ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.

BACKGROUND: Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy. METHODS: Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379). RESULTS: Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549). CONCLUSIONS: Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.

Phl p 5 levels more strongly associated than grass pollen counts with allergic respiratory health.

BACKGROUND: Studies have linked daily pollen counts to respiratory allergic health outcomes, but few have considered allergen levels. OBJECTIVE: We sought to assess associations of grass pollen counts and grass allergen levels (Phl p 5) with respiratory allergic health symptoms in a panel of 93 adults with moderate-severe allergic rhinitis and daily asthma hospital admissions in London, United Kingdom. METHODS: Daily symptom and medication scores were collected from adult participants in an allergy clinical trial. Daily counts of asthma hospital admissions in the London general population were obtained from Hospital Episode Statistics data. Daily grass pollen counts were measured using a volumetric air sampler, and novel Phl p 5 levels were measured using a ChemVol High Volume Cascade Impactor and ELISA analyses (May through August). Associations between the 2 pollen variables and daily health scores (dichotomized based on within-person 75th percentiles) were assessed using generalized estimating equation logistic models and with asthma hospital admissions using Poisson regression models. RESULTS: Daily pollen counts and Phl p 5 levels were each positively associated with reporting a high combined symptom and medication health score in separate models. However, in mutually adjusted models including terms for both pollen counts and Phl p 5 levels, associations remained for Phl p 5 levels (odds ratio [95% CI]: 1.18 [1.12, 1.24]), but were heavily attenuated for pollen counts (odds ratio [95% CI]: 1.00 [0.93, 1.07]). Similar trends were not observed for asthma hospital admissions in London. CONCLUSIONS: Grass allergen (Phl p 5) levels are more consistently associated with allergic respiratory symptoms than grass pollen counts.

The impact of outpatient versus inpatient management on health-related quality of life outcomes for patients with malignant pleural effusion: the OPTIMUM randomised clinical trial.

BACKGROUND: The principal aim of malignant pleural effusion (MPE) management is to improve health-related quality of life (HRQoL) and symptoms. METHODS: In this open-label randomised controlled trial, patients with symptomatic MPE were randomly assigned to either indwelling pleural catheter (IPC) insertion with the option of talc pleurodesis or chest drain and talc pleurodesis. The primary end-point was global health status, measured with the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) at 30 days post-intervention. 142 participants were enrolled from July 2015 to December 2019. RESULTS: Of participants randomly assigned to the IPC (n=70) and chest drain (n=72) groups, primary outcome data were available in 58 and 56 patients, respectively. Global health status improved in both groups at day 30 compared with baseline: IPC (mean difference 13.11; p=0.001) and chest drain (mean difference 10.11; p=0.001). However, there was no significant between-group difference at day 30 (mean intergroup difference in baseline-adjusted global health status 2.06, 95% CI -5.86-9.99; p=0.61), day 60 or day 90. No significant differences were identified between groups in breathlessness and chest pain scores. All chest drain arm patients were admitted (median length of stay 4 days); seven patients in the IPC arm required intervention-related hospitalisation. CONCLUSIONS: While HRQoL significantly improved in both groups, there were no differences in patient-reported global health status at 30 days. The outpatient pathway using an IPC was not superior to inpatient treatment with a chest drain.

Application of information from external data to correct for collider bias in a Covid-19 hospitalised cohort.

BACKGROUND: Throughout the Covid-19 pandemic, researchers have made use of electronic health records to research this disease in a rapidly evolving environment of questions and discoveries. These studies are prone to collider bias as they restrict the population of Covid-19 patients to only those with severe disease. Inverse probability weighting is typically used to correct for this bias but requires information from the unrestricted population. Using electronic health records from a South London NHS trust, this work demonstrates a method to correct for collider bias using externally sourced data while examining the relationship between minority ethnicities and poor Covid-19 outcomes. METHODS: The probability of inclusion within the observed hospitalised cohort was modelled based on estimates from published national data. The model described the relationship between patient ethnicity, hospitalisation, and death due to Covid-19 - a relationship suggested to be susceptible to collider bias. The obtained probabilities (as applied to the observed patient cohort) were used as inverse probability weights in survival analysis examining ethnicity (and covariates) as a risk factor for death due to Covid-19. RESULTS: Within the observed cohort, unweighted analysis of survival suggested a reduced risk of death in those of Black ethnicity - differing from the published literature. Applying inverse probability weights to this analysis amended this aberrant result to one more compatible with the literature. This effect was consistent when the analysis was applied to patients within only the first wave of Covid-19 and across two waves of Covid-19 and was robust against adjustments to the modelled relationship between hospitalisation, patient ethnicity, and death due to Covid-19 made as part of a sensitivity analysis. CONCLUSIONS: In conclusion, this analysis demonstrates the feasibility of using external publications to correct for collider bias (or other forms of selection bias) induced by the restriction of a population to a hospitalised cohort using an example from the recent Covid-19 pandemic.

