Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

BACKGROUND: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example. STUDY DESIGN AND SETTING: A systematic review of randomized controlled trials and observational studies was conducted. The primary outcome was the annualized relapse rate. Using (network) meta-analysis together with posterior predictive distributions, the drug-specific rate ratios from the network of randomized controlled trials were compared with those from the network of observational studies. RESULTS: Effect estimates from 26 observational studies showed greater magnitudes and were less precise compared to estimates obtained from 21 randomized controlled trials. Twenty of the 28 treatment comparisons between designs had similar rate ratios. Seven inconsistencies in observed rate ratios could be attributed to two specific disease-modifying therapies. CONCLUSION: In this case study, estimates from observational studies predominantly agreed with estimates from randomized controlled trials given their posterior predictive distributions. Multiple observational studies together may therefore supplement additional pivotal randomized controlled trials in relapsing-remitting multiple sclerosis, for instance facilitating the extrapolation of trial results to the broader patient population.

Recommendations on self-management interventions for adults living with obesity: COMPAR-EU project.

Self-management interventions (SMIs) may improve disease management in adults living with obesity. We formulated evidence-based recommendations for SMIs within the context of the COMPAR-EU project. The multidisciplinary panel selected critical outcomes based on the COMPAR-EU core outcome set and established decision thresholds for each outcome. Recommendations were informed by systematic reviews of effects, cost-effectiveness, and a contextual assessment. To assess the certainty of the evidence and formulate the recommendations, we used the GRADE approach guidance. Overall, SMIs were deemed to have a small impact, but the absence of harmful effects and potential cumulative benefits indicated a favourable balance of effects, despite low certainty. SMIs showed variations in structure, intensity, and resource utilisation, but overall are likely to be cost-effective. Adapting SMIs to local contexts would enhance equity, acceptability, and feasibility, considering patients' values, and availability of resources and teamwork. Consequently, the panel made conditional recommendations favouring SMIs over usual care. The rigorous and explicit recommendations demonstrated the effectiveness of SMIs for adults living with obesity. However, the gaps in the literature influenced the panel to make only conditional recommendations in favour of SMIs. Further research is needed to strengthen the evidence base and improve recommendations' certainty and applicability.

Deap-seated infection and nonunion following internal fixation for Charcot foot deformity correction. A proportional meta-analysis of level 4 evidence.

BACKGROUND: Given the paucity of literature on the management of infected metalwork and nonunion in neuropathic diabetic patients, a meta-analysis was designed to investigate the two major complications following Charcot reconstruction performed by means of internal fixation methods. METHODS: We searched PubMed, Scopus and CENTRAL until the 17th of May 2022 for completed studies investigating outcomes following midfoot and/or hindfoot and/or ankle diabetic Charcot reconstruction. For a paper to qualify for inclusion, an internal fixation element should have been considered. Random effects meta-analysis of proportion was performed to calculate the rate of post-operative deep-seated infections with the associated amputation rate and nonunions by using Open Meta-analyst software. Sub-analysis linked to anatomical location of reconstruction was performed and the quality of the included studies was appraised using the Moga tool. RESULTS: Thirty studies with 492 eligible reconstructions were considered. Of those, deep-seated infections were diagnosed in 46 cases (Estimated proportion was 6.7%, 95% CI [4.2%-9.2%]). Debridement and antibiotic administration with or without metalwork removal were considered in the majority of the participants with successful clinical outcomes. Amputation was performed in 15 patients due to unmanageable post-operative infection and nonunion was reported in 17 studies (Estimated rates were 36.6%, 95% CI [18.4%-56.3%]; and 11.9%, 95%CI [6.6%-18.1%]; respectively). CONCLUSIONS: Meta-analysis showed that although the overall risk of infection development is less than 10%, just below one third of the infected cases undergo late amputation. Moreover, internal fixation reconstructions carry a nonunion risk of just above 10%.

COMPAR-EU Recommendations on Self-Management Interventions in Type 2 Diabetes Mellitus.

