A vein bypass first versus a best endovascular treatment first revascularisation strategy for patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal revascularisation procedure to restore limb perfusion (BASIL-2): an open-label, randomised, multicentre, phase 3 trial.

BACKGROUND: Chronic limb-threatening ischaemia is the severest manifestation of peripheral arterial disease and presents with ischaemic pain at rest or tissue loss (ulceration, gangrene, or both), or both. We compared the effectiveness of a vein bypass first with a best endovascular treatment first revascularisation strategy in terms of preventing major amputation and death in patients with chronic limb threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. METHODS: Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-2 was an open-label, pragmatic, multicentre, phase 3, randomised trial done at 41 vascular surgery units in the UK (n=39), Sweden (n=1), and Denmark (n=1). Eligible patients were those who presented to hospital-based vascular surgery units with chronic limb-threatening ischaemia due to atherosclerotic disease and who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion. Participants were randomly assigned (1:1) to receive either vein bypass (vein bypass group) or best endovascular treatment (best endovascular treatment group) as their first revascularisation procedure through a secure online randomisation system. Participants were excluded if they had ischaemic pain or tissue loss considered not to be primarily due to atherosclerotic peripheral artery disease. Most vein bypasses used the great saphenous vein and originated from the common or superficial femoral arteries. Most endovascular interventions comprised plain balloon angioplasty with selective use of plain or drug eluting stents. Participants were followed up for a minimum of 2 years. Data were collected locally at participating centres. In England, Wales, and Sweden, centralised databases were used to collect information on amputations and deaths. Data were analysed centrally at the Birmingham Clinical Trials Unit. The primary outcome was amputation-free survival defined as time to first major (above the ankle) amputation or death from any cause measured in the intention-to-treat population. Safety was assessed by monitoring serious adverse events up to 30-days after first revascularisation. The trial is registered with the ISRCTN registry, ISRCTN27728689. FINDINGS: Between July 22, 2014, and Nov 30, 2020, 345 participants (65 [19%] women and 280 [81%] men; median age 72·5 years [62·7-79·3]) with chronic limb-threatening ischaemia were enrolled in the trial and randomly assigned: 172 (50%) to the vein bypass group and 173 (50%) to the best endovascular treatment group. Major amputation or death occurred in 108 (63%) of 172 patients in the vein bypass group and 92 (53%) of 173 patients in the best endovascular treatment group (adjusted hazard ratio [HR] 1·35 [95% CI 1·02-1·80]; p=0·037). 91 (53%) of 172 patients in the vein bypass group and 77 (45%) of 173 patients in the best endovascular treatment group died (adjusted HR 1·37 [95% CI 1·00-1·87]). In both groups the most common causes of morbidity and death, including that occurring within 30 days of their first revascularisation, were cardiovascular (61 deaths in the vein bypass group and 49 in the best endovascular treatment group) and respiratory events (25 deaths in the vein bypass group and 23 in the best endovascular treatment group; number of cardiovascular and respiratory deaths were not mutually exclusive). INTERPRETATION: In the BASIL-2 trial, a best endovascular treatment first revascularisation strategy was associated with a better amputation-free survival, which was largely driven by fewer deaths in the best endovascular treatment group. These data suggest that more patients with chronic limb-threatening ischaemia who required an infra-popliteal, with or without an additional more proximal infra-inguinal, revascularisation procedure to restore limb perfusion should be considered for a best endovascular treatment first revascularisation strategy. FUNDING: UK National Institute of Health Research Health Technology Programme.

Comparison of femoropopliteal plain balloon angioplasty for chronic limb-threatening ischemia in the BASIL trial and in a UK contemporary series.

BACKGROUND: Since the turn of the millennium, there has been a worldwide trend towards an endovascular-first strategy where possible revascularization strategy for chronic limb-threatening ischemia. There is concern that this may be inappropriate and can result in net patient harm. The aim of this study, therefore, is to compare important clinical outcomes following femoropopliteal plain balloon angioplasty (FP-PBA), with selective use of bare metal stents (BMSs), in a contemporary series (CS) of patients treated in our unit between 2009 and 2014 with those observed following FP-PBA ± BMS in the United Kingdom National Institute of Health Research Health Technology Assessment-funded Bypass vs Angioplasty in Severe Ischaemia of the Leg (BASIL-1 [B1]) trial (treated 1999-2004). METHODS: Baseline and clinical outcome data (amputation-free survival [AFS], overall survival [OS], limb salvage, freedom from reintervention, and freedom from major adverse limb events) were obtained from prospectively gathered hospital data and B1 trial case record forms. RESULTS: There were 237 CS and 218 B1 patients. CS patients were older (77 vs 73 years; P = .0002). B1 patients were more likely to be current smokers, less likely to be on best medical therapy, and underwent more extensive endovascular interventions. CS had more hospital admissions (4 vs 2; P < .0001) before they reached their primary endpoint (AFS). Immediate technical success was nonsignificantly higher in the CS patients (87% vs 83%; P = .2). BMS were used in 20 CS (8%) and 2 B1 (1%) patients (P = .0002). AFS (hazard ratio, 0.64; 95% confidence interval, 0.49-0.82; P = .0005) and OS (hazard ratio, 0.58; 95% confidence interval, 0.44-0.76; P = .0001) were significantly worse in the CS cohort. There was no significant difference in limb salvage, freedom from reintervention, or freedom from major adverse limb events. CONCLUSIONS: Patients with chronic limb-threatening ischemia managed in our unit (2009-2014) by means of a FP-PBA ± BMS first (where possible) revascularization strategy experienced significantly worse AFS and OS than patients treated with FP-PBA ± BMS in the B1 trial 10 years earlier (1999-2004).