Predicting progression to Alzheimer's disease with human hippocampal progenitors exposed to serum.

Adult hippocampal neurogenesis is important for learning and memory and is altered early in Alzheimer's disease. As hippocampal neurogenesis is modulated by the circulatory systemic environment, evaluating a proxy of how hippocampal neurogenesis is affected by the systemic milieu could serve as an early biomarker for Alzheimer's disease progression. Here, we used an in vitro assay to model the impact of systemic environment on hippocampal neurogenesis. A human hippocampal progenitor cell line was treated with longitudinal serum samples from individuals with mild cognitive impairment, who either progressed to Alzheimer's disease or remained cognitively stable. Mild cognitive impairment to Alzheimer's disease progression was characterized most prominently with decreased proliferation, increased cell death and increased neurogenesis. A subset of 'baseline' cellular readouts together with education level were able to predict Alzheimer's disease progression. The assay could provide a powerful platform for early prognosis, monitoring disease progression and further mechanistic studies.

Prevalence, Associated Factors, and Outcomes of Severe Acute Kidney Injury in Pediatric Acute Liver Failure: Single-Center Retrospective Study, 2003-2017.

OBJECTIVES: Our aim was to determine the prevalence and explanatory factors associated with outcomes in children with acute liver failure (ALF) admitted to the PICU, who also develop severe acute kidney injury (AKI). DESIGN: Retrospective cohort, 2003 to 2017. SETTING: Sixteen-bed PICU in a university-affiliated tertiary care hospital. PATIENTS: Admissions to the PICU with ALF underwent data review of the first week and at least 90-day follow-up. Patients with stages 2-3 AKI using the British Association of pediatric Nephrology definitions, or receiving continuous renal replacement therapy (CRRT) for renal indications, were defined as severe AKI. We excluded ALF cases on CRRT for hepatic-only indications. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline characteristics, proportion with severe AKI, illness severity and interventions, and outcomes (i.e., transplant, survival with native liver, overall survival, duration of PICU stay, and mechanical ventilation). Ninety-four children with ALF admitted to the PICU were included. Over the first week, 29 had severe AKI, and another eight received CRRT for renal/mixed reno-hepatic indications; hence, the total severe AKI cohort was 37 of 94 (39.4%). In a multivariable logistic regression model, peak aspartate aminotransferase (AST) and requirement for inotropes on arrival were associated with severe AKI. Severe AKI was associated with longer PICU stay and duration of ventilation, and lower spontaneous survival with native liver. In another model, severe AKI was associated with greater odds of mortality (odds ratio 7.34 [95% CI, 1.90-28.28], p = 0.004). After 90 days, 3 of 17 survivors of severe AKI had serum creatinine greater than the upper limit of normal for age. CONCLUSIONS: Many children with ALF in the PICU develop severe AKI. Severe AKI is associated with the timecourse of PICU admission and outcome, including survival with native liver. Future work should look at ALF goal directed renoprotective strategies at the time of presentation.

A systematic review of the incidence and outcomes of ICD-11 defined stroke.