Self-management interventions (SMIs) offer a promising approach to actively engage patients in the management of their chronic diseases. Within the scope of the COMPAR-EU project, our goal is to provide evidence-based recommendations for the utilisation and implementation of SMIs in the care of adult individuals with type 2 diabetes mellitus (T2DM). A multidisciplinary panel of experts, utilising a core outcome set (COS), identified critical outcomes and established effect thresholds for each outcome. The panel formulated recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach, a transparent and rigorous framework for developing and presenting the best available evidence for the formulation of recommendations. All recommendations are based on systematic reviews (SR) of the effects and of values and preferences, a contextual analysis, and a cost-effectiveness analysis. The COMPAR-EU panel is in favour of using SMIs rather than usual care (UC) alone (conditional, very low certainty of the evidence). Furthermore, the panel specifically is in favour of using ten selected SMIs, rather than UC alone (conditional, low certainty of the evidence), mostly encompassing education, self-monitoring, and behavioural techniques. The panel acknowledges that, for most SMIs, moderate resource requirements exist, and cost-effectiveness analyses do not distinctly favour either the SMI or UC. Additionally, it recognises that SMIs are likely to enhance equity, deeming them acceptable and feasible for implementation.

Building capacity for network meta-analysis in Sub-Saharan Africa: reflections and future direction.

Robust, relevant, comprehensive, and up-to-date evidence syntheses are the cornerstone for evidence-informed healthcare decisions. When considering multiple treatment options, network meta-analysis (NMA) systematic reviews play a key role in informing impactful decisions and clinical practice guidelines. However, the capacity and literacy to conduct NMA systematic reviews and interpret its results remains out of reach for many clinicians and review authors, especially in low-to-middle-income countries. Despite ample resources and guides, NMA capacity and training opportunities remain limited to non-existent in Sub-Saharan Africa. Towards solutions and strengthening evidence synthesis and NMA capacity in the Sub-Saharan African region, we describe and reflect on two courses that build NMA capacity and aim to address NMA literacy in Sub-Saharan Africa.The Primer in NMA systematic reviews aimed for participants to be able to find, appraise, interpret, and consider the use of NMA SRs of intervention effects. It is a 6-week online course for clinicians, policy-makers, and researchers wanting to learn more about using NMA systematic reviews. The Global NMA Masterclass workshop aimed for participants to be able to understand and apply pairwise and NMA in STATA and R, evaluate NMA assumptions and confidence in NMA results, and appropriately report NMA results. This course was offered over 5 weeks to clinicians, biostatisticians, and researchers with basic knowledge of epidemiology and biostatics. Although the bulk of learning occurred through self-study, we had weekly, synchronous question-and-answer sessions for both courses. Using relevant examples throughout the courses helped to enable an authentic learning environment.This was the first NMA training developed in Africa for Africa. Development of the courses was a collaborative effort from a multi-disciplinary team. Both NMA courses were well received and attended by a diverse group of participants spread across Sub-Saharan African countries. Participants felt the courses were applicable to their setting. Although most participants appreciated the benefits of online learning, we also experienced some challenges. There is great potential to conduct NMA systematic reviews in Sub-Saharan Africa. The NMA Primer and NMA workshop can play an essential role in expanding and developing NMA SR capacity and literacy in SSA.

Self-Management Interventions for Adults Living with Type II Diabetes to Improve Patient-Important Outcomes: An Evidence Map.

