Expedited transfer to a cardiac arrest centre for non-ST-elevation out-of-hospital cardiac arrest (ARREST): a UK prospective, multicentre, parallel, randomised clinical trial.

BACKGROUND: The International Liaison Committee on Resuscitation has called for a randomised trial of delivery to a cardiac arrest centre. We aimed to assess whether expedited delivery to a cardiac arrest centre compared with current standard of care following resuscitated cardiac arrest reduces deaths. METHODS: ARREST is a prospective, parallel, multicentre, open-label, randomised superiority trial. Patients (aged ≥18 years) with return of spontaneous circulation following out-of-hospital cardiac arrest without ST elevation were randomly assigned (1:1) at the scene of their cardiac arrest by London Ambulance Service staff using a secure online randomisation system to expedited delivery to the cardiac catheter laboratory at one of seven cardiac arrest centres or standard of care with delivery to the geographically closest emergency department at one of 32 hospitals in London, UK. Masking of the ambulance staff who delivered the interventions and those reporting treatment outcomes in hospital was not possible. The primary outcome was all-cause mortality at 30 days, analysed in the intention-to-treat (ITT) population excluding those with unknown mortality status. Safety outcomes were analysed in the ITT population. The trial was prospectively registered with the International Standard Randomised Controlled Trials Registry, 96585404. FINDINGS: Between Jan 15, 2018, and Dec 1, 2022, 862 patients were enrolled, of whom 431 (50%) were randomly assigned to a cardiac arrest centre and 431 (50%) to standard care. 20 participants withdrew from the cardiac arrest centre group and 19 from the standard care group, due to lack of consent or unknown mortality status, leaving 411 participants in the cardiac arrest centre group and 412 in the standard care group for the primary analysis. Of 822 participants for whom data were available, 560 (68%) were male and 262 (32%) were female. The primary endpoint of 30-day mortality occurred in 258 (63%) of 411 participants in the cardiac arrest centre group and in 258 (63%) of 412 in the standard care group (unadjusted risk ratio for survival 1·00, 95% CI 0·90-1·11; p=0·96). Eight (2%) of 414 patients in the cardiac arrest centre group and three (1%) of 413 in the standard care group had serious adverse events, none of which were deemed related to the trial intervention. INTERPRETATION: In adult patients without ST elevation, transfer to a cardiac arrest centre following resuscitated cardiac arrest in the community did not reduce deaths. FUNDING: British Heart Foundation.

Translation of experimental cardioprotective capability of P2Y12 inhibitors into clinical outcome in patients with ST-elevation myocardial infarction.

We studied the translational cardioprotective potential of P2Y12 inhibitors against acute myocardial ischemia/reperfusion injury (IRI) in an animal model of acute myocardial infarction and in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). P2Y12 inhibitors may have pleiotropic effects to induce cardioprotection against acute myocardial IRI beyond their inhibitory effects on platelet aggregation. We compared the cardioprotective effects of clopidogrel, prasugrel, and ticagrelor on infarct size in an in vivo rat model of acute myocardial IRI, and investigated the effects of the P2Y12 inhibitors on enzymatic infarct size (48-h area-under-the-curve (AUC) troponin T release) and clinical outcomes in a retrospective study of STEMI patients from the CONDI-2/ERIC-PPCI trial using propensity score analyses. Loading with ticagrelor in rats reduced infarct size after acute myocardial IRI compared to controls (37 ± 11% vs 52 ± 8%, p < 0.01), whereas clopidogrel and prasugrel did not (50 ± 11%, p > 0.99 and 49 ± 9%, p > 0.99, respectively). Correspondingly, troponin release was reduced in STEMI patients treated with ticagrelor compared to clopidogrel (adjusted 48-h AUC ratio: 0.67, 95% CI 0.47-0.94). Compared to clopidogrel, the composite endpoint of cardiac death or hospitalization for heart failure within 12 months was reduced in STEMI patients loaded with ticagrelor (HR 0.63; 95% CI 0.42-0.94) but not prasugrel (HR 0.84, 95% CI 0.43-1.63), prior to PPCI. Major adverse cardiovascular events did not differ between clopidogrel, ticagrelor, or prasugrel. The cardioprotective effects of ticagrelor in reducing infarct size may contribute to the clinical benefit observed in STEMI patients undergoing PPCI.

