Impact of a Best Practices Program in Patients with Relapsed/Refractory Multiple Myeloma Receiving Selinexor.

Best practice (BP) in cancer care consists of a multifaceted approach comprising individualized treatment plans, evidence-based medicine, the optimal use of supportive care and patient education. We investigated the impact of a BP program in patients with relapsed/refractory multiple myeloma (RRMM) receiving selinexor. Features of the BP program that were specific to selinexor were initiating selinexor at doses ≤80 mg once weekly and the upfront use of standardized antiemetics. Study endpoints included time to treatment failure (TTF), duration of therapy, dose limiting toxicities and overall survival. Comparative analysis on TTF and duration of therapy was conducted using a log-rank test and multivariate Cox proportional hazard regression. Over the ensuing 12-month post-BP period, 41 patients received selinexor-based therapy compared to 68 patients who received selinexor-based therapy pre-BP implementation. Patients treated in the post-BP period had reductions in TTF (hazard ratio [HR] = 0.50; 95% CI: 0.27 to 0.92). Patients in the pre-BP period were four times more likely to stop therapy than those in the post-period (odds ratio [OR] = 4.0, 95% CI: 1.75 to 9.3). The findings suggest a BP program tailored to selinexor could increase the time to treatment failure, increase treatment duration and lower the incidence of drug limiting toxicities.

Supporting Behavior Change After AECOPD - Development of a Hospital-Initiated Intervention Using the Behavior Change Wheel.

After hospitalization due to acute COPD exacerbations, patient-manageable behaviors influence rehospitalization frequency. This study's aim was to develop a hospital-ward-initiated Behaviour-Change-Wheel (BCW)-based intervention targeting patients' key health behaviors, with the aim to increase quality of life and reduce rehospitalization frequency. Intervention development was performed by University Hospital Zurich working groups and followed the three BCW stages for each of the three key literature-identified problems: insufficient exacerbation management, lack of physical activity and ongoing smoking. In stage one, by analyzing published evidence - including but not limited to patients' perspective - and health professionals' perspectives regarding these problems, we identified six target behaviors. In stage two, we identified six corresponding intervention functions. As our policy category, we chose developing guidelines and service provision. For stage three, we defined eighteen basic intervention packages using 46 Behaviour Change Techniques in our basic intervention. The delivery modes will be face-to-face and telephone contact. In the inpatient setting, this behavioral intervention will be delivered by a multi-professional team. For at least 3 months following discharge, an advanced nursing practice team will continue and coordinate the necessary care package via telephone. The intervention is embedded in a broader self-management intervention complemented by integrated care components. The BCW is a promising foundation upon which to develop our COPD intervention. In future, the interaction between the therapeutic care team-patient relationships and the delivery of the behavioral intervention will also be evaluated.

'Shape-Up', a Modified Cognitive-Behavioural Community Programme for Weight Management: Real-World Evaluation as an Approach for Delivering Public Health Goals.

Obesity is widespread, with serious health consequences; addressing it requires considerable effort at a public health level, incorporating prevention and management along with policies to support implementation. Behavioural weight-management programmes are widely used by public health bodies to address overweight and obesity. Shape-Up is an evidence-based programme combining a structured behavioural intervention (targeting nutrition and physical activity behaviours) within a peer-learning framework. This study was a service-evaluation of Shape-Up, as delivered in Rotherham by a local leisure provider, and included a secondary analysis of data collected in the community by service providers. The RE-AIM (Reach Effectiveness Adoption Implementation Maintenance) framework was used to explore programme effectiveness, implementation, and whom it reached. A total of 141 participants were included. Compared to local demographics, participants were older, at 48.9 (SD 14.47) years, with a lower employment rate (41% employed) and greater proportion female (67% female). Mean BMI was 38.0 (SD 7.54) kg/m2. Mean weight-change between baseline and endpoint (12 weeks, 10 group sessions) was -4.4 (SD 3.38) kg, and degree of weight change was associated with session attendance (F (9, 131) = 6.356, p < 0.0005). There were positive effects on participants' weight, health-related behaviours, and quality of life. The intervention content (including the focus of nutritional recommendations) and structure were adapted during implementation to better suit national guidelines and local population needs. RE-AIM was found to be a useful framework for evaluating and adapting an existing evidence-based weight management programme in line with local population needs. This could be a more cost-effective approach, compared to developing new programmes, for delivering public health goals relating to obesity, nutrition, and physical activity.

Exclusively Digital Health Interventions Targeting Diet, Physical Activity, and Weight Gain in Pregnant Women: Systematic Review and Meta-Analysis.

