Explore the vast range of titles available.

Pioglitazone, a thiazolidinedione, effectively reduces stroke and cardiovascular events in individuals with type 2 diabetes, insulin resistance, and/or stroke. However, its potential to increase fracture risk, particularly among women and those with pre-existing skeletal conditions, has not yet been completely understood. This meta-analysis aims to clarify fracture risk associated with pioglitazone, thereby focusing on individuals with a history of stroke. A systematic review was performed for clinical trials conducted up to March 2024, focusing on trials comparing pioglitazone to placebo or other antihyperglycemic drugs that reported fracture outcomes. From 860 trials identified, 78 satisfied the inclusion criteria: 34 with a high risk of bias, 8 with unclear risk, and 36 with low risk. The meta-analysis revealed an association between pioglitazone and a significant increase in fracture risk (risk ratio [RR] 1.21; 95% CI 1.01-1.45; = 0.04), including non-serious (RR 1.25; 95% CI 1.03-1.51; = 0.02) and serious fractures (RR 1.48; 95% CI 1.10-1.98; = 0.01). Notably, the risk was exacerbated for low-energy fractures, particularly resulting from falls (RR 1.49; 95% CI 1.20-1.87; = 0.0004), in insulin resistance individuals (RR 0.87; 95% CI 0.43-1.76; = 0.69), and stroke survivors (RR 1.41; 95% CI 1.09-1.83; = 0.008). Fractures were most frequently observed in lower extremities (RR 1.85; 95% CI 1.33-2.56; = 0.0002), with women at a greater risk (RR 1.56; 95% CI 1.20-2.02; = 0.0008). When compared with other antihyperglycemic drugs, no significant difference in fracture risk was noted (RR 1.08; 95% CI 0.73-1.59; = 0.70), except rosiglitazone, which showed higher fracture risk (RR 1.42; 95% CI 1.23-1.64; < 0.00001). Fracture risk was significant in the fixed-effect model but not in the random-effects model. Though pioglitazone offers several cardiovascular benefits, its association with increased fracture risk, especially among women and non-diabetic individuals post-stroke, warrants careful consideration. Individualized treatment interventions balancing cardiovascular and skeletal outcomes are essential, and further research is needed to optimize therapeutic strategies in this population. https://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42016038242, identifier CRD42016038242.

Stroke is a leading cause of disability worldwide, and in approximately 60% of individuals, upper limb deficits persist 6 months after stroke. These deficits adversely affect the functional use of the upper limb and restrict participation in day to day activities. An important goal of stroke rehabilitation is to improve the quality of life by enhancing functional independence and participation in activities. Since upper limb deficits are one of the best predictors of quality of life after stroke, effective interventions targeting these deficits may represent a means to improve quality of life. An increased understanding of the neurobiological processes underlying stroke recovery has led to the development of targeted approaches to improve motor deficits. One such targeted strategy uses brief bursts of Vagus Nerve Stimulation (VNS) paired with rehabilitation to enhance plasticity and support recovery of upper limb function after chronic stroke. Stimulation of the vagus nerve triggers release of plasticity promoting neuromodulators, such as acetylcholine and norepinephrine, throughout the cortex. Timed engagement of neuromodulators concurrent with motor training drives task-specific plasticity in the motor cortex to improve function and provides the basis for paired VNS therapy. A number of studies in preclinical models of ischemic stroke demonstrated that VNS paired with rehabilitative training significantly improved the recovery of forelimb motor function compared to rehabilitative training without VNS. The improvements were associated with synaptic reorganization of cortical motor networks and recruitment of residual motor neurons controlling the impaired forelimb, demonstrating the putative neurobiological mechanisms underlying recovery of motor function. These preclinical studies provided the basis for conducting two multi-site, randomized controlled pilot trials in individuals with moderate to severe upper limb weakness after chronic ischemic stroke. In both studies, VNS paired with rehabilitation improved motor deficits compared to rehabilitation alone. The trials provided support for a 120-patient pivotal study designed to evaluate the efficacy of paired VNS therapy in individuals with chronic ischemic stroke. This manuscript will discuss the neurobiological rationale for VNS therapy, provide an in-depth discussion of both animal and human studies of VNS therapy for stroke, and outline the challenges and opportunities for the future use of VNS therapy.

