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.

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.

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.

Effect of an Intravenous Dexamethasone Added to Caudal Local Anesthetics to Improve Postoperative Pain: A Systematic Review and Meta-analysis With Trial Sequential Analysis.

BACKGROUND: Caudal anesthesia has been used for postoperative pain control in pediatric surgical patients, but the duration of the analgesic effect is occasionally unsatisfactory. Intravenous steroids have been shown to be effective for postsurgical pain management after certain surgeries. The aim of this meta-analysis with trial sequential analysis (TSA) was to evaluate the analgesic effect of steroids in patients administered with caudal anesthesia. METHODS: This study was a systematic review and meta-analysis. A search of published literature was conducted in the MEDLINE, EMBASE, Web of Science, and Cochrane Central Register of Controlled Trials databases and in trial registration sites. Randomized controlled trials that compared intravenous steroids with a placebo in pediatric patients who had received caudal anesthesia for surgery were included in the study. The primary outcomes from the present meta-analysis were the analgesic duration and the number of patients who required rescue analgesics. The analgesic duration and incidence of rescue use were summarized using mean difference or risk ratio with a 97.5% confidence interval (CI), respectively. If the 97.5% CI of the mean difference or risk ratio included a value of 0 or 1, respectively, we considered the difference not to be significant. We used the random effects model to combine the results. Heterogeneity was quantified with the I statistic. The quality of the trials was evaluated using the Cochrane methodology. Moreover, a TSA with a risk of type 1 error of 2.5% and power of 90% was performed. We established the minimum clinically meaningful difference of analgesic duration as 3 hours. The target sample size for meta-analysis was also calculated in the TSA. We also assessed adverse events. RESULTS: Six trials with 424 patients were included; 211 patients received intravenous steroids. All trials compared dexamethasone of at least 0.5 mg/kg dose with a placebo. Dexamethasone prolonged the duration of caudal analgesia (mean difference, 244 minutes; 97.5% CI, 188-300). Heterogeneity was considerable with an I value of 94.8%. Quality of evidence was very low. The TSA suggested that only 17.0% of the target sample size had been reached, but the cumulative Z score crossed the trial sequential monitoring boundary to indicate a benefit. Rescue use was reported in 4 studies with 260 patients. Rescue use was not significantly reduced in the dexamethasone group (risk ratio, 0.53; 97.5% CI, 0.09-3.30; I, 98.7%). No increase in adverse events was reported. CONCLUSIONS: Intravenous dexamethasone prolongs the analgesic duration of caudal anesthesia. Trials to investigate the effectiveness of a lower dose of the dexamethasone in prolonging analgesic effects would be of interest. Further trials with a low risk of bias are necessary.

Pre-cardiac transplant amiodarone use is not associated with postoperative mortality: An updated meta-analysis.

BACKGROUND: Amiodarone remains the preferred agent for the treatment and prevention of life-threatening ventricular arrhythmias in patients with end-stage heart failure. While several reports suggest that pre-operative amiodarone exposure worsens outcomes in heart transplant recipients, other studies have failed to validate this relationship. We sought to clarify this issue by performing a meta-analysis of the available literature surrounding this topic. METHODS: We searched Medline, SCOPUS and the Cochrane Central Register of Controlled Trials through December 15th 2016, as well as proceedings from related conferences over the prior 3years. Included studies evaluated patients undergoing cardiac transplantation who had received pre-transplant amiodarone and reported postoperative mortality. Outcomes were pooled using a Hartung-Knapp random-effects model producing odds ratios (OR) and 95% confidence intervals (CI). Statistical heterogeneity was evaluated using the Cochrane Q statistic p-value and I2 value. Publication bias was assessed by visual inspection of funnel plots and using Egger's weighted regression statistic. RESULTS: Nine studies including 16,509 participants were included in the overall analysis. Use of pre-transplant amiodarone was not associated with an increase in postoperative mortality versus control (OR 1.38, 95% 0.8 to 2.36). Moderate statistical heterogeneity was present (I2=45.8%, p=0.06); visual inspection of funnel plot analysis did not suggest publication bias. No association was noted between a longer duration of follow-up and higher odds of mortality with amiodarone use (p=0.91). CONCLUSION: Meta-analysis of the available evidence suggests that pre-operative amiodarone exposure does not increase mortality in cardiac transplant recipients.

