Overcrowded housing during adolescence and future risk of premature mortality: a 28-year follow-up of 556,191 adolescents from Switzerland

BACKGROUND: Few large-scale studies have examined the health impacts of overcrowded housing in European countries. The aim of this study was to assess whether household crowding during adolescence increases the risk of all-cause and cause-specific mortality in Switzerland. METHODS: Study participants were 556,191 adolescents aged 10-19 years at the 1990 census from the Swiss National Cohort. Household crowding at baseline was measured as the ratio between the number of persons living in the household and the number of available rooms, categorized as none (ratio ≤ 1), moderate (1 1.5). Participants were linked to administrative mortality records through 2018 and followed for premature mortality from all causes, cardiometabolic disease and self-harm or substance use. Cumulative risk differences between ages 10 and 45 were standardized by parental occupation, residential area, permit status and household type. FINDINGS: Of the sample, 19% lived in moderately and 5% lived in severely crowded households. During an average follow-up of 23 years, 9766 participants died. Cumulative risk of death from all causes was 2359 (95% compatibility intervals: 2296-2415) per 100,000 persons when living in non-crowded households. Living in moderately crowded households led to 99 additional deaths (-63 to 256) per 100,000 persons and living in severely crowded households 258 additional deaths (-37 to 607) per 100,000 persons. The effect of crowding on mortality from cardiometabolic diseases, self-harm or substance use was negligible. INTERPRETATION: Excess risk of premature mortality in adolescents living in overcrowded households appears to be small or negligible in Switzerland. FUNDING: University of Fribourg Scholarship Programme for foreign post-doctoral researchers

Major Histocompatibility Complex Class II Presentation of Cell-associated Antigen Is Mediated by CD8α+ Dendritic Cells In Vivo

Antigen-specific B cells express major histocompatibility complex class II and can present antigen directly to T cells. Adoptive transfer experiments using transgenic B and T cells demonstrated that antigen-specific B cells can also efficiently transfer antigen to another cell for presentation to T cells in vivo. To identify the antigen-presenting cell that receives antigens from B cells, a strategy was developed to follow the traffic of B cell–derived proteins in vivo. B cells were labeled with the fluorescent dye CFSE and loaded with antigen, before adoptive transfer into recipient mice. Populations of splenocytes from the recipient mice were later assayed for the presence of fluorescent proteins and for the ability to activate T cells. A small number of CD8α+CD4−CD11blo dendritic cells (DCs) contain proteins transferred from B cells and these DCs effectively present antigens derived from the B cells to T cells. The results suggest that CD8α+ DCs sample the cells and membranes in their environment for presentation to T cells circulating through the T cell zone. This function of CD8α+ DCs may be relevant to the priming of an immune response or the induction of T cell tolerance

International comparison in walkable environments and hospital burden in type 2 diabetes patients

Introduction While some comparative work has provided evidence for a universally positive impact of built environment features that promote physical activity, less is known about chronic diseases and hospitalization among different social contexts and health care systems. Parallel international linkage efforts present an opportunity to study health impacts of the built environment. Objectives and Approach This study compares the impact of neighbourhood environments on health outcomes for patients with type 2 diabetes (T2D) in two countries. Neighborhood-level measures for walkable environments were derived for Canada and Wales using Geographic Information Systems. Hospitalization admissions from routine data sources and linked survey data responses (from the Welsh Health Survey and Canadian Community Health Survey) allow for the generation of population-based descriptive statistics on socio-demographic information, self-reported health, diagnostic patterns, and health care use. We examine the feasibility of investigating contextual differences in walkable environments, T2D, and hospitalization between Wales and Canada. Results Data linkage in respective privacy protecting safe havens in the Canada Research Data Centre Network (CRDCN) and the Wales Secure Anonymised Information Linkage (SAIL) Databank show promise for a comparative study, enabling parallel modelling of environmental and socio-demographic factors with hospitalization data. Both the Canadian and Welsh surveys ask respondents about their current diabetes status, allowing us to compare hospitalization rates and neighborhood effects of those who report having diabetes with the those who do not. Moreover, the linking of survey responses and similarity in geographic scale permitted consistent measurement of walkable environments across countries. Key administrative variables have been identified relating to health and behaviors, such as socio-demographic information, smoking status, and body mass index, and hospitalization metrics in both countries are commensurable. Conclusion/Implications The generation of comparable linked datasets, built environment indicators and comparative research for T2D patients will have wider implications for international assessment of the impacts of environment on chronic diseases, and the hospital burden associated with these conditions

