The effect of preoperative stoma site marking on risk of stoma-related complications in patients with intestinal ostomy - A systematic review and meta-analysis.

AIM: This systematic review and meta-analysis aimed to investigate the effect of preoperative stoma site marking on stoma-related complications in patients with intestinal ostomy. METHODS: MEDLINE, Embase, CENTRAL, CINHAL, and Google Scholar were searched up to August 2021 for randomised controlled trials (RCTs) and nonrandomised studies of interventions (NRSI) that involved patients with intestinal ostomies comparing preoperative stoma site marking to no marking and which reported at least one patient-relevant outcome. Outcomes were prioritised by stakeholder involvement. Random-effects meta-analyses produced odds ratios (ORs) or standardised mean differences (SMD) and 95% confidence intervals (CIs). The ROBINS-I tool and the GRADE approach were used to assess the risk of bias and certainty of evidence, respectively. RESULTS: This review included two RCTs and 25 NRSI. The risk of bias was high in RCTs and serious to critical in NRSI. Although preoperative site marking reduced stoma-related complications (OR: 0.45, 95% CI: [0.31-0.65]), dependence on professional or unprofessional care (narrative synthesis), and increased health-related quality of life (SMD: 1.13 [0.38-1.88]), the evidence is very uncertain. Preoperative site marking may probably reduce leakage (OR: 0.14 [0.06-0.37]) and may decrease dermatological complications (OR: 0.38 [0.29-0.50]) and surgical revision (OR: 0.09 [0.02-0.49]). The confidence in the cumulative evidence was moderate to very low. CONCLUSION: Despite low quality evidence, preoperative stoma site marking can prevent stoma-related complications and should be performed in patients undergoing gastrointestinal surgery given that this intervention poses no harm to patients.

Attitude toward second opinions in Germany - a survey of the general population.

BACKGROUND: Second medical opinions (SOs) can assist patients in making informed treatment decisions and improve the understanding of their diagnosis. In Germany, there are different approaches to obtain a structured SO procedure: SO programs by health insurers and SOs according to the SO Directive. Through a direct survey of the population, we aimed to assess how structured SOs should be provided to fulfil patients' needs. METHODS: A stratified sample of 9990 adults (≥18 years) living in the federal states of Berlin and Brandenburg (Germany) were initially contacted by post in April and sent a reminder in May 2020. The survey results were analyzed descriptively. RESULTS: Among 1349 participants (response rate 14%), 56% were female and the median age was 58 years (interquartile range (IQR) 44-69). Participants wanted to be informed directly and personally about the possibility of obtaining an SO (89%; 1201/1349). They preferred to be informed by their physician (93%; 1249/1349). A majority of participants would consider it important to obtain an SO for oncological indications (78%; 1049/1349). Only a subset of the participants would seek an SO via their health insurer or via an online portal (43%; 577/1349 and 16%; 221/1349). A personally delivered SO was the preferred route of SO delivery, as 97% (1305/1349) would (tend to) consider this way of obtaining an SO. Participants were asked to imagine having moderate knee pain for years, resulting in a treatment recommendation for knee joint replacement. They were requested to rate potential qualification criteria for a physician providing the SO. The criteria rated to be most important were experience with the recommended diagnosis/treatment (criterion (very) important for 93%; 1257/1349) and knowledge of the current state of research (criterion (very) important for 86%; 1158/1349). Participants were willing to travel 60 min (median; IQR 60-120) and wait 4 weeks (median; IQR 2-4) for their SO in the hypothetical case of knee pain. CONCLUSION: In general, SOs were viewed positively. We found that participants have clear preferences regarding SOs. We propose that these preferences should be taken into account in the future design and development of SO programs.

A new method for testing reproducibility in systematic reviews was developed, but needs more testing.

BACKGROUND: To develop and test an approach to test reproducibility of SRs. METHODS: Case study. We have developed an approach to test reproducibility retrospectively while focusing on the whole conduct of an SR instead of single steps of it. We replicated the literature searches and drew a 25% random sample followed by study selection, data extraction, and risk of bias (ROB) assessments performed by two reviewers independently. These results were compared narratively with the original review. RESULTS: We were not able to fully reproduce the original search resulting in minor differences in the number of citations retrieved. The biggest disagreements were found in study selection. The most difficult section to be reproduced was the RoB assessment due to the lack of reporting clear criteria to support the judgement of RoB ratings, although agreement was still found to be satisfactory. CONCLUSION: Our approach as well as other approaches needs to undergo testing and comparison in the future as the area of testing for reproducibility of SRs is still in its infancy.

