Service organisation for the secondary prevention of ischaemic heart disease in primary care.

BACKGROUND: Ischaemic heart disease (IHD) is a major cause of mortality and morbidity and its prevalence is set to increase. Secondary prevention aims to prevent subsequent acute events in people with established IHD. While the benefits of individual medical and lifestyle interventions is established, the effectiveness of interventions which seek to improve the way secondary preventive care is delivered in primary care or community settings is less so. OBJECTIVES: To assess the effectiveness of service organisation interventions, identifying which types and elements of service change are associated with most improvement in clinician and patient adherence to secondary prevention recommendations relating to risk factor levels and monitoring (blood pressure, cholesterol and lifestyle factors such as diet, exercise, smoking and obesity) and appropriate prophylactic medication. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2007, Issue 4), MEDLINE (1966 to Feb 2008), EMBASE (1980 to Feb 2008), and CINAHL (1981 to Feb 2008). Bibliographies were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of service organisation interventions in primary care or community settings in populations with established IHD. DATA COLLECTION AND ANALYSIS: Analyses were conducted according to Cochrane recommendations and Odds Ratios (with 95% confidence intervals) reported for dichotomous outcomes, mean differences (with 95% CIs) for continuous outcomes. MAIN RESULTS: Eleven studies involving 12,074 people with IHD were included. Increased proportions of patients with total cholesterol levels within recommended levels at 12 months, OR 1.90 (1.04 to 3.48), were associated with interventions that included regular planned appointments, patient education and structured monitoring of medication and risk factors, but significant heterogeneity was apparent. Results relating to blood pressure within target levels bordered on statistical significance. There were no significant effects of interventions on mean blood pressure or cholesterol levels, prescribing, smoking status or body mass index. Few data were available on the effect on diet. There was some suggestion of a \u22ceiling effect\u22 whereby interventions have a diminishing beneficial effect once certain levels of risk factor management are reached. AUTHORS\u27 CONCLUSIONS: There is weak evidence that regular planned recall of patients for appointments, structured monitoring of risk factors and prescribing, and education for patients can be effective in increasing the proportions of patients within target levels for cholesterol control and blood pressure. Further research in this area would benefit from greater standardisation of the outcomes measured

Massively parallel cis-regulatory analysis in the mammalian central nervous system

Cis-regulatory elements (CREs, e.g., promoters and enhancers) regulate gene expression, and variants within CREs can modulate disease risk. Next-generation sequencing has enabled the rapid generation of genomic data that predict the locations of CREs, but a bottleneck lies in functionally interpreting these data. To address this issue, massively parallel reporter assays (MPRAs) have emerged, in which barcoded reporter libraries are introduced into cells, and the resulting barcoded transcripts are quantified by next-generation sequencing. Thus far, MPRAs have been largely restricted to assaying short CREs in a limited repertoire of cultured cell types. Here, we present two advances that extend the biological relevance and applicability of MPRAs. First, we adapt exome capture technology to instead capture candidate CREs, thereby tiling across the targeted regions and markedly increasing the length of CREs that can be readily assayed. Second, we package the library into adeno-associated virus (AAV), thereby allowing delivery to target organs in vivo. As a proof of concept, we introduce a capture library of about 46,000 constructs, corresponding to roughly 3500 DNase I hypersensitive (DHS) sites, into the mouse retina by ex vivo plasmid electroporation and into the mouse cerebral cortex by in vivo AAV injection. We demonstrate tissue-specific cis-regulatory activity of DHSs and provide examples of high-resolution truncation mutation analysis for multiplex parsing of CREs. Our approach should enable massively parallel functional analysis of a wide range of CREs in any organ or species that can be infected by AAV, such as nonhuman primates and human stem cell-derived organoids

Selectively bred oysters can alter their biomineralization pathways, promoting resilience to environmental acidification