Neighbourhood built environments as correlates of hospital burden and premature mortality in Canada

Introduction The built environment can shape modifiable risk factors such as obesity, poor diet, and physical inactivity, and could be a policy lever for the reduction of chronic disease. In Canada, the health care costs related to chronic disease continue to rise and there have been few policy options offered. Objectives and Approach We examine the role of the built environment in hospital burden and premature mortality, with an emphasis on one of the highest burden diseases, Type 2 Diabetes (T2D). Neighbourhood built environment measures for active living were derived using geographic information systems for respondents of the Canadian Community Health Survey, for whom we have linked hospitalization and mortality records. A combination of ICD codes, self-reported diabetes status, as well as a population-based algorithm identifying those at higher risk of developing diabetes were used to identify cases. Differences in hospitalization frequency, cumulative length of stay, and mortality are investigated. Results Over half a million hospitalization records were identified in our cohort of roughly 450,000 survey respondents. Key factors such as age, gender, race, and socioeconomic status are accounted for in modelling the association between neighborhood environment and hospitalization. Hospital burden and mortality in T2D patients are much higher than that of patients who do not report having the condition, and those at elevated risk of T2D display intermediate levels of hospitalization. Two-part hurdle models show evidence of an association between more walkable neighborhoods and lower hospitalization risk in non-T2D patients as well as those at elevated risk of developing T2D. The relationship between neighborhoods and the volume of chronic-disease related episodes as well as mortality is unclear, and under further investigation. Conclusion/Implications Elucidating the role of neighbourhood built environments on hospital burden and premature mortality for individuals with diabetes will provide insight as to the full range of clinical and non-clinical interventions that could feasibly address the needs of some the highest health care system users

Prenatal antidepressant exposure associated with CYP2E1 DNA methylation change in neonates

Some but not all neonates are affected by prenatal exposure to serotonin reuptake inhibitor antidepressants (SRI) and maternal mood disturbances. Distinguishing the impact of these 2 exposures is challenging and raises critical questions about whether pharmacological, genetic, or epigenetic factors can explain the spectrum of reported outcomes. Using unbiased DNA methylation array measurements followed by a detailed candidate gene approach, we examined whether prenatal SRI exposure was associated with neonatal DNA methylation changes and whether such changes were associated with differences in birth outcomes. Prenatal SRI exposure was first associated with increased DNA methylation status primarily at CYP2E1(βNon-exposed = 0.06, βSRI-exposed = 0.30, FDR = 0); however, this finding could not be distinguished from the potential impact of prenatal maternal depressed mood. Then, using pyrosequencing of CYP2E1 regulatory regions in an expanded cohort, higher DNA methylation status both the mean across 16 CpG sites (P < 0.01) and at each specific CpG site (P < 0.05) was associated with exposure to lower 3rd trimester maternal depressed mood symptoms only in the SRI-exposed neonates, indicating a maternal mood x SRI exposure interaction. In addition, higher DNA methylation levels at CpG2 (P = 0.04), CpG9 (P = 0.04) and CpG10 (P = 0.02), in the interrogated CYP2E1 region, were associated with increased birth weight independently of prenatal maternal mood, SRI drug exposure, or gestational age at birth. Prenatal SRI antidepressant exposure and maternal depressed mood were associated with altered neonatal CYP2E1 DNA methylation status, which, in turn, appeared to be associated with birth weight

Insulin receptor isoform switching in intestinal stem cells, progenitors, differentiated lineages and tumors: evidence that IR-B limits proliferation