Cost-Effectiveness of Dopamine Agonists and Monoamine Oxidase B Inhibitors in Early Parkinson's Disease.

BACKGROUND: The PD MED study reported small but persistent benefits in patient-rated mobility scores and quality of life from initiating therapy with levodopa compared with levodopa-sparing therapies in early Parkinson's disease (PD). OBJECTIVES: The objective was to estimate the cost-effectiveness of levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors compared with levodopa alone. METHODS: PD MED is a pragmatic, open-label randomized, controlled trial in which patients newly diagnosed with PD were randomly assigned between levodopa-sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors ) and levodopa alone. Mean quality-adjusted life-years and costs were calculated for each participant. Differences in mean quality-adjusted life-years and costs between levodopa and levodopa-sparing therapies and between dopamine agonists and monoamine oxidase type B inhibitors were estimated using linear regression. RESULTS: Over a mean observation period of 4 years, levodopa was associated with significantly higher quality-adjusted life-years (difference, 0.18; 95% CI, 0.05-0.30; P < 0.01) and lower mean costs (£3390; £2671-£4109; P < 0.01) than levodopa-sparing therapies, the difference in costs driven by the higher costs of levodopa-sparing therapies. There were no significant differences in the costs of inpatient, social care, and institutional care between arms. There was no significant difference in quality-adjusted life-years between those allocated dopamine agonists and monoamine oxidase type B inhibitors (0.02; -0.17 to 0.13 in favor of dopamine agonists; P = 0.81); however costs were significantly lower for those allocated monoamine oxidase type B inhibitors (£2321; £1628-£3015; P < 0.01) because of the higher costs of dopamine agonists. There were no significant differences between arms for other costs. CONCLUSIONS: Initial treatment with levodopa is highly cost-effective compared with levodopa-sparing therapies. Monoamine oxidase type B inhibitors, as initial levodopa-sparing therapy was more cost-effective, with similar quality-adjusted life-years but lower costs than dopamine agonists. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Contemporary (2009-2014) clinical outcomes after femoropopliteal bypass surgery for chronic limb threatening ischemia are inferior to those reported in the UK Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL) trial (1999-2004).

BACKGROUND: Bypass surgery (BS) remains the gold standard revascularization strategy in patients with chronic limb-threatening ischemia (CLTI) owing to infrainguinal disease. The Bypass versus Angioplasty for Severe Ischaemia of the Leg (BASIL)-1 trial showed that, in patients with CLTI who survived for 2 years or more, BS resulted in better clinical outcomes. Despite this finding, there has been an increasing trend toward an endovascular-first approach to infrainguinal CLTI. Our aim was to investigate whether changes in practice have impacted the clinical outcomes of BS in our unit 10 years after BASIL-1. METHODS: Data for patients who underwent femoropopliteal (FP) BS in BASIL-1 (1999-2004) were retrieved from trial case record forms. The comparator contemporary series (CS) comprised all patients undergoing FP BS for CLTI in our unit between 2009 and 2014. Demographic and clinical outcome data on patients in the CS were collected from the prospectively collected hospital electronic notes. Anatomic patterns of disease in the BASIL-1 and CS cohorts were scored using the Bollinger and GLASS criteria. Statistical analysis was performed in SAS v9.4. RESULTS: There were 128 patients from BASIL-1 and 50 patients in the CS. Baseline age, gender, affected limb, and diabetes prevalence were similar, as were days spent in hospital out to 12 months and length of follow-up. BASIL-1 patients were more likely to be current smokers (P = .000) and had a higher creatinine (P = .04). The 30-day morbidity and mortality were higher in BASIL-1 (45.3% vs 22%; P = .004). There was no significant difference between BASIL-1 and CS with regard to run-off Bollinger (37.7 vs 32.1; P = .167) and IP GLASS (0 vs 0; P = .390) scores, with both groups having a median of two runoff vessels. Amputation-free survival (62% vs 28%; hazard ratio [HR], 1.86; 95% confidence interval [CI], 1.18-2.93; P = .007), limb salvage (85% vs 69%; HR, 2.31; 95% CI, 1.14-4.68; P = .02), overall survival (69% vs 35%; HR, 1.66; 95% CI, 1.00-2.74; P = .05) and major adverse limb events (67% vs 47%; HR, 1.93; 95% CI, 1.15-3.22; P = .01) were all significantly better in BASIL-1. CONCLUSIONS: Although 30-day mortality and morbidity were significantly lower, all of the examined longer term clinical outcomes after FP BS were significantly worse in the CS group a decade on from BASIL-1. Further research in the form of prospective cohort studies and randomized controlled trials is urgently required to determine if the CS data reported herein are generalizable to current vascular surgical practice and, if so, to determine the reasons for these unexpected outcomes.

A Comparison of Clinical Outcomes Following Femoropopliteal Bypass or Plain Balloon Angioplasty with Selective Bare Metal Stenting in the Bypass Versus Angioplasty in Severe Ischaemia of the Limb (BASIL) Trial.