Accurate diagnosis in suspected ischaemic stroke can be difficult. We explored the urinary proteome in patients with stroke (n = 69), compared to controls (n = 33), and developed a biomarker model for the diagnosis of stroke. We performed capillary electrophoresis online coupled to micro-time-of-flight mass spectrometry. Potentially disease-specific peptides were identified and a classifier based on these was generated using support vector machine-based software. Candidate biomarkers were sequenced by liquid chromatography-tandem mass spectrometry. We developed two biomarker-based classifiers, employing 14 biomarkers (nominal p-value <0.004) or 35 biomarkers (nominal p-value <0.01). When tested on a blinded test set of 47 independent samples, the classification factor was significantly different between groups; for the 35 biomarker model, median value of the classifier was 0.49 (-0.30 to 1.25) in cases compared to -1.04 (IQR -1.86 to -0.09) in controls, p<0.001. The 35 biomarker classifier gave sensitivity of 56%, specificity was 93% and the AUC on ROC analysis was 0.86. This study supports the potential for urinary proteomic biomarker models to assist with the diagnosis of acute stroke in those with mild symptoms. We now plan to refine further and explore the clinical utility of such a test in large prospective clinical trials.

Background: Among the currently approved antiobesity medications, the glucagon-like-peptide-1 receptor-agonists (GLP-1 RAs) liraglutide and semaglutide, and the dual glucose-dependent-insulinotropic-polypeptide (GIP)/GLP-1 RA tirzepatide have been suggested to reduce cardiovascular-risk in overweight or obesity without diabetes. Objectives: The objective of this study was to evaluate the cardio- and neuroprotective potential of these novel agents in the nondiabetic overweight/obese adult population. Data sources and methods: A systematic review and meta-analysis of randomized-controlled clinical trials (RCTs) was performed to estimate the risk of major adverse cardiovascular events (MACE), all-cause and cardiovascular mortality in overweight or obese adults without diabetes treated with GLP-1 or GIP/GLP-1 RAs (vs placebo). Secondary outcomes included the risk of myocardial infarction (MI) and stroke. Results: Sixteen RCTs (13 and 3 on GLP-1 RAs and tirzepatide, respectively) comprising 28,168 participants were included. GLP-1 or GIP/GLP-1 RAs reduced MACE (odds ratio (OR): 0.79; 95% confidence interval (CI): 0.71–0.89; p < 0.01; I2 = 0) and all-cause mortality (OR: 0.80; 95% CI: 0.70–0.92; p < 0.01; I2 = 0), while there was a trend toward lower cardiovascular-mortality (OR: 0.84; 95% CI: 0.71–1.01; p = 0.06; I2 = 0%) compared to placebo. Additionally, GLP-1 or GIP/GLP-1 RAs reduced the odds of MI (OR: 0.72; 95% CI: 0.61–0.86; p < 0.01; I2 = 0%) and nonfatal-MI (OR: 0.72; 95% CI: 0.61–0.85; p < 0.01; I2 = 0%); while no associations between antiobesity treatment and fatal-MI, stroke, nonfatal, or fatal stroke were uncovered. Conclusion: GLP-1 and GIP/GLP-1 RAs reduce cardiovascular-risk and all-cause mortality in overweight or obese adults without diabetes. Additionally, GLP-1 RAs and GIP/GLP-1 RAs attenuate the risk of MI. Since data on stroke are still limited, future RCTs are warranted to evaluate the neuroprotective potential of these novel antiobesity agents. Trial registration: PROSPERO CRD42024515966.