Analysis of second opinion programs provided by German statutory and private health insurance - a survey of statutory and private health insurers.

BACKGROUND: Second medical opinions can give patients confidence when choosing among treatment options and help them understand their diagnosis. Health insurers in several countries, including Germany, offer formal second opinion programs (SecOPs). We systematically collected and analyzed information on German health insurers' approach to SecOPs, how the SecOPs are structured, and to what extent they are evaluated. METHODS: In April 2019, we sent a questionnaire by post to all German statutory (n = 109) and private health insurers (n = 52). In September 2019, we contacted the nonresponders by email. The results were analyzed descriptively. They are presented overall and grouped by type of insurance (statutory/private health insurer). RESULTS: Thirty one of One hundred sixty one health insurers (response rate 19%) agreed to participate. The participating insurers covered approximately 40% of the statutory and 34% of the private health insured people. A total of 44 SecOPs were identified with a median of 1 SecOP (interquartile range (IQR) 1-2) offered by a health insurer. SecOPs were in place mainly for orthopedic (21/28 insurers with SecOPs; 75%) and oncologic indications (20/28; 71%). Indications were chosen principally based on their potential impact on a patient (22/28; 79%). The key qualification criterion for second opinion providers was their expertise (30/44 SecOPs; 68%). Second opinions were usually provided based on submitted documents only (21/44; 48%) or on direct contact between a patient and a doctor (20/44; 45%). They were delivered after a median of 9 days (IQR 5-15). A median of 31 (IQR 7-85) insured persons per year used SecOPs. Only 12 of 44 SecOPs were confirmed to have conducted a formal evaluation process (27%) or, if not, plan such a process in the future (10/22; 45%). CONCLUSION: Health insurers' SecOPs focus on orthopedic and oncologic indications and are based on submitted documents or on direct patient-physician contact. The formal evaluation of SecOPs needs to be expanded and the results should be published. This can allow the evaluation of the impact of SecOPs on insured persons' health status and satisfaction, as well as on the number of interventions performed. Our results should be interpreted with caution due to the low participation rate.

Perspective of potential patients on the hospital volume-outcome relationship and the minimum volume threshold for total knee arthroplasty: a qualitative focus group and interview study.

BACKGROUND: Total knee arthroplasty (TKA) is performed to treat end-stage knee osteoarthritis. In Germany, a minimum volume threshold of 50 TKAs/hospital/year was implemented to ensure outcome quality. This study, embedded within a systematic review, aimed to investigate the perspectives of potential TKA patients on the hospital volume-outcome relationship for TKA (higher volumes associated with better outcomes). METHODS: A convenience sample of adults with knee problems and heterogeneous demographic characteristics participated in the study. Qualitative data were collected during a focus group prior to the systematic review (n = 5) and during telephone interviews, in which preliminary results of the systematic review were discussed (n = 16). The data were synthesised using content analysis. RESULTS: All participants (n = 21) believed that a hospital volume-outcome relationship exists for TKA while recognising that patient behaviour or the surgeon could also influence outcomes. All participants would be willing to travel longer for better outcomes. Most interviewees would choose a hospital for TKA depending on reputation, recommendations, and service quality. However, some would also choose a hospital based on the results of the systematic review that showed slightly lower mortality/revision rates at higher-volume hospitals. Half of the interviewees supported raising the minimum volume threshold even if this were to increase travel time to receive TKA. CONCLUSIONS: Potential patients believe that a hospital volume-outcome relationship exists for TKA. Hospital preference is based mainly on subjective factors, although some potential patients would consider scientific evidence when making their choice. Policy makers and physicians should consider the patient perspectives when deciding on minimum volume thresholds or recommending hospitals for TKA, respectively.

Icodextrin Versus Glucose Solutions for the Once-Daily Long Dwell in Peritoneal Dialysis: An Enriched Systematic Review and Meta-analysis of Randomized Controlled Trials.