OBJECTIVE: To compare outcomes in patients with chronic limb threatening ischaemia (CLTI) due to femoropopliteal (FP), with or without infrapopliteal (IP), disease who underwent FP (vein or synthetic) open surgical bypass (OSB), or plain balloon angioplasty (PBA), with or without bare metal stenting (BMS), in the Bypass versus Angioplasty in Severe Ischaemia of the Limb (BASIL-1) trial. METHODS: Data were extracted from BASIL-1 case record forms. Outcomes reported include immediate technical success, freedom from major adverse limb events (FF-MALE) and further re-intervention (FF-R), amputation free survival (AFS), overall survival (OS), and limb salvage (LS). RESULTS: Patients underwent primary OSB (n = 128; 89 vein, 39 synthetic) or primary PBA (n = 183; six had BMS). Mean follow up was 46.2 and 43.6 months respectively. Patients were well matched at baseline except that PBA ± BMS patients were significantly more likely to be current smokers. There was no difference in overall or IP (runoff) Bollinger angiogram scores between groups. Immediate technical success was significantly higher for OSB (98% vs. 81%; p < .001). OSB was associated with a longer mean index hospital admission (p = .001), but there was no difference in hospital days at 12 months. FF-MALE (hazard ratio [HR] 1.51; p = .04) and FF-R (HR 1.68; p = .02) but not AFS (HR 1.18; p = .4), OS (HR 1.14; p = .5), and LS (HR 1.09; p = .8) were significantly better after OSB. CONCLUSION: Although AFS, OS, and LS were similar in the two groups, OSB was associated with significantly fewer MALE and re-interventions. So, while PBA ± BMS may be a less resource intensive (expensive) and morbid option in the short term, this appears unlikely to be the case in the longer term. Present data add further weight to the argument that, where possible, patients presenting with CLTI due to FP disease should be offered OSB as their primary revascularisation procedure.

Rating the intelligibility of dysarthic speech amongst people with Parkinson's Disease: a comparison of trained and untrained listeners.

Intelligibility of speech is a key outcome in speech and language therapy (SLT) and research. SLT students frequently participate as raters of intelligibility but we lack information about whether they rate intelligibility in the same way as the general public. This paper aims to determine if there is a difference in the intelligibility ratings made by SLT students (trained in speech related topics) compared to individuals from the general public (untrained). The SLT students were in year 2 of a BSc programme or the first 6 months of a MSc programme. We recorded 10 speakers with Parkinson's disease (PD) related speech reading aloud the words and sentences from the Assessment of Intelligibility of Dysarthric Speech. These speech recordings were rated for intelligibility by 'trained' raters and 'untrained' raters. The effort required to understand the speech was also reported. There were no significant differences in the measures of intelligibility from the trained and untrained raters for words or sentences after adjusting for speaker by including them as a covariate in the model. There was a slight increase in effort reported by the untrained raters for the sentences. This difference in reported effort was not evident with the words. SLT students can be recruited alongside individuals from the general public as naïve raters for evaluating intelligibility in people with speech disorders.

Editor's Choice - A Comparison of Clinical Outcomes Between Primary Bypass and Secondary Bypass After Failed Plain Balloon Angioplasty in the Bypass versus Angioplasty for Severe Ischaemia of the Limb (BASIL) Trial.

OBJECTIVE: Chronic limb threatening ischaemia (CLTI) is a growing global health problem. The UK NIHR HTA funded BASIL trial is still the only randomised controlled trial to have compared a "bypass surgery first" with a "plain balloon angioplasty (PBA) first" strategy for the management of CLTI. In patients who were likely to survive for 2 years and had a suitable vein, primary bypass (PB) was associated with better clinical outcomes. Furthermore, PBA was associated with a high technical and clinical failure rate and many went on to have secondary bypass (SB). This study aimed at comparing clinical outcomes following PB and SB in the BASIL trial. METHODS: Demographic, procedural, and outcome data were obtained from the BASIL case report forms. Outcomes were amputation free survival (AFS), limb salvage (LS), overall survival (OS), and freedom from revascularisation (FFR). The SB cohort comprises patients whose first trial intervention was PBA and who subsequently underwent bypass during follow up. The PB cohort comprises those patients whose first trial intervention was bypass. RESULTS: The 190 PB and 49 SB patients were well matched except that the SB patients were more likely to be current smokers. At a median of 7 years, PB was associated with better AFS (PB 60% vs. SB 40%; HR 1.58, p = .04), LS (PB 85% vs. SB 73%, p = .06), and OS (PB 68% vs. 51%, p = .06). FFR was equivalent (PB 53% vs. 53%, p = .3). CONCLUSION: In the BASIL trial, clinical outcomes following PB were significantly better than in patients undergoing SB after failed PBA. Prior to treating patients with CLTI with primary PBA, clinicians should consider that if this should fail, the outcome of attempted subsequent bypass is likely to be significantly worse than if PB were attempted.

Cost-utility analysis of deep brain stimulation surgery plus best medical therapy versus best medical therapy in patients with Parkinson's: Economic evaluation alongside the PD SURG trial.