Despite evidence for the impact of insulin on intestinal epithelial physiology and pathophysiology, the expression patterns, roles, and regulation of insulin receptor (IR) and IR isoforms in the intestinal epithelium are not well characterized. IR-A is thought to mediate the proliferative effects of insulin or insulin growth factors (IGFs) in fetal or cancer cells. IR-B is considered to be the metabolic receptor for insulin in specialized tissues. This study used a novel Sox9-EGFP reporter mouse that permits isolation of intestinal epithelial stem cells (IESCs), progenitors, enteroendocrine cells and differentiated lineages, the ApcMin/+ mouse model of precancerous adenoma and normal human intestinal and colorectal cancer (CRC) cell lines. We tested the hypothesis that there is differential expression of IR-A or IR-B in stem and tumor cells versus differentiated intestinal epithelial cells (IECs) and that IR-B impacts cell proliferation. Our findings provide evidence that IR-B expression is significantly lower in highly proliferative IESCs and progenitor cells versus post-mitotic, differentiated IECs and in subconfluent and undifferentiated versus differentiated Caco-2 cells. IR-B is also reduced in ApcMin/+ tumors and highly tumorigenic CRC cells. These differences in IR-B were accompanied by altered levels of mRNAs encoding muscleblind-like 2 (MBNL2), a known regulator of IR alternative splicing. Forced IR-B expression in subconfluent and undifferentiated Caco-2 cells reduced proliferation and increased biomarkers of differentiation. Our findings indicate that the impact of insulin on different cell types in the intestinal epithelium might differ depending on relative IR-B∶ IR-A expression levels and provide new evidence for the roles of IR-B to limit proliferation of CRC cells

Quantitative magnetic resonance imaging measures as biomarkers of disease progression in boys with Duchenne muscular dystrophy: a phase 2 trial of domagrozumab

Duchenne muscular dystrophy (DMD) is a progressive, neuromuscular disorder caused by mutations in the DMD gene that results in a lack of functional dystrophin protein. Herein, we report the use of quantitative magnetic resonance imaging (MRI) measures as biomarkers in the context of a multicenter phase 2, randomized, placebo-controlled clinical trial evaluating the myostatin inhibitor domagrozumab in ambulatory boys with DMD (n = 120 aged 6 to < 16 years). MRI scans of the thigh to measure muscle volume, muscle volume index (MVI), fat fraction, and T2 relaxation time were obtained at baseline and at weeks 17, 33, 49, and 97 as per protocol. These quantitative MRI measurements appeared to be sensitive and objective biomarkers for evaluating disease progression, with significant changes observed in muscle volume, MVI, and T2 mapping measures over time. To further explore the utility of quantitative MRI measures as biomarkers to inform longer term functional changes in this cohort, a regression analysis was performed and demonstrated that muscle volume, MVI, T2 mapping measures, and fat fraction assessment were significantly correlated with longer term changes in four-stair climb times and North Star Ambulatory Assessment functional scores. Finally, less favorable baseline measures of MVI, fat fraction of the muscle bundle, and fat fraction of lean muscle were significant risk factors for loss of ambulation over a 2-year monitoring period. These analyses suggest that MRI can be a valuable tool for use in clinical trials and may help inform future functional changes in DMD.Trial registration: ClinicalTrials.gov identifier, NCT02310763; registered December 2014

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy.

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to \u3c16 \u3eyears) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619

Corrigendum: the unknown and the unexplored: insights into the Pacific deep-sea following NOAA CAPSTONE expeditions

Published versio

The unknown and the unexplored: insights Into the Pacific deep-sea following NOAA CAPSTONE expeditions

Over a 3-year period, the National Oceanic and Atmospheric Administration (NOAA) organized and implemented a Pacific-wide field campaign entitled CAPSTONE: Campaign to Address Pacific monument Science, Technology, and Ocean NEeds. Under the auspices of CAPSTONE, NOAA mapped 597,230 km2 of the Pacific seafloor (with ∼61% of mapped area located within US waters), including 323 seamounts, conducted 187 ROV dives totaling 891.5 h of ROV benthic imaging time, and documented >347,000 individual organisms. This comprehensive effort yielded dramatic insight into differences in biodiversity across depths, regions, and features, at multiple taxonomic scales. For all deep sea taxonomic groups large enough to be visualized with the ROV, we found that fewer than 20% of the species were able to be identified. The most abundant and highest diversity taxa across the dataset were from three phyla (Cnidaria, Porifera, and Echinodermata). We further examined these phyla for taxonomic assemblage patterns by depth, geographic region, and geologic feature. Within each taxa, there were multiple genera with specific distribution and abundance by depth, region, and feature. Additionally, we observed multiple genera with broad abundance and distribution, which may focus future ecological research efforts. Novel taxa, records, and behaviors were observed, suggestive of many new types of species interactions, drivers of community composition, and overall diversity patterns. To date, only 13.8% of the Pacific has been mapped using modern methods. Despite the incredible amount of new known and unknown information about the Pacific deep-sea, CAPSTONE is far from the culminating experience the name suggests. Rather, it marks the beginning of a new era for exploration that will offer extensive opportunities via mapping, technology, analysis, and insights.Published versio