Self-management interventions (SMIs) may be promising in the treatment of Diabetes Mellitus Type 2 (T2DM). However, accurate comparisons of their relative effectiveness are challenging, partly due to a lack of clarity and detail regarding the intervention content being evaluated. This study summarizes intervention components and characteristics in randomized controlled trials (RCTs) related to T2DM using a taxonomy for SMIs as a framework and identifies components that are insufficiently incorporated into the design of the intervention or insufficiently reported. Following evidence mapping methodology, we searched MEDLINE, CINAHL, Embase, Cochrane, and PsycINFO from 2010 to 2018 for randomized controlled trials (RCTs) on SMIs for T2DM. We used the terms 'self-management', 'adult' and 'T2DM' for content. For data extraction, we used an online platform based on the taxonomy for SMIs. Two independent reviewers assessed eligible references; one reviewer extracted data, and a second checked accuracy. We identified 665 RCTs for SMIs (34% US, 21% Europe) including 164,437 (median 123, range 10-14,559) adults with T2DM. SMIs highly differed in design and content, and characteristics such as mode of delivery, intensity, location and providers involved were poorly described. The majority of interventions aimed to improve clinical outcomes like HbA1c (83%), weight (53%), lipid profile (45%) or blood pressure (42%); 27% (also) targeted quality of life. Improved knowledge, health literacy, patient activation or satisfaction with care were hardly used as outcomes (<16%). SMIs most often used education (98%), self-monitoring (56%), goal-setting (48%) and skills training (42%) to improve outcomes. Management of emotions (17%) and shared decision-making (5%) were almost never mentioned. Although diabetes is highly prevalent in some minority groups, in only 13% of the SMIs, these groups were included. Our findings highlight the large heterogeneity that exists in the design of SMIs for T2DM and the way studies are reported, making accurate comparisons of their relative effectiveness challenging. In addition, SMIs pay limited attention to outcomes other than clinical, despite the importance attached to these outcomes by patients. More standardized and streamlined research is needed to better understand the effectiveness and cost-effectiveness of SMIs of T2DM and benefit patient care.

Comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression in adults: a systematic review and network meta-analysis.

BACKGROUND: Bipolar depression constitutes a major public health problem due to its substantial burden of disease. Although pharmacological interventions are available, guidelines required updated evidence synthesis to improve their current recommendations. In order to inform evidence-based prescribing, we investigated the comparative efficacy and tolerability of pharmacological interventions for acute bipolar depression. METHODS: We conducted a systematic review and network meta-analysis. We searched for randomised controlled trials comparing pharmacological interventions with each other or placebo in adults with acute bipolar depression (type I, type II, or not otherwise specified), excluding those with substance misuse, unipolar depression, or schizophrenia, in MEDLINE, Embase, PsycINFO, Google Scholar, Cochrane Library, Web of Knowledge, CINAHL, and LILACS from database inception up to April 13, 2023. Criteria for eligibility were a duration of 2-16 weeks with masked outcome assessments, and we included combination, add-on design, and monotherapy studies. The co-primary outcomes were depressive symptoms, examined with standardised mean differences (SMDs), and manic switch, examined with odds ratios (ORs). We also investigated dropouts due to any reason, inefficacy, adverse events, and important side-effects as secondary outcomes. The confidence in the evidence was evaluated using Confidence-In-Network-Meta-Analysis (CINeMA). The study was registered with PROSPERO, CRD42020171726. RESULTS: We analysed data from 101 randomised controlled trials covering 20 081 participants, 8063 men (41·7%) and 11 263 women (58·3%; sex not available in four studies), mean age 41·0 years (range of means 28·7-53·6 years), and 68 medications and placebo. Ethnicity data were not available. With moderate confidence in the evidence, olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were more efficacious than placebo in reducing depressive symptoms, with SMDs ranging from 0·41 (95% CI 0·19-0·64) for olanzapine plus fluoxetine to 0·16 (0·03-0·29) for lamotrigine. Several other drugs might also be efficacious, but the confidence in the evidence was very low to low. Antidepressants as a class seem to be efficacious, but had a higher risk for manic switch compared to antipsychotics. Medications differed in their side-effect profiles. INTERPRETATION: This is, to our knowledge, the largest network meta-analysis of pharmacotherapy for bipolar depression to date. Olanzapine plus fluoxetine, quetiapine, olanzapine, lurasidone, lumateperone, cariprazine, and lamotrigine were found to be more efficacious than placebo in adults with acute bipolar depression, with good confidence in the evidence, and to differ in their side-effect profiles. These findings can inform evidence-based care and the development of treatment guidelines internationally. FUNDING: None.

Inconsistency identification in network meta-analysis via stochastic search variable selection.

