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ObjectivesTo investigate psychotropic prescribing in the intellectual disabilities population over 10 years, and associated mental ill health diagnoses.DesignComparison of cross-sectional data in 2002–2004 (T1) and 2014 (T2). Longitudinal cohort study with detailed health assessments at T1 and record linkage to T2 prescribing data.SettingGeneral community.Participants1190 adults with intellectual disabilities in T1 compared with 3906 adults with intellectual disabilities in T2. 545/1190 adults with intellectual disabilities in T1 were alive and their records linked to T2 prescribing data.Main outcome measuresEncashed regular and as-required psychotropic prescriptions.Results50.7% (603/1190) of adults in T1 and 48.2% (1881/3906) in T2 were prescribed at least one psychotropic; antipsychotics: 24.5% (292/1190) in T1 and 16.7% (653/3906) in T2; antidepressants: 11.2% (133/1190) in T1 and 19.1% (746/3906) in T2. 21.2% (62/292) prescribed antipsychotics in T1 had psychosis or bipolar disorder, 33.2% (97/292) had no mental ill health or problem behaviours, 20.6% (60/292) had problem behaviours but no psychosis or bipolar disorder. Psychotropics increased from 47.0% (256/545) in T1 to 57.8% (315/545) in T2 (p<0.001): antipsychotics did not change (OR 1.18; 95% CI 0.87 to 1.60; p=0.280), there was an increase for antidepressants (OR 2.80; 95% CI 1.96 to 4.00; p<0.001), hypnotics/anxiolytics (OR 2.19; 95% CI 1.34 to 3.61; p=0.002), and antiepileptics (OR 1.40; 95% CI 1.06 to 1.84; p=0.017). Antipsychotic prescribing increased for people with problem behaviours in T1 (OR 6.45; 95% CI 4.41 to 9.45; p<0.001), more so than for people with other mental ill health in T1 (OR 4.11; 95% CI 2.76 to 6.11; p<0.001).ConclusionsDespite concerns about antipsychotic prescribing and guidelines recommending their withdrawal, it appears that while fewer antipsychotic prescriptions were initiated by T2 than in T1, people were not withdrawn from them once commenced. People with problem behaviours had increased prescribing. There was also a striking increase in antidepressant prescriptions. Adults with intellectual disabilities need frequent and careful medication reviews.

BackgroundWe investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals.Methods and resultsOne hundred and sixty-eight patients were evaluated 28–60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p<0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14–165) vs 112 mg/L (52–181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2–6) vs 6 days (3–12)).In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28–60 days postdischarge).After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934).ConclusionHealthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome.Trial registration numberNCT04403607.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [ 11 C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = −6.5 to 24.1%) and 3.8% (95% confidence interval = −11.9 to 9.4) lay within the pre-specified −17% margin for non-inferiority ( P  = 0.00055 and P  = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA. Comparison of non-invasive [ 11 C]metomidate PET-CT with adrenal vein sampling for predicting biochemical remission of primary aldosteronism showed non-superiority, suggesting that the non-invasive method is suitable for the diagnosis of unilateral primary aldosteronism.

Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage 1 , 2 . Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS–PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus . Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation. How MICL recognizes and autoregulates the formation of neutrophil extracellular traps is explored in mouse models and human patients where disease severity is associated with aberrant neutrophil extracellular trap formation.

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607 ). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28–60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls ( n  = 29), at 28–60 days post-discharge, people with COVID-19 ( n  = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was ‘very likely’ in 21 (13%) patients, ‘probable’ in 65 (41%) patients, ‘unlikely’ in 56 (35%) patients and ‘not present’ in 17 (11%) patients. At 28–60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P  < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care ( P  = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future. Deep clinical phenotyping at 28–60 days post-discharge of patients who had been hospitalized with COVID-19 and subsequent long-term follow-up with electronic health records reveal evidence of persistent cardio-renal involvement.

