Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

High-flow nasal oxygen versus conventional oxygen therapy and noninvasive ventilation in COVID-19 respiratory failure: a systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Noninvasive methods of respiratory support, including noninvasive ventilation (NIV), continuous positive airway pressure (CPAP), and high-flow nasal oxygen (HFNO), are potential strategies to prevent progression to requirement for invasive mechanical ventilation in acute hypoxaemic respiratory failure. The COVID-19 pandemic provided an opportunity to understand the utility of noninvasive respiratory support among a homogeneous cohort of patients with contemporary management of acute respiratory distress syndrome. We performed a network meta-analysis of studies evaluating the efficacy of NIV (including CPAP) and HFNO, compared with conventional oxygen therapy (COT), in patients with COVID-19. METHODS: PubMed, Embase, and the Cochrane library were searched in May 2023. Standard random-effects meta-analysis was used first to estimate all direct pairwise associations and the results from all studies were combined using frequentist network meta-analysis. Primary outcome was treatment failure, defined as discontinuation of HFNO, NIV, or COT despite progressive disease. Secondary outcome was mortality. RESULTS: We included data from eight RCTs with 2302 patients, (756 [33%] assigned to COT, 371 [16%] to NIV, and 1175 [51%] to HFNO). The odds of treatment failure were similar for NIV (P=0.33) and HFNO (P=0.25), and both were similar to that for COT (reference category). The odds of mortality were similar for all three treatments (odds ratio for NIV vs COT: 1.06 [0.46-2.44] and HFNO vs COT: 0.97 [0.57-1.65]). CONCLUSIONS: Noninvasive ventilation, high-flow nasal oxygen, and conventional oxygen therapy are comparable with regards to treatment failure and mortality in COVID-19-associated acute respiratory failure. PROSPERO REGISTRATION: CRD42023426495.

Clinical and cost-effectiveness of an adapted intervention for preschoolers with moderate to severe intellectual disabilities displaying behaviours that challenge: the EPICC-ID RCT.

Background: Stepping Stones Triple P is an adapted intervention for parents of young children with developmental disabilities who display behaviours that challenge, aiming at teaching positive parenting techniques and promoting a positive parent-child relationship. Objective: To evaluate the clinical and cost-effectiveness of level 4 Stepping Stones Triple P in reducing behaviours that challenge in children with moderate to severe intellectual disabilities. Design, setting, participants: A parallel two-arm pragmatic multisite single-blind randomised controlled trial recruited a total of 261 dyads (parent and child). The children were aged 30-59 months and had moderate to severe intellectual disabilities. Participants were randomised, using a 3 : 2 allocation ratio, into the intervention arm (Stepping Stones Triple P; n = 155) or treatment as usual arm (n = 106). Participants were recruited from four study sites in Blackpool, North and South London and Newcastle. Intervention: Level 4 Stepping Stones Triple P consists of six group sessions and three individual phone or face-to-face contacts over 9 weeks. These were changed to remote sessions after 16 March 2020 due to the coronavirus disease 2019 pandemic. Main outcome measure: The primary outcome measure was the parent-reported Child Behaviour Checklist, which assesses the severity of behaviours that challenge. Results: We found a small non-significant difference in the mean Child Behaviour Checklist scores (-4.23, 95% CI -9.98 to 1.52, p = 0.146) in the intervention arm compared to treatment as usual at 12 months. Per protocol and complier average causal effect sensitivity analyses, which took into consideration the number of sessions attended, showed the Child Behaviour Checklist mean score difference at 12 months was lower in the intervention arm by -10.77 (95% CI -19.12 to -2.42, p = 0.014) and -11.53 (95% CI -26.97 to 3.91, p = 0.143), respectively. The Child Behaviour Checklist mean score difference between participants who were recruited before and after the coronavirus disease 2019 pandemic was estimated as -7.12 (95% CI -13.44 to -0.81) and 7.61 (95% CI -5.43 to 20.64), respectively (p = 0.046), suggesting that any effect pre-pandemic may have reversed during the pandemic. There were no differences in all secondary measures. Stepping Stones Triple P is probably value for money to deliver (-£1057.88; 95% CI -£3218.6 to -£46.67), but decisions to roll this out as an alternative to existing parenting interventions or treatment as usual may be dependent on policymaker willingness to invest in early interventions to reduce behaviours that challenge. Parents reported the intervention boosted their confidence and skills, and the group format enabled them to learn from others and benefit from peer support. There were 20 serious adverse events reported during the study, but none were associated with the intervention. Limitations: There were low attendance rates in the Stepping Stones Triple P arm, as well as the coronavirus disease 2019-related challenges with recruitment and delivery of the intervention. Conclusions: Level 4 Stepping Stones Triple P did not reduce early onset behaviours that challenge in very young children with moderate to severe intellectual disabilities. However, there was an effect on child behaviours for those who received a sufficient dose of the intervention. There is a high probability of Stepping Stones Triple P being at least cost neutral and therefore worth considering as an early therapeutic option given the long-term consequences of behaviours that challenge on people and their social networks. Future work: Further research should investigate the implementation of parenting groups for behaviours that challenge in this population, as well as the optimal mode of delivery to maximise engagement and subsequent outcomes. Study registration: This study is registered as NCT03086876 (https://www.clinicaltrials.gov/ct2/show/NCT03086876?term=Hassiotis±Angela&draw=1&rank=1). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: HTA 15/162/02) and is published in full in Health Technology Assessment; Vol. 28, No. 6. See the NIHR Funding and Awards website for further award information.

