Murad, M Hassan

Introduction There is a considerable implementation gap in managing early stage chronic kidney disease (CKD) in primary care despite the high prevalence and risk for increased morbidity and mortality associated with CKD. This systematic review aims to synthesise the evidence of efficacy of implementation interventions aimed at primary care practitioners (PCPs) to improve CKD identification and management. We further aim to describe the interventions’ behavioural change components. Methods and analysis We will conduct a systematic review of studies from 2000 to October 2017 that evaluate implementation interventions targeting PCPs and which include at least one clinically meaningful CKD outcome. We will search several electronic data bases and conduct reference mining of related systematic reviews and publications. An interdisciplinary team will independently and in duplicate, screen publications, extract data and assess the risk of bias. Clinical outcomes will include all clinically meaningful medical management outcomes relevant to CKD management in primary care such as blood pressure, chronic heart disease and diabetes target achievements. Quantitative evidence synthesis will be performed, where possible. Planned subgroup analyses include by (1) study design, (2) length of follow-up, (3) type of intervention, (4) type of implementation strategy, (5) whether a behavioural or implementation theory was used to guide study, (6) baseline CKD severity, (7) patient minority status, (8) study location and (9) academic setting or not. Ethics and dissemination Approval by research ethics board is not required since the review will only include published and publicly accessible data. Review findings will inform a future trial of an intervention to promote uptake of CKD diagnosis and treatment guidelines in our primary care setting and the development of complementary tools to support its successful adoption and implementation. We will publish our findings in a peer-reviewed journal and develop accessible summaries of the results. PROSPERO registration number CRD42018102441.

Abstract Context The extent to which some pharmacological interventions reduce or increase the risk of biochemical conversion to type 2 diabetes mellitus (T2DM) in at-risk individuals is unclear. Methods We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus through 24 August 2017 for randomized controlled trials evaluating the effect of drugs suspected to modify the risk of biochemical conversion to T2DM. Results We included 43 trials with 192,156 subjects (mean age, 60 years; 56% men; mean body mass index, 30.4 kg/m2). α-Glucosidase inhibitors, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, metformin, orlistat, phentermine/topiramate, and pioglitazone significantly reduced the risk of biochemical conversion to T2DM, whereas statins and nateglinide increased the risk. There was insufficient direct evidence regarding the effects of sulfonylureas, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium-glucose cotransporter-2 inhibitors. Most trials were brief and evaluated this outcome during treatment without a withdrawal or washout period. Conclusions Several drugs modify the risk of biochemical conversation to T2DM, although whether this effect is persistent and clinically relevant is unclear. Future studies need to focus on cardiovascular disease prevention, mortality, and patient-important outcomes instead of biochemical conversion to T2DM.

Abstract Rationale Prompt diagnosis of invasive fungal infections is important because of the associated morbidity and mortality; however, diagnosis is challenging because of the nonspecific symptoms and radiographic findings. Objectives To conduct a systematic review and meta-analysis of studies that evaluated the diagnostic accuracy of serum and bronchoalveolar lavage (BAL) galactomannan (GM) and serum or BAL polymerase chain reaction (PCR) in patients with suspected invasive aspergillosis (IA), β-d-glucan in critically ill patients at risk for candidiasis or candidemia, and serology testing and antigen detection in patients with endemic mycoses (histoplasmosis, blastomycosis, and coccidioidomycosis). Methods Studies were selected and appraised by pairs of reviewers. Bivariate random effects meta-analysis was used to generate pooled sensitivity, specificity, and diagnostic likelihood ratios. Results Serum GM in patients with impaired immunity suspected of having IA had sensitivity of 0.71 (95% confidence interval [CI], 0.64–0.78) and specificity of 0.89 (95% CI, 0.84–0.92). A cutoff of 1 optical density index yielded optimal sensitivity and specificity. BAL GM in patients with impaired immunity suspected of having IA had sensitivity of 0.84 (95% CI, 0.73–0.91) and specificity of 0.88 (95% CI, 0.81–0.91). Serum or whole-blood PCR in immunocompromised patients with suspected IA had sensitivity of 0.81 (95% CI, 0.73–0.86) and specificity of 0.79 (95% CI, 0.68–0.86). BAL PCR in patients at high risk for IA had high sensitivity of 0.90 (95% CI, 0.77–0.96) and specificity of 0.96 (95% CI, 0.93–0.98) for diagnosing IA. β-d-glucan assay in patients in the intensive care unit at risk for invasive candidiasis or candidemia had sensitivity of 0.81 (95% CI, 0.74–0.86) and specificity of 0.60 (95% CI, 0.49–0.71). Data on diagnostic accuracy of antigen detection and serology testing for endemic mycoses were limited and heterogeneous (varied according to test, patient immunity, and suspected endemic disease). Conclusions The diagnosis of invasive fungal infections remains a challenge. Various serum and BAL markers can aid in diagnosis. This evidence supports the development of clinical practice recommendations by the American Thoracic Society.

