The Edinburgh Claudication Questionnaire has poor diagnostic accuracy in people with intermittent claudication.

BACKGROUND: The screening and diagnosis of intermittent claudication is a challenging process and often relies on the expertise of specialist vascular clinicians. We sought to investigate the diagnostic performance of the Edinburgh Claudication Questionnaire (ECQ) as a screening tool for referrals of suspected intermittent claudication from primary to secondary care. METHOD: Prospectively, 100 referrals from primary care with a stated diagnosis or query regarding intermittent claudication were recruited. All participants who completed the ECQ, underwent an anklebrachial pressure index (ABPI) assessment and treadmill exercise testing. Outcomes of the ECQ were compared to clinical diagnoses of intermittent claudication. RESULTS: The ECQ had a sensitivity of 46.8% (95% CI: 27-65%), specificity of 63.2% (95% CI: 43-82%) and accuracy of 53.0% (95% CI: 43-63%). The diagnostic performance was not changed by combining the ECQ with a positive ABPI or post-exercise ABPI outcome for PAD. CONCLUSION: The ECQ had a poor diagnostic performance in this cohort. Considering the results found here and in other recent studies, the utility of the ECQ as a screening tool and epidemiological survey tool must be questioned. Novel, low-resource diagnostic tools are needed in this population.

An updated systematic review and meta-analysis of home-based exercise programs for individuals with intermittent claudication.

OBJECTIVE: Supervised exercise programs (SEP) are effective for improving walking distance in patients with intermittent claudication (IC) but provision and uptake rates are suboptimal. Access to such programs has also been halted by the Coronavirus pandemic. The aim of this review is to provide a comprehensive overview of the evidence for home-based exercise programs (HEP). METHODS: This review was conducted in according with the published protocol and PRISMA guidance. Medline, EMBASE, CINAHL, PEDro, and Cochrane CENTRAL were searched for terms relating to HEP and IC. Randomized and nonrandomized trials that compared HEP with SEP, basic exercise advice, or no exercise controls for IC were included. A narrative synthesis was provided for all studies and meta-analyses conducted using data from randomized trials. The primary outcome was maximal walking distance. Subgroup analyses were performed to consider the effect of monitoring. Risk of bias was assessed using the Cochrane tool and quality of evidence via GRADE. RESULTS: We included 23 studies with 1907 participants. Considering the narrative review, HEPs were inferior to SEPs which was reflected in the meta-analysis (mean distance [MD], 139 m; 95% confidence interval [CI], 45-232 m; P = .004; very low quality of evidence). Monitoring was an important component, because HEPs adopting this strategy were equivalent to SEPs (MD, 8 m; 95% CI, -81 to 97; P = .86; moderate quality of evidence). For HEPs vs basic exercise advice, narrative review suggested HEPs can be superior, although not always significantly so. For HEPs vs no exercise controls, narrative review and meta-analysis suggested HEPs were potentially superior (MD, 136 m; 95% CI, -2 to 273 m; P = .05; very low quality of evidence). Monitoring was also a key element in these comparisons. Other elements such as appropriate frequency (≥3× a week), intensity (to moderate-maximum pain), duration (20 progressing to 60 minutes) and type (walking) of exercise were important, as was education, self-regulation, goal setting, feedback, and action planning. CONCLUSIONS: When SEPs are unavailable, HEPs are recommended. However, to elicit maximum benefit they should be structured, incorporating all elements of our evidence-based recommendations.

Presurgery exercise-based conditioning interventions (prehabilitation) in adults undergoing lower limb surgery for peripheral arterial disease.