Research shows that in children without learning disabilities, parenting groups which support parents to develop skills to manage behaviours that challenge in their child can be helpful. The National Institute of Health and Care Excellence recommended that more research was needed to strengthen the evidence for such interventions for children with moderate to severe learning disability who are more likely to display behaviours that challenge in England. In this study, we tested in real-world conditions a programme called level 4 Stepping Stones Triple P, which has shown positive results in trials outside of the United Kingdom. Trained therapists delivered six groups and three individual sessions over 9 weeks to parents of children aged 30­59 months with moderate to severe learning disabilities. Two hundred and sixty-one parents were allocated to one of two arms by chance (randomisation): one received Stepping Stones Triple P and treatment as usual and the other treatment as usual only. Treatment as usual included support and advice by general practitioners or community child development teams. Our primary outcome was parent-reported child behaviour at 12 months after randomisation. We also collected data on other outcomes and carried out interviews with parents, service managers and therapists to find out their views about Stepping Stones Triple P. We did not find that Stepping Stones Triple P reduces behaviours that challenge in the child more than treatment as usual at 12 months. However, when we looked at people who received more than half of the sessions, there was a larger reduction in behaviours which suggests that Stepping Stones Triple P works for families if they attend the full programme. Stepping Stones Triple P seems to be good value for money, as we found that at 12 months (covering 10 months of costs), the Stepping Stones Triple P cost £1058 less than treatment as usual from a health and social care perspective. As such, Stepping Stones Triple P is fairly cheap to deliver and a suitable early intervention for behaviours that challenge especially because of positive feedback from parents. Throughout the trial, we included a Parent Advisory Group that oversaw study materials, interview topic guides and promotion of the study.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Relationships between intracranial arterial dolichoectasia and small vessel disease in patients with ischaemic stroke: a systematic review and meta-analysis.

BACKGROUND: Intracranial arterial dolichoectasia (IADE) is a common arterial finding of dilation, elongation, or both, affecting large intracranial vessels, and associated with vascular risk factors, including hypertension. Associations of IADE with neuroimaging cerebral small vessel disease (CSVD) may be relevant for diagnosis and prognosis in patients with stroke. The study aimed to conduct an updated systematic review and meta-analysis of observational studies to investigate the relationships of IADE with well-defined CSVD markers in patients with ischaemic stroke. METHODS: We systematically searched PubMed, Embase, and Scopus for studies on IADE in ischaemic stroke patients with fulfilling predefined inclusion criteria. We pooled data to conduct a meta-analysis to compare the prevalence of SVD markers between patients with and without IADE groups using risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: From 157 retrieved abstracts, we included six studies from seven publications comprising 6102 patients with ischaemic stroke. The mean age of patients was 52.8 years, and 3691 (60.5%) were male. IADE was diagnosed in 11.4% (95% CI 8.9-13.9) (761) of included patients; 51.8% (3160) had hypertension. Compared to patients without IADE, individuals diagnosed with IADE had a significantly increased prevalence of lacune (RR 1.67, 95% CI 1.36-2.06, P < 0.01, I2 = 0.00%), cerebral microbleeds (CMBs) (RR 2.56, 95% CI 1.53-4.28, P < 0.01, I2 = 84.95%) and white matter hyperintensities (WMHs) (RR 2.17, 95% CI 1.84-2.56, P < 0.01, I2 = 0.00%). CONCLUSIONS: In patients with ischaemic stroke, IADE is associated with a higher prevalence of CSVD markers, including lacunes, CMBs, and WMHs. Further studies are needed to clarify the mechanisms underlying these associations and their potential relevance for the understanding, diagnosis, and treatment of CSVD.

Clinical and cost-effectiveness of 'Live Well with Parkinson's' self-management intervention versus treatment as usual for improving quality of life for people with Parkinson's: study protocol for a randomised controlled trial.

