Changing antibiotic prescribing practices in outpatient primary care settings in China: Study protocol for a health information system-based cluster-randomised crossover controlled trial.

BACKGROUND: The overuse and abuse of antibiotics is a major risk factor for antibiotic resistance in primary care settings of China. In this study, the effectiveness of an automatically-presented, privacy-protecting, computer information technology (IT)-based antibiotic feedback intervention will be evaluated to determine whether it can reduce antibiotic prescribing rates and unreasonable prescribing behaviours. METHODS: We will pilot and develop a cluster-randomised, open controlled, crossover, superiority trial. A total of 320 outpatient physicians in 6 counties of Guizhou province who met the standard will be randomly divided into intervention group and control group with a primary care hospital being the unit of cluster allocation. In the intervention group, the three components of the feedback intervention included: 1. Artificial intelligence (AI)-based real-time warnings of improper antibiotic use; 2. Pop-up windows of antibiotic prescription rate ranking; 3. Distribution of educational manuals. In the control group, no form of intervention will be provided. The trial will last for 6 months and will be divided into two phases of three months each. The two groups will crossover after 3 months. The primary outcome is the 10-day antibiotic prescription rate of physicians. The secondary outcome is the rational use of antibiotic prescriptions. The acceptability and feasibility of this feedback intervention study will be evaluated using both qualitative and quantitative assessment methods. DISCUSSION: This study will overcome limitations of our previous study, which only focused on reducing antibiotic prescription rates. AI techniques and an educational intervention will be used in this study to effectively reduce antibiotic prescription rates and antibiotic irregularities. This study will also provide new ideas and approaches for further research in this area. TRIAL REGISTRATION: ISRCTN, ID: ISRCTN13817256. Registered on 11 January 2020.

Exercise in Treatment of Migraine Including Chronic Migraine.

PURPOSE OF REVIEW: With this review, we aimed to investigate the effect of exercise on migraine and explored the possibility of exercise as a treatment option for migraine. RECENT FINDINGS: A close association of physical activity and exercise with migraine has been reported in clinical and population-based studies. Recent randomized controlled trials investigating the effect of aerobic exercise as a migraine-preventive treatment have revealed a notable improvement in migraine symptoms. Data on the effect of anaerobic exercise and exercise for flexibility, coordination, and relaxation on migraine are currently insufficient to make any recommendations. Possible pathways for the attenuation of migraine by exercise include the endogenous opioid and cannabinoid systems, brain-derived neurotrophic factor, inflammation, and behavioral/psychological factors. Regarding efficacy, side effects, and health benefits, aerobic exercise is a potentially beneficial strategy in the preventive treatment of migraine. Further studies are needed to delineate an evidence-based exercise program for migraine treatment.

The effectiveness of cognitive behaviour therapy for reducing anxiety symptoms following traumatic brain injury: A meta-analysis and systematic review.

BACKGROUND: Anxiety is a common neuropsychological sequela following traumatic brain injury (TBI). Cognitive Behaviour Therapy (CBT) is a recommended, first-line intervention for anxiety disorders in the non-TBI clinical population, however its effectiveness after TBI remains unclear and findings are inconsistent. OBJECTIVE: There are no current meta-analyses exploring the efficacy of CBT as an intervention for anxiety symptoms following TBI, using controlled trials. The aim of the current study, therefore, was to systematically review and synthesize the evidence from controlled trials for the effectiveness of CBT for anxiety, specifically within the TBI population. METHOD: Three electronic databases (Web of Science, PubMed and PsycInfo) were searched and a systematic review of intervention studies utilising CBT and anxiety related outcome measures in a TBI population was performed through searching three electronic databases. Studies were further evaluated for quality of evidence based on Reichow's (2011) quality appraisal tool. Baseline and outcome data were extracted from the 10 controlled trials that met the inclusion criteria, and effect sizes were calculated. RESULTS: A random effects meta-analysis identified a small overall effect size (Cohen's d) of d = -0.26 (95%CI -0.41 to -0.11) of CBT interventions reducing anxiety symptoms following TBI. CONCLUSIONS: This meta-analysis tentatively supports the view that CBT interventions may be effective in reducing anxiety symptoms in some patients following TBI, however the effect sizes are smaller than those reported for non-TBI clinical populations. Clinical implications and limitations of the current meta-analysis are discussed.

