The effect of relative hypotension on 30-day mortality in older people receiving emergency care

Research has observed increased mortality among older people attending the emergency department (ED) who had systolic pressure > 7 mmHg lower than baseline primary care values. This study aimed to (1) assess feasibility of identifying this ‘relative hypotension’ using readily available ED data, (2) externally validate the 7 mmHg threshold, and (3) refine a threshold for clinically important relative hypotension. A single-centre retrospective cohort study linked year 2019 data for ED attendances by people aged over 64 to hospital discharge vital signs within the previous 18 months. Frailty and comorbidity scores were calculated. Previous discharge (‘baseline’) vital signs were subtracted from initial ED values to give individuals’ relative change. Cox regression analysis compared relative hypotension > 7 mmHg with mean time to mortality censored at 30 days. The relative hypotension threshold was refined using a fully adjusted risk tool formed of logistic regression models. Receiver operating characteristics were compared to NEWS2 models with and without incorporation of relative systolic. 5136 (16%) of 32,548 ED attendances were linkable with recent discharge vital signs. Relative hypotension > 7 mmHg was associated with increased 30-day mortality (HR 1.98; 95% CI 1.66–2.35). The adjusted risk tool (AUC: 0.69; sensitivity: 0.61; specificity: 0.68) estimated each 1 mmHg relative hypotension to increase 30-day mortality by 2% (OR 1.02; 95% CI 1.02–1.02). 30-day mortality prediction was marginally better with NEWS2 (AUC: 0.73; sensitivity: 0.59; specificity: 0.78) and NEWS2 + relative systolic (AUC: 0.74; sensitivity: 0.63; specificity: 0.75). Comparison of ED vital signs with recent discharge observations was feasible for 16% individuals. The association of relative hypotension > 7 mmHg with 30-day mortality was externally validated. Indeed, any relative hypotension appeared to increase risk, but model characteristics were poor. These findings are limited to the context of older people with recent hospital admissions

Paediatric brain MRI findings following congenital heart surgery: a systematic review.

OBJECTIVE: This systematic review aimed to establish the relative incidence of new postoperative brain MRI findings following paediatric congenital cardiac surgery. DESIGN: To distinguish perioperative changes from pre-existing MR findings, our systematic search strategy focused on identifying original research studies reporting both presurgery and postsurgery brain MRI scans. Patient demographics, study methods and brain MR findings were extracted. RESULTS: Twenty-one eligible publications, including two case-control and one randomised controlled trial, were identified. Pre-existing brain MRI findings were noted in 43% (513/1205) of neonates prior to surgery, mainly white matter injuries (WMI). Surgery was performed at a median age of 8 days with comparison of preoperative and postoperative MR scans revealing additional new postoperative findings in 51% (550/1075) of patients, mainly WMI. Four studies adopted a brain injury scoring system, but the majority did not indicate the severity or time course of findings. In a subgroup analysis, approximately 32% of patients with pre-existing lesions went on to develop additional new lesions postsurgery. Pre-existing findings were not found to confer a higher risk of acquiring brain lesions postoperatively. No evidence was identified linking new MR findings with later neurodevelopmental delay. CONCLUSION: This systematic review suggests that surgery approximately doubles the number of patients with new brain lesions

Three-dimensional simulations of embolic stroke and an equation for sizing emboli from imaging

Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Antihypertensives in dementia: Good or bad for the brain?

Hypertension is associated with both ageing and dementia. Despite this, optimal blood pressure targets in dementia remain unclear. Both high and low blood pressure are associated with poorer cognition. Changes in vascular physiology in dementia may increase the vulnerability of the brain to hypoperfusion associated with antihypertensives. We discuss the potential risks of antihypertensives in the context of altered cerebral haemodynamics, and evidence from antihypertensive trials in dementia. We suggest that individualised blood pressure targets should be the focus for antihypertensive therapy in dementia, rather than strict control to uniform targets extrapolated from trials in cognitively healthy individuals. </jats:p

Polygenic risk-stratified screening for cancer: Responsibilization in public health genomics

In this article, we examine professional discourse around the development of polygenic risk-stratified screening (PRSS) for cancer. Analyzing a range of contemporary professional literatures from Europe, North America and Australia, we explore how the drive to screen for molecular markers of cancer risk makes professionals, screening recipients and publics responsible, in different ways, for acquiring, curating and analyzing molecular data. Investigating how these responsibilities are invoked in discussions of new data practices, technologies, organizational arrangements, engagement, education and protocols for participation, we argue that agendas for PRSS for cancer are both expanding and stratifying responsibilities. Data collection is to be achieved by intensified responsibilities for including, reassuring and recruiting populations, as well as by opening and enriching the datasets on which models and preventative screening arrangements are based. Enhanced responsibilities for screening recipients and publics are also invoked, not just in relation to personal health but for population health more generally, via research participation and consenting to data re-use in the public interest. Professionals, screening recipients and publics are also to become responsible for moderating expectations of screening according to genomic designations. Together these discourses go beyond individual risk management to extend and diversify the responsibilities of practitioners, screening recipients and publics as public health genomics develops

Principal component analysis to identify the major contributors to task-activated neurovascular responses

Background: Consensus on the optimal metrics for neurovascular coupling (NVC) is lacking. The aim of this study was to use principal component analysis (PCA) to determine the most significant contributors to NVC responses in healthy adults (HC), Alzheimer's disease (AD), and mild cognitive impairment (MCI). New method: PCA was applied to three datasets: 1) 69 HC, 2) 30 older HC, 34 AD, and 22 MCI, 3) 1&2 combined. Data were extracted on peak percentage change in cerebral blood flow velocity (CBFv), variance ratio (VR), cross-correlation function peak (CCF), and blood pressure, for five cognitive tasks. An equamax rotation was applied and factors were significant where the eignevalue was ≥1. Rotated factor loadings ≥0.4 determined significant NVC variables. Results: PCA identified 12 significant factors accounting for 78% of variance (all datasets). Contributing variables loaded differently on the factors across the datasets. In datasets 1&2, peak percentage change in CBFv contributed to factors explaining the most variance (45–58%), whereas cognitive test scores, fluency and memory domains contributed the least (15–37%). In the combined dataset, CBFv, CCF and fluency domain contributed the majority (33–43%), whereas VR and attention the least (6–24%). Conclusions: Peak percentage change in CBFv and the visuospatial task consistently accounted for a large proportion of the variance, suggesting these are robust NVC markers for future studies