BACKGROUND: The World Health Organisation has expanded the definition of stroke to include people with symptoms less than 24 h if they have evidence of stroke on neuroimaging. The impact is that people previously diagnosed as having a transient ischaemic attack (TIA) would now be considered to have had a stroke. This change will impact incidence and outcomes of stroke and increase eligibility for secondary prevention. We aimed to evaluate the new ICD-11 criteria retrospectively to previous TIA studies to understand the change in incidence and outcomes of this type of stroke. METHODS: We conducted a systematic review of observational studies of the incidence and outcomes of clinically defined TIA. We searched PubMed, EMBASE, and Google Scholar from inception to 23rd May 2023. Study quality was assessed using a risk of bias tool for prevalence studies. FINDINGS: Our review included 25 studies. The rate of scan positivity for stroke among those with clinically defined TIA was 24 %, (95 % CI, 16-33 %) but with high heterogeneity (I2 = 100 %, p <0.001). Sensitivity analyses provided evidence that heterogeneity could be explained by methodology and recruitment method. The scan positive rate when examining only studies at low risk of bias was substantially lower, at 13 % (95 % CI, 11-15 %, I2 = 0, p = 0.77). We estimate from population-based incidence studies that ICD-11 would result in an increase stroke incidence between 4.8 and 10.5 per 100,000 persons/year. Of those with DWI-MRI evidence of stroke, 6 % (95 % CI, 3-11 %) developed a recurrent stroke in the subsequent 90 days, but with substantial heterogeneity (I2 = 67 %, p = 0.02). CONCLUSION: The impact of the ICD-11 change in stroke definition on incidence and outcomes may have been overestimated by individual studies. Community-based stroke services with access to DWI MRI are likely to accurately diagnose greater numbers of people with mild ICD-11 stroke, increasing access to effective prevention.

Low dose interleukin-2 selectively expands circulating regulatory T cells but fails to promote liver allograft tolerance in humans.

BACKGROUND & AIMS: CD4+CD25+Foxp3+ regulatory T cells (Tregs) are essential to maintain immunological tolerance and have been shown to promote liver allograft tolerance in both rodents and humans. Low-dose IL-2 (LDIL-2) can expand human endogenous circulating Tregs in vivo, but its role in suppressing antigen-specific responses and promoting Treg trafficking to the sites of inflammation is unknown. Likewise, whether LDIL-2 facilitates the induction of allograft tolerance has not been investigated in humans. METHODS: We conducted a clinical trial in stable liver transplant recipients 2-6 years post-transplant to determine the capacity of LDIL-2 to suppress allospecific immune responses and allow for the complete discontinuation of maintenance immunosuppression (ClinicalTrials.gov NCT02949492). One month after LDIL-2 was initiated, those exhibiting at least a 2-fold increase in circulating Tregs gradually discontinued immunosuppression over a 4-month period while continuing LDIL-2 for a total treatment duration of 6 months. RESULTS: All participants achieved a marked and sustained increase in circulating Tregs. However, this was not associated with the preferential expansion of donor-reactive Tregs and did not promote the accumulation of intrahepatic Tregs. Furthermore, LDIL-2 induced a marked IFNγ-orchestrated transcriptional response in the liver even before immunosuppression weaning was initiated. The trial was terminated after the first 6 participants failed to reach the primary endpoint owing to rejection requiring reinstitution of immunosuppression. CONCLUSIONS: The expansion of circulating Tregs in response to LDIL-2 is not sufficient to control alloimmunity and to promote liver allograft tolerance, due, at least in part, to off-target effects that increase liver immunogenicity. Our trial provides unique insight into the mechanisms of action of immunomodulatory therapies such as LDIL-2 and their limitations in promoting alloantigen-specific effects and immunological tolerance. CLINICAL TRIALS REGISTRATION: The study is registered at ClinicalTrials.gov (NCT02949492). IMPACT AND IMPLICATIONS: The administration of low-dose IL-2 is an effective way of increasing the number of circulating regulatory T cells (Tregs), an immunosuppressive lymphocyte subset that is key for the establishment of immunological tolerance, but its use to promote allograft tolerance in the setting of clinical liver transplantation had not been explored before. In liver transplant recipients on tacrolimus monotherapy, low-dose IL-2 effectively expanded circulating Tregs but did not increase the number of Tregs with donor specificity, nor did it promote their trafficking to the transplanted liver. Low-dose IL-2 did not facilitate the discontinuation of tacrolimus and elicited, as an off-target effect, an IFNγ-orchestrated inflammatory response in the liver that resembled T cell-mediated rejection. These results, supporting an unexpected role for IL-2 in regulating the immunogenicity of the liver, highlight the need to carefully evaluate systemic immunoregulatory strategies with investigations that are not restricted to the blood compartment and involve target tissues such as the liver.

Estimating the attributable fraction of mortality from acute respiratory distress syndrome to inform enrichment in future randomised clinical trials.