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy.

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1-17.1)% of LV mass; control: 11.1 (7.0-17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial.

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden.

Men on the Move: A Randomized Controlled Feasibility Trial of a Scalable, Choice-Based, Physical Activity and Active Transportation Intervention for Older Men.

We conducted Men on the Move, a 12-week randomized controlled feasibility trial of a scalable, choice-based, physical activity (PA) and active transportation intervention. Participants were community-dwelling men aged 60 years and older (n = 29 intervention [INT] and n = 29 waitlist control [CON]). Trained activity coaches delivered: (a) one-on-one participant consultations to develop personal action plans for PA and active transportation, (b) monthly group-based motivational meetings, (c) weekly telephone support, (d) complimentary recreation and transit passes, and (e) pedometers and diaries for self-monitoring. Men on the Move demonstrated high rates of recruitment, retention, and intervention adherence. INT chose a variety of group-based and individual PAs and destinations for their personal action plans. At 12 weeks, INT achieved more steps, moderate-vigorous PA, and energy expenditure than CON. INT was also more likely to take transit and meet national guideline levels of PA. At 24 weeks follow-up, INT benefits were sustained for moderate-vigorous PA and energy expenditure.

Rationale and design of: A Randomized tRial of Expedited transfer to a cardiac arrest center for non-ST elevation out-of-hospital cardiac arrest: The ARREST randomized controlled trial.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a global public health issue. There is wide variation in both regional and inter-hospital survival rates from OHCA and overall survival remains poor at 7%. Regionalization of care into cardiac arrest centers (CAC) improves outcomes following cardiac arrest from ST elevation myocardial infarction (STEMI) through concentration of services and greater provider experience. The International Liaison Committee on Resuscitation (ILCOR) recommends delivery of all post-arrest patients to a CAC, but that randomized controlled trials are necessary in patients without ST elevation (STE). METHODS/DESIGN: Following completion of a pilot randomized trial to assess safety and feasibility of conducting a large-scale randomized controlled trial in patients following OHCA of presumed cardiac cause without STE, we present the rationale and design of A Randomized tRial of Expedited transfer to a cardiac arrest center for non-ST elevation OHCA (ARREST). In total 860 patients will be enrolled and randomized (1:1) to expedited transfer to CAC (24/7 access to interventional cardiology facilities, cooling and goal-directed therapies) or to the current standard of care, which comprises delivery to the nearest emergency department. Primary outcome is 30-day all-cause mortality and secondary outcomes are 30-day and 3-month neurological status and 3, 6 and 12-month mortality. Patients will be followed up for one year after enrolment. CONCLUSION: Post-arrest care is time-critical, requires a multi-disciplinary approach and may be more optimally delivered in centers with greater provider experience. This trial would help to demonstrate if regionalization of post-arrest care to CACs reduces mortality in patients without STE, which could dramatically reshape emergency care provision.

Routine cerebral embolic protection in transcatheter aortic valve implantation: rationale and design of the randomised British Heart Foundation PROTECT-TAVI trial.

Transcatheter aortic valve implantation (TAVI) is an established treatment for aortic stenosis. Cerebral embolic protection (CEP) devices may impact periprocedural stroke by capturing debris destined for the brain. However, there is a lack of high-quality randomised trial evidence supporting the use of CEP during TAVI. The British Heart Foundation (BHF) PROTECT-TAVI trial will address whether the routine use of CEP reduces the incidence of stroke in patients undergoing TAVI. BHF PROTECT-TAVI is a prospective, open-label, outcome-adjudicated, multicentre randomised controlled trial. The trial is open to all adult patients scheduled for TAVI at participating specialist cardiac centres across the United Kingdom who are able to receive the CEP device. The trial will recruit 7,730 participants. Participants will be randomised in a 1:1 ratio to undergo TAVI with CEP or TAVI without CEP (standard of care). The primary outcome is the incidence of stroke at 72 hours post-TAVI. Key secondary outcomes include the incidence of stroke and all-cause mortality up to 12 months post-TAVI, disability and cognitive outcomes, stroke severity, access site complications and a health economics analysis. The sample size of 7,730 participants has 80% power to detect a 33% relative risk reduction from a 3% incidence of the primary outcome in the controls. Trial recruitment commenced in October 2020. As of October 2022, 3,068 patients have been enrolled. BHF PROTECT-TAVI is designed to provide definitive evidence on the clinical efficacy and cost-effectiveness of using routine CEP with the SENTINEL device to reduce stroke in TAVI.