Power considerations for trials of two experimental arms versus a standard active control or placebo.

The power of the two-experimental arm trial depends on three choices: (1) when one arm is dropped (if at all); (2) the final testing procedure, assuming no dropping; and (3) the sampling ratio for the three arms. Multiple-arm designs require critical values which were calculated using Mathematica. Power calculations were exact based on probabilities from binomial distributions. The "drop the loser" strategy is optimal for the primary endpoint. The equal sized two treated arm trial gives reasonable power for the primary as well as good power to select the best treated arm. The best power was provided by the 3:3:4 sampling, but it was only marginally better.

Systematic review: knowledge and educational needs of patients with irritable bowel syndrome.

Educational programs have been used as a control condition in trials on psychological therapies for irritable bowel syndrome (IBS). An optimal control condition should have all logistic features of the experimental intervention, except the active component, but also have basic therapeutic benefit for the patient. The aim of the present study is to systematically determine patients' educational needs on the basis of the (mis)conceptions that they have of their disease and their reported desire for information to optimize the control intervention in IBS research. A systematic review of studies on the knowledge and educational needs of IBS patients in terms of their condition was performed. Studies published as full text in the English language in peer-reviewed journals and that included adult IBS patients diagnosed according to the Manning or Rome I, II, or III criteria were selected. Eight studies involving 2132 patients were included. When focusing on misconceptions of patients, the most prevalent are that IBS is caused by dietary factors, food allergies and intolerance (37-90%), heredity (52%), or a lack of digestive enzymes (52%); IBS is a form of colitis (43%); and will last a lifetime (31-54%), develop into cancer (15-49%), or worsens with age (48%). Patients are 'unhappy' with their level of knowledge or feel poorly informed (65%). They want information about the diagnostic process, which foods to avoid (63%), causes (62%), coping strategies (59%), new medications (55%), course (52%), and the role of psychological factors (51%). IBS patients do have a large variety of educational needs. Educational programs optimally addressing these needs can be used adequately as a placebo control condition in research on psychological interventions.

¿Cómo podemos obtener información más confiable de los estudios de las patogenesias? Una crítica a las experimentaciones puras / How can e get more reliable information studies of the pathogenesis ? A critique of pure experimentation

Ciertamente, un medicamento debe ser administrado en un cuerpo sano sin ninguna sustancia extraña; cuando el olor y el sabor hayan sido examinados debe tomarse una pequeña dosis y llevar un registro de cada uno de los cambios que se pudieran presentar, tanto en el pulso, la temperatura, la respiración y las secreciones.Una vez analizados los síntomas encontrados en una persona se puede entonces proceder a probarse en el cuerpo de una persona enferma.

Certainly, a drug must be administered in a healthy body without any foreign substance; when the smell and taste have been examined must take a small dose and keep a record of each of the changes that may arise, both the pulse, temperature, breathing and secreciones.Una after analyzing the symptoms found in a person can then proceed to try on in the body of a sick person.

Methodological issues in observational studies and non-randomized controlled trials in oncology in the era of big data.

Non-randomized controlled trials, cohort studies and database studies are appealing study designs when there are urgent needs for safety data, outcomes of interest are rare, generalizability is a matter of concern, or randomization is not feasible. This paper reviews four typical case studies from methodological viewpoints and clarifies how to minimize bias in observational studies in oncology. In summary, researchers planning observational studies should be cautious of selection of appropriate databases, validity of algorithms for identifying outcomes, comparison with incident users or self-control, rigorous collection of information on potential confounders and reporting details of subject selection. Further, a careful study protocol and statistical analysis plan are also necessary.

Failure to address potential bias in non-randomised controlled clinical trials may cause lack of evidence on patient-reported outcomes: a method study.