INTRODUCTION: Williams and colleagues reported that DBS surgery for patients with advanced PD improves motor function and quality of life compared to best medical therapy alone at 1 year, but with surgery-related side effects in a minority. This article reports on the economic evaluation alongside this trial. METHODS: Detailed resource use and quality of life over 12 months after randomization was obtained from the trial reported by Williams and colleagues. Outcomes were measured using the EQ-5D and quality-adjusted life years calculated. RESULTS: Year 1 costs for surgery were significantly higher than in best medical therapy, at £19,069 compared to £9,813, a difference of £9,256 (95% confidence interval [CI]: £7,625, £10,887). There was a small, significant gain in utility at 1 year but a statistically insignificant gain of 0.02 quality-adjusted life years (95% CI: -0.015, 0.05) in the surgical arm. The incremental cost per quality-adjusted life year of surgery at 1 year was £468,528. Extrapolation reveals that after 5 years, this ratio is likely to reduce to £45,180, but subsequently rise to £70,537 at 10 years owing to the increased probability of battery replacements (and re-replacements) beyond 5 years. CONCLUSION: In this patient group, DBS is not cost-effective at 1 year. Extrapolation, however, reveals an increasing likelihood of cost-effectiveness up to 5 years and reducing cost-effectiveness between 5 and 10 years. These models are sensitive to assumptions about future costs and quality-adjusted life years gained. © 2016 International Parkinson and Movement Disorder Society.

Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial.

BACKGROUND: Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. METHODS: In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. FINDINGS: Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001). INTERPRETATION: Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.

Headache determines quality of life in idiopathic intracranial hypertension.

BACKGROUND: The effect of idiopathic intracranial hypertension (IIH) on quality of life (QOL) is poorly understood. Our objectives were to compare QOL in IIH to the normal UK population; to investigate QOL changes with treatment of IIH, using a weight loss intervention, and to determine which clinical factors influence QOL. METHODS: This was a prospective cohort evaluation of QOL, using the 36-Item Short Form (SF-36) Health Survey questionnaire, before and after a therapeutic dietary intervention which resulted in significant reduction in body mass index (BMI), intracranial pressure (ICP), papilloedema, visual acuity, perimetric mean deviation (Humphrey 24-2) and headache (six-item headache impact test (HIT-6) and headache diary). Baseline QOL was compared to an age and gender matched population. The relationship between each clinical outcome and change in QOL was evaluated. RESULTS: At baseline, QOL was significantly lower in IIH compared to an age and gender matched population in most domains, p < 0.001. Therapeutic weight loss led to a significant improvement in 10 out of 11 QOL domains in conjunction with the previously published data demonstrating significant improvement in papilloedema, visual acuity, perimetry and headache (p < 0.001) and large effect size. Despite significant improvement in clinical measures only headache correlated significantly (p < 0.001) with improving QOL domains. CONCLUSIONS: QOL in IIH patients is significantly reduced. It improved with weight loss alongside significant improvement in clinical measures and headache. However, headache was the only clinical outcome that correlated with enhanced QOL. Effective headache management is required to improve QOL in IIH.

Physiotherapy for Parkinson's disease: a comparison of techniques.

BACKGROUND: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy is to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and wellbeing, thereby enhancing quality of life. Trials have shown that physiotherapy has short-term benefits in PD. However, which physiotherapy intervention is most effective remains unclear. OBJECTIVES: To assess the effectiveness of one physiotherapy intervention compared with a second approach in patients with PD. SEARCH METHODS: Relevant trials were identified by electronic searches of numerous literature databases (for example MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to the end of January 2012. SELECTION CRITERIA: Randomised controlled trials of one physiotherapy intervention versus another physiotherapy intervention in patients with PD. DATA COLLECTION AND ANALYSIS: Data were abstracted independently from each paper by two authors. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. MAIN RESULTS: A total of 43 trials were identified with 1673 participants. All trials used small patient numbers (average trial size of 39 participants); the methods of randomisation and concealment of allocation were poor or not stated in most trials. Blinded assessors were used in just over half of the trials and only 10 stated that they used intention-to-treat analysis.A wide variety of validated and customised outcome measures were used to assess the effectiveness of physiotherapy interventions. The most frequently reported physiotherapy outcomes were gait speed and timed up and go, in 19 and 15 trials respectively. Only five of the 43 trials reported data on falls (12%). The motor subscales of the Unified Parkinson's Disease Rating Scale and Parkinson's Disease Questionnaire-39 were the most commonly reported clinician-rated disability and patient-rated quality of life outcome measures, used in 22 and 13 trials respectively. The content and delivery of the physiotherapy interventions varied widely in the trials included within this review, so no quantitative meta-analysis could be performed. AUTHORS' CONCLUSIONS: Considering the small number of participants examined, the methodological flaws in many of the studies, the possibility of publication bias, and the variety of interventions, formal comparison of the different physiotherapy techniques could not be performed. There is insufficient evidence to support or refute the effectiveness of one physiotherapy intervention over another in PD.This review shows that a wide range of physiotherapy interventions to treat PD have been tested . There is a need for more specific trials with improved treatment strategies to underpin the most appropriate choice of physiotherapy intervention and the outcomes measured.

Lee Silverman voice treatment versus NHS speech and language therapy versus control for dysarthria in people with Parkinson's disease (PD COMM): pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial.