Placebo Surgery Controlled Trials: Do They Achieve What They Set Out To Do? A Systematic Review.

OBJECTIVE: To explore whether placebo surgery controlled trials achieve what they set out to do by investigating discrepancy between projected and actual design aspects of trials identified through systematic review methods. SUMMARY BACKGROUND: Interest in placebo surgery controlled trials is growing in response to concerns regarding unnecessary surgery and the societal cost of low-value healthcare. As questions about the justifiability of using placebo controls in surgery have been addressed, attention is now being paid to more practical concerns. METHODS: Six databases were searched from inception - May 2020 (MEDLINE, Embase, Emcare, APA PsycInfo, CINAHL, Cochrane Library). Placebo surgery controlled trials with a published protocol were included. Three authors extracted "projected" design aspects from protocols and "actual" design aspects from main findings papers. Absolute and relative difference between projected and actual design aspects were presented for each trial. Trials were grouped according to whether they met their target sample size ("completed") and were concluded in a timely fashion. Pairs of authors assessed risk of bias. RESULTS: Of 24 trials with data available to analyse; 3 were completed and concluded within target timeframe; 10 were completed and concluded outside the target timeline; 4 were completed without clear target timeframes; 2 were incomplete and concluded within the target framework; 5 were incomplete and concluded outside the target timeline. Trials which reached the recruitment target underestimated trial duration by 88% and number of recruitment sites by 87%. CONCLUSIONS: Trialists need to factor additional time and sites into future placebo surgery controlled trials. A robust reporting framework of projected and actual trial design is imperative for trialists to learn from their predecessors. REVIEW REGISTRATION: PROSPERO (CRD42019133296).

Does Virtual Reality Affect Children's Dental Anxiety, Pain, And Behaviour? A Randomised, Placebo-Controlled, Cross-Over Trial

ABSTRACT Objective: To evaluate the effect of virtual reality (VR) on dental anxiety, pain, and behaviour at different time points among children undergoing dental treatment under local anaesthesia. Material and Methods: This randomised, two‐armed, within-subject, cross-over, placebo-controlled trial included 76 children. Eligible participants were treated in two dental visits using the following methods: with protective glasses only, without distraction (attention placebo-controlled - APC); and with the treatment condition (i.e., VR). Primary outcomes were dental anxiety and pain; secondary outcome was dental visit behaviour. Heart rate scores were recorded as an objective measure to evaluate dental anxiety and pain. Subjective measurements for each variable were also performed. Results: Significant reduction in dental pain and anxiety was observed in the VR group, according to the heart rate scores; however, no statistical differences were observed according to the self-reported measures. Decreased dental anxiety and pain were associated with the first visit sequence with VR. Dental pain and anxiety scores were lower during local anaesthesia in the VR group than in the APC group. Conclusion: Virtual reality significantly reduced pain and anxiety during local anaesthesia in children undergoing dental treatment; therefore, it may be recommended during dental treatment in school-age children.

Simultaneous confidence interval for assessing non-inferiority with assay sensitivity in a three-arm trial with binary endpoints.

A three-arm trial including an experimental treatment, an active reference treatment and a placebo is often used to assess the non-inferiority (NI) with assay sensitivity of an experimental treatment. Various hypothesis-test-based approaches via a fraction or pre-specified margin have been proposed to assess the NI with assay sensitivity in a three-arm trial. There is little work done on confidence interval in a three-arm trial. This paper develops a hybrid approach to construct simultaneous confidence interval for assessing NI and assay sensitivity in a three-arm trial. For comparison, we present normal-approximation-based and bootstrap-resampling-based simultaneous confidence intervals. Simulation studies evidence that the hybrid approach with the Wilson score statistic performs better than other approaches in terms of empirical coverage probability and mesial-non-coverage probability. An example is used to illustrate the proposed approaches.