RATIONALE & OBJECTIVE: The efficacy and safety of icodextrin versus glucose-only peritoneal dialysis (PD) regimens is unclear. The aim of this study was to compare once-daily long-dwell icodextrin versus glucose among patients with kidney failure undergoing PD. STUDY DESIGN: Systematic review of randomized controlled trials (RCTs), enriched with unpublished data from investigator-initiated and industry-sponsored studies. SETTING & STUDY POPULATIONS: Individuals with kidney failure receiving regular PD treatment enrolled in clinical trials of dialysate composition. SELECTION CRITERIA FOR STUDIES: Medline, Embase, CENTRAL, Ichushi Web, 10 Chinese databases, clinical trials registries, conference proceedings, and citation lists from inception to November 2018. Further data were obtained from principal investigators and industry clinical study reports. DATA EXTRACTION: 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. ANALYTIC APPROACH: Qualitative synthesis of demographics, measurement scales, and outcomes. Quantitative synthesis with Mantel-Haenszel risk ratios (RRs), Peto odds ratios (ORs), or (standardized) mean differences (MDs). Risk of bias of included studies at the outcome level was assessed using the Cochrane risk-of-bias tool for RCTs. RESULTS: 19 RCTs that enrolled 1,693 participants were meta-analyzed. Ultrafiltration was improved with icodextrin (medium-term MD, 208.92 [95% CI, 99.69-318.14] mL/24h; high certainty of evidence), reflected also by fewer episodes of fluid overload (RR, 0.43 [95% CI, 0.24-0.78]; high certainty). Icodextrin-containing PD probably decreased mortality risk compared to glucose-only PD (Peto OR, 0.49 [95% CI, 0.24-1.00]; moderate certainty). Despite evidence of lower peritoneal glucose absorption with icodextrin-containing PD (medium-term MD, -40.84 [95% CI, -48.09 to-33.59] g/long dwell; high certainty), this did not directly translate to changes in fasting plasma glucose (-0.50 [95% CI, -1.19 to 0.18] mmol/L; low certainty) and hemoglobin A1c levels (-0.14% [95% CI, -0.34% to 0.05%]; high certainty). Safety outcomes and residual kidney function were similar in both groups; health-related quality-of-life and pain scores were inconclusive. LIMITATIONS: Trial quality was variable. The follow-up period was heterogeneous, with a paucity of assessments over the long term. Mortality results are based on just 32 events and were not corroborated using time-to-event analysis of individual patient data. CONCLUSIONS: Icodextrin for once-daily long-dwell PD has clinical benefit for some patients, including those not meeting ultrafiltration targets and at risk for fluid overload. Future research into patient-centered outcomes and cost-effectiveness associated with icodextrin is needed.

Database combinations to retrieve systematic reviews in overviews of reviews: a methodological study.

BACKGROUND: When conducting an Overviews of Reviews on health-related topics, it is unclear which combination of bibliographic databases authors should use for searching for SRs. Our goal was to determine which databases included the most systematic reviews and identify an optimal database combination for searching systematic reviews. METHODS: A set of 86 Overviews of Reviews with 1219 included systematic reviews was extracted from a previous study. Inclusion of the systematic reviews was assessed in MEDLINE, CINAHL, Embase, Epistemonikos, PsycINFO, and TRIP. The mean inclusion rate (% of included systematic reviews) and corresponding 95% confidence interval were calculated for each database individually, as well as for combinations of MEDLINE with each other database and reference checking. RESULTS: Inclusion of systematic reviews was higher in MEDLINE than in any other single database (mean inclusion rate 89.7%; 95% confidence interval [89.0-90.3%]). Combined with reference checking, this value increased to 93.7% [93.2-94.2%]. The best combination of two databases plus reference checking consisted of MEDLINE and Epistemonikos (99.2% [99.0-99.3%]). Stratification by Health Technology Assessment reports (97.7% [96.5-98.9%]) vs. Cochrane Overviews (100.0%) vs. non-Cochrane Overviews (99.3% [99.1-99.4%]) showed that inclusion was only slightly lower for Health Technology Assessment reports. However, MEDLINE, Epistemonikos, and reference checking remained the best combination. Among the 10/1219 systematic reviews not identified by this combination, five were published as websites rather than journals, two were included in CINAHL and Embase, and one was included in the database ERIC. CONCLUSIONS: MEDLINE and Epistemonikos, complemented by reference checking of included studies, is the best database combination to identify systematic reviews on health-related topics.