Complex and alternate consent pathways in clinical trials: methodological and ethical challenges encountered by underserved groups and a call to action.

BACKGROUND: Informed consent is considered a fundamental requirement for participation in trials, yet obtaining consent is challenging in a number of populations and settings. This may be due to participants having communication or other disabilities, their capacity to consent fluctuates or they lack capacity, or in emergency situations where their medical condition or the urgent nature of the treatment precludes seeking consent from either the participant or a representative. These challenges, and the subsequent complexity of designing and conducting trials where alternative consent pathways are required, contribute to these populations being underserved in research. Recognising and addressing these challenges is essential to support trials involving these populations and ensure that they have an equitable opportunity to participate in, and benefit from, research. Given the complex nature of these challenges, which are encountered by both adults and children, a cross-disciplinary approach is required. DISCUSSION: A UK-wide collaboration, a sub-group of the Trial Conduct Working Group in the MRC-NIHR Trial Methodology Research Partnership, was formed to collectively address these challenges. Members are drawn from disciplines including bioethics, qualitative research, trials methodology, healthcare professions, and social sciences. This commentary draws on our collective expertise to identify key populations where particular methodological and ethical challenges around consent are encountered, articulate the specific issues arising in each population, summarise ongoing and completed research, and identify targets for future research. Key populations include people with communication or other disabilities, people whose capacity to consent fluctuates, adults who lack the capacity to consent, and adults and children in emergency and urgent care settings. Work is ongoing by the sub-group to create a database of resources, to update NIHR guidance, and to develop proposals to address identified research gaps. CONCLUSION: Collaboration across disciplines, sectors, organisations, and countries is essential if the ethical and methodological challenges surrounding trials involving complex and alternate consent pathways are to be addressed. Explicating these challenges, sharing resources, and identifying gaps for future research is an essential first step. We hope that doing so will serve as a call to action for others seeking ways to address the current consent-based exclusion of underserved populations from trials.

Determining the optimal diagnostic and risk stratification approaches for people with hypertension in two rural populations in Kenya and The Gambia: a study protocol for IHCoR-Africa Work Package 2.

Background: Sub-Saharan Africa (SSA) has one of the highest prevalences of hypertension worldwide. The impact of hypertension is of particular concern in rural SSA, where access to clinics and hospitals is limited. Improvements in the management of people with hypertension in rural SSA could be achieved by sharing diagnosis and care tasks between the clinic and the community. To develop such a community-centred programme we need optimal approaches to identify and risk stratify patients with elevated blood pressure. The aim of the study is to improve the evidence base for diagnosis and risk estimation for a community-centred hypertension programme in two rural settings in SSA. Methods: We will conduct a cross-sectional study of 1250 adult participants in Kilifi, Kenya and Kiang West, The Gambia. The study has five objectives which will determine the: (1) accuracy of three blood pressure (BP) measurement methods performed by community health workers in identifying people with hypertension in rural SSA, compared to the reference standard method; (2) relationship between systolic BP and cardiovascular risk factors; (3) prevalence of hypertension-mediated organ damage (HMOD); (4) accuracy of innovative point-of-care (POC) technologies to identify patients with HMOD; and (5) cost-effectiveness of different combinations of BP and HMOD measurements for directing hypertension treatment initiation. Expected findings: This study will determine the accuracy of three methods for community BP measurement and POC technologies for HMOD assessment. Using the optimal methods in this setting it will estimate the prevalence of hypertension and provide the best estimate to date of HMOD prevalence in SSA populations. The cost-effectiveness of decision-making approaches for initiating treatment of hypertension will be modelled. These results will inform the development of a community-centred programme to improve care for hypertensive patients living in rural SSA. Existing community engagement networks will be used to disseminated within the research setting.

