The incidence of healthcare use, ill health and mortality in adults with intellectual disabilities and mealtime support needs

This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1111/jir.12167/full.Background\ud Adults with intellectual disabilities (ID) experience a wide range of eating, drinking and/or swallowing (EDS) problems, for which they receive diverse mealtime support interventions. Previous research has estimated that dysphagia (difficulty swallowing) affects 8% of all adults with ID and that 15% require some form of mealtime support. People with ID (whether they require mealtime support or not) also experience a greater burden of ill-health and die younger than their peers in the general population with no ID.\ud \ud Methods\ud Using an exploratory, population-based cohort study design, we set out to explore health-related outcomes in adults with ID who receive mealtime support for any eating, drinking or swallowing problem, by establishing the annual incidence of healthcare use, EDS-related ill-health, and all-cause mortality. This study was conducted in two counties in the East of England.\ud \ud Results\ud In 2009, 142 adults with mild to profound ID and a need for any type of mealtime support were recruited for a baseline survey. At follow-up one year later, 127 individuals were alive; eight had died; and seven could not be contacted. Almost all participants had one or more GP consultations each year (85-95%) and, in the first year, 20% reportedly had one or more emergency hospitalisations. Although their annual number of GP visits was broadly comparable to that of the general population, one-fifth of this population?s primary healthcare use was directly attributable to EDS-related ill-health. Respiratory infections were the most common cause of morbidity, and the immediate cause of all eight deaths, while concerns about nutrition and dehydration were surprisingly minor. Our participants had a high annual incidence of death (5%) and, with a standardised mortality ratio of 267, their observed mortality was more than twice that expected in the general population of adults with ID (not selected because of mealtime support for EDS problems).\ud \ud Conclusions\ud All Annual Health Checks now offered to adults with ID should include questions about respiratory infections and EDS functioning, in order to focus attention on EDS problems in this population. This has the potential to reduce life-threatening illness

C-type natriuretic peptide is a pivotal regulator of metabolic homeostasis

Thermogenesis and adipogenesis are tightly regulated mechanisms that maintain lipid homeostasis and energy balance; dysfunction of these critical processes underpins obesity and contributes to cardiometabolic disease. C-type natriuretic peptide (CNP) fulfills a multimodal protective role in the cardiovascular system governing local blood flow, angiogenesis, cardiac function, and immune cell reactivity. Herein, we investigated a parallel, preservative function for CNP in coordinating metabolic homeostasis. Global inducible CNP knockout mice exhibited reduced body weight, higher temperature, lower adiposity, and greater energy expenditure in vivo. This thermogenic phenotype was associated with increased expression of uncoupling protein-1 and preferential lipid utilization by mitochondria, a switch corroborated by a corresponding diminution of insulin secretion and glucose clearance. Complementary studies in isolated murine and human adipocytes revealed that CNP exerts these metabolic regulatory actions by inhibiting sympathetic thermogenic programming via G(i)-coupled natriuretic peptide receptor (NPR)-C and reducing peroxisome proliferator-activated receptor-γ coactivator-1α expression, while concomitantly driving adipogenesis via NPR-B/protein kinase-G. Finally, we identified an association between CNP/NPR-C expression and obesity in patient samples. These findings establish a pivotal physiological role for CNP as a metabolic switch to balance energy homeostasis. Pharmacological targeting of these receptors may offer therapeutic utility in the metabolic syndrome and related cardiovascular disorders

Liberalism, lack and living the dream : re-considering youth, consumer sovereignty and the attractions of night-time leisure in Magaluf

Much of the academic literature on alcohol-based leisure focuses on the pleasures of hedonism and youthful cultural exploration in environments free from the prescriptions, pressures and routines of everyday life. In this article – in which we present data from our ongoing ethnographic research exploring the experiences and attitudes of young British tourists in the Spanish resort of Magaluf on the island of Majorca – we argue that the standard liberal social-scientific image of youth leisure is naive and misrepresents its variegated reality. Our research indicates that many young British tourists gain little contentment from their holiday in the sun. Rather than embarking on a leisure experience composed of boundless freedom, choice, indulgence, excess and that is indicative of personal consumer sovereignty, many of our interviewees could identify the regimented and commodified nature of alcohol-based tourism. Rather than satisfaction, they felt an imprecise dissatisfaction. Drawing upon elements of psychoanalytic theory, we argue that underneath our interviewees’ accounts of drunkenness and promiscuity lies an obdurate but imprecise sense of lack. Yet, it is precisely this absence which only recharges their motivation to do more of the same the year after in similar destinations, thus confirming the presence, power and domination of consumer sovereignty

Starch Digestion Enhances Bioaccessibility of Anti-Inflammatory Polyphenols from Borlotti Beans (Phaseolus vulgaris)