[Compilation of Second Opinion Programs in the German Statutory Health Insurance]. / Bestandsaufnahme zu Zweitmeinungsverfahren in der Gesetzlichen Krankenversicherung (GKV).

OBJECTIVE: According to a new legislation passed in 2016, patients with an indication for elective procedures have the right to obtain a second opinion. The Federal Joint Committee has not yet provided a list of indications that this legislation will cover. Independently of this, the statutory health insurances can, nonetheless, pay for a second opinion. The aim of this article is to give an overview of current second opinion programs delivered by the statutory health insurance schemes. METHODS: Websites of all German statutory health insurance schemes (n=117) were searched for second opinion programs and their features in November 2016. All data was extracted by one person and verified by a second person. RESULTS: In total, 78 second-opinion programs were identified. Half of all statutory health insurance schemes (50%, n=59) provide at least one second-opinion program. The majority of them was in the field of orthopedics (78%, n=61) and oncology (58%, n=45). Multiple replies were possible. In most cases, second-opinion programs were outsourced (58%; n=44), followed by forwarding patients to health service providers contracted with the statutory health insurance scheme (45% n=34). Only in 11% (n=8) was the second opinion delivered by staff of the statutory health insurance scheme. The second opinion was delivered based on submitted documents only (63%; n=48), direct patient-physician contact (43%; n=33), and contact by phone (14%; n=11). The delivery of the second opinion took 7 days in median, while the delivery based on submitted documents only (median 7) was faster than the delivery by direct-physician contact (median 14). CONCLUSIONS: The majority of those living in Germany have the possibility to obtain a second opinion. However, second-opinion programs are very heterogeneous so that patients are confused about their rights to second opinion.

Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication.

Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.

Safety outcomes of direct oral anticoagulants in older adults with atrial fibrillation: a systematic review and meta-analysis of (subgroup analyses from) randomized controlled trials.

Balancing stroke prevention and risk of bleeding in patients with atrial fibrillation (AF) is challenging. Direct oral anticoagulants (DOACs) are by now considered standard of care for treating patients with AF in international guidelines. Our objective was to assess the safety of long-term intake of DOACs in older adults with AF. We included RCTs in elderly (≥ 65 years) patients with AF. A systematic search in MEDLINE and EMBASE was performed on 19 April 2022. For determination of risk of bias, the RoB 2 tool was applied. We pooled outcomes using random-effects meta-analyses. The quality of evidence was assessed using GRADE. Eleven RCTs with a total of 63,374 patients were identified. Two RCTs compared apixaban with either warfarin or aspirin, four edoxaban with either placebo, aspirin, or vitamin K antagonists (VKAs), two dabigatran with warfarin and three rivaroxaban with warfarin. DOACs probably reduce mortality in elderly patients with AF (HR 0.89 95%CI 0.77 to 1.02). Low-dose DOACs likely reduce bleeding compared to VKAs (HR ranged from 0.47 to 1.01). For high-dose DOACS the risk of bleeding varied widely (HR ranged from 0.80 to 1.40). We found that low-dose DOACs probably decrease mortality in AF patients. Moreover, apixaban and probably edoxaban are associated with fewer major or clinically relevant bleeding (MCRB) events compared to VKAs. For dabigatran and rivaroxaban, the risk of MCRB varies depending on dose. Moreover, subgroup analyses indicate that in the very old (≥ 85) the risk for MCRB events might be increased when using DOACs.Registration: PROSPERO: CRD42020187876.

Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation.

The signaling mechanisms leading to the formation of neutrophil extracellular traps (NETs), relevant in infections, sepsis and autoimmune diseases, are poorly understood. Neutrophils are not amenable to studies with conventional genetic techniques. Using a new chemical genetic analysis we show that the Raf-MEK-ERK pathway is involved in NET formation through activation of NADPH oxidase and upregulation of antiapoptotic proteins. We identify potential targets for drugs addressing NET-associated diseases.

The effects of modifying elements of written informed consent forms for elective surgical or invasive procedures: A systematic review.