BACKGROUND: Interventions to promote a healthy diet, physical activity, and weight management during pregnancy are increasingly embracing digital technologies. Although some interventions have combined digital with interpersonal (face-to-face or telephone) delivery, others have relied exclusively on digital delivery. Exclusively digital interventions have the advantages of greater cost-effectiveness and broader reach and as such can be a valuable resource for health care providers. OBJECTIVE: This systematic review aims to focus on exclusively digital interventions to determine their effectiveness, identify behavior change techniques (BCTs), and investigate user engagement. METHODS: A total of 6 databases (Medical Literature Analysis and Retrieval System Online [MEDLINE], Excerpta Medica dataBASE [EMBASE], PsycINFO, Cumulated Index to Nursing and Allied Health Literature [CINAHL] Plus, Web of Science, and ProQuest) were searched for randomized controlled trials or pilot control trials of exclusively digital interventions to encourage healthy eating, physical activity, or appropriate weight gain during pregnancy. The outcome measures were gestational weight gain (GWG) and changes in physical activity and dietary behaviors. Study quality was assessed using the Cochrane Risk of Bias tool 2.0. Where possible, pooled effect sizes were calculated using a random effects meta-analysis. RESULTS: In total, 11 studies met the inclusion criteria. The risk of bias was mostly high (n=5) or moderate (n=3). Of the 11 studies, 6 reported on GWG as the primary outcome, 4 of which also measured changes in physical activity and dietary behaviors, and 5 studies focused either on dietary behaviors only (n=2) or physical activity only (n=3). The meta-analyses showed no significant benefit of interventions on total GWG for either intention-to-treat data (-0.28 kg; 95% CI -1.43 to 0.87) or per-protocol data (-0.65 kg; 95% CI -1.98 to 0.67). Substantial heterogeneity in outcome measures of change in dietary behaviors and physical activity precluded further meta-analyses. BCT coding identified 7 BCTs that were common to all effective interventions. Effective interventions averaged over twice as many BCTs from the goals and planning, and feedback and monitoring domains as ineffective interventions. Data from the 6 studies reporting on user engagement indicated a positive association between high engagement with key BCTs and greater intervention effectiveness. Interventions using proactive messaging and feedback appeared to have higher levels of engagement. CONCLUSIONS: In contrast to interpersonal interventions, there is little evidence of the effectiveness of exclusively digital interventions to encourage a healthy diet, physical activity, or weight management during pregnancy. In this review, effective interventions used proactive messaging, such as reminders to engage in BCTs, feedback on progress, or tips, suggesting that interactivity may drive engagement and lead to greater effectiveness. Given the benefits of cost and reach of digital interventions, further research is needed to understand how to use advancing technologies to enhance user engagement and improve effectiveness.

Why? What? How? Using an Intervention Mapping approach to develop a personalised intervention to improve adherence to photoprotection in patients with Xeroderma Pigmentosum.

Background: Intervention Mapping (IM) is a systematic approach for developing theory-based interventions across a variety of contexts and settings. This paper describes the development of a complex intervention designed to reduce the dose of ultraviolet radiation (UVR) reaching the face of adults with Xeroderma Pigmentosum (XP), by improving photoprotection. XP is a genetic condition that without extreme UVR photoprotection, leads to high risk of developing skin cancer. Methods: The IM protocol of 6 steps was applied, involving comprehensive mixed-methods formative research. Key stakeholders (XP clinical staff and Patient and Public Involvement Panel), were instrumental at every step. Behaviour change methods were informed by the IM taxonomy, therapeutic approaches (e.g. ACT, CBT) and coded according to the taxonomy of behaviour change techniques (version 1). Results: We designed a personalised modular intervention to target psychosocial determinants of photoprotective activities that influence the amount of UVR reaching the face. Content was developed to target determinants of motivation to protect and factors preventing the enactment of behaviours. Participants received personalised content addressing determinants/barriers most relevant to them, as well as core 'behaviour-change' material, considered important for all (e.g. SMART goals). Core and personalised content was delivered via 7 one-to-one sessions with a trained facilitator using a manual and purpose designed materials: Magazine; text messages; sunscreen application video; goal-setting tools (e.g. UVR dial and face protection guide); activity sheets. Novel features included use of ACT-based values to enhance intrinsic motivation, targeting of emotional barriers to photoprotection, addressing appearance concerns and facilitating habit formation. Conclusion: IM was an effective approach for complex intervention design. The structure (e.g. use of matrices) tethered the intervention tightly to theory and evidence-based approaches. The significant amount of time required needs to be considered and may hinder translation of IM into clinical and non-academic settings.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. 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. 22, No. 59. See the NIHR Journals Library website for further project information.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

Central Venous Catheter Salvage in Home Parenteral Nutrition Catheter-Related Bloodstream Infections: Long-Term Safety and Efficacy Data.

BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are a serious complication in the provision of home parenteral nutrition (HPN). Antibiotic salvage of central venous catheters (CVCs) in CRBSI is recommended; however, this is based on limited reports. We assessed the efficacy of antibiotic salvage of CRBSIs in HPN patients. MATERIALS AND METHODS: All confirmed CRBSIs occurring in patients receiving HPN in a national intestinal failure unit (IFU), between 1993 and 2011, were analyzed. A standardized protocol involving antibiotic and urokinase CVC locks and systemic antibiotics was used. RESULTS: In total, 588 patients were identified with a total of 2134 HPN years, and 297 CRBSIs occurred in 137 patients (65 single and 72 multiple CRBSIs). The overall rate of CRBSI in all patients was 0.38 per 1000 catheter days. Most (87.9%) infections were attributable to a single microorganism. In total, 72.5% (180/248) of CRBSIs were salvaged when attempted (coagulase-negative staphylococcus, 79.8% [103/129], Staphylococcus aureus, 56.7% [17/30]; polymicrobial infections, 67.7% [21/30]; and miscellaneous, 66.1% [39/59]). CVC salvage was not attempted in 49 episodes because of life-threatening sepsis (n = 18), fungal infection (n = 7), catheter problems (n = 20), and CVC tunnel infection (n = 4). Overall, the CVC was removed in 33.7% (100/297) of cases. There were 5 deaths in patients admitted to the IFU for management of the CRBSI (2 severe sepsis at presentation, 3 metastatic infection). CONCLUSIONS: This is the largest reported series of catheter salvage in CRBSIs and demonstrates successful catheter salvage in most cases when using a standardized protocol.

Complications and outcomes of trimethoprim-sulphamethoxazole as chemoprophylaxis for pneumocystis pneumonia in renal transplant recipients.

BACKGROUND: Following a pneumocystis pneumonia (PCP) outbreak in our nephrology unit, all transplant patients were offered chemoprophylaxis with trimethoprim-sulphamethoxazole (TMP-SMX) as the first line agent. A high rate of complications was noted. We aimed to quantify TMP-SMX associated adverse events and evaluate its prophylactic benefit in their light. Potential risk factors for complications' development were also investigated. METHOD: This was an observational study of outcomes in transplant recipients commenced on TMP-SMX prophylaxis for 1year period. End-points were adverse events due to TMP-SMX, the additional medical burden resulting from these events, and PCP diagnosis. RESULTS: 290 patients commenced on TMP-SMX. 110 (38%) developed complications with most common being rise in serum creatinine (Cr) (n = 63, 22%) followed by gastrointestinal symptoms (n = 15, 5%), and leucopenia (n = 5, 2%). PCP incidence fell from 19 cases in 19 months to 2 cases in 12 months. Baseline renal function (P = 0.019) was an independent predictors for developing rise in Cr with TMP-SMX. CONCLUSION: Use of chemoprophylaxis is an effective strategy in dealing with a PCP outbreak but can lead to a high number of complications. Rises in serum Cr can cause significant concern and increase in the number of investigations.

In search of the ideal immunopanel to distinguish metastatic mammary carcinoma from primary lung carcinoma: a tissue microarray study of 207 cases.

BACKGROUND: Distinguishing metastatic carcinoma of breast origin (MCBO) to lung from primary lung carcinomas (PLC) is a diagnostic quandary with clinical ramifications. Immunostains CK7, CK20, ER, PR, and Mammaglobin as well as pertinent negative stains are utilized but prove insufficient. We set out to identify stains either alone or as a group that would better discern between these 2 entities. DESIGN: Tissue microarrays of 109 MCBO to lung and 102 PLC were stained with CK7, CK20, ER, PR, AR, Mammaglobin, Napsin A, GATA-3, and TTF-1. An H-score was calculated for each case and stain. RESULTS: The highest area under the receiver-operating characteristic curves for each stain was seen with GATA-3 (0.817), Napsin A (0.817), and TTF-1 (0.854). When all possible combinations were analyzed, GATA-3 and TTF-1 proved to correctly classify with the highest accuracy (0.934). Combinations of GATA-3 and Napsin A (0.920) and GATA-3, Napsin A, and TTF-1 (0.933) were not significantly different from GATA-3 and TTF-1. The odds ratios for each stain and combination of stains showed that those for GATA-3 and TTF-1 were divergent, signifying that cases with higher H-scores for GATA-3 and TTF-1 were more likely to be classified as MCBO and PLC, respectively. CONCLUSIONS: GATA-3 and TTF-1 can correctly classify a case as either MCBO or PLC in 93.4% of cases. Although highly specific and sensitive for PLC, Napsin A in lieu of TTF-1 or as an additional stain did not improve classification accuracy.