BACKGROUND: Efficiency of randomised clinical trials of acute respiratory distress syndrome (ARDS) depends on the fraction of deaths attributable to ARDS (AFARDS) to which interventions are targeted. Estimates of AFARDS in subpopulations of ARDS could improve design of ARDS trials. METHODS: We performed a matched case-control study using the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE cohort. Primary outcome was intensive care unit mortality. We used nearest neighbour propensity score matching without replacement to match ARDS to non-ARDS populations. We derived two separate AFARDS estimates by matching patients with ARDS to patients with non-acute hypoxaemic respiratory failure (non-AHRF) and to patients with AHRF with unilateral infiltrates only (AHRF-UL). We also estimated AFARDS in subgroups based on severity of hypoxaemia, number of lung quadrants involved and hyperinflammatory versus hypoinflammatory phenotypes. Additionally, we derived AFAHRF estimates by matching patients with AHRF to non-AHRF controls, and AFAHRF-UL estimates by matching patients with AHRF-UL to non-AHRF controls. RESULTS: Estimated AFARDS was 20.9% (95% CI 10.5% to 31.4%) when compared with AHRF-UL controls and 38.0% (95% CI 34.4% to 41.6%) compared with non-AHRF controls. Within subgroups, estimates for AFARDS compared with AHRF-UL controls were highest in patients with severe hypoxaemia (41.1% (95% CI 25.2% to 57.1%)), in those with four quadrant involvement on chest radiography (28.9% (95% CI 13.4% to 44.3%)) and in the hyperinflammatory subphenotype (26.8% (95% CI 6.9% to 46.7%)). Estimated AFAHRF was 33.8% (95% CI 30.5% to 37.1%) compared with non-AHRF controls. Estimated AFAHRF-UL was 21.3% (95% CI 312.8% to 29.7%) compared with non-AHRF controls. CONCLUSIONS: Overall AFARDS mean values were between 20.9% and 38.0%, with higher AFARDS seen with severe hypoxaemia, four quadrant involvement on chest radiography and hyperinflammatory ARDS.

Cost-effectiveness of outpatient versus inpatient non-invasive ventilation setup in obesity hypoventilation syndrome: the OPIP trial.

BACKGROUND: Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective. METHODS: Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO2) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP). RESULTS: Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m2 and PaCO2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO2 (difference -0.27 kPa, 95% CI -0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI -£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference -0.006, 95% CI -0.05 to 0.04). There were no differences in secondary outcomes. DISCUSSION: There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference. TRIAL REGISTRATION NUMBERS: NCT02342899 and ISRCTN51420481.

Laparoscopic adjustable gastric banding with liraglutide in adults with obesity and type 2 diabetes (GLIDE): a pilot randomised placebo controlled trial.

INTRODUCTION: Obesity drives type 2 diabetes (T2DM) development. Laparoscopic adjustable gastric banding (LAGB) has lower weight reduction than other bariatric procedures. Liraglutide, a GLP-1 receptor agonist, improves weight and glycaemic control in patients with T2DM. This study aimed to determine the efficacy and safety of liraglutide 1.8 mg in participants undergoing LAGB. METHODS: GLIDE, a pilot randomised, double-blind, placebo-controlled trial, evaluated LAGB with either liraglutide 1.8 mg or placebo in participants with T2DM and obesity. Participants were randomised (1:1) to 6-months therapy post-LAGB, with further 6 months off-treatment follow-up. The primary outcome was change in HbA1c from randomisation to the end of treatment, secondary outcomes included body weight change. A sample size of 58 (29 per group) had 80% power to detect a 0.6% difference in HbA1c between groups. RESULTS: Twenty-seven participants were randomised to liraglutide (n = 13) or placebo (n = 14). Multivariate analysis showed no difference between placebo and liraglutide arms in HbA1c at 6 months (HbA1c:0.2 mmol/mol, -11.3, 11.6, p = 0.98) however, at 12 months HbA1c was significantly higher in the liraglutide arm (HbA1c:10.9 mmol/mol, 1.1, 20.6, p = 0.032). There was no difference between arms in weight at 6 months (BW:2.0 kg, -4.2, 8.1, p = 0.50), however, at 12 months weight was significantly higher in the liraglutide arm (BW:8.2 kg, 1.6, 14.9, p = 0.02). There were no significant differences in adverse events between groups. CONCLUSIONS: Our pilot data suggest no additional improvement in glycaemic control or BW with LAGB and liraglutide therapy. However, this trial was significantly underpowered to detect a significant change in the primary or secondary outcomes. Further trials are needed to investigate whether GLP-1 agonists, and particularly with more effective weekly agents (i.e. semaglutide or tirzepatide), are of benefit following metabolic surgery. CLINICAL TRIAL REGISTRATION: EudraCT number 2015-005402-11.