Placebo-To be or not to be? Are there really alternatives to placebo-controlled trials?

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.

Run-in periods and clinical outcomes of antipsychotics in dementia: A meta-epidemiological study of placebo-controlled trials.

PURPOSE: Run-in periods are used to identify placebo-responders and washout. Our aim was to assess the association of run-in periods with clinical outcomes of antipsychotics in dementia. METHODS: We searched randomized placebo-controlled trials of conventional and atypical antipsychotics for neuropsychiatric symptoms (NPS) in dementia in electronic sources and references of selected articles. We extracted (a) the presence of a run-in period, use of placebo/investigated drug during run-in (versus washout only), and run-in duration (1 week or more) and (b) the reduction in NPS, number of participants with somnolence, extrapyramidal symptoms (EPS), and deaths per treatment group. We pooled clinical outcomes comparing antipsychotic and placebo groups in trials with and without run-in. RESULTS: We identified 35 trials. Twenty-nine trials used run-in. The pooled standardized mean difference in the reduction of NPS was -0.170 (95% CI, -0.227 to -0.112) in trials with run-in and -0.142 (95% CI, -0.331 to 0.047) in trials without run-in. The pooled odds ratio for somnolence was 2.8 (95% CI, 2.3-3.5) in trials with run-in and 3.5 (95% CI, 1.2-10.7) in trials without run-in; for EPS, these ORs were 1.8 (95% CI, 1.4-2.2) and 2.0 (95% CI, 1.3-3.1) respectively, and for mortality 1.4 (95% CI, 1.0-2.0) and 1.6 (95% CI, 0.7-3.4). The use of placebo/investigated drug during run-in and run-in duration did not affect the estimates in a consistent way. CONCLUSIONS: The use of run-in in trials might have led to overestimated efficacy and especially underestimated risks of side effects of antipsychotics compared with placebo for NPS in dementia.

Improvement of perioperative care of the elderly patient (PeriAge): protocol of a controlled interventional feasibility study.

INTRODUCTION: Geriatric patients have a pronounced risk to suffer from postoperative complications. While effective risk-specific perioperative measures have been studied in controlled experimental settings, they are rarely found in routine healthcare. This study aims (1) to implement a multicomponent preoperative and intraoperative intervention, and investigate its feasibility, and (2) exploratorily assess the effectiveness of the intervention in routine healthcare. METHODS AND ANALYSIS: Feasibility and exploratory effectiveness of the intervention will be investigated in a monocentric, prospective, non-randomised, controlled trial. The intervention includes systematic information for patients and family about measures to prevent postoperative complications; preoperative screening for frailty, malnutrition, strength and mobility with nutrient supplementation and physical exercise (prehabilitation) as needed. Further components focus on potentially inadequate medication, patient blood-management and carbohydrate loading prior to surgery, retainment of orientation aids in the operating room and a geriatric anaesthesia concept. Data will successively be collected from control, implementation and intervention groups. Patients aged 65+ with impending surgery will be included. A sample size of 240, n=80 per group, is planned. Assessments will take place at inclusion and 2, 30 and 180 days after surgery. Mixed-methods analyses will be performed. Exploratory effectiveness will be assessed using mixed segmented regressions. The primary endpoint is functional status. Secondary endpoints include cognitive performance, health-related quality of life, length of inpatient stay and occurrence of postoperative complications. Feasibility will be assessed through semi-structured interviews with staff and patients and quantitative analyses of the data quality, focussing on practicability, acceptance, adoption and fidelity to protocol. ETHICS AND DISSEMINATION: The study will be carried out in accordance with the Helsinki Declaration and to principles of good scientific practice. The Ethics Committee of the Medical Association Hamburg, Germany, approved the protocol (study ID: PV5596). Results will be disseminated in scientific journals and healthcare conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT03325413.