BACKGROUND: Lower limb peripheral arterial disease (PAD) is a type of cardiovascular disease where the blood vessels that carry the blood to the legs are hardened and narrowed. The most severe manifestation of PAD is critical limb ischaemia (CLI). This condition results in symptoms of intractable rest pain, non-healing wounds and ulceration, gangrene or both. PAD affects more than 200 million people worldwide and approximately 3% to 5% of people aged over 40 have PAD, rising to 18% in people over 70 years of age. Between 5% to 10% of symptomatic PAD patients will progress to CLI over a five-year period and the five year cumulative incidence rate for asymptomatic patients with PAD deteriorating to intermittent claudication is 7%, with 21% of these progressing to CLI. Treatment options include angioplasty, bypass or amputation of the limb, when life or limb is threatened. People with CLI have a high risk of mortality and morbidity. The mortality rates during a surgical admission are approximately 5%. Within one year of surgery, the mortality rate rises to 22%. Postoperative complications are as high as 30% and readmission rates vary between 7% to 18% in people with CLI. Despite recent advances in surgical technology, anaesthesia and perioperative care, a proportion of surgical patients have a suboptimal recovery. Presurgery conditioning (prehabilitation) is a multimodal conditioning intervention carried out prior to surgery using a combination of exercise, with or without nutritional or psychological interventions, or both. The use of prehabilitation is gaining momentum, particularly in elderly patients undergoing surgery and patients undergoing colorectal cancer surgery, as a means of optimising fitness to improve the prognosis for people undergoing the physiological stress of surgery. People with PAD are characterised by poor mobility and physical function and have a lower level of fitness as a result of disease progression. Therefore, prehabilitation may be an opportunity to improve their recovery following surgery. However, as multimodal prehabilitation requires considerable resources, it is important to assess whether it is superior to usual care. This review aimed to compare prehabilitation with usual care (defined as a preoperative assessment, including blood and urine tests). The key outcomes were postoperative complications, mortality and readmissions within 30 days of the surgical procedure, and one-year survival rates. OBJECTIVES: To assess the effectiveness of prehabilitation (preoperative exercise, either alone or in combination with nutritional or psychological interventions, or both) on postoperative outcomes in adults with PAD undergoing open lower limb surgery. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 25 September 2019. SELECTION CRITERIA: We considered all published and unpublished randomised controlled trials (RCTs) comparing presurgery interventions and usual care. Primary outcomes were postoperative complications, mortality and readmission to hospital within 30 days of the surgical procedure. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed all records identified by the searches conducted by the Cochrane Vascular Information Specialist. We planned to undertake data collection and analysis in accordance with recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions. MAIN RESULTS: We found no RCTs that met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: We found no RCTs conducted to determine the effects of prehabilitation on mortality or other postoperative outcomes when compared to usual care for patients with PAD. As a consequence, we were unable to provide any evidence to guide the treatment of patients with PAD undergoing surgery. To perform a randomised controlled trial of presurgery conditioning would be challenging but trials are warranted to provide solid evidence on this topic.

A systematic review of high-intensity interval training as an exercise intervention for intermittent claudication.

BACKGROUND: Intermittent claudication (IC) is the most common symptom of peripheral arterial disease, which significantly affects walking ability, functional capacity and quality of life. Supervised exercise programs (SEP) are recommended as first-line treatment, but recruitment and adherence rates are poor. The time required to complete a SEP is the most common barrier to participation cited by patients who decline. High-intensity interval training (HIIT) is more time efficient than current SEPs and therefore has the potential to overcome this barrier. We conducted a systematic review to appraise the evidence for HIIT programs for IC. METHODS: MEDLINE, Embase, and CENTRAL databases were searched for terms related to HIIT and IC. Randomized and nonrandomized trials that investigated HIIT for the treatment of IC were included, with no exclusions based on exercise modality, protocol, or use of a comparator arm. Outcome measures were walking distances, peak oxygen uptake, recruitment and adherence rates, and quality of life. The risk of bias was assessed using the Cochrane tool and study quality using a modified Physiotherapy Evidence Database scale. RESULTS: Nine articles reporting eight studies were included in the review. HIIT seems to improve walking distances and oxygen uptake in relation to controls, with improvements attainable in just 6 weeks. When HIIT was compared with low-intensity exercise, it seemed that longer low-intensity programs were required to obtain similar benefits to those from short-term HIIT. CONCLUSIONS: Initial evidence suggests that HIIT may provide benefits for patients with IC. Initially, pilot studies of low-volume, short-term HIIT vs usual SEPs are required. This strategy will allow for larger randomized, controlled trials to be appropriately designed and adequately powered to further explore the potential benefits of HIIT in IC.

