Pharmacological interventions for pruritus in adult palliative care patients.

BACKGROUND: This is the second update of the original Cochrane review published in 2013 (issue 6), which was updated in 2016 (issue 11). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is a burdening symptom. It can cause considerable discomfort and negatively affect patients' quality of life. OBJECTIVES: To assess the effects of different pharmacological treatments compared with active control or placebo for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS: For this update, we searched CENTRAL (the Cochrane Library), MEDLINE (OVID) and Embase (OVID) up to 6 July 2022. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE and created 13 summary of findings tables. MAIN RESULTS: In total, we included 91 studies and 4652 participants in the review. We added 42 studies with 2839 participants for this update. Altogether, we included 51 different treatments for pruritus in four different patient groups. The overall risk of bias profile was heterogeneous and ranged from high to low risk. The main reason for giving a high risk of bias rating was a small sample size (fewer than 50 participants per treatment arm). Seventy-nine of 91 studies (87%) had fewer than 50 participants per treatment arm. Eight (9%) studies had low risk of bias in the specified key domains; the remaining studies had an unclear risk of bias (70 studies, 77%) or a high risk of bias (13 studies, 14%). Using GRADE criteria, we judged that the certainty of evidence for the primary outcome (i.e. pruritus) was high for kappa-opioid agonists compared to placebo and moderate for GABA-analogues compared to placebo. Certainty of evidence was low for naltrexone, fish-oil/omega-3 fatty acids, topical capsaicin, ondansetron and zinc sulphate compared to placebo and gabapentin compared to pregabalin, and very low for cromolyn sodium, paroxetine, montelukast, flumecinol, and rifampicin compared to placebo. We downgraded the certainty of the evidence mainly due to serious study limitations regarding risk of bias, imprecision, and inconsistency. For participants suffering from uraemic pruritus (UP; also known as chronic kidney disease (CKD)-associated pruritus (CKD-aP)), treatment with GABA-analogues compared to placebo likely resulted in a large reduction of pruritus (visual analogue scale (VAS) 0 to 10 cm): mean difference (MD) -5.10, 95% confidence interval (CI) -5.56 to -4.55; five RCTs, N = 297, certainty of evidence: moderate. Treatment with kappa-opioid receptor agonists (difelikefalin, nalbuphine, nalfurafine) compared to placebo reduced pruritus slightly (VAS 0 to 10 cm, MD -0.96, 95% CI -1.22 to -0.71; six RCTs, N = 1292, certainty of evidence: high); thus, this treatment was less effective than GABA-analogues. Treatment with montelukast compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (two studies, 87 participants): SMD -1.40, 95% CI -1.87 to -0.92; certainty of evidence: very low. Treatment with fish-oil/omega-3 fatty acids compared to placebo may result in a large reduction of pruritus (four studies, 160 observations): SMD -1.60, 95% CI -1.97 to -1.22; certainty of evidence: low. Treatment with cromolyn sodium compared to placebo may result in a reduction of pruritus, but the evidence is very uncertain (VAS 0 to 10 cm, MD -3.27, 95% CI -5.91 to -0.63; two RCTs, N = 100, certainty of evidence: very low). Treatment with topical capsaicin compared with placebo may result in a large reduction of pruritus (two studies; 112 participants): SMD -1.06, 95% CI -1.55 to -0.57; certainty of evidence: low. Ondansetron, zinc sulphate and several other treatments may not reduce pruritus in participants suffering from UP. In participants with cholestatic pruritus (CP), treatment with rifampicin compared to placebo may reduce pruritus, but the evidence is very uncertain (VAS: 0 to 100, MD -42.00, 95% CI -87.31 to 3.31; two RCTs, N = 42, certainty of evidence: very low). Treatment with flumecinol compared to placebo may reduce pruritus, but the evidence is very uncertain (RR > 1 favours treatment group; RR 2.32, 95% CI 0.54 to 10.1; two RCTs, N = 69, certainty of evidence: very low). Treatment with the opioid antagonist naltrexone compared to placebo may reduce pruritus (VAS: 0 to 10 cm, MD -2.42, 95% CI -3.90 to -0.94; two RCTs, N = 52, certainty of evidence: low). However, effects in participants with UP were inconclusive (percentage of difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). In palliative care participants with pruritus of a different nature, the treatment with the drug paroxetine (one study), a selective serotonin reuptake inhibitor, compared to placebo may reduce pruritus slightly by 0.78 (numerical analogue scale from 0 to 10 points; 95% CI -1.19 to -0.37; one RCT, N = 48, certainty of evidence: low). Most adverse events were mild or moderate. Two interventions showed multiple major adverse events (naltrexone and nalfurafine). AUTHORS CONCLUSIONS: Different interventions (GABA-analogues, kappa-opioid receptor agonists, cromolyn sodium, montelukast, fish-oil/omega-3 fatty acids and topical capsaicin compared to placebo) were effective for uraemic pruritus. GABA-analogues had the largest effect on pruritus. Rifampin, naltrexone and flumecinol tended to be effective for cholestatic pruritus. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES: To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS: This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS: In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