OBJECTIVES: To assess the clinical effectiveness of two speech and language therapy approaches versus no speech and language therapy for dysarthria in people with Parkinson's disease. DESIGN: Pragmatic, UK based, multicentre, three arm, parallel group, unblinded, randomised controlled trial. SETTING: The speech and language therapy interventions were delivered in outpatient or home settings between 26 September 2016 and 16 March 2020. PARTICIPANTS: 388 people with Parkinson's disease and dysarthria. INTERVENTIONS: Participants were randomly assigned to one of three groups (1:1:1): 130 to Lee Silverman voice treatment (LSVT LOUD), 129 to NHS speech and language therapy, and 129 to no speech and language therapy. LSVT LOUD consisted of four, face-to-face or remote, 50 min sessions each week delivered over four weeks. Home based practice activities were set for up to 5-10 mins daily on treatment days and 15 mins twice daily on non-treatment days. Dosage for the NHS speech and language therapy was determined by the local therapist in response to the participants' needs (estimated from prior research that NHS speech and language therapy participants would receive an average of one session per week over six to eight weeks). Local practices for NHS speech and language therapy were accepted, except for those within the LSVT LOUD protocol. Analyses were based on the intention to treat principle. MAIN OUTCOME MEASURES: The primary outcome was total score at three months of self-reported voice handicap index. RESULTS: People who received LSVT LOUD reported lower voice handicap index scores at three months after randomisation than those who did not receive speech and language therapy (-8.0 points (99% confidence interval -13.3 to -2.6); P<0.001). No evidence suggests a difference in voice handicap index scores between NHS speech and language therapy and no speech and language therapy (1.7 points (-3.8 to 7.1); P=0.43). Patients in the LSVT LOUD group also reported lower voice handicap index scores than did those randomised to NHS speech and language therapy (-9.6 points (-14.9 to -4.4); P<0.001). 93 adverse events (predominately vocal strain) were reported in the LSVT LOUD group, 46 in the NHS speech and language therapy group, and none in the no speech and language therapy group. No serious adverse events were recorded. CONCLUSIONS: LSVT LOUD was more effective at reducing the participant reported impact of voice problems than was no speech and language therapy and NHS speech and language therapy. NHS speech and language therapy showed no evidence of benefit compared with no speech and language therapy. TRIAL REGISTRATION: ISRCTN registry ISRCTN12421382.

The impact of obstructive sleep apnea treatment on microvascular complications in patients with type 2 diabetes: a feasibility randomized controlled trial.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with an increased risk of diabetes-related complications. Hence, it is plausible that continuous positive airway pressure (CPAP) could have a favorable impact on these complications. We assessed the feasibility of conducting a randomized control trial in patients with type 2 diabetes and OSA over 2 years. METHODS: We conducted an open-label multicenter feasibility randomized control trial of CPAP vs no CPAP in patients with type 2 diabetes and OSA. Patients with resting oxygen saturation < 90%, central apnea index > 15 events/h, or Epworth Sleepiness Scale ≥ 11 were excluded. OSA was diagnosed using a multichannel portable device (ApneaLink Air, ResMed). The primary outcome measures were related to feasibility and the secondary outcomes were changes in various clinical and biochemical parameters related to diabetes outcomes. RESULTS: Eighty-three (40 CPAP vs 43 no CPAP) patients were randomly assigned, with a median (interquartile range) follow-up of 645 (545, 861) days. CPAP compliance was inadequate, with a median usage of approximately 3.5 hours/night. Early CPAP use predicted longer-term compliance. The adjusted analysis showed a possible favorable association between being randomly assigned to CPAP and several diabetes-related end points (chronic kidney disease, neuropathy, and quality of life). CONCLUSIONS: It was feasible to recruit, randomly assign, and achieve a high follow-up rate over 2 years in patients with OSA and type 2 diabetes. CPAP compliance might improve by a run-in period before randomization. A full randomized control trial is necessary to assess the observed favorable association between CPAP and chronic kidney disease , neuropathy, and quality of life in patients with type 2 diabetes. CLINICAL TRIAL REGISTRATION: Registry: ISRCTN; Name: The impact of sleep disorders in patients with type 2 diabetes; URL: https://www.isrctn.com/ISRCTN12361838; Identifier: ISRCTN12361838. CITATION: Makhdom EA, Maher A, Ottridge R, et al. The impact of obstructive sleep apnea treatment on microvascular complications in patients with type 2 diabetes: a feasibility randomized controlled trial. J Clin Sleep Med. 2024;20(6):947-957.

Physiotherapy versus placebo or no intervention in Parkinson's disease.