OBJECTIVES: We conducted a workup of a previously published systematic review and aimed to analyse why most of the identified non-randomised controlled clinical trials with patient-reported outcomes did not match a set of basic quality criteria. SETTING: There were no limits on the level of care and the geographical location. PARTICIPANTS: The review evaluated permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer and compared that intervention with alternative procedures such as external beam radiotherapy, radical prostatectomy and no primary therapy. PRIMARY OUTCOME MEASURE: Fulfilment of basic inclusion criteria according to a Participants, Interventions, Comparisons, Outcomes (PICO) framework and accomplishment of requirements to contain superimposed risk of bias. RESULTS: We found that 21 of 50 excluded non-randomised controlled trials did not meet the PICO inclusion criteria. The remaining 29 studies showed a lack in the quality of reporting. The resulting flaws included attrition bias due to loss of follow-up, lack of reporting baseline data, potential confounding due to unadjusted data and lack of statistical comparison between groups. CONCLUSIONS: With respect to the reporting of patient-reported outcomes, active efforts are required to improve the quality of reporting in non-randomised controlled trials concerning permanent interstitial low-dose rate brachytherapy in patients with localised prostate cancer.

Hybrid surgery for multilevel cervical degenerative disc diseases: a systematic review of biomechanical and clinical evidence.

PURPOSE: The optimal surgical technique for multilevel cervical degenerative disc diseases (DDD) remains controversial. Hybrid surgery (HS) incorporating anterior cervical discectomy and fusion (ACDF) and cervical disc replacement (CDR) is increasingly performed for cervical DDD. This study aims to evaluate the biomechanical and clinical evidence available for HS and to provide a systematic review of current understanding of HS. METHODS: This systematic review was undertaken by following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement. Multiple databases and online registers of clinical trials were searched up to February 2014. The biomechanical and clinical studies on HS for cervical DDD written in English were included. Two authors independently assessed methodological quality and extracted data. RESULTS: Fifteen studies including eight biomechanical studies and seven clinical studies were indentified. The biomechanical studies showed that HS was benefit to motion preservation of the operative levels and revealed less adverse effect on adjacent segments. All clinical studies demonstrated improvement in validated functional scores after HS. Segment motion and immobilization were achieved at the arthroplasty level and arthrodesis level, respectively. Postoperative assessments and complication rate were similar or in favor of HS when comparing with ACDF or CDR. However, the overall quality of evidence for HS was low to very low. CONCLUSIONS: There is a paucity of high quality evidence for HS. HS may be a safe and efficacious technique to benefit a select group of multilevel cervical DDD, which is needed to be confirmed by further prospective, randomized controlled trials.

The influence of computer-assisted surgery on rotational, coronal and sagittal alignment in revision total knee arthroplasty.

BACKGROUND: Despite good results of primary total knee arthroplasty (TKA), the number of revision total knee arthroplasties (rTKAs) is rising. Proper implant position is essential, since malposition leads to worse clinical outcome. In rTKA most anatomical landmarks have disappeared because of extensive bone loss, making it more difficult to adequately implant the knee prosthesis. In primary TKA, computer-assisted surgery (CAS) leads to better prosthetic alignment than mechanical navigation guides. Literature about the use of CAS in rTKA is scarce though, and the effect on rotational prosthetic alignment has not been investigated yet. Hence the primary objective of this study is to compare rotational prosthetic alignment when using CAS in rTKA compared to a mechanical navigation guide. Secondary objectives are to compare prosthetic alignment in the coronal and sagittal planes. It is hypothesized that CAS leads to better rotational, coronal and sagittal prosthetic alignment when used during rTKA. METHODS/DESIGN: A prospective clinical intervention study with use of a historical control group will be conducted. Forty-four patients with a minimum age of 18 to be admitted for CAS-rTKA between September 2012 and September 2015 will be included in the intervention group. Forty-four patients with a minimum age of 18 who underwent rTKA with the use of a mechanical navigation guide between January 2002 and April 2012 will form the historical control group. Both groups will be matched according to gender and type of revision prosthesis. Rotational prosthesis alignment will be evaluated using a CT-scan of the knee joint. DISCUSSION: Proper implant position is essential, since malposition leads to worse clinical outcome. Several studies show a significantly positive influence of CAS on prosthetic alignment in primary TKA, but literature about the use of CAS in rTKA is limited. The purpose of this study is thus to investigate the influence of CAS during rTKA on postoperative prosthetic alignment, compared to mechanical navigation guides. TRIAL REGISTRATION: Netherlands National Trial Register NTR3512.

The association of α-blockers and 5-α reductase inhibitors in benign prostatic hyperplasia with fractures.