OBJECTIVE: To study the effect of modifying content and design elements within written informed-consent-forms (ICF) for patients undergoing elective surgical or invasive procedures. METHODS: We included (quasi-)randomized trials in which a modified written ICF (e.g. visual aids) was compared to a standard written ICF. We searched PubMed, Web-of-Science and PsycINFO until 08/2021. Risk of Bias was assessed. The complexity of intervention was assessed using the Intervention Complexity Assessment Tool for Systematic Reviews. RESULTS: Eleven trials with 1091 participants were eligible. Effect sizes and levels of evidence varied from trivial to moderate andthere were contradictory findings for some outcomes. Providing patients with more informationin general or specific information on risks and complications mostly increased anxiety. The use of verbal risk presentation decreased anxiety and increased satisfaction.A lower readability level decreased anxiety and improved comprehension and knowledge. CONCLUSION: Our results suggest that providing more information and addressing certain types of risks have differential effects. While more information improved knowledge, it also increased anxiety. We did not find any or only insufficient evidence for many other possible ICF modifications. PRACTICE IMPLICATIONS: When developing ICFs the differential impact of different elements on patient important outcomes should be carefully considered.

Association of Tranexamic Acid Administration With Mortality and Thromboembolic Events in Patients With Traumatic Injury: A Systematic Review and Meta-analysis.

IMPORTANCE: Tranexamic acid is widely available and used off-label in patients with bleeding traumatic injury, although the literature does not consistently agree on its efficacy and safety. OBJECTIVE: To examine the association of tranexamic acid administration with mortality and thromboembolic events compared with no treatment or with placebo in patients with traumatic injury in the literature. DATA SOURCES: On March 23, 2021, PubMed, Embase, and the Cochrane Library were searched for eligible studies published between 1986 and 2021. STUDY SELECTION: Randomized clinical trials and observational studies investigating tranexamic acid administration compared with no treatment or placebo among patients with traumatic injury and traumatic brain injury who were 15 years or older were included. Included studies were published in English or German. The electronic search yielded 1546 records, of which 71 were considered for full-text screening. The selection process was performed independently by 2 reviewers. DATA EXTRACTION AND SYNTHESIS: The study followed the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data were extracted by 2 independent reviewers and pooled using the inverse-variance random-effects model. MAIN OUTCOMES AND MEASURES: Outcomes were formulated before data collection and included mortality at 24 hours and 28 and 30 days (1 month) as well as the incidence of thromboembolic events and the amount of blood products administered. Owing to missing data, overall mortality was added and the amount of blood products administered was discarded. RESULTS: Thirty-one studies with a total of 43 473 patients were included in the systematic review. The meta-analysis demonstrated that administration of tranexamic acid was associated with a significant decrease in 1-month mortality compared with the control cohort (risk ratio, 0.83 [95% CI, 0.71-0.97]; I2 = 35%). The results of meta-analyses for 24-hour and overall mortality and thromboembolic events were heterogeneous and could not be pooled. Further investigations on clinical heterogeneity showed that populations with trauma and trial conditions differed markedly. CONCLUSIONS AND RELEVANCE: These findings suggest that tranexamic acid may be beneficial in various patient populations with trauma. However, reasonable concerns about potential thromboembolic events with tranexamic acid remain.

An adapted 'Ottawa' method allowed assessing the need to update topic areas within clinical practice guidelines.

OBJECTIVES: To adapt and evaluate a method for assessing the need to update guideline topic areas involving multiple recommendations. STUDY DESIGN AND SETTING: The 'Ottawa method' uses literature signals to determine changes in evidence that trigger a need to update individual guideline questions. We adapted the Ottawa method to include a process for aggregating updating signals by topic area (e.g., resuscitation) and tested this method using the German guideline on the treatment of patients with severe/multiple injuries. This involved a focused systematic evaluation of current evidence to identify updating signals and classifying the need to update for each topic area. Then, we surveyed the guideline group online about the modified method. RESULTS: We conducted focused literature searches for 37 topic areas and screened a mean of 97 abstracts per topic area in 2021. The need to update was high for eight (21.6%), intermediate for eight (21.6%), and low for 21 topic areas (56.8%) based on updating signals. The survey response rate was 56% (24/43). Most guideline group members (94%, 16/17 responders) would use the Ottawa method again but their comments identified some weaknesses. CONCLUSION: The modified Ottawa method is a suitable, efficient tool to generate evidence-based updating signals for guideline topic areas involving multiple recommendations. Further fine-tuning is recommended.

Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.

REGISTRATION: PROSPERO: CRD42020210645. INTRODUCTION: We aimed to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older patients with type 2 diabetes with inadequate glycaemic control. METHODS: We included randomized controlled trials (RCTs) in older (⩾65 years) patients with type 2 diabetes. The intervention group was randomized to treatment with any DPP-4 inhibitors. A systematic search in MEDLINE and Embase was performed in December 2020. For assessing the risk of bias, RoB 2 tool was applied. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We pooled outcomes using random effects meta-analyses. RESULTS: We identified 16 RCTs that included 19,317 patients with a mean age of greater than 70 years. The mean HbA1c level ranged between 7.1 and 10.0 g/dl. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly [risk ratio (RR) 1.04; 95% confidence interval (CI) 0.89-1.21]. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia (RR 1.08; 95% CI 1.01-1.16), but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas (RR 0.88; 95% CI 0.75-1.04). DPP-4 inhibitors probably reduce the risk for hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis. CONCLUSION: There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase hypoglycaemia risk. Second-line therapy in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case second-line treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas. PLAIN LANGUAGE SUMMARY: Safety of dipeptidyl peptidase-4 inhibitors in older adults with type 2 diabetes: Introduction:: We performed the review to assess the safety of dipeptidyl peptidase-4 (DPP-4) inhibitors in older type 2 diabetes patients with blood sugar outside the normal level.Methods:: To answer the question, we searched various electronic databases. We included studies in older (⩾65 years) patients with type 2 diabetes that assessed the safety of DPP-4 inhibitors. The data from the different studies were quantitatively summarized using statistical methods. We assessed the quality of the data to judge the certainty of the findings.Results:: We identified 16 studies that included 19,317 patients with a mean age greater than 70 years. The average blood sugar level of patients in the included studies was slightly or moderately increased. Adding DPP-4 inhibitors to standard care alone may increase mortality slightly. Adding DPP-4 inhibitors to standard care increases the risk for hypoglycaemia, but difference in overall adverse events is negligible. DPP-4 inhibitors added to standard care may reduce mortality compared with sulfonylureas. DPP-4s probably reduce the risk of hypoglycaemia compared with sulfonylureas (magnitude of effect not quantifiable because of heterogeneity) but difference in overall adverse events is negligible. There is insufficient evidence on hospitalizations, falls, fractures, renal impairment and pancreatitis.Conclusion:: There is no evidence that DPP-4 inhibitors in addition to standard care decrease mortality but DPP-4 inhibitors increase the risk that blood sugar falls below normal. Adding DPP-4 inhibitorss to standard care in older patients should be considered cautiously even in drugs with a good safety profile such as DPP-4 inhibitors. In case additional treatment is necessary, DPP-4 inhibitors appear to be preferable to sulfonylureas.

A review found heterogeneous approaches and insufficient reporting in overviews on adverse events.

OBJECTIVES: To investigate reporting and methodological characteristics of overviews on adverse (drug-associated) events (AEs) of pharmacological interventions. STUDY DESIGN AND SETTING: We searched MEDLINE, Embase, Epistemonikos, and the Cochrane Database of Systematic Reviews from inception to May 17, 2021 for overviews exclusively investigating AEs of pharmacological interventions. We extracted general, reporting, and methodological characteristics and analyzed data descriptively. RESULTS: We included 27 overviews, 70% of which were published in 2016 or later. The most common nomenclature in the title was "overview" (56%), followed by "umbrella review" (26%). The median number of included systematic reviews (SRs) in each overview was 15 (interquartile range 7-34). Study selection methods were reported in 52%, methods for data extraction in 67%, and methods for critical appraisal in 63% of overviews. An assessment of methodological quality of included SRs was performed in 70% of overviews. Only 22% of overviews reported strategies for dealing with overlapping SRs. An assessment of the certainty of the evidence was performed in 33% of overviews. CONCLUSION: To ensure methodological rigor, authors of overviews on AEs should follow available guidance for the conduct and reporting of overviews.