Consultations on human infection studies in India: Do people's voices really count?

The Controlled Human Infection Model or CHIM, sometimes described as a human challenge study, is a relatively specialised medical research technique. Researchers infect healthy participants with a weakened strain of a pathogen in a controlled setting, in order to learn more about the infection and the disease, or to develop new vaccines for that disease. Unlike in other human clinical trials, where participants face a risk of harm because of, for example, the drug's side effects, healthy participants in CHIM trials are deliberately harmed through infection - contrary to every principle and guideline of medical practice and research.

To add or not to add a new treatment arm to a multiarm study: A decision-theoretic framework.

Multiarm clinical trials, which compare several experimental treatments against control, are frequently recommended due to their efficiency gain. In practise, all potential treatments may not be ready to be tested in a phase II/III trial at the same time. It has become appealing to allow new treatment arms to be added into on-going clinical trials using a "platform" trial approach. To the best of our knowledge, many aspects of when to add arms to an existing trial have not been explored in the literature. Most works on adding arm(s) assume that a new arm is opened whenever a new treatment becomes available. This strategy may prolong the overall duration of a study or cause reduction in marginal power for each hypothesis if the adaptation is not well accommodated. Within a two-stage trial setting, we propose a decision-theoretic framework to investigate when to add or not to add a new treatment arm based on the observed stage one treatment responses. To account for different prospect of multiarm studies, we define utility in two different ways; one for a trial that aims to maximise the number of rejected hypotheses; the other for a trial that would declare a success when at least one hypothesis is rejected from the study. Our framework shows that it is not always optimal to add a new treatment arm to an existing trial. We illustrate a case study by considering a completed trial on knee osteoarthritis.

Health professionals' and researchers' opinions on conducting clinical deprescribing trials.

While clinical deprescribing trials are increasingly being performed, there is no guidance on the optimum conduction of such studies. The aim of this survey was to explore the perspectives, attitudes, interests, barriers, and enablers of conducting clinical deprescribing trials among health professionals and researchers. An anonymous survey was developed, reviewed, and piloted by all investigators and informed by consultation with experts, as well as current deprescribing guidelines. The questions were formulated around current clinical trial frameworks and incorporated identified enablers and barriers of performing deprescribing studies. The survey was sent to members of Australian and international deprescribing, pharmacological, and pharmacy organizations, and other researchers published in deprescribing. A total of 96 respondents completed the survey (92.3% completion rate). Respondents indicated the main deprescribing trial rationale is to generate evidence to optimize patient-centered outcomes (79.2%). Common barriers identified included the time and effort required (18.2%), and apprehension of health professionals involved in trials (17.1%). Studies are enabled by positive attitudes toward deprescribing of treating prescribers (24.4%) and patients (20.9%). Classical randomized controlled trials (RCTs) were deemed the most appropriate methodology (93.2%). Sixty percent of participants indicated a good clinical practice framework is required to guide the conduct of deprescribing trials. There were no significant differences in responses based on previous experience in conducting clinical deprescribing trials. In conclusion, clinical deprescribing trials should be conducted to investigate whether deprescribing medications improves patient care. A future deprescribing trial framework should use classical RCTs as a model, ensure participant safety, and target patient-centered outcomes.

Kids in Action: the protocol of a Youth Participatory Action Research project to promote physical activity and dietary behaviour.