Soluble adenylyl cyclase defines a nuclear cAMP microdomain in keratinocyte hyperproliferative skin diseases.

Cyclic adenosine monophosphate (cAMP) is a nearly ubiquitous signaling molecule important for numerous signaling pathways in human skin. We studied a novel class of mammalian adenylyl cyclase, the soluble adenylyl cyclase (sAC). We examined sAC localization in normal human skin and found it to be present in keratinocytes, melanocytes, mononuclear cells, eccrine ducts, and nerves. In normal skin, sAC keratinocyte staining was evenly distributed throughout the cell. However, in certain hyperproliferative disorders of the skin, including psoriasis, verruca vulgaris, and SCCIS on sun-damaged skin, sAC keratinocyte staining was predominantly nuclear. In contrast, in other hyperproliferative disorders, such as basal cell carcinoma, sAC staining was similar to normal human skin. Using a model of epithelial differentiation, we established that sAC migrates into the nucleus when differentiated cells are induced to reenter the cell cycle. Previous work had determined that nuclear sAC activates the cAMP-response-element-binding (CREB) transcription factor, and we found that in psoriasis lesions, nuclear sAC occurs concomitantly with activation of CREB. Hence, sAC may play a role in the pathogenesis of certain hyperproliferative skin disorders via modulation of gene expression.

CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival.

OBJECTIVES: Although the chemokine CXCL12 and its receptor CXCR4 have been implicated in metastasis of non-small cell lung carcinoma, the prognostic significance of these molecules is poorly defined. This study aimed to determine whether expression of these molecules is associated with clinicopathologic features and disease-free survival in non-small cell lung carcinoma. METHODS: Immunohistochemical staining for CXCL12 and CXCR4 was performed on 154 primary non-small cell lung carcinomas. Staining intensity was compared with tumor histotype, TNM stage, and disease-free survival; correlation was assessed by using the Fisher's exact test, and Kaplan-Meier and Cox multivariate proportional hazards regression analysis. RESULTS: Intense CXCL12 immunostaining was associated with nodal metastasis, although no difference in survival was observed. The prognostic relevance of CXCR4 was dependent on its subcellular location: in univariate analysis intense nuclear staining was significantly associated with lower T classification and improved disease-free survival in patients with adenocarcinoma, whereas cytomembranous staining was associated with distant metastasis and decreased disease-free survival. On multivariate analysis, cytomembranous CXCR4 expression conferred a significantly worse disease-free survival (relative risk, 2.8; 95% confidence interval, 1.4-5.7; P = .004). CONCLUSIONS: Cytomembranous expression of the chemokine receptor CXCR4 in adenocarcinoma of the lung is an independent risk factor associated with worse disease-free survival, whereas nuclear staining confers a survival benefit. These findings are consistent with a model in which CXCR4 promotes tumor cell proliferation and metastasis when present in the cytoplasm or cell membrane, whereas localization of this molecule in the nucleus prevents it from exerting these effects.

Exercise and body image distress in overweight and obese women with polycystic ovary syndrome: a pilot investigation.

OBJECTIVE: The objectives of the present pilot study were to: (1) examine the prevalence of body image distress in overweight and obese women with polycystic ovary syndrome (PCOS); (2) assess the effects of a low-cost intervention in the form of a self-directed brisk walking program on body image distress; and (3) assess the level of participation, the feasibility of a larger study and the sample size required. METHODS: This was an observational study whereby volunteers acted as their own control. Thirty-five women with PCOS (mean age 29.26 +/- 7.57 years) with body mass index (BMI) > 25 kg/m(2) volunteered for the study. Twenty-three returned six months later for reassessment. Of these, 12 completed the exercise program (completers) and 11 did not (non-completers). Pre and post assessments comprised the exercise tolerance test, the Body Dysmorphic Disorder Examination - Self-Report (BDDE-SR), a questionnaire on self-perceived hirsutism and dietary and activity records. RESULTS: Distress with body size was highly prevalent for the overall sample. However, completers had significantly higher BDDE-SR scores at baseline compared with non-completers (p < 0.005). Pre and post assessments showed a significant reduction in body image distress only for completers (p < 0.01) despite no significant change in BMI. CONCLUSIONS: A self-directed walking program is a low-cost intervention that can have psychological benefits for overweight women with PCOS. Specific recommendations for a randomized study are put forward.