Preoperative combined mechanical and oral antibiotic bowel preparation for preventing complications in elective colorectal surgery.

BACKGROUND: The success of elective colorectal surgery is mainly influenced by the surgical procedure and postoperative complications. The most serious complications include anastomotic leakages and surgical site infections (SSI)s, which can lead to prolonged recovery with impaired long-term health.  Compared with other abdominal procedures, colorectal resections have an increased risk of adverse events due to the physiological bacterial colonisation of the large bowel. Preoperative bowel preparation is used to remove faeces from the bowel lumen and reduce bacterial colonisation. This bowel preparation can be performed mechanically and/or with oral antibiotics. While mechanical bowel preparation alone is not beneficial, the benefits and harms of combined mechanical and oral antibiotic bowel preparation is still unclear. OBJECTIVES: To assess the evidence for the use of combined mechanical and oral antibiotic bowel preparation for preventing complications in elective colorectal surgery. SEARCH METHODS: We searched MEDLINE, Embase, CENTRAL and trial registries on 15 December 2021. In addition, we searched reference lists and contacted colorectal surgery organisations. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of adult participants undergoing elective colorectal surgery comparing combined mechanical and oral antibiotic bowel preparation (MBP+oAB) with either MBP alone, oAB alone, or no bowel preparation (nBP). We excluded studies in which no perioperative intravenous antibiotic prophylaxis was given. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. Pooled results were reported as mean difference (MD) or risk ratio (RR) and 95 % confidence intervals (CIs) using the Mantel-Haenszel method. The certainty of the evidence was assessed with GRADE. MAIN RESULTS: We included 21 RCTs analysing 5264 participants who underwent elective colorectal surgery. None of the included studies had a high risk of bias, but two-thirds of the included studies raised some concerns. This was mainly due to the lack of a predefined analysis plan or missing information about the randomisation process. Most included studies investigated both colon and rectal resections due to malignant and benign surgical indications. For MBP as well as oAB, the included studies used different regimens in terms of agent(s), dosage and timing.  Data for all predefined outcomes could be extracted from the included studies. However, only four studies reported on side effects of bowel preparation, and none recorded the occurrence of adverse effects such as dehydration, electrolyte imbalances or the need to discontinue the intervention due to side effects. Seventeen trials compared MBP+oAB with sole MBP. The incidence of SSI could be reduced through MBP+oAB by 44% (RR 0.56, 95% CI 0.42 to 0.74; 3917 participants from 16 studies; moderate-certainty evidence) and the risk of anastomotic leakage could be reduced by 40% (RR 0.60, 95% CI 0.36 to 0.99; 2356 participants from 10 studies; moderate-certainty evidence). No difference between the two comparison groups was found with regard to mortality (RR 0.87, 95% CI 0.27 to 2.82; 639 participants from 3 studies; moderate-certainty evidence), the incidence of postoperative ileus (RR 0.89, 95% CI 0.59 to 1.32; 2013 participants from 6 studies, low-certainty of evidence) and length of hospital stay (MD -0.19, 95% CI -1.81 to 1.44; 621 participants from 3 studies; moderate-certainty evidence). Three trials compared MBP+oAB with sole oAB. No difference was demonstrated between the two treatment alternatives in terms of SSI (RR 0.87, 95% CI 0.34 to 2.21; 960 participants from 3 studies; very low-certainty evidence), anastomotic leakage (RR 0.84, 95% CI 0.21 to 3.45; 960 participants from 3 studies; low-certainty evidence), mortality (RR 1.02, 95% CI 0.30 to 3.50; 709 participants from 2 studies; low-certainty evidence), incidence of postoperative ileus (RR 1.25, 95% CI 0.68 to 2.33; 709 participants from 2 studies; low-certainty evidence) or length of hospital stay (MD 0.1 respectively 0.2, 95% CI -0.68 to 1.08; data from 2 studies; moderate-certainty evidence). One trial (396 participants) compared MBP+oAB versus nBP. The evidence is uncertain about the effect of MBP+oAB on the incidence of SSI as well as mortality (RR 0.63, 95% CI 0.33 to 1.23 respectively RR 0.20, 95% CI 0.01 to 4.22; low-certainty evidence), while no effect on the risk of anastomotic leakages (RR 0.89, 95% CI 0.33 to 2.42; low-certainty evidence), the incidence of postoperative ileus (RR 1.18, 95% CI 0.77 to 1.81; low-certainty evidence) or the length of hospital stay (MD 0.1, 95% CI -0.8 to 1; low-certainty evidence) could be demonstrated. AUTHORS' CONCLUSIONS: Based on moderate-certainty evidence, our results suggest that MBP+oAB is probably more effective than MBP alone in preventing postoperative complications. In particular, with respect to our primary outcomes, SSI and anastomotic leakage, a lower incidence was demonstrated using MBP+oAB. Whether oAB alone is actually equivalent to MBP+oAB, or leads to a reduction or increase in the risk of postoperative complications, cannot be clarified in light of the low- to very low-certainty evidence. Similarly, it remains unclear whether omitting preoperative bowel preparation leads to an increase in the risk of postoperative complications due to limited evidence. Additional RCTs, particularly on the comparisons of MBP+oAB versus oAB alone or nBP, are needed to assess the impact of oAB alone or nBP compared with MBP+oAB on postoperative complications and to improve confidence in the estimated effect. In addition, RCTs focusing on subgroups (e.g. in relation to type and location of colon resections) or reporting side effects of the intervention are needed to determine the most effective approach of preoperative bowel preparation.