The reliability of the results of network meta-analysis (NMA) lies in the plausibility of the key assumption of transitivity. This assumption implies that the effect modifiers' distribution is similar across treatment comparisons. Transitivity is statistically manifested through the consistency assumption which suggests that direct and indirect evidence are in agreement. Several methods have been suggested to evaluate consistency. A popular approach suggests adding inconsistency factors to the NMA model. We follow a different direction by describing each inconsistency factor with a candidate covariate whose choice relies on variable selection techniques. Our proposed method, stochastic search inconsistency factor selection (SSIFS), evaluates the consistency assumption both locally and globally, by applying the stochastic search variable selection method to determine whether the inconsistency factors should be included in the model. The posterior inclusion probability of each inconsistency factor quantifies how likely is a specific comparison to be inconsistent. We use posterior model odds or the median probability model to decide on the importance of inconsistency factors. Differences between direct and indirect evidence can be incorporated into the inconsistency detection process. A key point of our proposed approach is the construction of a reasonable "informative" prior concerning network consistency. The prior is based on the elicitation of information derived historical data from 201 published network meta-analyses. The performance of our proposed method is evaluated in two published network meta-analyses. The proposed methodology is publicly available in an R package called ssifs, published on CRAN and developed and maintained by the authors of this work.

Incidence, prevalence, and global burden of schizophrenia - data, with critical appraisal, from the Global Burden of Disease (GBD) 2019.

Schizophrenia substantially contributes to the burden of mental disorders. Schizophrenia's burden and epidemiological estimates in some countries have been published, but updated estimates of prevalence, incidence, and schizophrenia-related disability at the global level are lacking. Here, we present the data from and critically discuss the Global Burden of Diseases, Injuries, and Risk Factors Study data, focusing on temporal changes in schizophrenia's prevalence, incidence, and disability-adjusted life years (DALYs) globally. From 1990 to 2019, schizophrenia raw prevalence (14.2 to 23.6 million), incidence (941,000 to 1.3 million), and DALYs (9.1 to 15.1 million) increased by over 65%, 37%, and 65% respectively, while age-standardized estimates remained stable globally. In countries with high socio-demographic index (SDI), both prevalence and DALYs increased, while in those with low SDI, the age-standardized incidence decreased and DALYs remained stable. The male/female ratio of burden of schizophrenia has remained stable in the overall population over the past 30 years (i.e., M/F = 1.1), yet decreasing from younger to older age groups (raw prevalence in females higher than males after age 65, with males having earlier age of onset, and females longer life expectancy). Results of this work suggest that schizophrenia's raw prevalence, incidence, and burden have been increasing since 1990. Age-adjusted estimates did not reduce. Schizophrenia detection in low SDI countries is suboptimal, and its prevention/treatment in high SDI countries should be improved, considering its increasing prevalence. Schizophrenia sex ratio inverts throughout the lifespan, suggesting different age of onset and survival by sex. However, prevalence and burden estimates for schizophrenia are probably underestimated. GBD does not account for mortality from schizophrenia (and other mental disorders, apart from anorexia nervosa).

Comparative effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents: a systematic review and network meta-analysis.

OBJECTIVE: Arterial stiffness is an early and detectable marker of vascular changes leading to atherosclerotic cardiovascular disease (ACVD). Our objective was to compare the effectiveness of different types of exercise in reducing arterial stiffness in children and adolescents. DESIGN: A systematic review and network meta-analysis (NMA) was conducted including experimental studies reporting the effects of exercise interventions on pulse wave velocity (PWV) in children and adolescents. DATA SOURCES: Cochrane Central Register of Controlled Trials, EMBASE (via Scopus), PubMed (via Medline) and Web of Science from database inception to 25 March 2022. ELIGIBILITY CRITERIA: Experimental studies reporting the effects of exercise interventions on PWV in children and adolescents. RESULTS: Fourteen studies were included in the NMA, all of them were randomised controlled trials except one quasi-experimental study, with an overall risk of bias of some concern. Regarding PWV reduction, all exercise modalities were more effective than control, with standardised mean difference ranging from -1.93 (95% CI: -2.84 to -1.02) and -1.11 (95% CI: -2.01 to -0.21) for aerobic exercise and high intensity interval training (HIIT), respectively, to -0.59 (95% CI: -1.39 to 0.22) for combined exercise. Only sensorimotor training was not superior to the control group 0.11 (95% CI: -1.10 to 1.32). CONCLUSION: Our results support that exercise interventions, especially aerobic exercise or HIIT, can improve arterial stiffness at early ages. The potential to address ACVD early and mitigate long-term consequences via exercise interventions in children and adolescents with higher arterial stiffness requires further investigation. PROSPERO REGISTRATION NUMBER: CRD42022322536.