BACKGROUND: Alpha-blockers and 5-alpha reductase inhibitors are common drugs used to treat benign prostatic hyperplasia (BPH), a prevalent problem in older men associated with significant morbidity and cost. Data regarding how these medications affect skeletal health and fracture risk remain scarce. METHODS: Studies were identified by searching PubMed, EMBASE, the Cochrane library and Thomson Reuters Web of Knowledge. Studies involving BPH patients that reported odds ratio (OR) estimates with 95% confidence intervals (CIs) for the association between fractures and exposure to 5-alpha reductase inhibitors or alpha-blockers were included. Pooled ORs were calculated using the random-effects model. RESULTS: Three studies addressed fracture risk in patients exposed to 5-alpha reductase inhibitors (21,366 fracture cases). Four studies addressed fracture risk in patients exposed to alpha-blockers (22,051 fracture cases). The pooled OR for fractures with 5-alpha reductase inhibitor use was 0.9 (95% CI = 0.7-1.1). For hip/femur fractures with 5-alpha reductase inhibitor use, the pooled OR was 0.8 (95% CI = 0.7-1.0). The pooled OR for fractures with alpha-blockers was 1.1 (95% CI = 0.9-1.3). There was significant statistical heterogeneity among studies for alpha-blockers. CONCLUSIONS: In patients with BPH, exposure to 5-alpha reductase inhibitors was not associated with change in fracture risk. The 5-alpha reductase inhibitors may have a small protective effect against hip/femur fractures although this was not statistically significant. Although alpha-blockers were not associated with change in fracture risk, caution is required when interpreting the results as significant heterogeneity was present.

A comparison of the clinical and experimental characteristics of four acute surgical pain models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery.

When a clinical trial of an analgesic produces a negative finding, it is important to consider the influence (if any) of experimental error on the validity of that result. Although efforts to identify and minimize experimental error in chronic pain investigations have begun in earnest, less work has been performed on the optimization of acute pain methodology. Of the acute surgical pain methodology articles that have been published over the last decade, almost all focus on either the dental or bunion model. Analgesics are typically evaluated in a variety of surgical models that eventually include hospital-based models (eg, joint replacement and soft tissue surgery). Every surgical procedure has unique clinical characteristics that must be considered to optimize study design and conduct. Much of the methodological knowledge garnered from bunion and dental studies is applicable to other surgical models, but some extrapolations are hazardous. The purposes of this review were (1) to qualitatively describe the clinical and experimental characteristics of the 4 classic surgical models: dental extraction, bunionectomy, joint replacement, and soft tissue surgery; and (2) to quantitatively compare the models by analyzing 3 factors: effect size, enrollment rate, and demographics. We found that the dental extraction and bunionectomy models had higher assay sensitivity than the joint replacement and soft tissue surgery models. It is probable that this finding is secondary to the superior experimental conditions under which the dental and bunion models are executed (utilization of few centers that have the ability to reduce surgical, anesthetic, and postoperative confounders).

Health information technology in screening and treatment of child obesity: a systematic review.

BACKGROUND AND OBJECTIVES: Childhood obesity is a major problem in the United States, yet screening and treatment are often inaccessible or ineffective. Health information technology (IT) may improve the quality, efficiency, and reach of chronic disease management. The objective of this study was to review the effect of health IT (electronic health records [EHRs], telemedicine, text message or telephone support) on patient outcomes and care processes in pediatric obesity management. METHODS: Medline, Embase, and the Cochrane Registry of Controlled Trials were searched from January 2006 to April 2012. Controlled trials, before-and-after studies, and cross-sectional studies were included if they used IT to deliver obesity screening or treatment to children aged 2 to 18 and reported impact on patient outcomes (BMI, dietary or physical activity behavior change) or care processes (BMI screening, comorbidity testing, diet, or physical activity counseling). Two independent reviewers extracted data and assessed trial quality. RESULTS: Thirteen studies met inclusion criteria. EHR use was associated with increased BMI screening rates in 5 of 8 studies. Telemedicine counseling was associated with changes in BMI percentile similar to that of in-person counseling and improved treatment access in 2 studies. Text message or telephone support was associated with weight loss maintenance in 1 of 3 studies. CONCLUSIONS: To date, health IT interventions have improved access to obesity treatment and rates of screening. However, the impact on weight loss and other health outcomes remains understudied and inconsistent. More interactive and time-intensive interventions may enhance health IT's clinical effectiveness in chronic disease management.