The GIN-McMaster guideline tool extension for the integration of quality improvement and quality assurance in guidelines: a description of the methods for its development.

BACKGROUND AND OBJECTIVES: Our objective was to develop an extension of the widely used GIN-McMaster Guideline Development Checklist and Tool for the integration of quality assurance and improvement (QAI) schemes with guideline development. METHODS: We used a mixed-methods approach incorporating evidence from a systematic review, an expert workshop and a survey of experts to iteratively create an extension of the checklist for QAI through three rounds of feedback. As a part of this process, we also refined criteria of a good guideline-based quality indicator. RESULTS: We developed a 40-item checklist extension addressing steps for the integration of QAI into guideline development across the existing 18 topics and created one new topic specific to QAI. The steps span from 'organization, budget, planning and training', to updating of QAI and guideline implementation. CONCLUSION: The tool supports integration of QAI schemes with guideline development initiatives and it will be used in the forthcoming integrated European Commission Initiative on Colorectal Cancer. Future work should evaluate this extension and QAI items requiring additional support for guideline developers and links to QAI schemes.

Women's attitudes towards a human papillomavirus-based cervical cancer screening strategy: a systematic review.

OBJECTIVE: To provide insights into women's attitudes towards a human papillomavirus (HPV)-based cervical cancer screening strategy. DATA SOURCES: Medline, Web of Science Core Collection, Cochrane Library, PsycINFO, CINAHL and ClinicalTrials.gov were systematically searched for published and ongoing studies (last search conducted in August 2021). METHODS OF STUDY SELECTION: The search identified 3162 references. Qualitative and quantitative studies dealing with women's attitudes towards, and acceptance of, an HPV-based cervical cancer screening strategy in Western healthcare systems were included. For data analysis, thematic analysis was used and synthesised findings were presented descriptively. TABULATION, INTEGRATION, AND RESULTS: Twelve studies (including 9928 women) from USA, Canada, UK and Australia met the inclusion criteria. Women's attitudes towards HPV-based screening strategies were mainly affected by the understanding of (i) the personal risk of an HPV infection, (ii) the implication of a positive finding and (iii) the overall screening purpose. Women who considered their personal risk of HPV to be low and women who feared negative implications of a positive finding were more likely to express negative attitudes, whereas positive attitudes were particularly expressed by women understanding the screening purpose. Overall acceptance of an HPV-based screening strategy ranged between 13% and 84%. CONCLUSION: This systematic review provides insights into the attitudes towards HPV-based cervical cancer screening and its acceptability based on studies conducted with women from USA, Canada, UK and Australia. This knowledge is essential for the development of education and information strategies to support the implementation of HPV-based cervical cancer screening. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42020178957).