Commercial shellfish aquaculture is vulnerable to the impacts of ocean acidification driven by increasing carbon dioxide (CO2) absorption by the ocean as well as to coastal acidification driven by land run off and rising sea level. These drivers of environmental acidification have deleterious effects on biomineralization. We investigated shell biomineralization of selectively bred and wild‐type families of the Sydney rock oyster Saccostrea glomerata in a study of oysters being farmed in estuaries at aquaculture leases differing in environmental acidification. The contrasting estuarine pH regimes enabled us to determine the mechanisms of shell growth and the vulnerability of this species to contemporary environmental acidification. Determination of the source of carbon, the mechanism of carbon uptake and use of carbon in biomineral formation are key to understanding the vulnerability of shellfish aquaculture to contemporary and future environmental acidification. We, therefore, characterized the crystallography and carbon uptake in the shells of S. glomerata, resident in habitats subjected to coastal acidification, using high‐resolution electron backscatter diffraction and carbon isotope analyses (as δ13C). We show that oyster families selectively bred for fast growth and families selected for disease resistance can alter their mechanisms of calcite crystal biomineralization, promoting resilience to acidification. The responses of S. glomerata to acidification in their estuarine habitat provide key insights into mechanisms of mollusc shell growth under future climate change conditions. Importantly, we show that selective breeding in oysters is likely to be an important global mitigation strategy for sustainable shellfish aquaculture to withstand future climate‐driven change to habitat acidification

Comparison of proteomic profiles of serum, plasma, and modified media supplements used for cell culture and expansion

BACKGROUND: The culture and expansion of human cells for clinical use requires the presence of human serum or plasma in culture media. Although these supplements have been extensively characterized in their chemical composition, only recently it has been possible to provide by high throughput protein analysis, a comprehensive profile of the soluble factors contributing to cell survival. This study analyzed and compared the presence of 100 proteins including chemokines, cytokines and soluble factors in six different types of media supplements: serum, plasma, recalcified plasma, heat inactivated serum, heat inactivated plasma and heat inactivated recalcified plasma. METHODS: Serum, plasma, recalcified plasma, and heat inactivated supplements were prepared from ten healthy subjects. The levels of 100 soluble factors were measured in each sample using a multiplexed ELISA assay and compared by Eisen hierarchical clustering analysis. RESULTS: A comparison of serum and plasma levels of soluble factors found that 2 were greater in plasma but 18 factors were greater in serum including 11 chemokines. The levels of only four factors differed between recalcified plasma and plasma. Heat inactivation had the greatest effect on soluble factors. Supervised Eisen hierarchical clustering indicated that the differences between heat inactivated supplements and those that were not were greater than the differences within these two groups. The levels of 36 factors differed between heat inactivated plasma and plasma. Thirty one of these factors had a lower concentration in heat inactivated plasma including 12 chemokines, 4 growth factors, 4 matrix metalloproteases, and 3 adhesion molecules. Heat inactivated decalcified plasma is often used in place of heat inactivated serum and the levels of 19 soluble factors differed between these two supplements. CONCLUSION: Our report provides a comprehensive protein profile of serum, plasma recalcified plasma, and heat inactivated supplements. This profile represents a qualitative and quantitative database that can aid in the selection of the appropriate blood derived supplement for human cell cultures with special requirements

Evidence That the Clinical Impairment Assessment (CIA) Subscales Should Not Be Scored: Bifactor Modelling, Reliability, and Validity in Clinical and Community Samples

Aim: The Clinical Impairment Assessment (CIA 3.0) is the most widely used instrument assessing psychosocial impairment secondary to eating disorder symptoms. However, there is conflicting advice regarding the dimensionality and optimal method of scoring the CIA. We sought to resolve this confusion by conducting a comprehensive factor analytic study of the CIA in a community sample (N = 301) and clinical sample comprising patients with a diagnosed eating disorder (N = 209). Convergent and discriminant validity were also assessed. Method: The CIA and measures of eating disorder symptoms were administered to both samples. Results: Factor analyses indicated there is a general impairment factor underlying all items on the CIA that is reliably measured by the CIA Global score. CIA Global demonstrated good convergent and discriminant validity. Conclusions: CIA Global is a reliable and valid measure of psychosocial impairment secondary to eating disorder symptoms; however, subscale scores should not be computed

Combining genomics and epidemiology to track mumps virus transmission in the United States.