A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity.

The use of chemically synthesized short interfering RNAs (siRNAs) is currently the method of choice to manipulate gene expression in mammalian cell culture, yet improvements of siRNA design is expectably required for successful application in vivo. Several studies have aimed at improving siRNA performance through the introduction of chemical modifications but a direct comparison of these results is difficult. We have directly compared the effect of 21 types of chemical modifications on siRNA activity and toxicity in a total of 2160 siRNA duplexes. We demonstrate that siRNA activity is primarily enhanced by favouring the incorporation of the intended antisense strand during RNA-induced silencing complex (RISC) loading by modulation of siRNA thermodynamic asymmetry and engineering of siRNA 3'-overhangs. Collectively, our results provide unique insights into the tolerance for chemical modifications and provide a simple guide to successful chemical modification of siRNAs with improved activity, stability and low toxicity.

The effect of preoperative stoma site marking on risk of stoma-related complications in patients with intestinal ostomy-protocol of a systematic review and meta-analysis.

BACKGROUND: An intestinal ostomy is an artificial bowel opening created on the skin. Procedure-related mortality is extremely rare. However, the presence of an ostomy may be associated with significant morbidity. Complications negatively affect the quality of life of ostomates. Preoperative stoma site marking can reduce stoma-related complications and is recommended by several guidelines. However, there is no consensus on the procedure and recommendations are based on low-quality evidence. The objective of the systematic review will be to investigate if preoperative stoma site marking compared to no preoperative marking in patients undergoing intestinal stoma surgery reduces or prevents the rate of stoma-related complications. METHODS: We will include (cluster-) randomised controlled trials and cohort studies that involve patients with intestinal ostomies comparing preoperative stoma site marking to no preoperative marking and report at least one patient-relevant outcome. For study identification, we will systematically search MEDLINE/PubMed, EMBASE, CENTRAL and CINHAL as well as Google Scholar, trial registries, conference proceedings and reference lists. Additionally, we will contact experts in the field. Two reviewers will independently perform study selection and data extraction. Outcomes will be prioritised based on findings from telephone interviews with five ostomates and five ostomy and wound nurses prior to conducting the review. Outcomes may include but are not limited to stoma-related complications (infection, parastomal abscess, hernia, mucocutaneous separation, dermatological complications, stoma necrosis, stenosis, retraction and prolapse) or other patient-relevant postoperative endpoints (quality of life, revision rate, dependence on professional care, mortality, length of stay and readmission). We will use the ROBINS-I or the Cochrane risk of bias tool to assess the risk of bias of the included studies. We will perform a meta-analysis and assess the certainty of evidence using the GRADE approach. DISCUSSION: With the results of the systematic review, we aim to provide information for future clinical guidelines and influence clinical routine with regard to preoperative stoma site marking in patients undergoing ostomy surgery. When the evidence of our systematic review is low, it would still be a useful basis for future clinical trials by identifying data gaps. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42021226647.

Communication strategies in the prevention of type 2 diabetes and gestational diabetes in vulnerable groups: a scoping review.

BACKGROUND: The global prevalence of diabetes is nearly 9%, with an upward trend in type 2 diabetes mellitus (T2DM) and gestational diabetes (GDM). Although evidence shows that vulnerable groups are affected disproportionally, these groups are difficult to reach in terms of preventive measures. Currently, there is no gold standard regarding communication strategies and/or public awareness campaigns. METHODS: We conducted a scoping review in September 2019. Two reviewers independently screened the results of the electronic literature search in several databases, including Medline, EMBASE, and PsycINFO. Extracted data were charted, categorized, and summarized. RESULTS: All of the included articles (n=24) targeted T2DM; none targeted GDM. We identified the following five different vulnerable groups within the identified studies: migrants (n=9), ethnic groups such as African Americans (n=8), people with low socioeconomic status (n=3), older people (n=1), and people in need of care (n=1). Three categories of communication strategies were identified as follows: adapted diabetes prevention programs (n=21), community health workers (n=5), and technical approaches (n=9). CONCLUSION: We found different approaches for preventive interventions for T2DM. Some of these approaches were already adapted to known barriers. Communication strategies should be adapted to barriers and facilitating factors to increase participation and motivation.