Treat-to-target urate-lowering therapy and hospitalizations for gout: results from a nationwide cohort study in England.

OBJECTIVE: To investigate associations between treat-to-target urate-lowering therapy (ULT) and hospitalizations for gout. METHODS: Using linked Clinical Practice Research Datalink and NHS Digital Hospital Episode Statistics data, we described the incidence and timing of hospitalizations for flares in people with index gout diagnoses in England from 2004-2020. Using Cox proportional hazards and propensity models, we investigated associations between ULT initiation, serum urate target attainment, colchicine prophylaxis, and the risk of hospitalizations for gout. RESULTS: Of 292 270 people with incident gout, 7719 (2.64%) had one or more hospitalizations for gout, with an incidence rate of 4.64 hospitalizations per 1000 person-years (95% CI 4.54, 4.73). There was an associated increased risk of hospitalizations within the first 6 months after ULT initiation, when compared with people who did not initiate ULT [adjusted Hazard Ratio (aHR) 4.54; 95% CI 3.70, 5.58; P < 0.001]. Hospitalizations did not differ significantly between people prescribed vs not prescribed colchicine prophylaxis in fully adjusted models. From 12 months after initiation, ULT associated with a reduced risk of hospitalizations (aHR 0.77; 95% CI 0.71, 0.83; P < 0.001). In ULT initiators, attainment of a serum urate <360 micromol/l within 12 months of initiation associated with a reduced risk of hospitalizations (aHR 0.57; 95% CI 0.49, 0.67; P < 0.001) when compared with people initiating ULT but not attaining this target. CONCLUSION: ULT associates with an increased risk of hospitalizations within the first 6 months of initiation but reduces hospitalizations in the long term, particularly when serum urate targets are achieved.

The effect of ethnicity on anatomic success following macular hole surgery: a multicentre cohort study.

PURPOSE: The purpose is to assess the effect of ethnicity on surgical macular hole closure. METHODS: A retrospective cohort study was undertaken in five UK National Health Service Hospitals. We included all patients with known ethnicity undergoing vitrectomy, internal limiting membrane peel, and gas/oil tamponade for all stages of primary full-thickness macular hole (FTMH). The primary outcome was anatomic success, defined as FTMH closure with one operation. The secondary outcome was mean change in best-corrected visual acuity (BCVA) comparing baseline with final review. RESULTS: Of 334 operations, the ethnicity profile comprised 78.7% White patients, 11.7% Black patients, 8.1% Asian patients, and 1.5% in mixed/other ethnicities. Mean age was 69.7 years with 68.5% females. Overall, 280 (83.8%) had anatomic success. Anatomic failure occurred in 38.5% of Black patients versus 12.6% of White patients (relative risk: 1.788; 95% CI: 1.012 to 3.159; P = 0.045). Overall, baseline logarithm of the minimum angle of resolution BCVA improved by 0.34, from 0.95 (95% CI: 0.894 to 1.008) to 0.62 (95% CI: 0.556 to 0.676). Mean BCVA improved by 0.35 in White patients, 0.37 in Black patients, 0.23 in Asian patients, and 0.38 in mixed/other ethnicity (P = 0.689). Greater FTMH minimum linear diameter was associated with an increased risk of anatomic failure (relative risk: 1.004; 95% CI: 1.002 to 1.005; P < 0.0001), whereas better pre-operative BCVA (F [1,19] = 162.90; P < 0.0001) and anatomic success (F [1,19] = 97.69; P < 0.0001) were associated with greater BCVA improvement. Socio-economic status did not significantly influence anatomic success or BCVA change. CONCLUSIONS: Black ethnicity is associated with an approximately twofold greater risk of failed FTMH surgery. The reasons for this difference warrant further study.

Physical multimorbidity, depressive symptoms, and social participation in adults over 50 years of age: findings from the English Longitudinal Study of Ageing.