Incidence and predictive factors for positive 75SeHCAT test: improving the diagnosis of bile acid diarrhoea.

AIMS: To determine the value of 75SeHCAT retention in determining bile acid diarrhoea (BAD), treatment response and predictors of a positive result. METHODS: Retrospective casenote review of consecutive patients undergoing 75SeHCAT from 2008 to 2014, including gender, age, history, clinical, and laboratory parameters. This included diseases associated with Type 1 BAD (ileal resection, Crohn's disease) and Type 3 BAD. Chi-squared test and logistic regression determined factors predictive of BAD. Subjective response to treatment with bile acid sequestrants (BAS) was analysed with respect to the 75SeHCAT result. RESULTS: Of 387 patients, 154 (39.7%) were male and average age was 50 years. Ninety-five patients (24.5%) were investigated for Type 1 BAD, 86 (22.2%) for Type 3, and 206 patients (53.2%) for Type 2 or idiopathic BAD. There was a large increase in the number performed with time but no difference in percentage positive tests. One hundred and seventy-nine patients (46.2%) had BAD. Positive result was commonest in possible Type 1 and they had most severe BAD. Ninety-nine patients had severe BAD (<5% 75SeHCAT retention), 47 moderate BAD (5% to <10% retention), and 33 mild BAD (10% to <15% retention). Predictors of a positive 75SeHCAT were right hemicolectomy (OR 4.88), cholecystectomy (OR 2.44), and Crohn's (OR 1.86). A positive 75SeHCAT predicted a good or partial response to BAS of 66.7% (mild), 78.6% (moderate), or 75.9% (severe BAD). CONCLUSION: 75SeHCAT test use increased in 2008-2014, with high positive results throughout. Ileal resection, Crohn's, and cholecystectomy independently predict BAD. 75SeHCAT predicted response to BAS.

Mental health professionals and media professionals: a survey of attitudes towards one another.

BACKGROUND: The general public regard mass media as their main source of information about mental illness. Psychiatrists are reluctant to engage with the media. There is little understanding of why this is the case. AIMS: The paper looks to explore attitudes of mental health clinicians and the media towards one another. METHOD: Media and mental health clinicians in the southwest of England completed self-report surveys. RESULTS: Of 119 questionnaires returned 85 were mental health clinicians and 34 media professionals. Both groups agreed that stigma is a major issue and clinicians have a key role influencing media portrayal of mental illness. The media view their reporting to be more balanced than clinicians and lack awareness of clinician mistrust towards them. Those clinicians with media training (13%) felt significantly more comfortable talking to media and significantly less mistrustful of them. Clinicians who had experience of working with media felt more comfortable doing media work. Only 15% of media professionals had received mental health awareness training. CONCLUSIONS: Media training and experience are associated with an increased willingness of mental health professionals to engage with the media. Reciprocal awareness training between media and mental health professionals may be a simple intervention worth pursuing.

Incidence and features of eosinophilic esophagitis in dysphagia: a prospective observational study.

OBJECTIVE: The incidence and symptoms associated with eosinophilic esophagitis (EoE) varies with geographic location, present in 7-15% dysphagic European or North American adults. We aimed to determine incidence and features of EoE in a dysphagic New Zealand population. MATERIALS AND METHODS: 101 consecutive patients presenting with dysphagia to a New Zealand teaching hospital completed a questionnaire (demographics and history) before upper gastrointestinal endoscopy and esophageal biopsies. RESULTS: The incidence of EoE was 14.1% in those having esophageal biopsies. Patients with EoE were younger (median age 38 years, cohort 58 years: OR 9.2 for age ≤ 40; p < 0.001), more frequently male (19.1% versus 7.4% of females: OR 4.7; p < 0.05), and had longer symptom duration (median 262 weeks versus 130.6 weeks: p = NS) with non-continuous symptoms (continuous symptoms 8.3% EoE versus 16.2% cohort: p = NS). Progressive symptoms, level of dysphagia and history of allergy/atopy occurred with almost identical frequency in those with and without EoE. Classic endoscopic features of EoE had a sensitivity and specificity of 30.6 and 93.2%, respectively. CONCLUSIONS: EoE occurs in an adult dysphagic population in New Zealand with similar frequency to that reported in Europe and North America. Demographics and features of history associated with EoE are described and the need to take esophageal biopsies in this population emphasized by the relatively low sensitivity of endoscopic features for the condition.