BACKGROUND: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. Physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety, and well-being, thereby enhancing quality of life. OBJECTIVES: To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD. SEARCH METHODS: We identified relevant trials by conducting electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, and by handsearching major journals, abstract books, conference proceedings, and reference lists of retrieved publications. The literature search included trials published up to the end of January 2012. SELECTION CRITERIA: Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance, and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions. MAIN RESULTS: We identified 39 trials with 1827 participants. We considered the trials to be at a mixed risk of bias as the result of unreported allocation concealment and probable detection bias. Compared with no intervention, physiotherapy significantly improved the gait outcomes of speed (mean difference 0.04 m/s, 95% confidence interval (CI) 0.02 to 0.06, P = 0.0002); two- or six-minute walk test (13.37 m, 95% CI 0.55 to 26.20, P = 0.04) and Freezing of Gait questionnaire (-1.41, 95% CI -2.63 to -0.19, P = 0.02); functional mobility and balance outcomes of Timed Up & Go test (-0.63 s, 95% CI -1.05 to -0.21, P = 0.003), Functional Reach Test (2.16 cm, 95% CI 0.89 to 3.43, P = 0.0008), and Berg Balance Scale (3.71 points, 95% CI 2.30 to 5.11, P < 0.00001); and clinician-rated disability using the Unified Parkinson's Disease Rating Scale (UPDRS) (total -6.15 points, 95% CI-8.57 to -3.73, P < 0.00001; activities of daily living: -1.36, 95% CI -2.41 to -0.30, P = 0.01; and motor: -5.01, 95% CI -6.30 to -3.72, P < 0.00001). No difference between arms was noted in falls (Falls Efficacy Scale: -1.91 points, 95% CI -4.76 to 0.94, P = 0.19) or patient-rated quality of life (PDQ-39 Summary Index: -0.38 points, 95% CI -2.58 to 1.81, P = 0.73). One study reported that adverse events were rare; no other studies reported data on this outcome. Indirect comparisons of the different physiotherapy interventions revealed no evidence that the treatment effect differed across physiotherapy interventions for any of the outcomes assessed. AUTHORS' CONCLUSIONS: Benefit for physiotherapy was found in most outcomes over the short term (i.e. < 3 months) but was significant only for speed, two- or six-minute walk test, Freezing of Gait questionnaire, Timed Up & Go, Functional Reach Test, Berg Balance Scale, and clinician-rated UPDRS. Most of the observed differences between treatments were small. However, for some outcomes (e.g. speed, Berg Balance Scale, UPDRS), the differences observed were at, or approaching, what are considered minimal clinically important changes. These benefits should be interpreted with caution because the quality of most of the included trials was not high. Variation in measurements of outcome between studies meant that our analyses include a small proportion of the participants recruited.This review illustrates that a wide range of approaches are employed by physiotherapists to treat patients with PD. However, no evidence of differences in treatment effect was noted between the different types of physiotherapy interventions being used, although this was based on indirect comparisons. A consensus menu of 'best practice' physiotherapy is needed, as are large, well-designed randomised controlled trials undertaken to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.

Antidepressants for the prevention of depression following first-episode psychosis (ADEPP): study protocol for a multi-centre, double-blind, randomised controlled trial.

BACKGROUND: Depressive episodes are common after first-episode psychosis (FEP), affecting more than 40% of people, adding to individual burden, poor outcomes, and healthcare costs. If the risks of developing depression were lower, this could have a beneficial effect on morbidity and mortality, as well as improving outcomes. Sertraline is a selective serotonin reuptake inhibitor and a common first-line medication for the treatment of depression in adults. It has been shown to be safe when co-prescribed with antipsychotic medication, and there is evidence that it is an effective treatment for depression in established schizophrenia. We present a protocol for a multi-centre, double-blind, randomised, placebo-controlled clinical trial called ADEPP that aims to investigate the efficacy and cost-effectiveness of sertraline in preventing depression after FEP. METHODS: The recruitment target is 452 participants between the ages of 18 and 65 years who are within 12 months of treatment initiation for FEP. Having provided informed consent, participants will be randomised to receive either 50 mg of sertraline daily or matched placebo for 6 months, in addition to treatment as usual. The primary outcome measure will be a comparison of the number of new cases of depression between the treatment and placebo arms over the 6-month intervention phase. Secondary outcomes include suicidal behaviour, anxiety, rates of relapse, functional outcome, quality of life, and resource use. DISCUSSION: The ADEPP trial will test whether the addition of sertraline following FEP is a clinically useful, acceptable, and cost-effective way of improving outcomes following FEP. TRIAL REGISTRATION: ISRCTN12682719 registration date 24/11/2020.

Physiotherapy versus placebo or no intervention in Parkinson's disease.

BACKGROUND: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and well-being, thereby enhancing quality of life. OBJECTIVES: To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD. SEARCH METHODS: We identified relevant trials by electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to end of December 2010. SELECTION CRITERIA: Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions. MAIN RESULTS: We identified 33 trials with 1518 participants. Compared with no-intervention, physiotherapy significantly improved the gait outcomes of velocity (mean difference 0.05 m/s, 95% confidence interval (CI): 0.02 to 0.07, P = 0.0002), two- or six-minute walk test (16.40 m, CI: 1.90 to 30.90, P = 0.03) and step length (0.03 m, CI: 0 to 0.06, P = 0.04); functional mobility and balance outcomes of Timed Up & Go test (-0.61 s, CI: -1.06 to -0.17, P = 0.006), Functional Reach Test (2.16 cm, CI: 0.89 to 3.43, P = 0.0008) and Berg Balance Scale (3.36 points, CI: 1.91 to 4.81, P < 0.00001); and clinician-rated disability using the Unified Parkinson's Disease Rating Scale (UPDRS) (total: -4.46 points, CI -7.16 to -1.75, P = 0.001; activities of daily living: -1.36, CI -2.41 to -0.30, P = 0.01; and motor: -4.09, CI: -5.59 to -2.59, P < 0.00001). There was no difference between arms in falls or patient-rated quality of life. Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the physiotherapy interventions for any of the outcomes assessed. AUTHORS' CONCLUSIONS: Benefit for physiotherapy was found in most outcomes over the short-term (i.e. < three months), but was only significant for velocity, two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance Scale and clinician-rated UPDRS. Most of the observed differences between the treatments were small. However, for some outcomes (e.g. velocity, Berg Balance Scale and UPDRS), the differences observed were at, or approaching, what are considered minimally clinical important changes.The review illustrates that a wide range of approaches are employed by physiotherapists to treat PD. However, there was no evidence of differences in treatment effect between the different types of physiotherapy interventions being used, though this was based on indirect comparisons. There is a need to develop a consensus menu of 'best-practice' physiotherapy, and to perform large well-designed randomised controlled trials to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.