BackgroundAcute intracerebral haemorrhage (ICH) is devastating with a 1 month mortality rate of ~40%. Cerebral oedema can complicate acute ICH and is associated with poor outcome. In patients with large ICH, the accompanying swelling increases mass effect and causes brain herniation. Mannitol, an osmotic diuretic, is used to treat cerebral oedema after traumatic brain injury, but its safety and efficacy in ICH is unclear. We aim to assess the feasibility of a phase II randomised, controlled trial of mannitol in patients with ICH with, or at risk of, cerebral oedema to inform a definitive trial.MethodsThe mannitol for cerebral oedema after acute intracerebral haemorrhage trial (MACE-ICH) aims to include 45 ICH participants from 10 UK sites with estimated largest diameter of haematoma volume >2 cm, presenting within 72 hours of onset with, or at risk of, cerebral oedema (limited Glasgow Coma Scale (GCS)<9, including motor and visual components only, and National Institutes of Health Stroke Scale>8) with or without mass effect. Participants will be randomised (1:1:1) to 1 g/kg 10% single-dose intravenous mannitol, 1 g/kg 10% mannitol followed by a second dose at 24 hours, or standard care alone. Outcome assessors will be masked to treatment allocation. Feasibility outcomes include proportion of patients approached being randomised, participants receiving allocated treatment, recruitment rate, treatment adherence and follow-up. Secondary outcomes include serum electrolytes and osmolality at days 1–2; change in ICH and oedema volume at day 5; number of participants who developed urinary tract infection, GCS and National Institutes of Health Stroke Scale at day 5±2; length of hospital stay, discharge destination and death up to day 28; death and death or dependency by day 180 and disability (Barthel Index), quality of life (EuroQol, 5-D) and cognition (telephone mini-mental state examination) at day 180.Ethics and disseminationMACE-ICH received ethics approval from the East Midlands-Leicester Central research ethics committee (22/EM/0242). The trial is funded by a National Institute for Health and Care Research RfPB grant (203080). The results will be published in an academic journal and disseminated through academic conferences and patient support groups. Reporting will be in line with Consolidated Standards of Reporting Trials recommendations.Trial registration numbersISRCTN15383301; EUDRACT 2022-000283-22.

IntroductionArm weakness after stroke is one of the leading causes of adult-onset disability. Invasive vagus nerve stimulation (VNS) paired with rehabilitation has been shown to improve arm recovery in chronic stroke. Small studies of non-invasive or transcutaneous VNS (tVNS) suggest it is safe and tolerable. However, it is not known whether tVNS paired with rehabilitation is effective in promoting arm recovery in chronic stroke and what the mechanisms of action are.Methods and analysisTRICEPS is a UK multicentre, double-blinded, superiority, parallel-group, three-arm two-stage with an option to select promising arm(s) at 50% accrual, individually randomised, sham-controlled trial. Up to 243 participants will be randomised (1:1:1) using minimisation via a restricted, web-based centralised system. tVNS will be delivered by a movement-activated tVNS system (TVNS Technologies), which delivers stimulation during repetitive task practice. Rehabilitation will consist of repetitive task training for 1 hour a day, 5 days per week for 12 weeks. Participants will be adults with anterior circulation ischaemic stroke between 6 months and 10 years prior with moderate-severe arm weakness. The primary outcome measure will be the change in Upper Limb Fugl-Meyer total motor score at 91 days after the start of treatment. Secondary outcome measures include the Wolf Motor Function Test, the Modified Ashworth Scale to assess spasticity in the affected arm and the Stroke-Specific Quality of Life Scale. A mechanistic substudy including 40 participants will explore the mechanisms of active versus sham tVNS using multimodal MRI and serum inflammatory cytokine levels. Participant recruitment started on 30 November 2023.Ethics and disseminationThe study has received ethical approval from the Cambridge Central Research Ethics Committee (REC reference: 22/NI/0134). Dissemination of results will be via publications in scientific journals, meetings, written reports and articles in stakeholder publications.Trial registration numberISRCTN20221867.