Many people live with high blood pressure in sub-Saharan Africa. In this region, the proportion of people with high blood pressure is one of the highest in the world. However, few people with high blood pressure are treated and this can lead to serious medical issues and even death. This is particularly true in rural areas where treatment and understanding of blood pressure is lower than in cities. There are many reasons why high blood pressure is a major health problem in rural sub-Saharan Africa, such as a lack of clear symptoms; less access to healthcare; and limited time to travel to clinics for care. One option for improving the management of blood pressure is to use a community-centred approach, where care is brought into the community making it easier to access. To bring care into the community, we need to find out what is the best way for community health workers to identify who needs to be treated. Standard techniques may not be useful in a rural community and could require too many resources to make them practical. This study aims to determine what is the best way to identify high blood pressure and related health complications in a community setting. The study will take place across two sites: one in Kilifi, Kenya and the other in Kiang West, The Gambia. We will enrol 1250 participants, with 625 in each country. The people living in these areas have been involved in the design of this study through community engagement and have helped identify the need for improving how blood pressure is treated in a rural areas. Throughout this study, we will continue to meet with the communities. Once the study is completed, we will use our strong links with the communities, healthcare providers and policymakers to share the results.

Analysis of integrin turnover in fly myotendinous junctions.

Transient (short-term) cell adhesion underlies dynamic processes such as cell migration, whereas stable (long-term) cell adhesion maintains tissue architecture. Ongoing adhesion complex turnover is essential for transient cell adhesion, but it is not known whether turnover is also required for maintenance of long-term adhesion. We used fluorescence recovery after photobleaching to analyze the dynamics of an integrin adhesion complex (IAC) in a model of long-term cell-ECM adhesion, myotendinous junctions (MTJs), in fly embryos and larvae. We found that the IAC undergoes turnover in MTJs and that this process is mediated by clathrin-dependent endocytosis. Moreover, the small GTPase Rab5 can regulate the proportion of IAC components that undergo turnover. Also, altering Rab5 activity weakened MTJs, resulting in muscle defects. In addition, growth of MTJs was concomitant with a decrease in the proportion of IAC components undergoing turnover. We propose that IAC turnover is tightly regulated in long-term cell-ECM adhesions to allow normal tissue growth and maintenance.

Integrin-mediated adhesion maintains sarcomeric integrity.

Integrin-mediated adhesion to the ECM is essential for normal development of animal tissues. During muscle development, integrins provide the structural stability required to construct such a highly tensile, force generating tissue. Mutations that disrupt integrin-mediated adhesion in skeletal muscles give rise to a myopathy in humans and mice. To determine if this is due to defects in formation or defects in maintenance of muscle tissue, we used an inducible, targeted RNAi based approach to disrupt integrin-mediated adhesion in fully formed adult fly muscles. A decrease in integrin-mediated adhesion in adult muscles led to a progressive loss of muscle function due to a failure to maintain normal sarcomeric cytoarchitecture. This defect was due to a gradual, age dependent disorganization of the sarcomeric actin, Z-line, and M-line. Electron microscopic analysis showed that reduction in integrin-mediated adhesion resulted in detachment of actin filaments from the Z-lines, separation of the Z-lines from the membrane, and eventually to disintegration of the Z-lines. Our results show that integrin-mediated adhesion is essential for maintaining sarcomeric integrity and illustrate that the seemingly stable adhesive contacts underlying sarcomeric architecture are inherently dynamic.

Statins do not commonly cause muscle pain and stiffness.

The studyHerrett E, Williamson E, Brack K, et al. The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs. Health Technol Assess 2021;25:16.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/statins-not-likely-to-cause-muscle-pain-stiffness/.

Patient and public involvement prior to trial initiation: lessons learnt for rapid partnership in the COVID-19 era.