An Introduction to Individual Participant Data Meta-analysis.

Meta-analysis using individual participant data (IPD-MA) from randomized controlled trials (RCTs) can strengthen evidence used for decision making and is considered the "gold standard" approach. In this study, we present the importance, properties, and main approaches of conducting an IPD-MA. We exemplify the main approaches of conducting an IPD-MA and how these can be used to obtain subgroup effects through estimation of interaction terms. IPD-MA has several benefits over traditional aggregate data (AD) meta-analysis. These include standardization of definitions of outcomes and/or scales, reanalysis of eligible RCTs using the same analysis model across all studies, accounting for missing outcome data, detecting outliers, using participant-level covariates to explore intervention-by-covariate interactions, and tailoring intervention effects to participant characteristics. IPD-MA can be performed in either a 2-stage or 1-stage approach. We exemplify the presented methods using 2 illustrative examples. The first real-life example includes 6 studies assessing sonothrombolysis with or without addition of microspheres against IV thrombolysis alone (i.e., control) in acute ischemic stroke participants with large vessel occlusions. The second real-life example includes 7 studies evaluating the association between blood pressure levels after endovascular thrombectomy and functional improvement of acute ischemic stroke in patients with large vessel occlusion. IPD reviews can be associated with higher quality statistical analysis and may differ from AD reviews. Unlike individual trials that lack power and AD meta-analysis results, which suffer from confounding and aggregation bias, the use of IPD allows us to explore intervention-by-covariate interactions. However, a key limitation of conducting an IPD-MA is retrieval of IPD from original RCTs. Time and resources should be carefully planned before embarking on retrieving IPD.

Psychometric properties of the Greek versions of the Pandemic-Related Pregnancy Stress Scale and the Pandemic-Related Postpartum Stress Scale and associated risk factors during the second year of the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has affected perinatal mental health. Reliable tools are needed to assess perinatal stress during pandemic situations. AIMS: To assess the psychometric properties of the Greek versions of the Pandemic-Related Pregnancy Stress Scale (PREPS) and the Pandemic-Related Postpartum Stress Scale (PREPS-PP) and to explore the associations between women's characteristics and perinatal stress during the second pandemic wave. METHODS: The PREPS and PREPS-PP were completed by 264 pregnant and 188 postpartum women, respectively, who also completed the State-Trait Anxiety Inventory (STAI) and the Edinburgh Perinatal Depression Scale (EPDS). RESULTS: The internal consistency was similar for PREPS and PREPS-PP. It was good for preparedness stress (a = 0.77 and α = 0.71, respectively) and infection stress (α = 0.83 for both scales) but low for positive appraisal (α = 0.46 and α = 0.41, respectively). Of the pregnant women, 55.33% and 55.27%, respectively, reported scores of ≥40 on STAI-S and STAI-T, and the respective percentages for the postpartum women were 47.34% and 46.80%. In addition, 14.39% of the pregnant women and 20.74% of the postpartum women scored ≥13 on the EPDS. Higher preparedness stress on PREPS and PREPS-PP was associated with primiparity (P = 0.022 and P = 0.021, respectively) and disrupted perinatal care (P = 0.069 and P = 0.007, respectively). In postpartum women, higher infection stress was associated with chronic disease (P = 0.037), primiparity (P = 0.02) and perceived risk of infection (P = 0.065). Higher score on infection stress was associated with disrupted perinatal care in both groups (P = 0.107 and P = 0.010, respectively). CONCLUSIONS: The Greek versions of PREPS and PREPS-PP are valid tools for the assessment of women at risk of perinatal stress during a health crisis.

Self-management interventions for adults living with obesity to improve patient-relevant outcomes: An evidence map.