OBJECTIVES: The aim of the current study was to identify specific patterns of physical multimorbidity and examine how these patterns associated with changes in social participation over time. METHODS: We used latent class analysis to identify clusters of physical multimorbidity in 11,391 older adults. Mixed effects regression models were used to assess associations between physical multimorbidity clusters and changes in social participation over 15 years. RESULTS: Four clusters of physical multimorbidity were identified. All physical multimorbidity clusters were associated with a reduction in cultural engagement (e.g. visits to theatre, cinema, museums) over time, with the strongest association seen in the complex/multisystem cluster (ß = -0.26, 95% CI = -0.38 to -0.15). Similar results emerged for leisure activities. Adjusting for depressive symptoms fully attenuated some associations. All physical multimorbidity clusters were associated with an increase in civic participation over time. CONCLUSIONS: Physical multimorbidity reduced some aspects of social participation over time, with specific combinations of conditions having increased risk of reductions.Supplemental data for this article is available online at http://dx.doi.org/10.1080/13607863.2021.2017847.

Cohort profile: The South London Stroke Register - a population-based register measuring the incidence and outcomes of stroke.

PURPOSE: The South London Stroke Register (SLSR) is a population-based cohort study, which was established in 1995 to study the causes, incidence, and outcomes of stroke. The SLSR aims to estimate incidence, and acute and long term needs in a multi-ethnic inner-city population, with follow-up durations for some participants exceeding 20 years. PARTICIPANTS: The SLSR aims to recruit residents of a defined area within Lambeth and Southwark who experience a first stroke. More than 7700 people have been registered since inception, and >2750 people continue to be followed up. At the 2011 census, the source population was 357,308. FINDINGS TO DATE: The SLSR was instrumental in highlighting the inequalities in risk and outcomes in the UK, and demonstrating the dramatic improvements in care quality and outcomes in recent decades. Data from the SLSR informed the UK National Audit Office in its 2005 report criticising the poor state of stroke care in England. For people living in the SLSR area the likelihood of being treated in a stroke unit increased from 19% in 1995-7 to 75% in 2007-9. The SLSR has investigated health inequalities in stroke incidence and outcome. SLSR analyses have demonstrated that lower socioeconomic status was associated with poorer outcome, and that Black people and younger people have not experienced the same improvements in stroke incidence as other groups. FUTURE PLANS: As part of an NIHR Programme Grant for Applied Research, from April 2022 the SLSR has expanded to recruit ICD-11 defined stroke (including those with <24 h symptoms where there are neuroimaging findings), and have expanded the follow up interviews to collect more detailed information on quality of life, cognition, and care needs. Additional data items will be added over the Programme based on feedback from patients and other stakeholders.

Stroke Outcomes in Women: A Population-Based Cohort Study.

BACKGROUND: Limited data are available on sex-related disparities in long-term outcomes after stroke. We estimated sex differences in various stroke long-term outcomes among survivors after stroke in a prospective 25-year follow-up study. METHODS: Individuals recruited to the South London Stroke Register, an ongoing multi-ethnic urban-based population stroke register, from 1995 onward were included in the analyses (n=6687). The outcomes were death, subsequent stroke, activity of daily living, instrumental activity of daily living, cognitive impairment, depression, anxiety, and health-related quality of life. Kaplan-Meier curves were generated for mortality, stroke recurrence, and recurrence-free survival by sex and Cox proportional hazards model used to model sex differences up to 25 years. Generalized estimating equation were used to model sex differences in risk of self-reported stroke outcomes over 10 years poststroke outcomes, adjusting for age, preexisting activity of daily living, case-mix, stroke subtypes, and other potential confounding risk factors. RESULTS: There were 49% women (mean age, 72 years; SD, 15.6) and 51% men (mean age, 67 years; SD, 14.3) in 6687 participants. Compared with men, women had 9% (95% CI, 3%-15%) lower covariate-adjusted risk of death and 6% (0%-13%) lower risk of stroke recurrence or death. Generally, women had significantly poorer outcomes in activity of daily living and anxiety than men, and the sex differences persisted to up to 5 years after stroke. Women also had poorer health-related quality of life in physical (ß=-2.06 [95% CI, -3.01 to -1.10]) and mental domains (ß=-1.48 [95% CI, -2.44 to -0.52]). Although not significant, there was a suggestive trend for poorer outcomes in cognitive impairment and depression in women. No significant difference in stroke recurrence were found between men and women. CONCLUSIONS: Female patients with stroke tended to have better covariate-adjusted survival but poorer outcomes among survivors than male patients, with deficits persisting to up to 5 years poststroke.