The value of standards for health datasets in artificial intelligence-based applications.

Artificial intelligence as a medical device is increasingly being applied to healthcare for diagnosis, risk stratification and resource allocation. However, a growing body of evidence has highlighted the risk of algorithmic bias, which may perpetuate existing health inequity. This problem arises in part because of systemic inequalities in dataset curation, unequal opportunity to participate in research and inequalities of access. This study aims to explore existing standards, frameworks and best practices for ensuring adequate data diversity in health datasets. Exploring the body of existing literature and expert views is an important step towards the development of consensus-based guidelines. The study comprises two parts: a systematic review of existing standards, frameworks and best practices for healthcare datasets; and a survey and thematic analysis of stakeholder views of bias, health equity and best practices for artificial intelligence as a medical device. We found that the need for dataset diversity was well described in literature, and experts generally favored the development of a robust set of guidelines, but there were mixed views about how these could be implemented practically. The outputs of this study will be used to inform the development of standards for transparency of data diversity in health datasets (the STANDING Together initiative).

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers.

Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here, we report the safety, tolerability, and pharmacokinetics of a voltage-dependent and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single ascending dose (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to 5 dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A twofold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady-state was achieved from day 5 onward. These data indicate that oral vixotrigine is well-tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Considering the Feasibility, Tolerability, and Safety of High-Intensity Interval Training as a Novel Treatment for Patients With Intermittent Claudication.

PURPOSE: This study assessed the feasibility, tolerability, safety, and potential efficacy of a novel, 6-wk, high-intensity interval training (HIIT) program for patients with intermittent claudication (IC). METHODS: Patients referred to a usual-care supervised exercise program were invited to undertake a HIIT program. All recruited patients performed a baseline cardiopulmonary exercise test (CPX) to inform their exercise prescription. HIIT involved 10, 1-min high-intensity cycling intervals interspersed with 1-min recovery intervals, performed 3 d/wk for 6 wk. Outcomes included feasibility, tolerability, safety, walking distance, and quality of life. RESULTS: A total of 144 patients with IC were referred, 95 met initial eligibility criteria (66%) and 30 (32%) were recruited for HIIT, of which 15 (50%) completed. Of the recruited patients, 90% were on optimal medical therapy and 40% had concomitant cardiac, cerebrovascular, and/or respiratory disease. Patients who completed the program attended 100% of the sessions and one serious adverse event was recorded. Improvements in walking distances and quality of life were observed. Following recruitment of the first 20 patients, the inclusion criteria were refined on the basis of CPX, leading to improved completion rates. CONCLUSIONS: This study provides preliminary findings indicating that patients with IC can complete a short-term HIIT program. We provide very early evidence that HIIT may be safe and well-tolerated. In addition, walking distances seem to improve following HIIT. After a small change in the exclusion criteria, the intervention and inclusion/exclusion criteria now seem appropriate for this population, meaning further research to evaluate HIIT in patients with IC is warranted.

Prolonged pharmacodynamic effects of S-0139, an intravenously administered endothelin A (ET) antagonist, in the human forearm blood flow model.

AIMS: To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect. METHODS: Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first. RESULTS: Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2. CONCLUSIONS: S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.

Design of Phase 3 Studies Evaluating Vixotrigine for Treatment of Trigeminal Neuralgia.