INTRODUCTION: In this study, researchers collaborate with children from a low socioeconomic neighbourhood in Amsterdam in developing, implementing and evaluating interventions targeting their health behaviours. This Youth Participatory Action Research project focuses on the promotion of physical activity and healthy dietary behaviour. METHODS AND ANALYSIS: This study is a controlled trial using participatory methods to develop interventions together with children aged 9-12 years. At four primary schools in a low socioeconomic neighbourhood in Amsterdam, an 'Action Team' is installed: a group of six to eight children who actively participate as co-researchers in developing, implementing and evaluating interventions. An academic researcher facilitates the participatory process. Four control schools, also located in low socioeconomic areas in and around Amsterdam, continue with their regular curriculum and do not participate in the participatory process. For the effect evaluation, physical activity and sedentary behaviour are assessed using accelerometers and self-reporting; dietary behaviour using self-reporting and motor fitness (strength, flexibility, coordination, speed and endurance) using the motor performance fitness test. Effectiveness of the interventions is evaluated by multilevel regression analysis. The process of co-creating interventions and the implemented interventions is continually evaluated during meetings of the Action Teams and with children participating in the interventions. Empowerment of children is evaluated during focus groups. Summaries and transcripts of meetings are coded and analysed to enrich children's findings. ETHICS AND DISSEMINATION: The Medical Ethics Committee of the VU Medical Center approved the study protocol (2016.366). TRIAL REGISTRATION NUMBER: TC=6604.

Application of speCtraL computed tomogrAphy to impRove specIficity of cardiac compuTed tomographY (CLARITY study): rationale and design.

INTRODUCTION: Anatomic stenosis evaluation on coronary CT angiography (CCTA) lacks specificity in indicating the functional significance of a stenosis. Recent developments in CT techniques (including dual-layer spectral detector CT [SDCT] and static stress CT perfusion [CTP]) and image analyses (including fractional flow reserve [FFR] derived from CCTA images [FFRCT] and deep learning analysis [DL]) are potential strategies to increase the specificity of CCTA by combining both anatomical and functional information in one investigation. The aim of the current study is to assess the diagnostic performance of (combinations of) SDCT, CTP, FFRCT and DL for the identification of functionally significant coronary artery stenosis. METHODS AND ANALYSIS: Seventy-five patients aged 18 years and older with stable angina and known coronary artery disease and scheduled to undergo clinically indicated invasive FFR will be enrolled. All subjects will undergo the following SDCT scans: coronary calcium scoring, static stress CTP, rest CCTA and if indicated (history of myocardial infarction) a delayed enhancement acquisition. Invasive FFR of ≤0.80, measured within 30 days after the SDCT scans, will be used as reference to indicate a functionally significant stenosis. The primary study endpoint is the diagnostic performance of SDCT (including CTP) for the identification of functionally significant coronary artery stenosis. Secondary study endpoint is the diagnostic performance of SDCT, CTP, FFRCT and DL separately and combined for the identification of functionally significant coronary artery stenosis. ETHICS AND DISSEMINATION: Ethical approval was obtained. All subjects will provide written informed consent. Study findings will be disseminated through peer-reviewed conference presentations and journal publications. TRIAL REGISTRATION NUMBER: NCT03139006; Pre-results.

Evidence-based and tailored medication in type 2 diabetes: a pathway learned from clinical trials.

In Japan, the choice of anti-diabetic medication is officially recommended according to the patient's glycemic condition and disease phenotype, unlike most other regions where metformin is recommended as the first-line medication. There has been an increase in the number of available glucose-lowering agents, making it necessary to select these agents based on ever-improving evidence obtained from clinical trials. For the dipeptidyl peptidase-4 inhibitor class of drugs, nine drugs are currently available on the market in Japan. Although previous cardiovascular outcome trials (CVOTs) demonstrated non-inferiority for both major adverse cardiovascular events (MACEs) and safety for some drugs of the class, the design and results of the CARMELINA trial seemed to be slightly different from earlier trials in that it showed the drugs were safe and partially effective even in patients with renal impairment. Thus, recent CVOTs on newer glucose-lowering agents have mainly focused on the major impacts of individual classes and drugs on clinical outcomes behind their glucose-lowering action. The diverse features of the classes and individual drugs may have also highlighted not only the class-effects, but also the drug-effects of glucose-lowering agents. This will lead to clinical-based evidence and assist with optimum selection of the class and/or drug for tailored medication in patients with type 2 diabetes.