IntroductionWe aimed to understand the impact of being a healthcare worker on the progression and outcomes of illness in individuals hospitalised because of post-COVID-19 complications.Materials and MethodsThe CISCO-19 study included patients hospitalised with COVID-19 and assessed baseline characteristics at index and multi-system phenotyping 28–60 days following discharge from hospital. Our analysis sought to compare the health and recovery metrics of healthcare workers within this cohort against those of non-healthcare professionals, considering variables like age, gender, cardiovascular risk, and severity of inflammation.ResultsA total of 168 patients, 28–60 days post their last hospital care, were assessed. Among them, 36 identified as healthcare workers. Comparatively, healthcare workers were found to be predominantly of a similar age to non-healthcare workers but had a higher proportion of females. In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (odds ratio: 2.99; 95% confidence interval (1.01, 8.89) by 28–60 days post-discharge.After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were re-hospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934).DiscussionAlmost one-quarter of the patients were healthcare workers and they were mostly women. Despite less severe acute illness and better antecedent health, compared with non-healthcare workers, healthcare workers had a 3-fold higher likelihood of adjudicated myocarditis, reflecting deep organ involvement of COVID-19. The aetiology of myocardial inflammation may be direct viral myocarditis or myocardial inflammation reflecting multisystem illness. Reverse causality may be relevant in that individuals with reasonably good background health have a greater reserve to withstand COVID-19 such that in those individuals who eventually become sufficiently unwell to require hospital care, the severity of COVID-19 is more pronounced. Healthcare workers have enhanced occupational exposure to SARS-CoV-2 in their workplace which may explain why healthcare workers had evidence of systemic involvement in deep organs, i.e., myocarditis, despite seemingly lower levels of systemic inflammation reflected by CRP.Abstract 12 Figure 1ConclusionHealthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome.AcknowledgementsThis was an investigator-initiated clinical study funded by the Chief Scientist Office of the Scottish Government (COV/GLA/Portfolio project number 311300). The funder had no role in the design, conduct (non-voting TSC member), data analysis and interpretation, manuscript writing, or dissemination of the results. C.B, C.D., N.S., R.M.T. were supported by the British Heart Foundation (RE/18/6134217).The MRI study involved technologies provided by Siemens Healthcare and the National Institutes of Health. HeartFlow (HeartFlow, Redwood City, CA) provided FFRCT. The study was co-sponsored by NHS Greater Glasgow & Clyde Health Board and the University of Glasgow.

This thesis aims to develop and implement population genetic models that are directly interpretable in terms of events such as population fission and admixture. Two competing methods of approximating the Wright--Fisher model of genetic drift are critically examined, one due to Balding and Nichols and another to Nicholson and colleagues. The model of population structure consisting of all present-day subpopulations arising from a common ancestral population at a single fission event (first described by Nicholson et al.) is reimplemented and applied to single-nucleotide polymorphism data from the HapMap project. This Bayesian hierarchical model is then elaborated to allow general phylogenetic representations of the genetic heritage of present-day subpopulations and the performance of this model is assessed on simulated and HapMap data. The drift model of Balding and Nichols is found to be problematic for use in this context as the need for allele fixation to be modelled becomes apparent. The model is then further developed to allow the inclusion of admixture events. This new model is, again, demonstrated using HapMap data and its performance compared to that of the TreeMix model of Pickrell and Pritchard, which is also critically evaluated.

Abstract Background In post-coronavirus disease-19 (post-COVID-19) conditions (long COVID), systemic vascular dysfunction is implicated, but the mechanisms are uncertain, and the treatment is imprecise. Methods and results Patients convalescing after hospitalization for COVID-19 and risk factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated. Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) 3 months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (P = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (P < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries {Masson's trichrome (MT) 69.7% [95% confidence interval (CI): 67.8–71.7]; picrosirius red 68.6% [95% CI: 64.4–72.8]} vs. controls [MT 64.9% (95% CI: 59.4–70.3) (P = 0.028); picrosirius red 60.1% (95% CI: 55.4–64.8), (P = 0.029)]. Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9–49.3) vs. controls (10.0%; 95% CI: 4.4–15.6) (P < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated. Conclusion Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials. Graphical Abstract Graphical Abstract Schematic illustration of the potential mechanisms affecting vascular smooth muscle cells and systemic vascular dysfunction that may contribute to impaired functional status and aerobic exercise capacity in post-COVID-19 conditions.

BackgroundThe radiological trajectory of post-COVID-19 is uncertain. We present a prospective, observational, multicentre cohort study using multimodality imaging to describe the pulmonary sequelae of patients hospitalised with COVID-19, predictors of persistent abnormal radiology and implications on health status.MethodsIn survivors of COVID-19, we performed convalescent CT pulmonary angiogram and high-resolution CT imaging as part of the CISCO-19 study (ClinicalTrials.gov ID NCT04403607). This included serial blood biomarkers and patient-reported outcomes 28–60 days following discharge from hospital.ResultsOf the COVID-19 cohort, 88 (56%) patients of the COVID-19 cohort (n = 159; mean age, 55 years; 43% female) had persisting radiological abnormalities at 28–60 days postdischarge. This included ground-glass opacification (45%), reticulation/architectural distortion (30%) or mixed pattern (19%). These features were very infrequent among a group of age-matched, sex-matched and cardiovascular risk factor-matched controls (n=29). The majority of COVID-19 cohort (68%) had less than 20% persisting radiological abnormalities, with 67% demonstrating overall improvement compared with admission imaging. Older age, premorbid performance status, typical acute COVID-19 radiological features, markers of severe acute COVID-19, convalescent ICAM-1 and P-selectin were associated with persisting lung abnormalities (all p<0.05). Patients with persisting abnormalities were shown to have lower levels of physical activity and predicted maximal oxygen utilisation (derived VO2) (both p<0.05). Higher percentage of abnormal lung parenchyma was associated with lower patient-assessed quality of life (EQ-5D-5L) score (p=0.03).ConclusionsPersistent radiological abnormalities post-COVID-19 were common at 28–60 days postdischarge from hospital, although most improved. Patients with persisting radiological abnormalities 28–60 days postdischarge are at risk of persisting health impairment in the longer term and represent a population for targeted intervention.Trial registration numberNCT04403607.