BACKGROUND: The Live Well with Parkinson's Self-Management Toolkit is designed for use in the NHS to support people with Parkinson's, their carers and health professionals in managing motor and non-motor symptoms and promoting well-being. The Toolkit was developed based on theory-based behaviour change and self-management techniques in consultation with people living with Parkinson's and health and social care practitioners. There are digital (e-Toolkit) and paper (manual) versions. METHODS: Single-blind two-arm randomised controlled trial RCT of clinical effectiveness and cost-effectiveness of the Toolkit, facilitated by up to six sessions with a trained non-specialist supporter, in improving quality of life. People with Parkinson's will be assessed at baseline, 6 and 12 months. Assessors will be blind to the treatment group. The primary outcome measure is the Parkinson's Disease Questionnaire (PDQ-39, Parkinson's related quality of life) score at 12 months. Secondary outcome measures include the MDS Unified Parkinson's Disease Rating Scale (Part I, II, III, IV), EQ-5D, and a Client Service Receipt Inventory shortened, adapted for Parkinson's. Carer outcomes include the Zarit Carer Burden Inventory and Carer Quality of Life Questionnaire for Parkinsonism. A total of 338 people with Parkinson's, and their carers if appropriate, will be recruited from diverse settings across England. Those with advanced dementia, at end-of-life or with atypical Parkinsonism will be excluded. A parallel mixed methods process evaluation will explore the factors promoting or inhibiting implementation, uptake, use, effectiveness and cost-effectiveness of the Toolkit and sessions. DISCUSSION: If successful, the Live Well with Parkinson's Toolkit could be used as a model for other complex long-term disorders, including dementia. This would bridge existing gaps in the NHS (as shown by the national Parkinson's audit data), by enabling patients and carers to access personalised information, advice and support on symptom management and 'living well' with Parkinson's. TRIAL REGISTRATION: ISRCTN92831552. Registered on 26th Oct 2021.

Prevalence, patterns, and predictors of patient-reported non-motor outcomes at 30 days after acute stroke: Prospective observational hospital cohort study.

BACKGROUND: Adverse non-motor outcomes are common after acute stroke and likely to substantially affect quality of life, yet few studies have comprehensively assessed their prevalence, patterns, and predictors across multiple health domains. AIMS: We aimed to identify the prevalence, patterns, and the factors associated with non-motor outcomes 30 days after stroke. METHODS: This prospective observational hospital cohort study-Stroke Investigation in North and Central London (SIGNAL)-identified patients with acute ischemic stroke or intracerebral hemorrhage (ICH) admitted to the Hyperacute Stroke Unit (HASU) at University College Hospital (UCH), London, between August 1, 2018 and August 31, 2019. We assessed non-motor outcomes (anxiety, depression, fatigue, sleep, participation in social roles and activities, pain, bowel function, and bladder function) at 30-day follow-up using the Patient-Reported Outcome Measurement Information System-Version 29 (PROMIS-29) scale and Barthel Index scale. RESULTS: We obtained follow-up data for 605/719 (84.1%) eligible patients (mean age 72.0 years; 48.3% female; 521 with ischemic stroke, 84 with ICH). Anxiety (57.0%), fatigue (52.7%), bladder dysfunction (50.2%), reduced social participation (49.2%), and pain (47.9%) were the commonest adverse non-motor outcomes. The rates of adverse non-motor outcomes in ⩾ 1, ⩾ 2 and ⩾ 3 domains were 89%, 66.3%, and 45.8%, respectively; in adjusted analyses, stroke due to ICH (compared to ischemic stroke) and admission stroke severity were the strongest and most consistent predictors. There were significant correlations between bowel dysfunction and bladder dysfunction (κ = 0.908); reduced social participation and bladder dysfunction (κ = 0.844); and anxiety and fatigue (κ = 0.613). We did not identify correlations for other pairs of non-motor domains. CONCLUSION: Adverse non-motor outcomes were very common at 30 days after stroke, affecting nearly 90% of evaluated patients in at least one health domain, about two-thirds in two or more domains, and almost 50% in three or more domains. Stroke due to ICH and admission stroke severity were the strongest and most consistent predictors. Adverse outcomes occurred in pairs of domains, such as with anxiety and fatigue. Our findings emphasize the importance of a multi-domain approach to effectively identify adverse non-motor outcomes after stroke to inform the development of more holistic patient care pathways after stroke.

Digital Tracking of Patients Undergoing Radical Cystectomy for Bladder Cancer: Daily Step Counts Before and After Surgery Within the iROC Randomised Controlled Trial.

