Family screening for bicuspid aortic valve and aortic dilatation: a meta-analysis.

AIMS: International guidelines recommend screening of first-degree relatives (FDR) of people with bicuspid aortic valves (BAVs). However, the prevalence of BAV and of aortic dilatation amongst family members is uncertain. METHODS AND RESULTS: A systematic review and meta-analysis of original reports of screening for BAV. Databases including MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to December 2021 using relevant search terms. Data were sought on the screened prevalence of BAV and aortic dilatation. The protocol was specified prior to the searches being performed, and standard meta-analytic techniques were used. Twenty-three observational studies met inclusion criteria (n = 2297 index cases; n = 6054 screened relatives). The prevalence of BAV amongst relatives was 7.3% [95% confidence interval (CI) 6.1%-8.6%] overall and per family was 23.6% (95% CI 18.1%-29.5%). The prevalence of aortic dilatation amongst relatives was 9.4% (95% CI 5.7%-13.9%). Whilst the prevalence of aortic dilatation was particularly high in relatives with BAV (29.2%; 95% CI 15.3%-45.1%), aortic dilatation alongside tricuspid aortic valves was a more frequent finding, as there were many more family members with tricuspid valves than BAV. The prevalence estimate amongst relatives with tricuspid valves (7.0%; 95% CI 3.2%-12.0%) was higher than reported in the general population. CONCLUSION: Screening family members of people with BAV can identify a cohort substantially enriched for the presence of bicuspid valve, aortic enlargement, or both. The implications for screening programmes are discussed, including in particular the substantial current uncertainties regarding the clinical implications of aortic findings.

Clinical support during COVID-19: An opportunity for service and learning? A cross-sectional survey of UK medical students.

PURPOSE: Medical students providing support to clinical teams during Covid-19 may have been an opportunity for service and learning. We aimed to understand why the reported educational impact has been mixed to inform future placements. METHODS: We conducted a cross-sectional survey of medical students at UK medical schools during the first Covid-19 'lockdown' period in the UK (March-July 2020). Analysis was informed by the conceptual framework of service and learning. RESULTS: 1245 medical students from 37 UK medical schools responded. 57% of respondents provided clinical support across a variety of roles and reported benefits including increased preparedness for foundation year one compared to those who did not (p < 0.0001). However, not every individual's experience was equal. For some, roles complemented the curriculum and provided opportunities for clinical skill development, reflection, and meaningful contribution to the health service. For others, the relevance of their role to their education was limited; these roles typically focused on service provision, with few opportunities to develop. CONCLUSION: The conceptual framework of service and learning can help explain why student experiences have been heterogeneous. We highlight how this conceptual framework can be used to inform clinical placements in the future, in particular the risks, benefits, and structures.[Box: see text].

An assessment of adherence to CARE reporting standards by case reports published in European Heart Journal - Case Reports in 2018.

BACKGROUND: Case reports are subject to significant variation in their content, and the absence of pertinent case details can limit their benefit to the medical community. To aid this, a reporting standard (CARE) has been developed. Case reports published in European Heart Journal - Case reports (EHJ-CR) are subject to specific checks by editors to confirm compliance with the CARE reporting standard. However, a degree to which case reports published by EHJ-CR comply with the CARE reporting standards has not been established. METHODS: Case reports published in EHJ-CR during 2018 were reviewed for compliance with the CARE reporting standards. Two authors assessed each article for compliance with each of the 31 criteria. RESULTS: In 2018, 130 case reports/series were published by EHJ-CR. The median number of CARE criteria achieved by each article was 21 (interquartile range 21-25) out of 31. CARE criteria with the highest adherence were timeline inclusion, a clear and well-referenced discussion, and declaration of competing interests, all present in 100% of articles. In contrast, some aspects were poorly adhered to including patient perspective, and details of funding sources. There was no difference in overall compliance with aspects of the CARE standard between diagnostic and interventional case reports. However, lower compliance was seen for the discussion of diagnostic challenges in interventional studies (19%), when compared to diagnostic studies (44%). The continent of authorship and month submitted did not affect CARE adherence. CONCLUSIONS: There was good compliance with the CARE reporting standards by case reports published in EHJ-CR. A number of specific areas for improvement have been identified which will be considered by the editorial board of EHJ-CR.

Supersaturated proteins are enriched at synapses and underlie cell and tissue vulnerability in Alzheimer's disease.

Neurodegenerative disorders progress across the brain in characteristic spatio-temporal patterns. A better understanding of the factors underlying the specific cell and tissue vulnerability responsible for such patterns could help identify the molecular origins of these conditions. To investigate these factors, based on the observation that neurodegenerative disorders are closely associated with the presence of aberrant protein deposits, we made the hypothesis that the vulnerability of cells and tissues is associated to the overall levels of supersaturated proteins, which are those most metastable against aggregation. By analyzing single-cell transcriptomic and subcellular proteomics data on healthy brains of ages much younger than those typical of disease onset, we found that the most supersaturated proteins are enriched in cells and tissues that succumb first to neurodegeneration. Then, by focusing the analysis on a metastable subproteome specific to Alzheimer's disease, we show that it is possible to recapitulate the pattern of disease progression using data from healthy brains. We found that this metastable subproteome is significantly enriched for synaptic processes and mitochondrial energy metabolism, thus rendering the synaptic environment dangerous for aggregation. The present identification of protein supersaturation as a signature of cell and tissue vulnerability in neurodegenerative disorders could facilitate the search for effective treatments by providing clearer points of intervention.

A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology.

Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.

Spinal motor neuron protein supersaturation patterns are associated with inclusion body formation in ALS.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous degenerative motor neuron disease linked to numerous genetic mutations in apparently unrelated proteins. These proteins, including SOD1, TDP-43, and FUS, are highly aggregation-prone and form a variety of intracellular inclusion bodies that are characteristic of different neuropathological subtypes of the disease. Contained within these inclusions are a variety of proteins that do not share obvious characteristics other than coaggregation. However, recent evidence from other neurodegenerative disorders suggests that disease-affected biochemical pathways can be characterized by the presence of proteins that are supersaturated, with cellular concentrations significantly greater than their solubilities. Here, we show that the proteins that form inclusions of mutant SOD1, TDP-43, and FUS are not merely a subset of the native interaction partners of these three proteins, which are themselves supersaturated. To explain the presence of coaggregating proteins in inclusions in the brain and spinal cord, we observe that they have an average supersaturation even greater than the average supersaturation of the native interaction partners in motor neurons, but not when scores are generated from an average of other human tissues. These results suggest that inclusion bodies in various forms of ALS result from a set of proteins that are metastable in motor neurons, and thus prone to aggregation upon a disease-related progressive collapse of protein homeostasis in this specific setting.

A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease.

In Alzheimer's disease, aggregates of Aß and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aß and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease.

A transcriptional signature of Alzheimer's disease is associated with a metastable subproteome at risk for aggregation.

It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer's disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction. To address this problem in a systematic manner, we performed a meta-analysis of about 1,600 microarrays from human central nervous system tissues to identify transcriptional changes upon aging and as a result of Alzheimer's disease. Our strategy to discover a transcriptional signature of Alzheimer's disease revealed a set of down-regulated genes that encode proteins metastable to aggregation. Using this approach, we identified a small number of biochemical pathways, notably oxidative phosphorylation, enriched in proteins vulnerable to aggregation in control brains and encoded by genes down-regulated in Alzheimer's disease. These results suggest that the down-regulation of a metastable subproteome may help mitigate aberrant protein aggregation when protein homeostasis becomes compromised in Alzheimer's disease.