Extracorporeal photopheresis versus standard treatment for acute graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents.

BACKGROUND: Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT), occurring in 8% to 85% of paediatric recipients. Currently, the therapeutic mainstay for aGvHD is treatment with corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and reinfusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and updated in 2015. OBJECTIVES: To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (PubMed) and Embase (Ovid) databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA: We sought to include randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in children and adolescents with aGvHD after HSCT. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author. MAIN RESULTS: We identified no additional studies in the 2021 review update, so there are still no studies that meet the criteria for inclusion in this review. AUTHORS' CONCLUSIONS: The efficacy of ECP in the treatment of aGvHD in children and adolescents after HSCT is unknown, and its use should be restricted to within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. The 2021 review update brought about no additions to these conclusions.

Extracorporeal photopheresis versus alternative treatment for chronic graft-versus-host disease after haematopoietic stem cell transplantation in children and adolescents.

BACKGROUND: Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015. OBJECTIVES: To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation. SEARCH METHODS: We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively. SELECTION CRITERIA: We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author. MAIN RESULTS: We found no studies meeting the criteria for inclusion in this 2021 review update. AUTHORS' CONCLUSIONS: We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.

A1- and A2 beta-casein on health-related outcomes: a scoping review of animal studies.

PURPOSE: Food-derived bioactive peptides may influence important physiological functions. An important example is beta-casomorphins, which are opioid peptides derived from A1 beta-casein in bovine milk and have been associated to be risk factors for non-communicable diseases in humans. A1 and A2 beta-casein are different with respect to the release of bioactive peptides, in particular BCM-7. However, evidence from human studies is limited and could be complemented with evidence derived from animal studies. We conducted a scoping review to identify animal studies investigating the effects of A1 beta-casein or BCM-7 compared to A2 beta-casein or any other intervention on health-related outcomes. METHODS: We systematically searched for relevant studies in two electronic databases (Medline, Embase; last search performed March 2020). Two reviewers independently undertook study selection and data extraction of included references. Results were summarized tabularly and narratively. RESULTS: We included 42 studies investigating various animal models, including rats, mice, rabbits, and dogs. Six studies investigated health-related outcomes of A1- vs. A2 milk, while most studies (n = 36) reported on physiological properties (e.g., analgesic effect) of BCM-7 as an opioid peptide. Included studies were extremely heterogeneous in terms of the study population, type of intervention and dose, and type of outcome measures. CONCLUSIONS: Only a few studies comparing the effects of A1- and A2 milk were identified. More studies addressing this research question in animal models are needed to provide essential information to inform research gaps. Results from future studies could eventually complement research for humans, particularly when the body of evidence remains uncertain as is the case in the A1- and A2 milk debate.

Reevaluation of statistically significant meta-analyses in advanced cancer patients using the Hartung-Knapp method and prediction intervals-A methodological study.

Using the Hartung-Knapp method and 95% prediction intervals (PIs) in random-effects meta-analyses is recommended by experts but rarely applied. Therefore, we aimed to reevaluate statistically significant meta-analyses using the Hartung-Knapp method and 95% PIs. In this methodological study, three databases were searched from January 2010 to July 2019. We included systematic reviews reporting a statistically significant meta-analysis of at least four randomized controlled trials in advanced cancer patients using either a fixed-effect or random-effects model. We investigated the impact of switching from fixed-effect to random-effects meta-analysis and of using the recommended Hartung-Knapp method in random-effects meta-analyses. Furthermore, we calculated 95% PIs for all included meta-analyses. We identified 6234 hits, of which 261 statistically significant meta-analyses were included. Our recalculations of these 261 meta-analyses produced statistically significant results in 132 of 138 fixed-effect and 114 of 123 random-effects meta-analyses. When switching to a random-effects model, 19 of 132 fixed-effect meta-analyses (14.4%) were no longer statistically significant. Using the Hartung-Knapp method in random-effects meta-analyses resulted in 34 of 114 nonsignificant meta-analyses (29.8%). In the full sample (N = 261), the null effect was included by the 95% PI in 195 (74.7%) and the opposite effect (e.g., hazard ratio 0.5, opposite effect 2) in 98 meta-analyses (37.5%). Using the Hartung-Knapp method and PIs substantially influenced the interpretation of many published, statistically significant meta-analyses. We strongly encourage researchers to check if using the Hartung-Knapp method and reporting 95% PIs is appropriate in random-effects meta-analyses.