Physiotherapy versus placebo or no intervention in Parkinson's disease.

BACKGROUND: Despite medical therapies and surgical interventions for Parkinson's disease (PD), patients develop progressive disability. The role of physiotherapy aims to maximise functional ability and minimise secondary complications through movement rehabilitation within a context of education and support for the whole person. The overall aim is to optimise independence, safety and well-being, thereby enhancing quality of life. OBJECTIVES: To assess the effectiveness of physiotherapy intervention compared with no intervention in patients with PD. SEARCH METHODS: We identified relevant trials by electronic searches of numerous literature databases (e.g. MEDLINE, EMBASE) and trial registers, plus handsearching of major journals, abstract books, conference proceedings and reference lists of retrieved publications. The literature search included trials published up to end of December 2010. SELECTION CRITERIA: Randomised controlled trials of physiotherapy intervention versus no physiotherapy intervention in patients with PD. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each article. We used standard meta-analysis methods to assess the effectiveness of physiotherapy intervention compared with no physiotherapy intervention. Trials were classified into the following intervention comparisons: general physiotherapy, exercise, treadmill training, cueing, dance and martial arts. We used tests for heterogeneity to assess for differences in treatment effect across these different physiotherapy interventions. MAIN RESULTS: We identified 33 trials with 1518 participants. Compared with no-intervention, physiotherapy significantly improved the gait outcomes of velocity (mean difference 0.05 m/s, 95% confidence interval (CI): 0.02 to 0.07, P = 0.0002), two- or six-minute walk test (16.40 m, CI: 1.90 to 30.90, P = 0.03) and step length (0.03 m, CI: 0 to 0.06, P = 0.04); functional mobility and balance outcomes of Timed Up & Go test (-0.61 s, CI: -1.06 to -0.17, P = 0.006), Functional Reach Test (2.16 cm, CI: 0.89 to 3.43, P = 0.0008) and Berg Balance Scale (3.36 points, CI: 1.91 to 4.81, P < 0.00001); and clinician-rated disability using the Unified Parkinson's Disease Rating Scale (UPDRS) (total: -4.46 points, CI -7.16 to -1.75, P = 0.001; activities of daily living: -1.36, CI -2.41 to -0.30, P = 0.01; and motor: -4.09, CI: -5.59 to -2.59, P < 0.00001). There was no difference between arms in falls or patient-rated quality of life. Indirect comparisons of the different physiotherapy interventions found no evidence that the treatment effect differed across the physiotherapy interventions for any of the outcomes assessed. AUTHORS' CONCLUSIONS: Benefit for physiotherapy was found in most outcomes over the short-term (i.e. < three months), but was only significant for velocity, two- or six-minute walk test, step length, Timed Up & Go, Functional Reach Test, Berg Balance Scale and clinician-rated UPDRS. Most of the observed differences between the treatments were small. However, for some outcomes (e.g. velocity, Berg Balance Scale and UPDRS), the differences observed were at, or approaching, what are considered minimally clinical important changes.The review illustrates that a wide range of approaches are employed by physiotherapists to treat PD. However, there was no evidence of differences in treatment effect between the different types of physiotherapy interventions being used, though this was based on indirect comparisons. There is a need to develop a consensus menu of 'best-practice' physiotherapy, and to perform large well-designed randomised controlled trials to demonstrate the longer-term efficacy and cost-effectiveness of 'best practice' physiotherapy in PD.

Structured follow-up pathway to support people after transient ischaemic attack and minor stroke (SUPPORT TIA): protocol for a feasibility study and process evaluation.

INTRODUCTION: People who experience transient ischaemic attack (TIA) and minor stroke have limited follow-up despite rapid specialist review in hospital. This means they often have unmet needs and feel abandoned following discharge. Care needs after TIA/minor stroke include information provision (diagnosis and stroke risk), stroke prevention (medication and lifestyle change) and holistic care (residual problems and return to work or usual activities). This protocol describes a feasibility study and process evaluation of an intervention to support people after TIA/minor stroke. The study aims to assess the feasibility and acceptability of (1) the intervention and (2) the trial procedures for a future randomised controlled trial of this intervention. METHODS AND ANALYSIS: This is a multicentre, randomised (1:1) feasibility study with a mixed-methods process evaluation. Sixty participants will be recruited from TIA clinics or stroke wards at three hospital sites (England). Intervention arm participants will be offered a nurse or allied health professional-led follow-up appointment 4 weeks after TIA/minor stroke. The multifaceted intervention includes: a needs checklist, action plan, resources to support management of needs, a general practitioner letter and training to deliver the intervention. Control arm participants will receive usual care. Follow-up will be self-completed questionnaires (12 weeks and 24 weeks) and a clinic appointment (24 weeks). Follow-up questionnaires will measure anxiety, depression, fatigue, health related quality of life, self-efficacy and medication adherence. The clinic appointment will collect body mass index, blood pressure, cholesterol and medication. Assessment of feasibility and acceptability will include quantitative process variables (such as recruitment and questionnaire response rates), structured observations of study processes, and interviews with a subsample of participants and clinical staff. ETHICS AND DISSEMINATION: Favourable ethical opinion was gained from the Wales Research Ethics Committee (REC) 1 (23 February 2021, REC reference: 21/WA/0036). Study results will be published in peer-reviewed journals and presented at conferences. A lay summary and dissemination strategy will be codesigned with consumers. The lay summary and journal publication will be distributed on social media. TRIAL REGISTRATION NUMBER: ISRCTN39864003.