BACKGROUND: Efforts to improve recovery after radical cystectomy (RC) are needed. OBJECTIVE: To investigate wrist-worn wearable activity trackers in RC participants. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study was conducted within the iROC randomised trial. INTERVENTION: Patients undergoing RC at nine cancer centres wore wrist-based trackers for 7 days (d) at intervals before and after surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Step counts were compared with participant and operative features, and recovery outcomes. RESULTS AND LIMITATIONS: Of 308 participants, 284 (92.2%) returned digital activity data at baseline (median 17 d [interquartile range: 8-32] before RC), and postoperatively (5 [5-6] d) and at weeks 5 (43 [38-43] d), 12 (94 [87-106] d), and 26 (192 [181-205] d) after RC. Compliance was affected by the time from surgery and a coronavirus disease 2019 pandemic lockdown (return rates fell to 0-7%, chi-square p < 0.001). Step counts dropped after surgery (mean of 28% of baseline), before recovering at 5 weeks (wk) (71% of baseline) and 12 wk (95% of baseline; all analysis of variance [ANOVA] p < 0.001). Baseline step counts were not associated with postoperative recovery or death. Patients with extended hospital stays had reduced postoperative step counts, with a difference of 2.2 d (95% confidence interval: 0.856-3.482 d) between the lowest third and highest two-third tertiles (linear regression analysis; p < 0.001). Additionally, they spent less time out of the hospital within 90 d of RC (80.3 vs 74.3 d, p = 0.013). Lower step counts at 5, 12, and 26 wk were seen in those seeking medical help and needing readmission (ANOVA p ≤ 0.002). CONCLUSIONS: Baseline step counts were not associated with recovery. Lower postoperative step counts were associated with longer length of stay at the hospital and postdischarge readmissions. Studies are required to determine whether low step counts can identify patients at a risk of developing complications. PATIENT SUMMARY: Postoperative step counts appear to be a promising tool to identify patients in the community needing medical help or readmission. More work is needed to understand which measures are most useful and how best to collect these.

Randomised controlled trial of the Community Navigator programme to reduce loneliness and depression for adults with treatment-resistant depression in secondary community mental health services: trial protocol.

BACKGROUND: New treatments are needed for people with treatment-resistant depression (TRD), who do not benefit from anti-depressants and many of whom do not recover fully with psychological treatments. The Community Navigator programme was co-produced with service users and practitioners. It is a novel social intervention which aims to reduce loneliness and thus improve health outcomes for people with TRD. Participants receive up to 10 individual meetings with a Community Navigator, who helps them to map their social world and set and enact goals to enhance their social connections and reduce loneliness. Participants may also access group meet-ups with others in the programme every 2 months, and may be offered modest financial support to enable activities to support social connections. METHODS: A researcher-blind, multi-site, 1:1 randomised controlled trial with N = 306 participants will test the effectiveness of the Community Navigator programme for people with TRD in secondary community mental health teams (CMHTs). Our primary hypothesis is that people who are offered the Community Navigator programme as an addition to usual CMHT care will be less depressed, assessed using the PHQ-9 self-report measure, at 8-month, end-of-treatment follow-up, compared to a control group receiving usual CMHT care and a booklet with information about local social groups and activities. We will follow participants up at end-of-treatment and at 14 months, 6 months after end-of-treatment follow-up. Secondary outcomes include the following: loneliness, anxiety, personal recovery, self-efficacy, social network, social identities. We will collect data about health-related quality of life and service use to investigate the cost-effectiveness of the Community Navigator programme. DISCUSSION: This trial will provide definitive evidence about the effectiveness and cost-effectiveness of the Community Navigator programme and whether it can be recommended for use in practice. The trial is due to finish in August 2025. TRIAL REGISTRATION: Prospectively registered on 8th July 2022 at: ISRCTN13205972.

Maternal PlGF and umbilical Dopplers predict pregnancy outcomes at diagnosis of early-onset fetal growth restriction.

BACKGROUNDSevere, early-onset fetal growth restriction (FGR) causes significant fetal and neonatal mortality and morbidity. Predicting the outcome of affected pregnancies at the time of diagnosis is difficult, thus preventing accurate patient counseling. We investigated the use of maternal serum protein and ultrasound measurements at diagnosis to predict fetal or neonatal death and 3 secondary outcomes: fetal death or delivery at or before 28+0 weeks, development of abnormal umbilical artery (UmA) Doppler velocimetry, and slow fetal growth.METHODSWomen with singleton pregnancies (n = 142, estimated fetal weights [EFWs] below the third centile, less than 600 g, 20+0 to 26+6 weeks of gestation, no known chromosomal, genetic, or major structural abnormalities) were recruited from 4 European centers. Maternal serum from the discovery set (n = 63) was analyzed for 7 proteins linked to angiogenesis, 90 additional proteins associated with cardiovascular disease, and 5 proteins identified through pooled liquid chromatography and tandem mass spectrometry. Patient and clinician stakeholder priorities were used to select models tested in the validation set (n = 60), with final models calculated from combined data.RESULTSThe most discriminative model for fetal or neonatal death included the EFW z score (Hadlock 3 formula/Marsal chart), gestational age, and UmA Doppler category (AUC, 0.91; 95% CI, 0.86-0.97) but was less well calibrated than the model containing only the EFW z score (Hadlock 3/Marsal). The most discriminative model for fetal death or delivery at or before 28+0 weeks included maternal serum placental growth factor (PlGF) concentration and UmA Doppler category (AUC, 0.89; 95% CI, 0.83-0.94).CONCLUSIONUltrasound measurements and maternal serum PlGF concentration at diagnosis of severe, early-onset FGR predicted pregnancy outcomes of importance to patients and clinicians.TRIAL REGISTRATIONClinicalTrials.gov NCT02097667.FUNDINGThe European Union, Rosetrees Trust, Mitchell Charitable Trust.

