Real-world use of glucocorticoids and clinical outcomes in adults hospitalized with community-acquired pneumonia on medical wards.

BACKGROUND: Little is known about the real-world use of systemic glucocorticoids to treat patients hospitalized with community-acquired pneumonia (CAP) outside of the intensive care unit (ICU). METHODS: This retrospective cohort study included 11,588 hospitalizations for CAP without chronic pulmonary disease at seven hospitals in Ontario, Canada. We report physician-level variation in the use of glucocorticoids and trends over time. We investigated the association between glucocorticoid prescriptions and clinical outcomes, using propensity score overlap weighting to account for confounding by indication. RESULTS: Glucocorticoids were prescribed in 1283 (11.1%) patients, increasing over time from 10.0% in 2010 to 11.9% in 2020 (p = .008). Physician glucocorticoid prescribing ranged from 2.9% to 34.6% (median 10.0%, inter quartile range [IQR]: 6.7%-14.6%). Patients receiving glucocorticoids tended to be younger (median age 73 vs. 79), have higher Charlson comorbidity scores (score of 2 or more: 42.4% vs. 31.0%), more cancer (26.6% vs. 13.2%), more renal disease (11.5% vs. 6.6%), and less dementia (7.8% vs. 14.8%). Patients treated with glucocorticoids had higher rates of in-hospital mortality (weighted Risk Difference = 1.72, 95% confidence interval [95% CI]: 0.16-3.3, p = .033). Glucocorticoid use was not associated with ICU admission, hospital length-of-stay, or 30-day readmission. CONCLUSION: Glucocorticoids were prescribed in 11.1% of patients hospitalized with CAP outside of ICU and one in four physicians prescribed glucocorticoids in more than 14% of patients. Glucocorticoid use was associated with greater in-hospital mortality, although these findings are limited by large selection effects. Clinicians should exercise caution in prescribing glucocorticoids for nonsevere CAP, and definitive trials are needed in this population.

Characteristics, Progression, and Output of Randomized Platform Trials: A Systematic Review.

Importance: Platform trials have become increasingly common, and evidence is needed to determine how this trial design is actually applied in current research practice. Objective: To determine the characteristics, progression, and output of randomized platform trials. Evidence Review: In this systematic review of randomized platform trials, Medline, Embase, Scopus, trial registries, gray literature, and preprint servers were searched, and citation tracking was performed in July 2022. Investigators were contacted in February 2023 to confirm data accuracy and to provide updated information on the status of platform trial arms. Randomized platform trials were eligible if they explicitly planned to add or drop arms. Data were extracted in duplicate from protocols, publications, websites, and registry entries. For each platform trial, design features such as the use of a common control arm, use of nonconcurrent control data, statistical framework, adjustment for multiplicity, and use of additional adaptive design features were collected. Progression and output of each platform trial were determined by the recruitment status of individual arms, the number of arms added or dropped, and the availability of results for each intervention arm. Findings: The search identified 127 randomized platform trials with a total of 823 arms; most trials were conducted in the field of oncology (57 [44.9%]) and COVID-19 (45 [35.4%]). After a more than twofold increase in the initiation of new platform trials at the beginning of the COVID-19 pandemic, the number of platform trials has since declined. Platform trial features were often not reported (not reported: nonconcurrent control, 61 of 127 [48.0%]; multiplicity adjustment for arms, 98 of 127 [77.2%]; statistical framework, 37 of 127 [29.1%]). Adaptive design features were only used by half the studies (63 of 127 [49.6%]). Results were available for 65.2% of closed arms (230 of 353). Premature closure of platform trial arms due to recruitment problems was infrequent (5 of 353 [1.4%]). Conclusions and Relevance: This systematic review found that platform trials were initiated most frequently during the COVID-19 pandemic and declined thereafter. The reporting of platform features and the availability of results were insufficient. Premature arm closure for poor recruitment was rare.

Recommandations pour des soins préventifs pour promouvoir l'équité en matière de santé.