Patient and Public Involvement (PPI) describes the active involvement of patients and the public in the research process. Through PPI, patients and members of the public are increasingly involved in the design and conduct of clinical trials. PPI has been shown to improve the quality and relevance of research. During the COVID-19 pandemic, clinical trials have been playing a vital role in helping us find ways to prevent and treat the infection and improve our understanding of the virus. It is important that patients and the public are actively involved in deciding how COVID-19 research is carried out. Unfortunately, Research Ethics Committees in the UK have seen far less PPI for COVID-19 research studies compared with research before the pandemic. A key reason for this is that research is being designed much faster than normal and researchers may feel they do not have time to properly involve patients and the public. In this paper, we share our experiences of PPI for a COVID-19 clinical trial. We show that it is possible to rapidly involve patients and the public in COVID-19 clinical trials. We also explain how the design of the clinical trial was changed in response to feedback from public contributors. Lastly, we discuss the wider learning from this process which might be useful for researchers planning PPI activities for COVID-19 clinical trials in the future. BACKGROUND: Clinical trials are playing a critical role in the global public health response to the COVID-19 pandemic. Despite the increasing recognition of the value of PPI in clinical trials, just 22% of the COVID-19 research proposals reviewed by Research Ethics Committees in the UK at the start of the pandemic reported PPI. There is a perception that PPI might result in delays in delivering research and therefore delays in obtaining important results. In this paper, we report our experience of rapid PPI for a COVID-19 clinical trial. METHODS: RAPID-19 is a COVID-19 clinical trial which was planned to be submitted for fast-track ethics review in the United Kingdom. During the development of the trial protocol, the PPI Panel at the London School of Hygiene & Tropical Medicine Clinical Trials Unit was involved in the design of the study. The meeting with the PPI Panel lasted just over 1 h and was conducted by teleconference. RESULTS: Although we only had a short period of time to explore the study with the PPI Panel, we were able to gain valuable insight into how the trial would be perceived by potential trial participants. Substantive changes were made to the trial to improve the acceptability of the research without compromising the study timelines. Having access to public contributors with relevant lived experience is an important resource for a Clinical Trials Unit and is critical for rapid PPI. The move to remote working due to lockdown required virtual discussions which helped to overcome some of the barriers to organising face-to-face meetings at short notice. CONCLUSIONS: PPI for clinical trials can be conducted in a time-efficient manner within the pressured environment of a pandemic. Involving PPI contributors at an early stage in protocol development maximised the opportunity to shape and influence the trial as well as limited potential delays which could occur if changes to the protocol had to be made at a later stage.

Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials.

OBJECTIVE: To establish the effect of statins on muscle symptoms in people who had previously reported muscle symptoms when taking statins. DESIGN: Series of randomised, placebo controlled n-of-1 trials. SETTING: Primary care across 50 sites in the United Kingdom, December 2016 to April 2018. PARTICIPANTS: 200 participants who had recently stopped or were considering stopping treatment with statins because of muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six double blinded treatment periods (two months each) of atorvastatin 20 mg daily or placebo. MAIN OUTCOME MEASURES: At the end of each treatment period, participants rated their muscle symptoms on a visual analogue scale (0-10). The primary analysis compared symptom scores in the statin and placebo periods. RESULTS: 151 participants provided symptoms scores for at least one statin period and one placebo period and were included in the primary analysis. Overall, no difference in muscle symptom scores was found between the statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; P=0.40)). Withdrawals because of intolerable muscle symptoms were 18 participants (9%) during a statin period and 13 (7%) during a placebo period. Two thirds of those completing the trial reported restarting long term treatment with statins. CONCLUSIONS: No overall effect of atorvastatin 20 mg on muscle symptoms compared with placebo was found in participants who had previously reported severe muscle symptoms when taking statins. Most people completing the trial intended to restart treatment with statins. N-of-1 trials can assess drug effects at the group level and guide individual treatment. TRIAL REGISTRATION: ISRCTN30952488, EUDRACT 2016-000141-31, NCT02781064.

The effect of statins on muscle symptoms in primary care: the StatinWISE series of 200 N-of-1 RCTs.