Patients' self-reported physical and psychological effects of opioid use in chronic noncancer pain-A retrospective cross-sectional analysis.

BACKGROUND: Strong opioids can have unintended effects. Clinical studies of strong opioids mainly report physical side effects, psychiatric or opioid use disorders. To date, too little attention has been paid to the psychological effects of opioids to treat patients with chronic noncancer pain (CNCP). This study aims to identify and measure (i) the nature and frequency of physical and psychological effects and (ii) the degree of physician counseling of patients with CNCP taking strong opioids. METHODS: Within a cross-sectional survey-conducted as part of a randomised controlled online intervention trial (ERONA [Experiencing the risk of overusing opioids among patients with chronic non-cancer pain in ambulatory care])-300 German CNCP patients were surveyed via patient-reported outcome measures regarding on both the side effects from their use of strong opioids as well as their counselling experience. RESULTS: Among the patients' reported effects, the psychological outcomes of the opioids in CNCP were: feeling relaxed (84%), fatigue (76%), dizziness (57%), listlessness (37%), difficulty with mental activities (23%), dulled emotions (17%) and poor memory (17%). Ninety-two per cent of the patients reported having received information about opioid effects, and 46% had discussed cessation of the opioid medication with their physicians before commencing the prescription. CONCLUSIONS: In addition to the well-known physical side effects, patients with CNCP taking strong opioids experience significant psychological effects. In view of these effects, discontinuation of opioid therapy should be discussed early to ensure their benefits do not outweigh their harm. SIGNIFICANCE: In this study, patients with non-cancer pain notice that opioids they have taken do not only cause physical side effects but also may have an impact on their psyche and their emotions and, thus, may also affect quality of life substantially. Clinical trial number: DRKS00020358.

American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation.

BACKGROUND: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. OBJECTIVE: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. METHODS: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. CONCLUSIONS: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

Treatment Regimens for Immunocompetent Elderly Patients with Primary Central Nervous System Lymphoma: A Scoping Review.

BACKGROUND: Most patients diagnosed with primary central nervous system lymphoma (PCNSL) are older than 60 years. Despite promising treatment options for younger patients, prognosis for the elderly remains poor and efficacy of available treatment options is limited. MATERIALS AND METHODS: We conducted a scoping review to identify and summarize the current study pool available evaluating different types and combinations of (immuno) chemotherapy with a special focus on HCT-ASCT in elderly PCNSL. Relevant studies were identified through systematic searches in the bibliographic databases Medline, Web of Science, Cochrane Library and ScienceDirect (last search conducted in September 2020). For ongoing studies, we searched ClinicalTrials.gov, the German study register and the WHO registry. RESULTS: In total, we identified six randomized controlled trials (RCT) with 1.346 patients, 26 prospective (with 1.366 patients) and 24 retrospective studies (with 2.629 patients). Of these, only six studies (one completed and one ongoing RCT (with 447 patients), one completed and one ongoing prospective single arm study (with 65 patients), and two retrospective single arm studies (with 122 patients)) evaluated HCT-ASCT. Patient relevant outcomes such as progression-free and overall survival and (neuro-)toxicity were adequately considered across almost all studies. The current study pool is, however, not conclusive in terms of the most effective treatment options for elderly. Main limitations were (very) small sample sizes and heterogeneous patient populations in terms of age ranges (particularly in RCTs) limiting the applicability of the results to the target population (elderly). CONCLUSIONS: Although it has been shown that HCT-ASCT is probably a feasible and effective treatment option, this approach has never been investigated within a RCT including a wide range of elderly patients. A RCT comparing conventional (immuno) chemotherapy with HCT-ASCT is crucial to evaluate benefit and harms in an un-biased manner to eventually provide older PCNSL patients with the most effective treatment.

Degarelix for treating advanced hormone-sensitive prostate cancer.