CONTEXTE: Malgré des investissements importants dans un système de soins de santé public qui comprend des services préventifs, on continue d'observer des disparités évitables en matière de santé au Canada. L'équipe avait pour objectif de formuler des recommandations pour des soins de santé préventifs qui puissent améliorer l'équité en matière de santé par la priorisation des interventions efficaces à l'intention des groupes défavorisés. MÉTHODES: La ligne directrice a été élaborée par un comité composé de spécialistes en soins primaires et de membres de la patientèle, avec la contribution d'un groupe de patientes-et patientspartenaires ayant vécu diverses expériences. Après avoir sélectionné les sujets à prioriser, nous avons recensé les revues systématiques, les essais randomisés et contrôlés récents sur les méthodes de dépistage et d'autres études pertinentes sur l'efficacité du dépistage et de la prise en charge. Nous avons utilisé l'approche GRADE (Grading of Recommendations, Assessment, Development and Evaluation) pour formuler les recommandations et avons suivi le guide AGREE II (Appraisal of Guidelines for Research and Evaluation) pour rédiger le rapport. Il en a été de même avec les principes du Guidelines International Network pour la gestion des intérêts concurrents. Les recommandations ont été passées en revue par un comité externe d'experts en contenu avant d'être distribuées à des intervenants à l'échelle nationale pour approbation. RECOMMANDATIONS: Nous avons formulé 15 recommandations concernant le dépistage et d'autres soins préventifs et 1 recommandation de nature politique visant à améliorer l'accès aux soins primaires. Ainsi, nous recommandons de prioriser une stratégie de communication pour le dépistage du cancer colorectal à partir de l'âge de 45 ans et pour l'évaluation du risque de maladie cardiovasculaire pour lutter contre les iniquités en matière de santé et promouvoir la santé. Les interventions particulières qui devraient être déployées pour lutter contre les iniquités comprennent l'autodépistage du virus du papillome humain (VPH) et du VIH, et le test de libération de l'interféron γ pour l'infection tuberculeuse. Le dépistage de la dépression, de la toxicomanie, de la violence conjugale et de la pauvreté devrait également permettre aux personnes touchées d'accéder plus facilement à des interventions éprouvées. Nous recommandons une prise de contact systématique avec des professionnels de la santé en soins primaires pour les personnes défavorisées. INTERPRÉTATION: Les interventions préventives éprouvées peuvent aider à combattre les iniquités en matière de santé si la priorité est accordée aux personnes défavorisées. Les médecins, les organisations de santé et les gouvernements devraient adopter des mesures fondées sur des données probantes et en faire le suivi s'ils veulent promouvoir l'équité en matière de santé partout au Canada.

Preventive care recommendations to promote health equity.

BACKGROUND: Avoidable disparities in health outcomes persist in Canada despite substantial investments in a publicly funded health care system that includes preventive services. Our objective was to provide preventive care recommendations that promote health equity by prioritizing effective interventions for people experiencing disadvantages. METHODS: The guideline was developed by a primary care provider-patient panel, with input from a patient-partner panel with diverse lived experiences. After selecting priority topics, we searched for systematic reviews and recent randomized controlled trials of screening and other relevant studies of screening accuracy and management efficacy. We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to develop recommendations and followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) reporting guidance. We managed competing interests using the Guideline International Network principles. The recommendations were externally reviewed by content experts and circulated for endorsement by national stakeholders. RECOMMENDATIONS: We developed 15 screening and other preventive care recommendations and 1 policy recommendation on improving access to primary care. We recommend prioritized outreach for colorectal cancer screening starting at age 45 years and for cardiovascular disease risk assessment, to help address inequities and promote health. Specific interventions that should be rolled out in ways that address inequities include human papillomavirus (HPV) self-testing, HIV self-testing and interferon-γ release assays for tuberculosis infection. Screening for depression, substance use, intimate partner violence and poverty should help connect people experiencing specific disadvantages with proven interventions. We recommend automatic connection to primary care for people experiencing disadvantages. INTERPRETATION: Proven preventive care interventions can address health inequities if people experiencing disadvantages are prioritized. Clinicians, health care organizations and governments should take evidence-based actions and track progress in promoting health equity across Canada.

Predictors of Recovery Following Lumbar Microdiscectomy for Sciatica: A Systematic Review and Meta-Analysis of Observational Studies.