PURPOSE: Vixotrigine (BIIB074) is a voltage- and use-dependent sodium channel blocker. These studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with trigeminal neuralgia (TN) using enriched enrollment randomized withdrawal trial designs. PATIENTS AND METHODS: Two double-blind randomized withdrawal studies are planned to evaluate the efficacy and safety of vixotrigine compared with placebo in participants with TN (NCT03070132 and NCT03637387). Participant criteria include ≥18 years old who have classical, purely paroxysmal TN diagnosed ≥3 months prior to study entry, who experience ≥3 paroxysms of pain/day. The two studies will include a screening period, 7-day run-in period, a 4- or 6-week single-dose-blind dose-optimization period (Study 1) or 4-week open-label period (Study 2), and 14-week double-blind period. Participants will receive vixotrigine 150 mg orally three times daily in the dose-optimization and open-label periods. The primary endpoint of both studies is the proportion of participants classified as responders at Week 12 of the double-blind period. Secondary endpoints include safety measures, quality of life, and evaluation of vixotrigine population pharmacokinetics. CONCLUSION: There is a need for an effective, well-tolerated, noninvasive treatment for the neuropathic pain associated with TN. The proposed studies will evaluate the efficacy and safety of vixotrigine in treating pain experienced by patients with TN.

Evaluation of the Pharmacokinetic Interaction Between the Voltage- and Use-Dependent Nav1.7 Channel Blocker Vixotrigine and Carbamazepine in Healthy Volunteers.

Vixotrigine is a voltage- and use-dependent Nav1.7 channel blocker under investigation for the treatment of peripheral neuropathic pain conditions, including trigeminal neuralgia. Vixotrigine is metabolized primarily via uridine diphosphate-glucuronosyltransferases (UGTs). Carbamazepine, a UGT and cytochrome P450 3A4 inducer, is a first-line treatment for trigeminal neuralgia. We conducted a double-blind, randomized, placebo-controlled, parallel-group, single-center phase 1 study to investigate the impact of coadministering vixotrigine and carbamazepine on their respective pharmacokinetics (PK) in healthy volunteers, the safety and tolerability of combined treatment, and PK recovery of vixotrigine following carbamazepine discontinuation. Randomly assigned treatments were carbamazepine (100 mg twice a day, days 1-3 and 200 mg twice a day, days 4-21) or placebo on days 1 to 21. All volunteers received vixotrigine 150 mg 3 times a day on days 16 to 28. At prespecified times, whole-blood samples were collected for PK assessment. Statistical analyses were performed on the log-transformed PK parameters area under the concentration-time curve within a dosing interval (AUC0-tau ) and maximum observed concentration (Cmax ) for vixotrigine, carbamazepine, and metabolites. Vixotrigine AUC0-tau and Cmax were reduced by 31.6% and 26.3%, respectively, when coadministered with carbamazepine compared with placebo. Seven days after carbamazepine discontinuation, vixotrigine AUC0-tau and Cmax remained 24.5% and 21.4% lower compared with placebo. Carbamazepine AUC0-tau and Cmax were <10% lower when coadministered with vixotrigine compared on days 15 and 21. Vixotrigine/carbamazepine coadministration was well tolerated. These results suggest that vixotrigine does not have an effect on carbamazepine PK, and although carbamazepine has an effect on the exposure of vixotrigine, the effect is not considered clinically relevant.

Discovery of Vixotrigine: A Novel Use-Dependent Sodium Channel Blocker for the Treatment of Trigeminal Neuralgia.

Drugs that block voltage-gated sodium channels (NaVs) have utility in treating conditions including pain, epilepsy, and cardiac arrhythmias and as anesthetics (Lancet Neurol.20109413424; Expert Opin. Ther. Pat.201020755779). The identification of compounds with improved efficacy and safety is a key aim for the discovery of improved NaV blocking drugs (Comprehensive Medicinal Chemistry III; (Elsevier, 2017; pp 131-175). We report the identification of a novel class of brain penetrant and voltage-gated sodium channel blockers, leading to the discovery of vixotrigine, a use-dependent sodium channel blocker with activity in in vivo models of pain. Vixotrigine has excellent physiocochemical properties for drug development, and both preclinical and clinical data support a safety profile suitable for potential use in neuropathic pain and other conditions. It has shown efficacy in a Phase II study for pain associated with trigeminal neuralgia.

Is virtual clinic follow-up of hip and knee joint replacement acceptable to patients and clinicians? A sequential mixed methods evaluation.