Biological sex is associated with heterogeneous responses to IL-6 receptor inhibitor treatment in COVID-19-A retrospective cohort study.

COVID-19 is associated with higher inflammatory markers, illness severity and mortality in males compared to females. Differences in immune responses to COVID-19 may underpin sex- specific outcome differences. We hypothesised that anti-IL-6 receptor monoclonal antibodies are associated with heterogenous treatment effects between male and female patients. We conducted a retrospective cohort study assessing the interaction between biological sex and anti-IL-6 receptor antibody treatment with respect to hospital mortality or progression of respiratory failure. We used a Cox proportional hazards regression model to adjust for age, ethnicity, steroid use, baseline C-reactive protein, and COVID-19 variant. We included 1274 patients, of which 58% were male and 15% received anti-IL-6 receptor antibodies. There was a significant interaction between sex and anti-IL-6 receptor antibody use on progression to respiratory failure or death (p = 0.05). For patients who did not receive anti-IL-6 receptor antibodies, the risk of death was slightly higher in males (HR = 1.13 (0.72-1.79)), whereas in patients who did receive anti-IL-6 receptor antibodies, the risk was lower in males (HR = 0.65 (0.32-1.33)). There was a heterogenous treatment effect with anti-IL-6 receptor antibodies between males and females; with anti-IL-6 receptor antibody use having a greater benefit in preventing progression to respiratory failure or death in males (p = 0.05).

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study.

BACKGROUND: Intracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. METHODS: Using data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0-3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. RESULTS: 1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR<60 group had moderate-to-severe SVD burden (score 2-3), compared with 14.0% of those with eGFR>60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04-1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47-0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65-1.38, p = 0.774). CONCLUSION: In acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed.

Can Simvastatin Reduce the Need for Immunomodulatory Drugs to Treat Uveitis?: A Prospective, Randomized, Placebo-Controlled Trial.

Objective: To assess the efficacy of simvastatin 80 mg/day versus placebo in patients with noninfectious nonanterior uveitis receiving prednisolone ≥ 10 mg/day. Design: Randomized, double-masked, controlled trial. Subjects: Adult patients with noninfectious nonanterior uveitis on oral prednisolone dose of ≥ 10 mg/day. Methods: Patients were randomly assigned at a 1:1 ratio to receive either simvastatin 80 mg/day or placebo. A total of 32 patients were enrolled (16 in each arm), all of whom completed the primary end point, and 21 reached the 2-year visit (secondary end points). Main Outcome Measures: The primary end point was mean reduction in the daily prednisolone dose at 12 months follow-up. Secondary end points were mean reduction in prednisolone dose at 24 months, percent of patients with a reduction in second-line immunomodulatory agents, time to disease relapse, and adverse events. Results: Our results show that simvastatin 80 mg/day did not have a significant corticosteroid-sparing effect at 12 months (estimate: 3.62; 95% confidence interval [CI]: -8.15 to 15.38; P = 0.54). There was no significant difference between the groups with regard to prednisolone dose or change in dose at 12 and 24 months. There was no difference between the 2 groups in percent of patients with reduction in second-line agent by 24 months. Among patients who achieved disease quiescence, the median time to first relapse was longer for those receiving simvastatin (38 weeks, 95% CI: 14-54) than placebo (14 weeks, 95% CI: 12-52), although this was not statistically significant. There was no significant difference in adverse events or serious adverse events between the 2 groups. Conclusions: Simvastatin 80 mg/day did not have an effect on the dose reduction of corticosteroids or conventional immunomodulatory drugs at 1 and 2 years. The results suggest that it may extend the time to disease relapse among those who achieve disease quiescence. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Cost-Effectiveness of Robot-Assisted Radical Cystectomy vs Open Radical Cystectomy for Patients With Bladder Cancer.