Chronic post-surgical pain is reported by up to 40% of patients after lumbar microdiscectomy for sciatica, a complaint associated with disability and loss of productivity. We conducted a systematic review of observational studies to explore factors associated with persistent leg pain and impairments after microdiscectomy for sciatica. We searched eligible studies in MEDLINE, Embase, and CINAHL that explored, in an adjusted model, predictors of persistent leg pain, physical impairment, or failure to return to work after microdiscectomy for sciatica. When possible, we pooled estimates of association using random-effects models using the Grading of Recommendations Assessment, Development, and Evaluation approach. Moderate-certainty evidence showed that the female sex probably has a small association with persistent post-surgical leg pain (odds ratio (OR) = 1.15, 95% confidence interval (CI) = 0.63 to 2.08; absolute risk increase (ARI) = 1.8%, 95% CI = -4.7% to 11.3%), large association with failure to return to work (OR = 2.79, 95% CI = 1.27 to 6.17; ARI = 10.6%, 95% CI = 1.8% to 25.2%), and older age is probably associated with greater postoperative disability (ß = 1.47 points on the 100-point Oswestry Disability Index for every 10-year increase from age (>/=18 years), 95% CI = -4.14 to 7.28). Among factors that were not possible to pool, two factors showed promise for future study, namely, legal representation and preoperative opioid use, which showed large associations with worse outcomes after surgery. The moderate-certainty evidence showed female sex is probably associated with persistent leg pain and failure to return to work and that older age is probably associated with greater post-surgical impairment after a microdiscectomy. Future research should explore the association between legal representation and preoperative opioid use with persistent pain and impairment after microdiscectomy for sciatica.

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials.

OBJECTIVE: To compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor agonist) to previously existing treatment options. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Ovid Medline, Embase, and Cochrane Central up to 14 October 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Eligible randomised controlled trials compared drugs of interest in adults with type 2 diabetes. Eligible trials had a follow-up of 24 weeks or longer. Trials systematically comparing combinations of more than one drug treatment class with no drug, subgroup analyses of randomised controlled trials, and non-English language studies were deemed ineligible. Certainty of evidence was assessed following the GRADE (grading of recommendations, assessment, development and evaluation) approach. RESULTS: The analysis identified 816 trials with 471 038 patients, together evaluating 13 different drug classes; all subsequent estimates refer to the comparison with standard treatments. Sodium glucose cotransporter-2 (SGLT-2) inhibitors (odds ratio 0.88, 95% confidence interval 0.83 to 0.94; high certainty) and GLP-1 receptor agonists (0.88, 0.82 to 0.93; high certainty) reduce all cause death; non-steroidal mineralocorticoid receptor antagonists, so far tested only with finerenone in patients with chronic kidney disease, probably reduce mortality (0.89, 0.79 to 1.00; moderate certainty); other drugs may not. The study confirmed the benefits of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing cardiovascular death, non-fatal myocardial infarction, admission to hospital for heart failure, and end stage kidney disease. Finerenone probably reduces admissions to hospital for heart failure and end stage kidney disease, and possibly cardiovascular death. Only GLP-1 receptor agonists reduce non-fatal stroke; SGLT-2 inhibitors are superior to other drugs in reducing end stage kidney disease. GLP-1 receptor agonists and probably SGLT-2 inhibitors and tirzepatide improve quality of life. Reported harms were largely specific to drug class (eg, genital infections with SGLT-2 inhibitors, severe gastrointestinal adverse events with tirzepatide and GLP-1 receptor agonists, hyperkalaemia leading to admission to hospital with finerenone). Tirzepatide probably results in the largest reduction in body weight (mean difference -8.57 kg; moderate certainty). Basal insulin (mean difference 2.15 kg; moderate certainty) and thiazolidinediones (mean difference 2.81 kg; moderate certainty) probably result in the largest increases in body weight. Absolute benefits of SGLT-2 inhibitors, GLP-1 receptor agonists, and finerenone vary in people with type 2 diabetes, depending on baseline risks for cardiovascular and kidney outcomes (https://matchit.magicevidence.org/230125dist-diabetes). CONCLUSIONS: This network meta-analysis extends knowledge beyond confirming the substantial benefits with the use of SGLT-2 inhibitors and GLP-1 receptor agonists in reducing adverse cardiovascular and kidney outcomes and death by adding information on finerenone and tirzepatide. These findings highlight the need for continuous assessment of scientific progress to introduce cutting edge updates in clinical practice guidelines for people with type 2 diabetes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022325948.