Long-term Effectiveness of Adjuvant Treatment With Catechol-O-Methyltransferase or Monoamine Oxidase B Inhibitors Compared With Dopamine Agonists Among Patients With Parkinson Disease Uncontrolled by Levodopa Therapy: The PD MED Randomized Clinical Trial.

Importance: Many people with Parkinson disease (PD) develop motor complications that are uncontrolled by levodopa dose adjustment. Among these patients, it is uncertain which drug class is more effective as adjuvant therapy. Objective: To compare the long-term effects on patient-rated quality of life of adding a dopamine agonist vs a dopamine reuptake inhibitor (DRI), either a monoamine oxidase type B (MAO-B) inhibitor or a catechol-O-methyltransferase (COMT) inhibitor, to levodopa therapy for the treatment of patients with motor complications of PD. Design, Setting, and Participants: This pragmatic semifactorial (2 × 1) randomized clinical trial recruited from 64 neurology and geriatric clinics (62 in the United Kingdom, 1 in the Czech Republic, and 1 in Russia) between February 23, 2001, and December 15, 2009. A total of 500 patients with idiopathic PD who developed uncontrolled motor complications and did not have dementia were randomly assigned on a 1:1:1 basis using a computerized minimization program. Data were analyzed between 2017 and 2020. Interventions: Open-label dopamine agonist, MAO-B inhibitor, or COMT inhibitor. Main Outcomes and Measures: Primary outcomes were scores on the 39-item Parkinson's Disease Questionnaire (PDQ-39) mobility domain and cost-effectiveness. Outcomes were assessed before study entry, at 6 and 12 months after randomization, and annually thereafter. Repeated-measures and log rank analyses were used in an intention-to-treat approach. Results: Among 500 participants, the mean (SD) age was 73.0 (8.2) years; 314 participants (62.8%) were men. Over a median of 4.5 years (range, 0-13.3 years) of follow-up, the participants in the dopamine agonist group had a mean PDQ-39 mobility score that was 2.4 points (95% CI, -1.3 to 6.0 points) better than that of the combined MAO-B and COMT groups; however, this difference was not significant (P=.20). With regard to DRIs, participants in the MAO-B group had mean PDQ-39 mobility scores that were 4.2 points (95% CI, 0.4-7.9 points; P=.03) better than those of the COMT group and EuroQol 5-dimension 3-level (EQ-5D-3L) utility scores that were 0.05 points (95% CI, 0.003-0.09 points; P=.04) better than the COMT group. Nonsignificant improvements were found in the PDQ-39 summary index (mean difference, 2.2 points; 95% CI, -0.2 to 4.5 points; P=.07) along with nonsignificant reductions in dementia (rate ratio [RR], 0.70; 95% CI, 0.47-1.03; P = .07) and mortality (RR, 0.76; 95% CI, 0.56-1.03; P=.07). When dopamine agonists were compared with MAO-B inhibitors only, the outcomes were similar. Conclusions and Relevance: In this study, patient-rated quality of life was inferior when COMT inhibitors were used as adjuvant treatment compared with MAO-B inhibitors or dopamine agonists among people with PD who experienced motor complications that were uncontrolled by levodopa therapy. The MAO-B inhibitors produced equivalent disease control, suggesting that these agents may be underused as adjuvant therapy. Trial Registration: isrctn.org Identifier: ISRCTN69812316; EU Clinical Trials Register Identifier: 2005-001813-16.

Use of core outcome sets was low in clinical trials published in major medical journals.

OBJECTIVES: To examine current practices in late-phase trials published in major medical journals and examine trialists' views about core outcome set (COS) use. STUDY DESIGN AND SETTING: A sequential multi-methods study was conducted. We examined late-phase trials published between October 2019 and March 2020 in JAMA, NEJM, The Lancet, BMJ, and Annals of Internal Medicine. The COMET database was searched for COS potentially relevant to trials not reporting using a COS; overlap of trial and COS outcomes was examined. An online survey examined awareness of, and decisions to search for and use a COS. RESULTS: Ninety-five trials were examined; 93 (98%) did not report using a COS. Relevant COS were identified for 31 trials (33%). Core outcomes were measured in 9 (23%) studies; all trials measured at least one core outcome. Thirty-one trialists (33%) completed our survey. The most common barrier to COS use was trialist's own outcome preferences and choice (68%). The most common perceived facilitator was awareness and knowledge about COS (90%). CONCLUSION: COS use in this cohort of trials was low, even when relevant COS were available. Increased use of COS in clinical trials can improve evaluation of intervention effects and evidence synthesis and reduce research waste.