Importance: The value to payers of robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) when compared with open radical cystectomy (ORC) for patients with bladder cancer is unclear. Objectives: To compare the cost-effectiveness of iRARC with that of ORC. Design, Setting, and Participants: This economic evaluation used individual patient data from a randomized clinical trial at 9 surgical centers in the United Kingdom. Patients with nonmetastatic bladder cancer were recruited from March 20, 2017, to January 29, 2020. The analysis used a health service perspective and a 90-day time horizon, with supplementary analyses exploring patient benefits up to 1 year. Deterministic and probabilistic sensitivity analyses were undertaken. Data were analyzed from January 13, 2022, to March 10, 2023. Interventions: Patients were randomized to receive either iRARC (n = 169) or ORC (n = 169). Main Outcomes and Measures: Costs of surgery were calculated using surgery timings and equipment costs, with other hospital data based on counts of activity. Quality-adjusted life-years were calculated from European Quality of Life 5-Dimension 5-Level instrument responses. Prespecified subgroup analyses were undertaken based on patient characteristics and type of diversion. Results: A total of 305 patients with available outcome data were included in the analysis, with a mean (SD) age of 68.3 (8.1) years, and of whom 241 (79.0%) were men. Robot-assisted radical cystectomy was associated with statistically significant reductions in admissions to intensive therapy (6.35% [95% CI, 0.42%-12.28%]), and readmissions to hospital (14.56% [95% CI, 5.00%-24.11%]), but increases in theater time (31.35 [95% CI, 13.67-49.02] minutes). The additional cost of iRARC per patient was £1124 (95% CI, -£576 to £2824 [US $1622 (95% CI, -$831 to $4075)]) with an associated gain in quality-adjusted life-years of 0.01124 (95% CI, 0.00391-0.01857). The incremental cost-effectiveness ratio was £100 008 (US $144 312) per quality-adjusted life-year gained. Robot-assisted radical cystectomy had a much higher probability of being cost-effective for subgroups defined by age, tumor stage, and performance status. Conclusions and Relevance: In this economic evaluation of surgery for patients with bladder cancer, iRARC reduced short-term morbidity and some associated costs. While the resulting cost-effectiveness ratio was in excess of thresholds used by many publicly funded health systems, patient subgroups were identified for which iRARC had a high probability of being cost-effective. Trial Registration: ClinicalTrials.gov Identifier: NCT03049410.

Cost-effectiveness of peer-supported self-management for people discharged from a mental health crisis team: methodological challenges and recommendations.

Background: Mental health acute crisis episodes are associated with high inpatient costs. Self-management interventions may reduce readmission by enabling individuals to manage their condition. Delivery of such interventions by Peer Support Workers (PSWs) may be cost-effective. CORE, a randomized control trial of a PSW self-management intervention compared to usual care, found a significant reduction in admissions to acute mental healthcare for participants receiving the intervention. This paper aims to evaluate the cost-effectiveness of the intervention over 12 months from a mental health service perspective. Analysis methods of increasing complexity were used to account for data missingness and distribution. Methods: Participants were recruited from six crisis resolution teams in England from 12 March 2014 to 3 July 2015 (trial registration ISRCTN: 01027104). Resource use was collected from patient records at baseline and 12 months. The EQ-5D-3L was collected at baseline and 4 and 18 months, and linear interpolation was used to calculate 12-month values for quality-adjusted life-years (QALYs). The primary analysis of adjusted mean incremental costs and QALYs for complete cases are calculated separately using OLS regression. Secondly, a complete-case non-parametric two-stage bootstrap (TSB) was performed. The impacts of missing data and skewed cost data were explored using multiple imputation using chained equations and general linear models, respectively. Results: Four hundred and forty-one participants were recruited to CORE; 221 randomized to the PSW intervention and 220 to usual care plus workbook. The probability that the PSW intervention was cost-effective compared with the workbook plus usual care control at 12 months varied with the method used, and ranged from 57% to 96% at a cost-effectiveness threshold of £20,000 per QALY gained. Discussion: There was a minimum 57% chance that the intervention was cost-effective compared to the control using 12-month costs and QALYs. The probability varied by 40% when methods were employed to account for the relationship between costs and QALYs, but which restricted the sample to those who provided both complete cost and utility data. Caution should therefore be applied when selecting methods for the evaluation of healthcare interventions that aim to increase precision but may introduce bias if missing data are heavily unbalanced between costs and outcomes.

Association of the Presence and Pattern of MRI Markers of Cerebral Small Vessel Disease With Recurrent Intracerebral Hemorrhage.

BACKGROUND AND OBJECTIVES: Assessing the risk of recurrent intracerebral hemorrhage (ICH) is of high clinical importance. MRI-based cerebral small vessel disease (SVD) markers may help establish ICH etiologic subtypes (including cryptogenic ICH) relevant for recurrence risk. METHODS: We investigated the risk of recurrent ICH in a large cohort of consecutive ICH survivors with available MRI at baseline. Patients with macrovascular, structural, or other identified secondary causes (other than SVD) were excluded. Based on MRI findings, ICH etiology was defined as probable cerebral amyloid angiopathy (CAA) according to the Boston 2.0 criteria, arteriolosclerosis (nonlobar ICH and additional markers of arteriolosclerosis, absent lobar hemorrhagic lesions), mixed SVD (mixed deep and lobar hemorrhagic changes), or cryptogenic ICH (no MRI markers of SVD). Recurrent ICH was determined using electronic health records and confirmed by neuroimaging. Data from an independent multicenter cohort (CROMIS-2 ICH) were used to confirm core findings. RESULTS: Of 443 patients with ICH (mean age 67 ± 13 years, 41% female), ICH etiology was mixed SVD in 36.7%, arteriolosclerosis in 23.6%, CAA in 23.0%, and cryptogenic ICH in 16.7%. During a median follow-up period of 5.7 years (interquartile range 2.9-10.0, 2,682 patient-years), recurrent ICH was found in 59 individual patients (13.3%). The highest recurrence rate per 100 person-years was detected in patients with CAA (8.5, 95% CI 6.1-11.7), followed by that in those with mixed SVD (1.8, 95% CI 1.1-2.9) and arteriolosclerosis (0.6, 95% CI 0.3-1.5). No recurrent ICH occurred in patients with cryptogenic ICH during 510 person-years follow-up (97.5% CI 0-0.7); this finding was confirmed in an independent cohort (CROMIS-2 ICH, n = 216), in which also there was no recurrence in patients with cryptogenic ICH. In patients with CAA, cortical superficial siderosis was the imaging feature strongest related to ICH recurrence (hazard ratio 5.7, 95% CI 2.4-13.6). DISCUSSION: MRI-based etiologic subtypes are helpful in determining the recurrence risk of ICH; while the highest recurrence risk was found in CAA, recurrence risk was low for arteriolosclerosis and negligible for cryptogenic ICH.