Objective: To evaluate the acceptability to key stake holders of a newly introduced virtual clinic follow-up pathway for hip and knee joint replacement. Design: A service evaluation comprising a questionnaire sent electronically to 115 patients and interviews with 10 individuals. Setting: A newly introduced virtual clinic follow-up pathway for hip and knee replacement patients in a district general hospital. Participants: The electronic questionnaire was distributed to all patients treated under the virtual clinic service over a 5-month period (n=115). Purposive sampling from volunteers among respondents, leading to semi-structured interviews with eight patients. Two orthopaedic consultants were also interviewed. Intervention: Consultant review of web-based patient reported outcome measures and digital radiographs, with feedback to patients via letter, replacing face-to-face outpatient appointments for the follow-up of hip and knee joint replacement. Results: The response rate to the questionnaire was 40%. 44% indicated they would prefer a virtual appointment over a face-to-face consultation in future. The most common word in the free text comments was 'good' (n=107).Seven main themes were identified from the patient interviews: patient understanding and expectations, patient confidence, patient voice, managing deterioration of condition, patient benefit, patient satisfaction using technology and navigating the website.Two main themes were identified from the staff interviews: the adapting patient pathway and project management.Combined analysis elucidated that patients who were doing well liked the 'click and go' approach but those with problems were concerned about how to report these and were therefore less satisfied. Conclusion: The virtual clinic process appears to be well accepted by both patients and clinicians. However, appropriate patient selection and clear pathways of communication to address patient concerns are pivotal to success.

Effects of a State- and Use-Dependent Nav1.7 Channel Blocker on Ambulatory Blood Pressure: A Randomized, Controlled Crossover Study.

Vixotrigine is a state- and use-dependent Nav1.7 channel blocker being investigated for the treatment of neuropathic pain conditions. This randomized, double-blind, placebo-controlled crossover trial was designed to evaluate changes in blood pressure with the administration of vixotrigine using ambulatory blood pressure monitoring (ABPM). Eligible participants were healthy adults 18 to 65 years of age without evidence of baseline systolic blood pressure (SBP) persistently > 140 mm Hg or diastolic blood pressure (DBP) persistently > 90 mm Hg. Vixotrigine (400 mg [men], 300 mg [women]) or placebo was administered orally twice daily for 36 days. Following a 7-day washout period, participants crossed over to the other treatment. Each dosing period was preceded by 1 inpatient visit and 1 outpatient baseline visit. Two 14-hour inpatient ABPM sessions occurred on days 14 and 35, with a return to the clinic the morning of days 15 and 36 for initiation of outpatient ABPM, which assessed blood pressure and heart rate every 15 minutes. Adverse events were collected throughout the study. The primary end point was the change from baseline in 24-hour mean SBP and DBP on day 36. Sixty participants were enrolled; 10 withdrew from the study owing to adverse events, investigator discretion, or withdrawal of consent. From baseline to day 36, mean changes in average SBP and DBP (vixotrigine treated) were -0.33 and 0.20 mm Hg, respectively. Adverse event rates were comparable for vixotrigine and placebo; the most common adverse events were headache, dizziness, and nausea. Vixotrigine administration is not associated with a clinically important increase in blood pressure.

Home-based exercise programmes for individuals with intermittent claudication: A protocol for an updated systematic review and meta-analysis.

BACKGROUND: The aim of this updated review is to consider the evidence base for the effectiveness of home-based exercise programmes as a treatment option for improving walking distance in patients with intermittent claudication. METHODS: The Medline, EMBASE, CINAHL, PEDro and Cochrane CENTRAL databases will be searched for terms including 'intermittent claudication', 'peripheral arterial disease', 'home-based exercise' and 'home-based walking'. No date restrictions will be used but only articles in the English language will be included. Both randomised and non-randomised trials of home-based exercise programmes versus a comparator arm will be included, and a meta-analysis using only the randomised controlled trials will be attempted if the assumptions of heterogeneity are met. Data extraction will include study details, sample description, intervention description, length of follow-up and outcomes measures. The primary outcome measure is objectively measured maximal walking distance or time, with secondary outcome measures including pain-free walking distance or time, changes in physical activity and quality of life. We will also provide a narrative description of the effective components of a home-based exercise intervention which can aid future recommendations. CONCLUSION: Overall, this proposed review and meta-analysis aims provide a comprehensive and complete overview of the evidence base for home-based exercise programmes, which can aid clinicians in the management of their patients.