BACKGROUND: Uncertainty persists about whether or not statins cause symptomatic muscle adverse effects (e.g. pain, stiffness and weakness) in the absence of severe myositis. OBJECTIVES: To establish the effect of statins on all muscle symptoms, and the effect of statins on muscle symptoms that are perceived to be statin related. DESIGN: A series of 200 double-blinded N-of-1 trials. SETTING: Participants were recruited from 50 general practices in England and Wales. PARTICIPANTS: Patients who were considering discontinuing statin use and those who had discontinued statin use in the last 3 years because of perceived muscle symptoms. INTERVENTIONS: Participants were randomised to a sequence of six 2-month treatment periods during which they received 20 mg of atorvastatin daily or a matched placebo. MAIN OUTCOME MEASURES: The primary outcome was self-reported muscle symptoms rated using a visual analogue scale on the last week of each treatment period. Secondary outcomes included the participant's belief about the cause of their muscle symptoms, the site of muscle symptoms, how the muscle symptoms affected the participant, any other symptoms they experienced, adherence to medication, the participant's decision about statin treatment following the trial, and whether or not they found their own trial result helpful. RESULTS: A total of 151 out of 200 (75.5%) randomised participants provided one or more visual analogue scale measurements in a placebo period and one or more measurements in a statin period, and were included in the primary analysis. There was no evidence of a difference in muscle symptom scores between statin and placebo periods (mean difference statin minus placebo -0.11, 95% confidence interval -0.36 to 0.14; p = 0.398). Withdrawals, adherence and missing data were similar during the statin periods and the placebo periods. CONCLUSIONS: Among people who previously reported severe muscle symptoms while taking statins, this series of randomised N-of-1 trials found no overall effect of statins on muscle symptoms compared with the placebo. The slight difference in withdrawals due to muscle symptoms suggests that statins may contribute to symptoms in a small number of patients. The results are generalisable to patients who are considering discontinuing or have already discontinued statins because of muscle symptoms, and who are willing to re-challenge or participate in their own N-of-1 trial. FUTURE WORK: We recommend that additional statins and doses are explored using N-of-1 trials. More broadly, N-of-1 trials present a useful tool for exploring transient symptoms with other medications. LIMITATIONS: This study used 20-mg doses of atorvastatin only. Furthermore, a dropout rate of 43% was observed, but this was accounted for in the power calculations. TRIAL REGISTRATION: Current Controlled Trials ISRCTN30952488 and EudraCT 2016-000141-31. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 16. See the NIHR Journals Library website for further project information.

Statins are one of the most commonly prescribed drugs in the UK. There is strong evidence that they are effective in safely reducing heart disease; however, there is some doubt about whether or not statins cause muscle pain, stiffness or weakness. This research has been carried out to understand the effect of statins on muscle symptoms. To answer our question, we asked 200 volunteers from across England and Wales to participate in the study. Patients who joined the study either had recently stopped taking statins because of muscle symptoms or were considering stopping because of muscle symptoms. Patients who participated were randomly assigned to a sequence of six 2-month treatment periods during which they received either statins or a placebo. Neither patients nor their general practitioner knew which tablet they were receiving. This helped to reduce bias in the data. At the end of each treatment period, patients were asked to report any muscle symptoms, or any other symptoms, that they experienced. The key result of this work is that patients reported no difference, on average, in their muscle symptoms between periods of taking a statin and periods of taking a placebo. We also assessed the impact on the patient's quality of life by looking at how statins affected the following areas: general activity, mood, walking ability, normal work, relations with other people, sleep and enjoyment of life. As with muscle symptoms, there was no evidence of a difference between statin and placebo periods. The majority of patients who finished the trial decided to continue using statins after the trial. Future research should be carried out to assess different statin doses, as higher doses are often used following a heart attack. In addition, further work is needed to see how the approach we used could be adopted into everyday clinical care.

[Successful treatment with voriconazol of a Pseudallescheria boydii fungus ball in a HIV positive patient and previous tuberculosis]. / Tratamiento eficaz con voriconazol de un fungoma pulmonar por Pseudallescheria boydii en un paciente con infección por VIH y tuberculosis previa.

We herein describe a patient with a Pseudallescheria boydii fungus ball in a tuberculous lung cavity, which was successfully treated four years earlier. The patient was HIV positive classified as C3 with a previous history of i.v. heroin abuse. The clinical presumptive diagnosis was radiologically established combined with histological examination. Culture of tissue confirmed and proved the fungal etiology. In vitro MIC values for voriconazole (0.5 mg/ml) guided antifungal prophylactic treatment before surgical eradication of the fungus ball since the patient was immunosuppressed. We discuss the clinical spectrum of P. boydii infections and currently medical approach.

An ongoing role for structural sarcomeric components in maintaining Drosophila melanogaster muscle function and structure.

