RESUMO
Human adult muscle-type acetylcholine receptors are heteropentameric ion channels formed from four different, but evolutionarily related, subunits. These subunits assemble with a precise stoichiometry and arrangement such that two chemically distinct agonist-binding sites are formed between specific subunit pairs. How this subunit complexity evolved and became entrenched is unclear. Here we show that a single historical amino acid substitution is able to constrain the subunit stoichiometry of functional acetylcholine receptors. Using a combination of ancestral sequence reconstruction, single-channel electrophysiology, and concatenated subunits, we reveal that an ancestral ß-subunit can not only replace the extant ß-subunit but can also supplant the neighboring δ-subunit. By forward evolving the ancestral ß-subunit with a single amino acid substitution, we restore the requirement for a δ-subunit for functional channels. These findings reveal that a single historical substitution necessitates an increase in acetylcholine receptor complexity and, more generally, that simple stepwise mutations can drive subunit entrenchment in this model heteromeric protein.
Assuntos
Substituição de Aminoácidos , Multimerização Proteica , Receptores Nicotínicos/genética , Linhagem Celular , Evolução Molecular , Humanos , Ligação Proteica , Domínios Proteicos , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismoAssuntos
COVID-19/epidemiologia , Ilustração Médica , Pandemias , Telemedicina , Humanos , SARS-CoV-2RESUMO
Mental health services continue to experience rising demand that exceeds capacity. The COVID-19 pandemic exacerbated this crisis, with access to services being reduced. Although video consultations (VCs) are a solution, usage in UK community mental healthcare settings remains limited. This study aims to investigate psychiatrists' and general practitioners' (GPs) perceptions of the benefits and challenges of VC for the diagnosis and follow-up of general adult mental health patients in the community during the COVID-19 pandemic. Semi-structured interviews in NHS community mental healthcare settings were conducted. Psychiatrists (n = 11) and GPs (n = 12) were recruited through purposive sampling. An explorative qualitative approach was employed. Data were analysed using thematic analysis. Four key themes were identified: (1) patient access to VC, (2) suitability of VC for mental health consultations, (3) information gathering with VC and (4) clinician satisfaction with VC. This study provides valuable insights into the experiences of psychiatrists and GPs working in the UK during the COVID-19 pandemic. To facilitate a digital-first future for the NHS, greater investment in remote technologies is required, particularly in the context of growing mental healthcare demand. Though face-to-face consultations remain the gold standard, VC provides an efficient way of communicating with patients, particularly those with less severe forms of mental illness.
Assuntos
COVID-19 , Saúde Mental , Adulto , Humanos , Pandemias , COVID-19/diagnóstico , COVID-19/epidemiologia , Encaminhamento e Consulta , Pesquisa Qualitativa , Teste para COVID-19RESUMO
Optimal performance is desired for decision-making in any field with binary classifiers and diagnostic tests, however common performance measures lack depth in information. The area under the receiver operating characteristic curve (AUC) and the area under the precision recall curve are too general because they evaluate all decision thresholds including unrealistic ones. Conversely, accuracy, sensitivity, specificity, positive predictive value and the F1 score are too specific-they are measured at a single threshold that is optimal for some instances, but not others, which is not equitable. In between both approaches, we propose deep ROC analysis to measure performance in multiple groups of predicted risk (like calibration), or groups of true positive rate or false positive rate. In each group, we measure the group AUC (properly), normalized group AUC, and averages of: sensitivity, specificity, positive and negative predictive value, and likelihood ratio positive and negative. The measurements can be compared between groups, to whole measures, to point measures and between models. We also provide a new interpretation of AUC in whole or part, as balanced average accuracy, relevant to individuals instead of pairs. We evaluate models in three case studies using our method and Python toolkit and confirm its utility.
RESUMO
BACKGROUND: Stoma closure is a widely performed surgical procedure, with 6295 undertaken in England in 2018 alone. This procedure is associated with significant complications; incisional hernias are the most severe, occurring in 30% of patients. Complications place considerable financial burden on the NHS; hernia costs are estimated at GBP 114 million annually. As recent evidence (ROCSS, 2020) found that prophylactic meshes significantly reduce rates of incisional hernias following stoma closure surgery, an evaluation of this intervention vs. standard procedure is essential. METHODS: A cost-utility analysis (CUA) was conducted using data from the ROCSS prospective multi-centre trial, which followed 790 patients, randomly assigned to mesh closure (n = 394) and standard closure (n = 396). Quality of life was assessed using mean EQ-5D-3L scores from the trial, and costs in GBP using UK-based sources over a 2-year time horizon. RESULTS: The CUA yielded an incremental cost-effectiveness ratio (ICER) of GBP 128,356.25 per QALY. Additionally, three univariate sensitivity analyses were performed to test the robustness of the model. CONCLUSION: The results demonstrate an increased benefit with mesh prophylaxis, but at an increased cost. Although the intervention is cost-ineffective and greater than the ICER threshold of GBP 30,000/QALY (NICE), further investigation into mesh prophylaxis for at risk population groups is needed.