Neonatal outcomes following early fetal growth restriction: a subgroup analysis of the EVERREST study.

OBJECTIVE: To quantify the risks of mortality, morbidity and postnatal characteristics associated with extreme preterm fetal growth restriction (EP-FGR). DESIGN: The EVERREST (Do e s v ascular endothelial growth factor gene therapy saf e ly imp r ove outcome in seve r e e arly-onset fetal growth re st riction?) prospective multicentre study of women diagnosed with EP-FGR (singleton, estimated fetal weight (EFW) <3rd percentile, <600 g, 20+0-26+6 weeks of gestation). The UK subgroup of EP-FGR infants (<36 weeks) were sex-matched and gestation-matched to appropriate for age (AGA) infants born in University College London Hospital (1:2 design, EFW 25th-75th percentile). SETTING: Four tertiary perinatal units (UK, Germany, Spain, Sweden). MAIN OUTCOMES: Antenatal and postnatal mortality, bronchopulmonary dysplasia (BPD), sepsis, surgically treated necrotising enterocolitis (NEC), treated retinopathy of prematurity (ROP). RESULTS: Of 135 mothers recruited with EP-FGR, 42 had a stillbirth or termination of pregnancy (31%) and 93 had live births (69%). Postnatal genetic abnormalities were identified in 7/93 (8%) live births. Mean gestational age at birth was 31.4 weeks (SD 4.6). 54 UK-born preterm EP-FGR infants (<36 weeks) were matched to AGA controls. EP-FGR was associated with increased BPD (43% vs 26%, OR 3.6, 95% CI 1.4 to 9.4, p=0.01), surgical NEC (6% vs 0%, p=0.036) and ROP treatment (11% vs 0%, p=0.001). Mortality was probably higher among FGR infants (9% vs 2%, OR 5.0, 95% CI 1.0 to 25.8, p=0.054). FGR infants more frequently received invasive ventilation (65% vs 50%, OR 2.6, 95% CI 1.1 to 6.1, p=0.03), took longer to achieve full feeds and had longer neonatal stays (median difference 6.1 days, 95% CI 3.8 to 8.9 and 19 days, 95% CI 9 to 30 days, respectively, p<0.0001). CONCLUSIONS: Mortality following diagnosis of EP-FGR is high. Survivors experience increased neonatal morbidity compared with AGA preterm infants. TRIAL REGISTRATION NUMBER: NCT02097667.

Future COVID-19 Booster Vaccine Refusal in Healthcare Workers after a Massive Breakthrough Infection Wave, a Nationwide Survey-Based Study.

Background: An unprecedented coronavirus disease 2019 (COVID-19) wave occurred in China between December 2022 and January 2023, challenging the efficacy of the primary series of COVID-19 vaccines. The attitudes toward future COVID-19 booster vaccines (CBV) after the massive breakthrough infection among healthcare workers remain unknown. This study aimed to explore the prevalence and determinants of future CBV refusal after the unprecedented COVID-19 wave among healthcare workers. Methods: Between 9 and 19 February 2023, a cross-sectional nationwide online survey was conducted using a self-administered questionnaire vaccine among healthcare workers in China. Sociodemographics, profession, presence of chronic medical conditions, previous COVID-19 infection, attitudes towards future CBV, and reasons for future CBV refusal were collected. We estimated odds ratio [OR] with 95% confidence interval [CI] using a multivariable logistic regression model to explore the factors associated with future CBV refusal. Results: Among the 1618 participants who completed the survey, 1511 respondents with two or more doses of COVID-19 vaccines were analyzed. A total of 648 (41.8%) of respondents were unwilling to receive a future CBV. Multivariable logistic regression analysis revealed the association of CBV refusal with profession (vs. other staff, physician-adjusted OR 1.17, 95%CI 0.79-1.72, nurse-adjusted OR 1.88, 95%CI 1.24-2.85, p = 0.008), history of allergy (adjusted OR 1.72, 95%CI 1.05-2.83, p = 0.032), a lower self-perceived risk of future COVID-19 infection (p < 0.001), and a lower belief in CBV effectiveness (p = 0.014), safety (p < 0.001), and necessities for healthcare workers and the public (p < 0.001, respectively). Conclusions: Our findings highlight that a considerable proportion of healthcare workers were against a future booster dose after an unprecedented COVID-19 wave. Self-perception of future COVID-19 risk, and potential harm or doubtful efficacy of vaccines are the main determinants. Our findings may help public health authorities to establish future COVID-19 vaccination programs.