Challenges recruiting to a proof-of-concept pharmaceutical trial for a rare disease: the trigeminal neuralgia experience.

BACKGROUND: This study aimed to describe recruitment challenges encountered during a phase IIa study of vixotrigine, a state and use-dependent Nav1.7 channel blocker, in individuals with trigeminal neuralgia. METHODS: This was an international, multicenter, placebo-controlled, randomized withdrawal study that included a 7-day run-in period, a 21-day open-label phase, and a 28-day double-blind phase in which patients (planned n = 30) were randomized to vixotrigine or placebo. Before recruitment, all antiepileptic drugs had to be stopped, except for gabapentin or pregabalin. After the trial, patients returned to their original medications. Patient recruitment was expanded beyond the original five planned (core) centers in order to meet target enrollment (total recruiting sites N = 25). Core sites contributed data related to patient identification for study participation (prescreening data). Data related to screening failures and study withdrawal were also analyzed using descriptive statistics. RESULTS: Approximately half (322/636; 50.6%) of the patients who were prescreened at core sites were considered eligible for the study and 56/322 (17.4%) were screened. Of those considered eligible, 26/322 (8.1%) enrolled in the study and 6/322 (1.9%) completed the study. In total, 125 patients were screened across all study sites and 67/125 (53.6%) were enrolled. At prescreening, reasons for noneligibility varied by site and were most commonly diagnosis change (78/314; 24.8%), age > 80 years (75/314; 23.9%), language/distance/mobility (61/314; 19.4%), and noncardiac medical problems (53/314; 16.9%). At screening, frequently cited reasons for noneligibility included failure based on electrocardiogram, insufficient pain, and diagnosis change. CONCLUSIONS: Factors contributing to recruitment challenges encountered in this study included diagnosis changes, anxiety over treatment changes, and issues relating to distance, language, and mobility. Wherever possible, future studies should be designed to address these challenges. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01540630 . EudraCT, 2010-023963-16. 07 Aug 2015.

Trial of intraoperative cell salvage versus transfusion in ovarian cancer (TIC TOC): protocol for a randomised controlled feasibility study.

INTRODUCTION: Ovarian cancer is the leading cause of death from gynaecological cancer, with more than 7000 new cases registered in the UK in 2014. In patients suitable for surgery, the National Institute of Health and Care Excellence guidance for treatment recommends surgical resection of all macroscopic tumour, followed by chemotherapy. The surgical procedure can be extensive and associated with substantial blood loss which is conventionally replaced with a donor blood transfusion. While often necessary and lifesaving, the use of donor blood is associated with increased risks of complications and adverse surgical outcomes. Intraoperative cell salvage (ICS) is a blood conservation strategy in which red cells collected from blood lost during surgery are returned to the patient thus minimising the use of donor blood. This is the protocol for a feasibility randomised controlled trial with an embedded qualitative study and feasibility economic evaluation. If feasible, a later definitive trial will test the effectiveness and cost-effectiveness of ICS reinfusion versus donor blood transfusion in ovarian cancer surgery. METHODS AND ANALYSIS: Sixty adult women scheduled for primary or interval ovarian cancer surgery at participating UK National Health Service Trusts will be recruited and individually randomised in a 1:1 ratio to receive ICS reinfusion or donor blood (as required) during surgery. Participants will be followed up by telephone at 30 days postoperatively for adverse events monitoring and by postal questionnaire at 6 weeks and 3 monthly thereafter, to capture quality of life and resource use data. Qualitative interviews will capture participants' and clinicians' experiences of the study. ETHICS AND DISSEMINATION: This study has been granted ethical approval by the South West-Exeter Research Ethics Committee (ref: 16/SW/0256). Results will be disseminated via peer-reviewed publications and will inform the design of a larger trial. TRIAL REGISTRATION NUMBER: ISRCTN19517317.