BACKGROUND: Degarelix is a gonadotropin-releasing hormone antagonist that leads to medical castration used to treat men with advanced or metastatic prostate cancer, or both. It is unclear how its effects compare to standard androgen suppression therapy. OBJECTIVES: To assess the effects of degree compared with standard androgen suppression therapy for men with advanced hormone-sensitive prostate cancer. SEARCH METHODS: We searched multiple databases (CENTRAL, MEDLINE, Embase, Scopus, Web of Science, LILACS until September 2020), trial registries (until October 2020), and conference proceedings (until December 2020). We identified other potentially eligible trials by reference checking, citation searching, and contacting study authors. SELECTION CRITERIA: We included randomized controlled trials comparing degarelix with standard androgen suppression therapy for men with advanced prostate cancer. DATA COLLECTION AND ANALYSIS: Three review authors independently classified studies and abstracted data from the included studies. The primary outcomes were overall survival and serious adverse events. Secondary outcomes were quality of life, cancer-specific survival, clinical progression, other adverse events, and biochemical progression. We used a random-effects model for meta-analyses and assessed the certainty of evidence for the main outcomes according to GRADE. MAIN RESULTS: We included 11 studies with a follow-up of between three and 14 months. We also identified five ongoing trials. Primary outcomes Data to evaluate overall survival were not available.  Degarelix may result in little to no difference in serious adverse events compared to standard androgen suppression therapy (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.62 to 1.05; low-certainty evidence; 2750 participants). Based on 114 serious adverse events in the standard androgen suppression group, this corresponds to 23 fewer serious adverse events per 1000 participants (43 fewer to 6 more). We downgraded the certainty of evidence for study limitations and imprecision. Secondary outcomes Degarelix likely results in little to no difference in quality of life assessed with a variety of validated questionnaires (standardized mean difference 0.06 higher, 95% CI 0.05 lower to 0.18 higher; moderate-certainty evidence; 2887 participants), with higher scores reflecting better quality of life. We downgraded the certainty of evidence for study limitations. Data to evaluate cancer-specific survival were not available. The effects of degarelix on cardiovascular events are very uncertain (RR 0.15, 95% CI 0.04 to 0.61; very low-certainty evidence; 80 participants). We downgraded the certainty of evidence for study limitations, imprecision, and indirectness as this trial was conducted in a unique group of high-risk participants with pre-existing cardiovascular morbidities. Degarelix likely results in an increase in injection site pain (RR 15.68, 95% CI 7.41 to 33.17; moderate-certainty evidence; 2670 participants). Based on 30 participants per 1000 with injection site pain with standard androgen suppression therapy, this corresponds to 440 more injection site pains per 1000 participants (192 more to 965 more). We downgraded the certainty of evidence for study limitations. We did not identify any relevant subgroup differences for different degarelix maintenance doses. AUTHORS' CONCLUSIONS: We did not find trial evidence for overall survival or cancer-specific survival comparing degarelix to standard androgen suppression, but serious adverse events and quality of life may be similar between groups. The effects of degarelix on cardiovascular events are very uncertain as the only eligible study had limitations, was small with few events, and was conducted in a high-risk population. Degarelix likely results in an increase in injection site pain compared to standard androgen suppression therapy. Maximum follow-up of included studies was 14 months, which is short. There is a need for methodologically better designed and executed studies with long-term follow-up evaluating men with metastatic prostate cancer.

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance. OBJECTIVES: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly. SEARCH METHODS: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events. MAIN RESULTS: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes. AUTHORS' CONCLUSIONS: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

Guideline-based quality assurance: a conceptual framework for the definition of key elements.

BACKGROUND: In 2017, the European Commission's Joint Research Centre (JRC) started developing a methodological framework for a guideline-based quality assurance (QA) scheme to improve cancer quality of care. During the first phase of the work, inconsistency emerged about the use of terminology for the definition, the conceptual underpinnings and the way QA relates to health questions that are answered in guidelines. The objective of this final of three articles is to propose a conceptual framework for an integrated approach to guideline and QA development and clarify terms and definitions for key elements. This work will inform the upcoming European Commission Initiative on Colorectal Cancer (ECICC). METHODS: A multidisciplinary group of 23 experts from key organizations in the fields of guideline development, performance measurement and quality assurance participated in a mixed method approach including face-to-face dialogue and several rounds of virtual meetings. Informed by results of a systematic literature review that indicated absence of an existing framework and practical examples, we first identified the relations of key elements in guideline-based QA and then developed appropriate concepts and terminology to provide guidance. RESULTS: Our framework connects the three key concepts of quality indicators, performance measures and performance indicators integrated with guideline development. Quality indicators are constructs used as a guide to monitor, evaluate, and improve the quality of the structure, process and outcomes of healthcare services; performance measures are tools that quantify or describe measurable elements of practice performance; and performance indicators are quantifiable and measurable units or scores of practice, which should be guided by guideline recommendations. CONCLUSIONS: The inconsistency in the way key terms of QA are used and defined has confused the field. Our conceptual framework defines the role, meaning and interactions of the key elements for improving quality in healthcare. It directly builds on the questions asked in guidelines and answered through recommendations. These findings will be applied in the forthcoming ECICC and for the future updates of ECIBC. These are large-scale integrated projects aimed at improving healthcare quality across Europe through the development of guideline-based QA schemes; this will help in implementing and improving our approach.