OBJECTIVES: To conduct an evidence map on self-management interventions and patient-relevant outcomes for adults living with overweight/obesity. METHODS: Following Arksey and O'Malley methodology, we searched in five electronical databases including randomized controlled trials (RCTs) on SMIs for overweight/obesity. We used the terms "self-management", "adult" and "obesity" for content. Two independent reviewers assessed eligible references; one reviewer extracted data, a second checked accuracy. RESULTS: We identified 497 RCTs (58% US, 20% Europe) including 99,741 (median 112, range 11-5145) adults living with overweight/obesity. Most research evaluated clinical outcomes (617, 55%) and behaviors adherence (255, 23%). Empowerment skills, quality of life and satisfaction were less targeted (8%, 7%, 0.2%, respectively). The most frequent techniques included sharing information (858, 99%), goal setting (619, 72%) and self-monitoring training (614, 71%), provided face-to-face (386, 45%) or in combination with remote techniques (256, 30%). Emotional management, social support and shared-decision were less frequent (18%, 26%, 4%). Socio-economic status, minorities or health literacy were seldom reported. CONCLUSION: There is a need of widening the scope of research by focusing on outcomes important to patients, assessing emotional/social/share-decision support, exploring remote techniques and including vulnerable populations.

Considering multiple outcomes with different weights informed the hierarchy of interventions in network meta-analysis.

OBJECTIVES: Ranking metrics in network meta-analysis (NMA) are computed separately for each outcome. Our aim is to 1) present graphical ways to group competing interventions considering multiple outcomes and 2) use conjoint analysis for placing weights on the various outcomes based on the stakeholders' preferences. STUDY DESIGN AND SETTING: We used multidimensional scaling (MDS) and hierarchical tree clustering to visualize the extent of similarity of interventions in terms of the relative effects they produce through a random effect NMA. We reanalyzed a published network of 212 psychosis trials taking three outcomes into account as follows: reduction in symptoms of schizophrenia, all-cause treatment discontinuation, and weight gain. RESULTS: Conjoint analysis provides a mathematical method to transform judgements into weights that can be subsequently used to visually represent interventions on a two-dimensional plane or through a dendrogram. These plots provide insightful information about the clustering of interventions. CONCLUSION: Grouping interventions can help decision makers not only to identify the optimal ones in terms of benefit-risk balance but also choose one from the best cluster based on other grounds, such as cost, implementation etc. Placing weights on outcomes allows considering patient profile or preferences.

Graphical tools for visualizing the results of network meta-analysis of multicomponent interventions.

Network meta-analysis (NMA) is an established method for assessing the comparative efficacy and safety of competing interventions. It is often the case that we deal with interventions that consist of multiple, possibly interacting, components. Examples of interventions' components include characteristics of the intervention, mode (face-to-face, remotely etc.), location (hospital, home etc.), provider (physician, nurse etc.), time of communication (synchronous, asynchronous etc.) and other context related components. Networks of multicomponent interventions are typically sparse and classical NMA inference is not straightforward and prone to confounding. Ideally, we would like to disentangle the effect of each component to find out what works (or does not work). To this aim, we propose novel ways of visualizing the NMA results, describe their use, and illustrate their application in real-life examples. We developed an R package viscomp to produce all the suggested figures.

EHS Rapid Guideline: Evidence-Informed European Recommendations on Parastomal Hernia Prevention-With ESCP and EAES Participation.

Background: Growing evidence on the use of mesh as a prophylactic measure to prevent parastomal hernia and advances in guideline development methods prompted an update of a previous guideline on parastomal hernia prevention. Objective: To develop evidence-based, trustworthy recommendations, informed by an interdisciplinary panel of stakeholders. Methods: We updated a previous systematic review on the use of a prophylactic mesh for end colostomy, and we synthesized evidence using pairwise meta-analysis. A European panel of surgeons, stoma care nurses, and patients developed an evidence-to-decision framework in line with GRADE and Guidelines International Network standards, moderated by a certified guideline methodologist. The framework considered benefits and harms, the certainty of the evidence, patients' preferences and values, cost and resources considerations, acceptability, equity and feasibility. Results: The certainty of the evidence was moderate for parastomal hernia and low for major morbidity, surgery for parastomal hernia, and quality of life. There was unanimous consensus among panel members for a conditional recommendation for the use of a prophylactic mesh in patients with an end colostomy and fair life expectancy, and a strong recommendation for the use of a prophylactic mesh in patients at high risk to develop a parastomal hernia. Conclusion: This rapid guideline provides evidence-informed, interdisciplinary recommendations on the use of prophylactic mesh in patients with an end colostomy. Further, it identifies research gaps, and discusses implications for stakeholders, including overcoming barriers to implementation and specific considerations regarding validity.