Stroke is a common cause of death and disability in both men and women. Differences in the incidence, presenting features and outcome after stroke have been reported between men and women. The global lifetime risk of stroke of approximately 25% is similar in men and women, although in women, the first cardiovascular event is more likely to be stroke than in men. Concerningly, there are reports of underuse of some treatments in women, although these differences may be diminishing over time. In addition, there are specific clinical challenges that can arise in women with stroke, such as stroke in people taking hormonal therapy, and stroke during pregnancy and stroke in the post-partum period. This review will cover these areas highlighting important differences and areas for future research. We found there are important differences in incidence of stroke, which differ by age. Further, there is concerning evidence that some treatments such as intravenous thrombolysis are underused in women. While there may be some differences in the relative effectiveness of treatments such as antiplatelet therapy and blood pressure reduction between men and women, for most aspects of stroke care, benefit is clear in both men and women and the emphasis must be on more equitable access. There is limited evidence to inform decision making during pregnancy and the post-partum period, but guidelines now exist and further research is needed in these areas.

Background Cerebral small vessel disease (cSVD) is a progressive neurovascular-degenerative condition without specific treatment that causes lacunar stroke, most intracerebral haemorrhage, vascular cognitive impairment (VCI) and several neuropsychiatric conditions. Objectives To conduct a rapid multi-stage scoping review to identify licensed interventions that could be repurposed for testing in cSVD at phase-3. Methods First, we screened preclinical studies of potential relevance to cSVD and used a drug dictionary to identify studies of potential interventions. Separately, we screened clinical studies of relevance to cSVD and VCI. Following merging, we removed drugs that were unsuitable or impractical to assess long-term in the UK. We then performed mini-meta-analyses for shortlisted interventions assessing effects on cognition and scored these for their relevance to cSVD. Results The preclinical review created a long-list of 1,757 deduplicated interventions. Those that were available in the UK, not expensive or impractical to administer long-term were merged with 62 interventions identified from 75 relevant clinical studies to create a medium-list of 52 interventions. Focussed literature review short-listed ten interventions for review by an Independent Scientific Advisory Group; they ranked three as most suitable for immediate testing: metformin, tadalafil and isosorbide mononitrate. Conclusion This rapid review identified three interventions that are suitable for testing in a late phase-3 (platform) trial involving patients with cSVD. The approach could be improved with partial automation, text mining and generative pre-trained transformer approaches which would help manage the large data volumes. Further, our data-driven approach could be combined with genetic or other mechanistic methods to further de-risk future trials.

ObjectiveTo determine whether robot-assisted training is cost-effective compared with an enhanced upper limb therapy (EULT) programme or usual care.DesignEconomic evaluation within a randomised controlled trial.SettingFour National Health Service (NHS) centres in the UK: Queen’s Hospital, Barking, Havering and Redbridge University Hospitals NHS Trust; Northwick Park Hospital, London Northwest Healthcare NHS Trust; Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde; and North Tyneside General Hospital, Northumbria Healthcare NHS Foundation Trust.Participants770 participants aged 18 years or older with moderate or severe upper limb functional limitation from first-ever stroke.InterventionsParticipants randomised to one of three programmes provided over a 12-week period: robot-assisted training plus usual care; the EULT programme plus usual care or usual care.Main economic outcome measuresMean healthcare resource use; costs to the NHS and personal social services in 2018 pounds; utility scores based on EQ-5D-5L responses and quality-adjusted life years (QALYs). Cost-effectiveness reported as incremental cost per QALY and cost-effectiveness acceptability curves.ResultsAt 6 months, on average usual care was the least costly option (£3785) followed by EULT (£4451) with robot-assisted training being the most costly (£5387). The mean difference in total costs between the usual care and robot-assisted training groups (£1601) was statistically significant (p<0.001). Mean QALYs were highest for the EULT group (0.23) but no evidence of a difference (p=0.995) was observed between the robot-assisted training (0.21) and usual care groups (0.21). The incremental cost per QALY at 6 months for participants randomised to EULT compared with usual care was £74 100. Cost-effectiveness acceptability curves showed that robot-assisted training was unlikely to be cost-effective and that EULT had a 19% chance of being cost-effective at the £20 000 willingness to pay (WTP) threshold. Usual care was most likely to be cost-effective at all the WTP values considered in the analysis.ConclusionsThe cost-effectiveness analysis suggested that neither robot-assisted training nor EULT, as delivered in this trial, were likely to be cost-effective at any of the cost per QALY thresholds considered.Trial registration numberISRCTN69371850.