Timing of symptomatic venous thromboembolism after surgery: meta-analysis.

BACKGROUND: The timing at which venous thromboembolism (VTE) occurs after major surgery has major implications for the optimal duration of thromboprophylaxis. The aim of this study was to perform a systematic review and meta-analysis of the timing of postoperative VTE up to 4 weeks after surgery. METHODS: A systematic search of MEDLINE, Scopus, and CINAHL databases was performed between 1 January 2009 and 1 April 2022. Prospective studies that recruited patients who underwent a surgical procedure and reported at least 20 symptomatic, postoperative VTE events by time were included. Two reviewers independently selected studies according to the eligibility criteria, extracted data, and evaluated risk of bias. Data were analysed with a Poisson regression model, and the GRADE approach was used to rate the certainty of evidence. RESULTS: Some 6258 studies were evaluated, of which 22 (11 general, 5 urological, 4 mixed, and 2 orthopaedic postoperative surgical populations; total 1 864 875 patients and 24 927 VTE events) were eligible. Pooled evidence of moderate certainty showed that 47.1 per cent of the VTE events occurred during the first, 26.9 per cent during the second, 15.8 per cent during the third, and 10.1 per cent during the fourth week after surgery. The timing of VTE was consistent between individual studies. CONCLUSION: Although nearly half of symptomatic VTE events in first 4 weeks occur during the first postoperative week, a substantial number of events occur several weeks after surgery. These data will inform clinicians and guideline developers about the duration of postoperative thromboprophylaxis.

Hundreds of millions of surgical procedures are performed annually worldwide. Blood clots in legs and lungs represent serious, and sometimes fatal, complications of surgery. To prevent these complications, clinicians often give blood thinners to patients. To optimize the starting time and duration of use of blood thinners, it is crucial to know when blood clots occur after surgery. This study summarized the timing of blood clots after surgery based on a systematic review and meta-analysis of 22 prospective studies including thousands of patients with blood clots from various surgical fields. Of blood clots occurring within 4 weeks after surgery, 47 per cent occurred by the first, 74 per cent by the second, and 90 per cent by the third week after surgery. These research results are useful for patients, clinicians, and guideline developers to guide the starting time and duration of use of blood thinners after surgery.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update - XIII - Oral immunotherapy for CMA - Systematic review.

Background: Allergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. Objective: To systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. Methods: We searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). Results: We identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2-8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%-91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6-30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12-770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%-10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. Conclusions: Moderate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Benefits and harms of direct oral anticoagulation and low molecular weight heparin for thromboprophylaxis in patients undergoing non-cardiac surgery: systematic review and network meta-analysis of randomised trials.

