diabetics from adverse insurance consequences due to operation of the registry, and protecting the privacy of physicians

SIC-8000 versus hetastarch as a submucosal injection fluid for endoscopic mucosal resection: a randomized controlled trial

Background and Aims Viscous solutions provide a superior submucosal cushion for endoscopic mucosal resection (EMR). SIC-8000 (Eleview, Aries Pharmaceuticals, La Jolla, Calif) is a commercially available FDA approved solution but hetastarch is also advocated. We performed a randomized trial comparing SIC-8000 to hetastarch as submucosal injection agents for colorectal EMR. Methods This was a single-center double-blinded randomized controlled trial performed at a tertiary referral center. Patients were referred to our center with flat or sessile lesions measuring ≥15 mm in size. The primary outcome measures were the Sydney Resection Quotient (SRQ) and the rate of en bloc resections. Secondary outcomes were total volume needed for a sufficient lift, number of resected pieces, and adverse events. Results There were 158 patients with 159 adenomas (84 SIC-8000 and 75 hetastarch) and 57 serrated lesions (30 SIC-8000 and 27 hetastarch). SRQ was significantly better in the SIC-8000 group compared with hetastarch group (9.3 vs 8.1, p=0.001). There was no difference in the proportion of lesions with en bloc resections. The total volume of injectate was significantly lower with SIC-8000 (14.8 mL vs 20.6 mL, p=0.038) Conclusions SIC-8000 is superior to hetastarch for use during EMR in terms of SRQ and total volume needed, although the absolute differences were small

Skeletal muscle metabolic responses to physical activity are muscle type specific in a rat model of chronic kidney disease

Chronic kidney disease (CKD) leads to musculoskeletal impairments that are impacted by muscle metabolism. We tested the hypothesis that 10-weeks of voluntary wheel running can improve skeletal muscle mitochondria activity and function in a rat model of CKD. Groups included (n = 12–14/group): (1) normal littermates (NL); (2) CKD, and; (3) CKD-10 weeks of voluntary wheel running (CKD-W). At 35-weeks old the following assays were performed in the soleus and extensor digitorum longus (EDL): targeted metabolomics, mitochondrial respiration, and protein expression. Amino acid-related compounds were reduced in CKD muscle and not restored by physical activity. Mitochondrial respiration in the CKD soleus was increased compared to NL, but not impacted by physical activity. The EDL respiration was not different between NL and CKD, but increased in CKD-wheel rats compared to CKD and NL groups. Our results demonstrate that the soleus may be more susceptible to CKD-induced changes of mitochondrial complex content and respiration, while in the EDL, these alterations were in response the physiological load induced by mild physical activity. Future studies should focus on therapies to improve mitochondrial function in both types of muscle to determine if such treatments can improve the ability to adapt to physical activity in CKD

Genome-wide association study of a nicotine metabolism biomarker in African American smokers:impact of chromosome 19 genetic influences

BACKGROUND AND AIMS: The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3'hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. DESIGN: Genome-wide association study (GWAS). SETTING: Multiple sites within Canada and the United States. PARTICIPANTS: AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n = 504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n = 450). MEASUREMENTS: Genome-wide SNP genotyping, the NMR (phenotype) and population substructure and NMR covariates. FINDINGS: Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190 and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P = 1.47e-39; beta = 0.59 per C (versus T) allele, SE = 0.045), located ~9.5 kb 3' of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in individuals of European descent. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n = 480). None of the hits were in UGT or OCT2 genes. CONCLUSIONS: Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours and tobacco-related disease risk

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Global, regional, and national under-5 mortality, adult mortality, age-specific mortality, and life expectancy, 1970–2016: a systematic analysis for the Global Burden of Disease Study 2016

BACKGROUND: Detailed assessments of mortality patterns, particularly age-specific mortality, represent a crucial input that enables health systems to target interventions to specific populations. Understanding how all-cause mortality has changed with respect to development status can identify exemplars for best practice. To accomplish this, the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) estimated age-specific and sex-specific all-cause mortality between 1970 and 2016 for 195 countries and territories and at the subnational level for the five countries with a population greater than 200 million in 2016. METHODS: We have evaluated how well civil registration systems captured deaths using a set of demographic methods called death distribution methods for adults and from consideration of survey and census data for children younger than 5 years. We generated an overall assessment of completeness of registration of deaths by dividing registered deaths in each location-year by our estimate of all-age deaths generated from our overall estimation process. For 163 locations, including subnational units in countries with a population greater than 200 million with complete vital registration (VR) systems, our estimates were largely driven by the observed data, with corrections for small fluctuations in numbers and estimation for recent years where there were lags in data reporting (lags were variable by location, generally between 1 year and 6 years). For other locations, we took advantage of different data sources available to measure under-5 mortality rates (U5MR) using complete birth histories, summary birth histories, and incomplete VR with adjustments; we measured adult mortality rate (the probability of death in individuals aged 15-60 years) using adjusted incomplete VR, sibling histories, and household death recall. We used the U5MR and adult mortality rate, together with crude death rate due to HIV in the GBD model life table system, to estimate age-specific and sex-specific death rates for each location-year. Using various international databases, we identified fatal discontinuities, which we defined as increases in the death rate of more than one death per million, resulting from conflict and terrorism, natural disasters, major transport or technological accidents, and a subset of epidemic infectious diseases; these were added to estimates in the relevant years. In 47 countries with an identified peak adult prevalence for HIV/AIDS of more than 0·5% and where VR systems were less than 65% complete, we informed our estimates of age-sex-specific mortality using the Estimation and Projection Package (EPP)-Spectrum model fitted to national HIV/AIDS prevalence surveys and antenatal clinic serosurveillance systems. We estimated stillbirths, early neonatal, late neonatal, and childhood mortality using both survey and VR data in spatiotemporal Gaussian process regression models. We estimated abridged life tables for all location-years using age-specific death rates. We grouped locations into development quintiles based on the Socio-demographic Index (SDI) and analysed mortality trends by quintile. Using spline regression, we estimated the expected mortality rate for each age-sex group as a function of SDI. We identified countries with higher life expectancy than expected by comparing observed life expectancy to anticipated life expectancy on the basis of development status alone. FINDINGS: Completeness in the registration of deaths increased from 28% in 1970 to a peak of 45% in 2013; completeness was lower after 2013 because of lags in reporting. Total deaths in children younger than 5 years decreased from 1970 to 2016, and slower decreases occurred at ages 5-24 years. By contrast, numbers of adult deaths increased in each 5-year age bracket above the age of 25 years. The distribution of annualised rates of change in age-specific mortality rate differed over the period 2000 to 2016 compared with earlier decades: increasing annualised rates of change were less frequent, although rising annualised rates of change still occurred in some locations, particularly for adolescent and younger adult age groups. Rates of stillbirths and under-5 mortality both decreased globally from 1970. Evidence for global convergence of death rates was mixed; although the absolute difference between age-standardised death rates narrowed between countries at the lowest and highest levels of SDI, the ratio of these death rates-a measure of relative inequality-increased slightly. There was a strong shift between 1970 and 2016 toward higher life expectancy, most noticeably at higher levels of SDI. Among countries with populations greater than 1 million in 2016, life expectancy at birth was highest for women in Japan, at 86·9 years (95% UI 86·7-87·2), and for men in Singapore, at 81·3 years (78·8-83·7) in 2016. Male life expectancy was generally lower than female life expectancy between 1970 and 2016, an