Bringing two worlds closer together: a critical analysis of an integrated approach to guideline development and quality assurance schemes.

BACKGROUND: Although quality indicators are frequently derived from guidelines, there is a substantial gap in collaboration between the corresponding parties. To optimise workflow, guideline recommendations and quality assurance should be aligned methodologically and practically. Learning from the European Commission Initiative on Breast Cancer (ECIBC), our objective was to bring the key knowledge and most important considerations from both worlds together to inform European Commission future initiatives. METHODS: We undertook several steps to address the problem. First, we conducted a feasibility study that included a survey, interviews and a review of manuals for an integrated guideline and quality assurance (QA) scheme that would support the European Commission. The feasibility study drew from an assessment of the ECIBC experience that followed commonly applied strategies leading to separation of the guideline and QA development processes. Secondly, we used results of a systematic review to inform our understanding of methodologies for integrating guideline and QA development. We then, in a third step, used the findings to prepare an evidence brief and identify key aspects of a methodological framework for integrating guidelines QA through meetings with key informants. RESULTS: Seven key themes emerged to be taken into account for integrating guidelines and QA schemes: (1) evidence-based integrated guideline and QA frameworks are possible, (2) transparency is key in clearly documenting the source and rationale for quality indicators, (3) intellectual and financial interests should be declared and managed appropriately, (4) selection processes and criteria for quality indicators need further refinement, (5) clear guidance on retirement of quality indicators should be included, (6) risks of an integrated guideline and QA Group can be mitigated, and (7) an extension of the GIN-McMaster Guideline Development Checklist should incorporate QA considerations. DISCUSSION: We concluded that the work of guideline and QA developers can be integrated under a common methodological framework and we provided key findings and recommendations. These two worlds, that are fundamental to improving health, can both benefit from integration.

Predicting negative health outcomes in older general practice patients with chronic illness: Rationale and development of the PROPERmed harmonized individual participant data database.

The prevalence of multimorbidity and polypharmacy increases significantly with age and are associated with negative health consequences. However, most current interventions to optimize medication have failed to show significant effects on patient-relevant outcomes. This may be due to ineffectiveness of interventions themselves but may also reflect other factors: insufficient sample sizes, heterogeneity of population. To address this issue, the international PROPERmed collaboration was set up to obtain/synthesize individual participant data (IPD) from five cluster-randomized trials. The trials took place in Germany and The Netherlands and aimed to optimize medication in older general practice patients with chronic illness. PROPERmed is the first database of IPD to be drawn from multiple trials in this patient population and setting. It offers the opportunity to derive prognostic models with increased statistical power for prediction of patient-relevant outcomes resulting from the interplay of multimorbidity and polypharmacy. This may help patients from this heterogeneous group to be stratified according to risk and enable clinicians to identify patients that are likely to benefit most from resource/time-intensive interventions. The aim of this manuscript is to describe the rationale behind PROPERmed collaboration, characteristics of the included studies/participants, development of the harmonized IPD database and challenges faced during this process.

Improving the trustworthiness of findings from nutrition evidence syntheses: assessing risk of bias and rating the certainty of evidence.