Update Systematic Review, Meta-Analysis and GRADE Assessment of the Evidence on Parastomal Hernia Prevention-A EHS, ESCP and EAES Collaborative Project.

Objective: To perform a systematic review and meta-analysis on the effectiveness of prophylactic mesh for the prevention of parastomal hernia in end colostomy, with the ultimate objective to summarize the evidence for an interdisciplinary, European rapid guideline. Methods: We updated a previous systematic review with de novo evidence search of PubMed from inception up to June 2022. Primary outcome was quality of life (QoL). Secondary outcomes were clinical diagnosis of parastomal hernia, surgery for parastomal hernia, and 30 day or in-hospital complications Clavien-Dindo ≥3. We utilised the revised Cochrane Tool for randomised trials (RoB 2 tool) for risk of bias assessment in the included studies. Minimally important differences were set a priori through voting of the panel members. We appraised the evidence using GRADE and we developed GRADE evidence tables. Results: We included 12 randomized trials. Meta-analysis suggested no difference in QoL between prophylactic mesh and no mesh for primary stoma construction (SMD = 0.03, 95% CI [-0.14 to 0.2], I2 = 0%, low certainty of evidence). With regard to parastomal hernia, the use of prophylactic synthetic mesh resulted in a significant risk reduction of the incidence of the event, according to data from all available randomized trials, irrespective of the follow-up period (OR = 0.33, 95% CI [0.18-0.62], I2 = 74%, moderate certainty of evidence). Sensitivity analyses according to follow-up period were in line with the primary analysis. Little to no difference in surgery for parastomal hernia was encountered after pooled analysis of 10 randomised trials (OR = 0.52, 95% CI [0.25-1.09], I2 = 14%). Finally, no significant difference was found in Clavien-Dindo grade 3 and 4 adverse events after surgery with or without the use of a prophylactic mesh (OR = 0.77, 95% CI [0.45-1.30], I2 = 0%, low certainty of evidence). Conclusion: Prophylactic synthetic mesh placement at the time of permanent end colostomy construction is likely associated with a reduced risk for parastomal hernia and may confer similar risk of peri-operative major morbidity compared to no mesh placement. There may be no difference in quality of life and surgical repair of parastomal hernia with the use of either approach.

Estimating the sample size of sham-controlled randomized controlled trials using existing evidence.

Background: In randomized controlled trials (RCTs), the power is often 'reverse engineered' based on the number of participants that can realistically be achieved. An attractive alternative is planning a new trial conditional on the available evidence; a design of particular interest in RCTs that use a sham control arm (sham-RCTs). Methods: We explore the design of sham-RCTs, the role of sequential meta-analysis and  conditional planning in a systematic review of renal sympathetic denervation for patients with arterial hypertension. The main efficacy endpoint was mean change in 24-hour systolic blood pressure. We performed sequential meta-analysis to identify the time point where the null hypothesis would be rejected in a prospective scenario. Evidence-based conditional sample size calculations were performed based on fixed-effect meta-analysis. Results: In total, six sham-RCTs (981 participants) were identified. The first RCT was considerably larger (535 participants) than those subsequently published (median sample size of 80). All trial sample sizes were calculated assuming an unrealistically large intervention effect which resulted in low power when each study is considered as a stand-alone experiment. Sequential meta-analysis provided firm evidence against the null hypothesis with the synthesis of the first four trials (755 patients, cumulative mean difference -2.75 (95%CI -4.93 to -0.58) favoring the active intervention)). Conditional planning resulted in much larger sample sizes compared to those in the original trials, due to overoptimistic expected effects made by the investigators in individual trials, and potentially a time-effect association. Conclusions: Sequential meta-analysis of sham-RCTs can reach conclusive findings earlier and hence avoid exposing patients to sham-related risks. Conditional planning of new sham-RCTs poses important challenges as many surgical/minimally invasive procedures improve over time, the intervention effect is expected to increase in new studies and this violates the underlying assumptions. Unless this is accounted for, conditional planning will not improve the design of sham-RCTs.