Unusually large outbreaks of mumps across the United States in 2016 and 2017 raised questions about the extent of mumps circulation and the relationship between these and prior outbreaks. We paired epidemiological data from public health investigations with analysis of mumps virus whole genome sequences from 201 infected individuals, focusing on Massachusetts university communities. Our analysis suggests continuous, undetected circulation of mumps locally and nationally, including multiple independent introductions into Massachusetts and into individual communities. Despite the presence of these multiple mumps virus lineages, the genomic data show that one lineage has dominated in the US since at least 2006. Widespread transmission was surprising given high vaccination rates, but we found no genetic evidence that variants arising during this outbreak contributed to vaccine escape. Viral genomic data allowed us to reconstruct mumps transmission links not evident from epidemiological data or standard single-gene surveillance efforts and also revealed connections between apparently unrelated mumps outbreaks

The spectrum of neurodevelopmental, neuromuscular and neurodegenerative disorders due to defective autophagy

Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.Peer reviewe

CRALBP supports the mammalian retinal visual cycle and cone vision

Mutations in the cellular retinaldehyde-binding protein (CRALBP, encoded by RLBP1) can lead to severe cone photoreceptor-mediated vision loss in patients. It is not known how CRALBP supports cone function or how altered CRALBP leads to cone dysfunction. Here, we determined that deletion of Rlbp1 in mice impairs the retinal visual cycle. Mice lacking CRALBP exhibited M-opsin mislocalization, M-cone loss, and impaired cone-driven visual behavior and light responses. Additionally, M-cone dark adaptation was largely suppressed in CRALBP-deficient animals. While rearing CRALBP-deficient mice in the dark prevented the deterioration of cone function, it did not rescue cone dark adaptation. Adeno-associated virus-mediated restoration of CRALBP expression specifically in Müller cells, but not retinal pigment epithelial (RPE) cells, rescued the retinal visual cycle and M-cone sensitivity in knockout mice. Our results identify Müller cell CRALBP as a key component of the retinal visual cycle and demonstrate that this pathway is important for maintaining normal cone-driven vision and accelerating cone dark adaptation

Process, improvisation, holarchic learning loops and all that jazz: experiences in transdisciplinary education for sustainable development

This paper explores the experiences of an ‘Interdisciplinary Sustainability Assessment Laboratory’ (‘ISA Lab’) workshop, which took place over a week at Universitat Politècnica de València during April 2017. The workshop drew together students from a range of disciplines from across engineering and science, law and the social sciences and from a range of countries and backgrounds, including North and South America, Europe and Asia. It also facilitated a rich co-creative learning environment as it was led by (engineering) academic faculty from across Europe (Spain, UK, Netherlands and Ireland) as well as North America (Canada), as well as local experts who helped provide participants with appropriate context and guidance. The workshops culminated with a number of presentations from respective student groups, where they outlined an integrated development plan for a selected real life local project

Genetic predisposition to metabolically unfavourable adiposity and prostate cancer risk:A Mendelian randomization analysis

BACKGROUND The associations of adiposity with aggressive prostate cancer risk are unclear. Using two-sample Mendelian randomization, we assessed the association of metabolically unfavourable adiposity (UFA), favourable adiposity (FA) and for comparison body mass index (BMI), with prostate cancer, including aggressive prostate cancer. METHODS We examined the association of these genetically predicted adiposity-related traits with risk of prostate cancer overall, aggressive and early onset disease using outcome summary statistics from the PRACTICAL consortium (including 15,167 aggressive cases). RESULTS In inverse-variance weighted models, there was little evidence that genetically predicted one standard deviation higher UFA, FA and BMI were associated with aggressive prostate cancer [OR: 0.85 (95% CI:0.61-1.19), 0.80 (0.53-1.23) and 0.97 (0.88-1.08), respectively]; these associations were largely consistent in sensitivity analyses accounting for horizontal pleiotropy. There was no strong evidence that genetically determined UFA, FA or BMI were associated with overall prostate cancer or early age of onset prostate cancer. CONCLUSIONS We did not find differences in the associations of UFA and FA with prostate cancer risk, which suggest that adiposity is unlikely to influence prostate cancer via the metabolic factors assessed; however, these did not cover some aspects related to metabolic health that may link obesity with aggressive prostate cancer, which should be explored in future studies