Aim To conduct a systematic review and meta‐analysis to understand the timing and factors associated with anti‐programmed cell death protein‐1 ( PD ‐1)/anti‐programmed cell death protein‐1 ligand ( PD ‐L1) inhibitor‐induced Type 1 diabetes. Methods We searched MEDLINE , EMBASE , SCOPUS and Cochrane databases (August 2000–2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t ‐tests. Results The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5–448) days with ketoacidosis in 76% of cases. The average ± sd HbA 1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes‐associated antibodies at presentation, and those with antibodies had a more rapid onset ( P =0.005) and higher incidence of diabetic ketoacidosis ( P =0.02) compared to people without antibodies. Conclusions Many people developed Type 1 diabetes within 3 months of initial PD ‐1/ PD ‐L1 inhibitor exposure. People presenting with Type 1 diabetes‐associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state‐of‐the‐art therapies need to be aware of this potential severe adverse event.

Abstract Objective Electronic (eHealth) and mobile (mHealth) technologies may be a useful adjunct to clinicians treating patients with chronic pain. The primary aim of this study was to investigate the effects of eHealth and mHealth interventions that do not require clinician contact or feedback on pain-related outcomes recommended by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines in adults with chronic pain. Methods We searched four databases and included English language randomized controlled trials of ambulatory adults with chronic pain from January, 1 2000, to January 31, 2018, with interventions that are independent of clinician contact or feedback. In the meta-analysis, outcomes were assessed at short- (three months or less), intermediate- (four to six months), and long-term (seven or more months) follow-up. Results Seventeen randomized controlled trials (N = 2,496) were included in the meta-analysis. Both eHealth and mHealth interventions had a significant effect on pain intensity at short- and intermediate-term follow-up. Similarly, a significant but small effect was observed for depression at short- and intermediate-term follow-up and self-efficacy at short-term follow-up. Finally, a significant effect was observed for pain catastrophizing at short-term follow-up. Conclusions eHealth and mHealth interventions had significant effects on multiple short- and intermediate-term outcome measures recommended in the IMMPACT guidelines. Given widespread availability and low cost to patients, clinicians treating patients with chronic pain could consider using eHealth and mHealth interventions as part of a multidisciplinary pain treatment strategy.

Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology is used to assess and report certainty of evidence and strength of recommendations. This GRADE concept article is not GRADE guidance but introduces certainty of net benefit, defined as the certainty that the balance between desirable and undesirable health effects is favourable. Determining certainty of net benefit requires considering certainty of effect estimates, the expected importance of outcomes and variability in importance, and the interaction of these concepts. Certainty of net harm is the certainty that the net effect is unfavourable. Guideline panels using or testing this approach might limit strong recommendations to actions with a high certainty of net benefit or against actions with a moderate or high certainty of net harm. Recommendations may differ in direction or strength from that suggested by the certainty of net benefit or harm when influenced by cost, equity, acceptability or feasibility.

Abstract Background Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies. Materials and Methods We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons. Results Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26–0.63; TAS-102: HR, 0.46 CI, 0.40–0.52) and OS (Rego 160: HR, 0.67; CI, 0.48–0.93; TAS-102: HR, 0.67; CI, 0.57–0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23–0.84) and PFS (HR, 0.37; CI, 0.21–0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160. Conclusion Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. Implications for Practice Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.

Introduction Chronic obstructive pulmonary disease (COPD) is a progressive lung disease, usually caused by tobacco smoking, but other important risk factors include exposures to combustion products of biomass fuels and environmental pollution. The introduction of several new (combination) inhaler therapies, increasing uncertainty about the role of inhaled corticosteroids and a rapid proliferation of the literature on management of stable COPD in general, call for novel ways of evidence synthesis in this area. A systematic review and evidence map can provide the basis for shared decision-making tools and help to establish a future research agenda. Methods and analysis This systematic review will follow an umbrella systematic review design (also called overview of reviews). We plan to conduct a comprehensive literature search of Ovid MEDLINE (including epub ahead of print, in process and other non-indexed citations), Ovid Embase, Ovid Cochrane Database of Systematic Reviews and Scopus from database inception to the present. We will include systematic reviews that assessed the effectiveness of any pharmacological or non-pharmacological intervention on one or more patient-important outcomes and/or lung function in patients with stable COPD. For every intervention/outcome pair, one systematic review will be included. An a priori protocol will guide, which systematic reviews will be chosen, how their credibility will be evaluated, and how the quality of the body of evidence will be rated. Data will be synthesised into an evidence map that will present a matrix that depicts each available treatment for stable COPD with a quantitative estimate on symptoms/outcomes from the patient perspective, along with an indication of the size and certainty in the evidence. Ethics and dissemination Approval by a research ethics committee is not required since the review will only include published data. The systematic review will be published in a peer-reviewed journal. PROSPERO registration number CRD42018095079