The consumption of beans has been associated with chronic disease prevention which may be attributed to the polyphenols present in the seed coat and endosperm. However, their bioaccessibility is likely to be limited by interactions with bean matrix components, including starch, protein and fibre. The aim of this project was to evaluate the effect of domestic processing and enzymatic digestion on the bioaccessibility of polyphenols from Borlotti beans (Phaseolus vulgaris) and to test their anti-inflammatory properties in a macrophage cell model. In vitro digestion of cooked beans released twenty times more polyphenols (40.4 ± 2.5 mg gallic acid equivalents (GAE)/g) than domestic processing (2.22 ± 0.1 mg GAE/g), with starch digestion contributing to the highest release (30.9 ± 0.75 mg GAE/g). Fluorescence microscopy visualization of isolated bean starch suggests that polyphenols are embedded within the granule structure. LC-MS analysis showed that cooked Borlotti bean contain flavonoids, flavones and hydroxycinnamic acids, and cooked bean extracts exerted moderate anti-inflammatory effects by decreasing mRNA levels of IL1β and iNOS by 25% and 40%, respectively. In conclusion, the bioaccessibility of bean polyphenols is strongly enhanced by starch digestion. These polyphenols may contribute to the health benefits associated with bean consumption

A rare case of renal oncocytoma associated with erythrocytosis: case report

BACKGROUND: Oncocytomas are benign tumors of the kidney that are usually diagnosed postoperatively due to differential diagnostic problems from renal cell carcinoma. Although the latter are neoplasms that have been associated with erythrocytosis in 3.5% of cases, there are no reports in the literature about a similar occurrence in oncocytomas. CASE PRESENTATION: In this case report we present a unique case of a right lower pole oncocytoma associated with erythrocytosis. Erythrocytosis subsided after partial nephrectomy. CONCLUSION: Erythrocytosis can sometimes occur in association with renal oncocytomas

Delineation of functionally essential protein regions for 242 neurodevelopmental genes

Neurodevelopmental disorders (NDDs), including severe paediatric epilepsy, autism and intellectual disabilities are heterogeneous conditions in which clinical genetic testing can often identify a pathogenic variant. For many of them, genetic therapies will be tested in this or the coming years in clinical trials. In contrast to first-generation symptomatic treatments, the new disease-modifying precision medicines require a genetic test-informed diagnosis before a patient can be enrolled in a clinical trial. However, even in 2022, most identified genetic variants in NDD genes are "variants of uncertain significance'. To safely enrol patients in precision medicine clinical trials, it is important to increase our knowledge about which regions in NDD-associated proteins can "tolerate' missense variants and which ones are "essential' and will cause a NDD when mutated. In addition, knowledge about functionally indispensable regions in the 3D structure context of proteins can also provide insights into the molecular mechanisms of disease variants. We developed a novel consensus approach that overlays evolutionary, and population based genomic scores to identify 3D essential sites (Essential3D) on protein structures. After extensive benchmarking of AlphaFold predicted and experimentally solved protein structures, we generated the currently largest expert curated protein structure set for 242 NDDs and identified 14 377 Essential3D sites across 189 gene disorders associated proteins. We demonstrate that the consensus annotation of Essential3D sites improves prioritization of disease mutations over single annotations. The identified Essential3D sites were enriched for functional features such as intermembrane regions or active sites and discovered key inter-molecule interactions in protein complexes that were otherwise not annotated. Using the currently largest autism, developmental disorders, and epilepsies exome sequencing studies including > 360 000 NDD patients and population controls, we found that missense variants at Essential3D sites are 8-fold enriched in patients.In summary, we developed a comprehensive protein structure set for 242 NDDs and identified 14377 Essential3D sites in these. All data are available at https://es-ndd.broadinstitute.org for interactive visual inspection to enhance variant interpretation and development of mechanistic hypotheses for 242 NDDs genes. The provided resources will enhance clinical variant interpretation and in silico drug target development for NDD-associated genes and encoded proteins.Peer reviewe

High-Fidelity Tissue Engineering of Patient-Specific Auricles for Reconstruction of Pediatric Microtia and Other Auricular Deformities

Introduction: Autologous techniques for the reconstruction of pediatric microtia often result in suboptimal aesthetic outcomes and morbidity at the costal cartilage donor site. We therefore sought to combine digital photogrammetry with CAD/CAM techniques to develop collagen type I hydrogel scaffolds and their respective molds that would precisely mimic the normal anatomy of the patient-specific external ear as well as recapitulate the complex biomechanical properties of native auricular elastic cartilage while avoiding the morbidity of traditional autologous reconstructions. Methods: Three-dimensional structures of normal pediatric ears were digitized and converted to virtual solids for mold design. Image-based synthetic reconstructions of these ears were fabricated from collagen type I hydrogels. Half were seeded with bovine auricular chondrocytes. Cellular and acellular constructs were implanted subcutaneously in the dorsa of nude rats and harvested after 1 and 3 months. Results: Gross inspection revealed that acellular implants had significantly decreased in size by 1 month. Cellular constructs retained their contour/projection from the animals' dorsa, even after 3 months. Post-harvest weight of cellular constructs was significantly greater than that of acellular constructs after 1 and 3 months. Safranin O-staining revealed that cellular constructs demonstrated evidence of a self-assembled perichondrial layer and copious neocartilage deposition. Verhoeff staining of 1 month cellular constructs revealed de novo elastic cartilage deposition, which was even more extensive and robust after 3 months. The equilibrium modulus and hydraulic permeability of cellular constructs were not significantly different from native bovine auricular cartilage after 3 months. Conclusions: We have developed high-fidelity, biocompatible, patient-specific tissue-engineered constructs for auricular reconstruction which largely mimic the native auricle both biomechanically and histologically, even after an extended period of implantation. This strategy holds immense potential for durable patient-specific tissue-engineered anatomically proper auricular reconstructions in the future. © 2013 Reiffel et al