Animal muscles must maintain their function while bearing substantial mechanical loads. How muscles withstand persistent mechanical strain is presently not well understood. The basic unit of muscle is the sarcomere, which is primarily composed of cytoskeletal proteins. We hypothesized that cytoskeletal protein turnover is required to maintain muscle function. Using the flight muscles of Drosophila melanogaster, we confirmed that the sarcomeric cytoskeleton undergoes turnover throughout adult life. To uncover which cytoskeletal components are required to maintain adult muscle function, we performed an RNAi-mediated knockdown screen targeting the entire fly cytoskeleton and associated proteins. Gene knockdown was restricted to adult flies and muscle function was analyzed with behavioural assays. Here we analyze the results of that screen and characterize the specific muscle maintenance role for several hits. The screen identified 46 genes required for muscle maintenance: 40 of which had no previously known role in this process. Bioinformatic analysis highlighted the structural sarcomeric proteins as a candidate group for further analysis. Detailed confocal and electron microscopic analysis showed that while muscle architecture was maintained after candidate gene knockdown, sarcomere length was disrupted. Specifically, we found that ongoing synthesis and turnover of the key sarcomere structural components Projectin, Myosin and Actin are required to maintain correct sarcomere length and thin filament length. Our results provide in vivo evidence of adult muscle protein turnover and uncover specific functional defects associated with reduced expression of a subset of cytoskeletal proteins in the adult animal.

The systematic identification of cytoskeletal genes required for Drosophila melanogaster muscle maintenance.

Animal muscles must maintain their function and structure while bearing substantial mechanical loads. How muscles withstand persistent mechanical strain is presently not well understood. Understanding the mechanisms by which tissues maintain their complex architecture is a key goal of cell biology. This dataset represents a systematic screen through the Drosophila melanogaster cytoskeleton to identify genes that are required to maintain tissue, specifically muscle, architecture. Using RNA interference (RNAi), we knocked down 238 genes in Drosophila and assayed for climbing ability with a robust behavioural assay. Here we present the summary of the screen and provide the complete results of the assays. We have uncovered a number of novel hits that would reward further study. The data are easy to use: the raw data are provided to allow researchers to perform their own analysis and analysed results are given indicating whether or not the genes are required for muscle maintenance. This dataset will allow other researchers to identify candidate genes for more detailed study and lead to better understanding of muscle maintenance.

Rates of antifungal resistance among Spanish clinical isolates of Cryptococcus neoformans var. neoformans.

OBJECTIVES: Activities in vitro of six antifungal agents were tested against a collection of 317 Cryptococcus neoformans var. neoformans clinical isolates. METHODS: The procedure described in document 7.1 by the European Committee on Antibiotic Susceptibility Testing with minor modifications was employed. RESULTS: Amphotericin B, itraconazole, voriconazole and ravuconazole exhibited a potent activity with geometric mean (GM) MICs under 0.26 mg/L. The GM MIC of flucytosine was 7.33 mg/L and that of fluconazole was 4.16 mg/L. The rates of antifungal resistance were 5.3% for amphotericin B, 0.9% for voriconazole and 3.1% for ravuconazole. Fifteen point eight per cent of strains had itraconazole MICs > or = 1 mg/L, and 46% of strains had flucytosine MICs > or = 8 mg/L. Fluconazole susceptibility (MIC < or = 8 mg/L) stood at 53.4%. CONCLUSIONS: The percentage of fluconazole susceptibility was significantly lower than that in other surveys. Cross-resistance to itraconazole was common (33.8%) but almost the whole collection was susceptible to voriconazole and ravuconazole. These results should be confirmed with prospective and population-based surveillance programmes.

Susceptibility patterns and molecular identification of Trichosporon species.

The physiological patterns, the sequence polymorphisms of the internal transcriber spacer (ITS), and intergenic spacer regions (IGS) of the rRNA genes and the antifungal susceptibility profile were evaluated for their ability to identify Trichosporon spp. and their specificity for the identification of 49 clinical isolates of Trichosporon spp. Morphological and biochemical methodologies were unable to differentiate among the Trichosporon species. ITS sequencing was also unable to differentiate several species. However, IGS1 sequencing unambiguously identified all Trichosporon isolates. Following the results of DNA-based identification, Trichosporon asahii was the species most frequently isolated from deep sites (15 of 25 strains; 60%). In the main, other Trichosporon species were recovered from cutaneous samples. The majority of T. asahii, T. faecale, and T. coremiiforme clinical isolates exhibited resistance in vitro to amphotericin B, with geometric mean (GM) MICs >4 mug/ml. The other species of Trichosporon did not show high MICs of amphotericin B, and GM MICs were <1 mug/ml. Azole agents were active in vitro against the majority of clinical strains. The most potent compound in vitro was voriconazole, with a GM MIC