Cardiometabolic outcomes up to 12 months after COVID-19 infection. A matched cohort study in the UK.

BACKGROUND: Acute Coronavirus Disease 2019 (COVID-19) has been associated with new-onset cardiovascular disease (CVD) and diabetes mellitus (DM), but it is not known whether COVID-19 has long-term impacts on cardiometabolic outcomes. This study aimed to determine whether the incidence of new DM and CVDs are increased over 12 months after COVID-19 compared with matched controls. METHODS AND FINDINGS: We conducted a cohort study from 2020 to 2021 analysing electronic records for 1,356 United Kingdom family practices with a population of 13.4 million. Participants were 428,650 COVID-19 patients without DM or CVD who were individually matched with 428,650 control patients on age, sex, and family practice and followed up to January 2022. Outcomes were incidence of DM and CVD. A difference-in-difference analysis estimated the net effect of COVID-19 allowing for baseline differences, age, ethnicity, smoking, body mass index (BMI), systolic blood pressure, Charlson score, index month, and matched set. Follow-up time was divided into 4 weeks from index date ("acute COVID-19"), 5 to 12 weeks from index date ("post-acute COVID-19"), and 13 to 52 weeks from index date ("long COVID-19"). Net incidence of DM increased in the first 4 weeks after COVID-19 (adjusted rate ratio, RR 1.81, 95% confidence interval (CI) 1.51 to 2.19) and remained elevated from 5 to 12 weeks (RR 1.27, 1.11 to 1.46) but not from 13 to 52 weeks overall (1.07, 0.99 to 1.16). Acute COVID-19 was associated with net increased CVD incidence (5.82, 4.82 to 7.03) including pulmonary embolism (RR 11.51, 7.07 to 18.73), atrial arrythmias (6.44, 4.17 to 9.96), and venous thromboses (5.43, 3.27 to 9.01). CVD incidence declined from 5 to 12 weeks (RR 1.49, 1.28 to 1.73) and showed a net decrease from 13 to 52 weeks (0.80, 0.73 to 0.88). The analyses were based on health records data and participants' exposure and outcome status might have been misclassified. CONCLUSIONS: In this study, we found that CVD was increased early after COVID-19 mainly from pulmonary embolism, atrial arrhythmias, and venous thromboses. DM incidence remained elevated for at least 12 weeks following COVID-19 before declining. People without preexisting CVD or DM who suffer from COVID-19 do not appear to have a long-term increase in incidence of these conditions.

Effect of a Home-Based, Walking Exercise Behavior Change Intervention vs Usual Care on Walking in Adults With Peripheral Artery Disease: The MOSAIC Randomized Clinical Trial.

Importance: Home-based walking exercise interventions are recommended for people with peripheral artery disease (PAD), but evidence of their efficacy has been mixed. Objective: To investigate the effect of a home-based, walking exercise behavior change intervention delivered by physical therapists in adults with PAD and intermittent claudication compared with usual care. Design, Setting, and Participants: Multicenter randomized clinical trial including 190 adults with PAD and intermittent claudication in 6 hospitals in the United Kingdom between January 2018 and March 2020; final follow-up was September 8, 2020. Interventions: Participants were randomized to receive a walking exercise behavior change intervention delivered by physical therapists trained to use a motivational approach (n = 95) or usual care (n = 95). Main Outcomes and Measures: The primary outcome was 6-minute walking distance at 3-month follow-up (minimal clinically important difference, 8-20 m). There were 8 secondary outcomes, 3 of which were the Walking Estimated Limitation Calculated by History (WELCH) questionnaire (score range, 0 [best performance] to 100), the Brief Illness Perceptions Questionnaire (score range, 0 to 80 [80 indicates negative perception of illness]), and the Theory of Planned Behavior Questionnaire (score range, 3 to 21 [21 indicates best attitude, subjective norms, perceived behavioral control, or intentions]); a minimal clinically important difference was not defined for these instruments. Results: Among 190 randomized participants (mean age 68 years, 30% women, 79% White race, mean baseline 6-minute walking distance, 361.0 m), 148 (78%) completed 3-month follow-up. The 6-minute walking distance changed from 352.9 m at baseline to 380.6 m at 3 months in the intervention group and from 369.8 m to 372.1 m in the usual care group (adjusted mean between-group difference, 16.7 m [95% CI, 4.2 m to 29.2 m]; P = .009). Of the 8 secondary outcomes, 5 were not statistically significant. At 6-month follow-up, baseline WELCH scores changed from 18.0 to 27.8 in the intervention group and from 20.7 to 20.7 in the usual care group (adjusted mean between-group difference, 7.4 [95% CI, 2.5 to 12.3]; P = .003), scores on the Brief Illness Perceptions Questionnaire changed from 45.7 to 38.9 in the intervention group and from 44.0 to 45.8 in the usual care group (adjusted mean between-group difference, -6.6 [95% CI, -9.9 to -3.4]; P < .001), and scores on the attitude component of the Theory of Planned Behavior Questionnaire changed from 14.7 to 15.4 in the intervention group and from 14.6 to 13.9 in the usual care group (adjusted mean between-group difference, 1.4 [95% CI, 0.3 to 2.5]; P = .02). Thirteen serious adverse events occurred in the intervention group, compared with 3 in the usual care group. All were determined to be unrelated or unlikely to be related to the study. Conclusions and Relevance: Among adults with PAD and intermittent claudication, a home-based, walking exercise behavior change intervention, compared with usual care, resulted in improved walking distance at 3 months. Further research is needed to determine the durability of these findings. Trial Registrations: ISRCTN Identifier: 14501418; ClinicalTrials.gov Identifier: NCT03238222.