Suboptimal diet is recognized as a leading modifiable risk factor for non-communicable diseases. Non-randomized studies (NRSs) with patient relevant outcomes provide many insights into diet-disease relationships. Dietary guidelines are based predominantly on findings from systematic reviews of NRSs-mostly prospective observational studies, despite that these have been repeatedly criticized for yielding potentially less trustworthy results than randomized controlled trials (RCTs). It is assumed that these are a result of bias due to prevalent-user designs, inappropriate comparators, residual confounding, and measurement error. In this article, we aim to highlight the importance of applying risk of bias (RoB) assessments in nutritional studies to improve the credibility of evidence of systematic reviews. First, we discuss the importance and challenges of dietary RCTs and NRSs, and provide reasons for potentially less trustworthy results of dietary studies. We describe currently used tools for RoB assessment (Cochrane RoB, and ROBINS-I), describe the importance of rigorous RoB assessment in dietary studies and provide examples that further the understanding of the key issues to overcome in nutrition research. We then illustrate, by comparing the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach with current approaches used by United States Department of Agriculture Dietary Guidelines for Americans, and the World Cancer Research Fund, how to establish trust in dietary recommendations. Our overview shows that the GRADE approach provides more transparency about the single domains for grading the certainty of the evidence and the strength of recommendations. Despite not increasing the certainty of evidence itself, we expect that the rigorous application of the Cochrane RoB and the ROBINS-I tools within systematic reviews of both RCTs and NRSs and their integration within the GRADE approach will strengthen the credibility of dietary recommendations.

A prognostic model predicted deterioration in health-related quality of life in older patients with multimorbidity and polypharmacy.

OBJECTIVES: To develop and validate a prognostic model to predict deterioration in health-related quality of life (dHRQoL) in older general practice patients with at least one chronic condition and one chronic prescription. STUDY DESIGN AND SETTING: We used individual participant data from five cluster-randomized trials conducted in the Netherlands and Germany to predict dHRQoL, defined as a decrease in EQ-5D-3 L index score of ≥5% after 6-month follow-up in logistic regression models with stratified intercepts to account for between-study heterogeneity. The model was validated internally and by using internal-external cross-validation (IECV). RESULTS: In 3,582 patients with complete data, of whom 1,046 (29.2%) showed deterioration in HRQoL, and 12/87 variables were selected that were related to single (chronic) conditions, inappropriate medication, medication underuse, functional status, well-being, and HRQoL. Bootstrap internal validation showed a C-statistic of 0.71 (0.69 to 0.72) and a calibration slope of 0.88 (0.78 to 0.98). In the IECV loop, the model provided a pooled C-statistic of 0.68 (0.65 to 0.70) and calibration-in-the-large of 0 (-0.13 to 0.13). HRQoL/functionality had the strongest prognostic value. CONCLUSION: The model performed well in terms of discrimination, calibration, and generalizability and might help clinicians identify older patients at high risk of dHRQoL. REGISTRATION: PROSPERO ID: CRD42018088129.

Experiencing the risk of overutilising opioids among patients with chronic non-cancer pain in ambulatory care (ERONA): the protocol of an exploratory, randomised controlled trial.

INTRODUCTION: The US opioid crisis and increasing prescription rates in Europe suggest inappropriate risk perceptions and behaviours of people who prescribe, take or advise on opioids: physicians, patients and pharmacists. Findings from cognitive and decision science in areas other than drug safety suggest that people's risk perception and behaviour can differ depending on whether they learnt about a risk through personal experience or description. Experiencing the risk of overutilising opioids among patients with chronic non-cancer pain in ambulatory care (ERONA) is the first-ever conducted trial that aims at investigating the effects of these two modes of learning on individuals' risk perception and behaviour in the long-term administration of WHO-III opioids in chronic non-cancer pain. METHODS AND ANALYSIS: ERONA-an exploratory, randomised controlled online survey intervention trial with two parallel arms-will examine the opioid-associated risk perception and behaviour of four groups involved in the long-term administration of WHO-III opioids: (1) family physicians, (2) physicians specialised in pain therapy, (3) patients with chronic (≥3 months) non-cancer pain and (4) pharmacists who regularly dispense narcotic substances. Participants will be randomly assigned to one of two online risk education interventions, description based or experiencebased. Both interventions will present the best medical evidence available. Participants will be queried at baseline and after intervention on their risk perception of opioids' benefit-harm ratio, their medical risk literacy and their current/intended risk behaviour (in terms of prescribing, taking or counselling, depending on study group). A follow-up will occur after 9 months, when participants will be queried on their actual risk behaviour. The study was developed by the authors and will be conducted by the market research institution IPSOS Health. ETHICS AND DISSEMINATION: The study was approved by the Institutional Review Board of the Max Planck Institute for Human Development. Results will be disseminated through peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER: DRKS00020358.