Association between Triglyceride-Glucose Index and Early Neurological Outcomes after Thrombolysis in Patients with Acute Ischemic Stroke.

BACKGROUND: The triglyceride-glucose (TyG) index is a novel biomarker of insulin resistance which might plausibly influence endogenous fibrinolysis and thus early neurological outcomes in patients with acute ischemic stroke (AIS) treated with intravenous thrombolysis using recombinant tissue-plasminogen activator. METHODS: We included consecutive AIS patients within 4.5 h of symptom onset undergoing intravenous thrombolysis between January 2015 and June 2022 in this multi-center retrospective observational study. Our primary outcome was early neurological deterioration (END), defined as ≥2 (END2) or ≥ 4 (END4) National Institutes of Health Stroke Scale (NIHSS) score worsening compared to the initial NIHSS score within 24 h of intravenous thrombolysis. Our secondary outcome was early neurological improvement (ENI), defined as a lower NIHSS score at discharge. TyG index was calculated using the log scale of fasting triglyceride (mg/dL) × fasting glucose (mg/dL)/2. We evaluated the association of END and ENI with TyG index using a logistic regression model. RESULTS: A total of 676 patients with AIS were evaluated. The median age was 68 (Interquartile range, IQR (60-76) years old), and 432 (63.9%) were males. A total of 89 (13.2%) patients developed END2, 61 (9.0%) patients developed END4, and 492 (72.7%) experienced ENI. In multivariable logistic regression analysis, after adjustment for confounding factors, TyG index was significantly associated with increased risks of END2 (categorical variable, vs. lowest tertile, medium tertile odds ratio [OR] 1.05, 95% confidence interval, CI 0.54-2.02, highest tertile OR 2.94, 95%CI 1.64-5.27, overall p < 0.001) and END4 (categorical variable, vs. lowest tertile, medium tertile OR 1.21, 95%CI 0.54-2.74, highest tertile OR 3.80, 95%CI 1.85-7.79, overall p < 0.001), and a lower probability of ENI (categorical variable, vs. lowest tertile, medium tertile OR 1.00, 95%CI 0.63-1.58, highest tertile OR 0.59, 95%CI 0.38-0.93, overall p = 0.022). CONCLUSIONS: Increasing TyG index was associated with a higher risk of END and a lower probability of ENI in patients with acute ischemic stroke treated with intravenous thrombolysis.

The use of basic fibroblast growth factor to improve vocal function: A systematic review and meta-analysis.

OBJECTIVES: This systematic review and meta-analysis examines if intralaryngeal injection of basic fibroblast growth factor 2 (FGF2) can improve voice outcomes in those with vocal disability. DESIGN: A Systematic review of original human studies reporting voice outcomes following intra-laryngeal injection of basic fibroblast growth factor 2 in those with vocal dysfunction. Databases searched were Medline (1946-July 2022), Embase (1947-July 2022), Cochrane database and Google Scholar. SETTING: Secondary or tertiary care centres that undertook the management of voice pathology Hospital. PARTICIPANTS: Inclusion criteria were original human studies reporting voice outcome measurements following intralaryngeal injection of FGF2 to treat vocal fold atrophy, vocal fold scarring, vocal fold sulcus or vocal fold palsy. Articles not written in English, studies that did not include human subjects and studies where voice outcome measures were not recorded before and after FGF2 injection were excluded from the review. MAIN OUTCOME MEASURES: The primary outcome measure was maximum phonation time. Secondary outcome measures included acoustic analysis, glottic closure, mucosal wave formation, voice handicap index and GRBAS scale. RESULTS: Fourteen articles were included out of a search of 1023 and one article was included from scanning reference lists. All studies had a single arm design without control groups. Conditions treated were vocal fold atrophy (n = 186), vocal cord paralysis (n = 74), vocal fold fibrosis (n = 74) and vocal fold sulcus (n = 56). A meta-analysis of six articles reporting on the use of FGF2 in patients with vocal fold atrophy showed a significant increase of mean maximum phonation time of 5.2 s (95% CI: 3.4-7.0) at 3-6 months following injection. A significant improvement in maximum phonation time, voice handicap index and glottic closure was found following injection in most studies assessed. No major adverse events were reported following injection. CONCLUSIONS: To date, intralaryngeal injection of basic FGF2 appears to be safe and it may be able to improve voice outcomes in those with vocal dysfunction, especially vocal fold atrophy. Randomised controlled trials are needed to further evaluate efficacy and support the wider use of this therapy.