Stroke Care in the United Kingdom During the COVID-19 Pandemic.

BACKGROUND AND PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has potentially caused indirect harm to patients with other conditions via reduced access to health care services. We aimed to describe the impact of the initial wave of the pandemic on admissions, care quality, and outcomes in patients with acute stroke in the United Kingdom. METHODS: Registry-based cohort study of patients with acute stroke admitted to hospital in England, Wales, and Northern Ireland between October 1, 2019, and April 30, 2020, and equivalent periods in the 3 prior years. RESULTS: One hundred fourteen hospitals provided data for a study cohort of 184 017 patients. During the lockdown period (March 23 to April 30), there was a 12% reduction (6923 versus 7902) in the number of admissions compared with the same period in the 3 previous years. Admissions fell more for ischemic than hemorrhagic stroke, for older patients, and for patients with less severe strokes. Quality of care was preserved for all measures and in some domains improved during lockdown (direct access to stroke unit care, 1-hour brain imaging, and swallow screening). Although there was no change in the proportion of patients discharged with good outcome (modified Rankin Scale score, ≤2; 48% versus 48%), 7-day inpatient case fatality increased from 6.9% to 9.4% (P<0.001) and was 22.0% in patients with confirmed or suspected COVID-19 (adjusted rate ratio, 1.41 [1.11-1.80]). CONCLUSIONS: Assuming that the true incidence of acute stroke did not change markedly during the pandemic, hospital avoidance may have created a cohort of untreated stroke patients at risk of poorer outcomes or recurrent events. Unanticipated improvements in stroke care quality should be used as an opportunity for quality improvement and to learn about how to develop resilient health care systems.

Ex vivo delivery of Mirococept: A dose-finding study in pig kidney after showing a low dose is insufficient to reduce delayed graft function in human kidney.

The complement system plays a pivotal role in the pathogenesis of ischemia-reperfusion injury in solid organ transplantation. Mirococept is a potent membrane-localizing complement inhibitor that can be administered ex vivo to the donor kidney prior to transplantation. To evaluate the efficacy of Mirococept in reducing delayed graft function (DGF) in deceased donor renal transplantation, we undertook the efficacy of mirococept (APT070) for preventing ischaemia-reperfusion injury in the kidney allograft (EMPIRIKAL) trial (ISRCTN49958194). A dose range of 5-25 mg would be tested, starting with 10 mg in cohort 1. No significant difference between Mirococept at 10 mg and control was detected; hence the study was stopped to enable a further dose saturation study in a porcine kidney model. The optimal dose of Mirococept in pig kidney was 80 mg. This dose did not induce any additional histological damage compared to controls or after a subsequent 3 hours of normothermic machine perfusion. The amount of unbound Mirococept postperfusion was found to be within the systemic dose range considered safe in the Phase I trial. The ex vivo administration of Mirococept is a safe and feasible approach to treat DGF in deceased donor kidney transplantation. The porcine kidney study identified an optimal dose of 80 mg (equivalent to 120 mg in human kidney) that provides a basis for further clinical development.