OBJECTIVE: To systematically compare the effect of direct oral anticoagulants and low molecular weight heparin for thromboprophylaxis on the benefits and harms to patients undergoing non-cardiac surgery. DESIGN: Systematic review and network meta-analysis of randomised controlled trials. DATA SOURCES: Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL), up to August 2021. REVIEW METHODS: Randomised controlled trials in adults undergoing non-cardiac surgery were selected, comparing low molecular weight heparin (prophylactic (low) or higher dose) with direct oral anticoagulants or with no active treatment. Main outcomes were symptomatic venous thromboembolism, symptomatic pulmonary embolism, and major bleeding. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used for network meta-analyses. Abstracts and full texts were screened independently in duplicate. Data were abstracted on study participants, interventions, and outcomes, and risk of bias was assessed independently in duplicate. Frequentist network meta-analysis with multivariate random effects models provided odds ratios with 95% confidence intervals, and GRADE (grading of recommendations, assessment, development, and evaluation) assessments indicated the certainty of the evidence. RESULTS: 68 randomised controlled trials were included (51 orthopaedic, 10 general, four gynaecological, two thoracic, and one urological surgery), involving 45 445 patients. Low dose (odds ratio 0.33, 95% confidence interval 0.16 to 0.67) and high dose (0.19, 0.07 to 0.54) low molecular weight heparin, and direct oral anticoagulants (0.17, 0.07 to 0.41) reduced symptomatic venous thromboembolism compared with no active treatment, with absolute risk differences of 1-100 per 1000 patients, depending on baseline risks (certainty of evidence, moderate to high). None of the active agents reduced symptomatic pulmonary embolism (certainty of evidence, low to moderate). Direct oral anticoagulants and low molecular weight heparin were associated with a 2-3-fold increase in the odds of major bleeding compared with no active treatment (certainty of evidence, moderate to high), with absolute risk differences as high as 50 per 1000 in patients at high risk. Compared with low dose low molecular weight heparin, high dose low molecular weight heparin did not reduce symptomatic venous thromboembolism (0.57, 0.26 to 1.27) but increased major bleeding (1.87, 1.06 to 3.31); direct oral anticoagulants reduced symptomatic venous thromboembolism (0.53, 0.32 to 0.89) and did not increase major bleeding (1.23, 0.89 to 1.69). CONCLUSIONS: Direct oral anticoagulants and low molecular weight heparin reduced venous thromboembolism compared with no active treatment but probably increased major bleeding to a similar extent. Direct oral anticoagulants probably prevent symptomatic venous thromboembolism to a greater extent than prophylactic low molecular weight heparin. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018106181.

Less intensive antileukemic therapies (monotherapy and/or combination) for older adults with acute myeloid leukemia who are not candidates for intensive antileukemic therapy: A systematic review and meta-analysis.

INTRODUCTION: Elderly patients with acute myeloid leukemia not eligible for intensive antileukemic therapy are treated with less intensive therapies, uncertainty remains regarding their relative merits. OBJECTIVES: To compare the effectiveness and safety of less intensive antileukemic therapies for older adults with newly diagnosed AML not candidates for intensive therapies. METHODS: We included randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing less intensive therapies in adults over 55 years with newly diagnosed AML. We searched MEDLINE and EMBASE from inception to August 2021. We assessed risk of bias of RCTs with a modified Cochrane Risk of Bias tool, and NRS with the Non-Randomized Studies of Interventions tool (ROBINS-I). We calculated pooled hazard ratios (HRs), risk ratios (RRs), mean differences (MD) and their 95% confidence intervals (CIs) using a random-effects pairwise meta-analyses and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We included 27 studies (17 RCTs, 10 NRS; n = 5,698), which reported 9 comparisons. Patients were treated with azacitidine, decitabine, and low-dose cytarabine (LDAC), as monotherapies or in combination with other agents. Moderate certainty of evidence suggests no convincing difference in overall survival of patients who receive azacitidine monotherapy compared to LDAC monotherapy (HR 0.69; 95% CI, 0.31-1.53), fewer febrile neutropenia events occurred between azacitidine monotherapy to azacitidine combination (RR 0.45; 95% CI, 0.31-0.65), and, fewer neutropenia events occurred between LDAC monotherapy to decitabine monotherapy (RR 0.62; 95% CI 0.44-0.86). All other comparisons and outcomes had low or very low certainty of evidence. CONCLUSION: There is no convincing superiority in OS when comparing less intensive therapies. Azacitidine monotherapy is likely to have fewer adverse events than azacitidine combination (febrile neutropenia), and LDAC monotherapy is likely to have fewer adverse events than decitabine monotherapy (neutropenia).

Developing an Education Pathway for Breast Cancer Patients Receiving Rapid Diagnostic Testing: Investigating Informational and Supportive Care Needs.

Several studies have examined the informational needs of patients undergoing the breast diagnostic process where needs are highest during testing and prior to receiving a diagnosis. To aid in the development of an education pathway, we identified patient information needs. A multi-method approach to identify areas of need and to understand when and how information should be provided to patients was undertaken. The methods included an environmental scan of consumer health information, ethnographic observation of the patient clinical experience, key informant interviews, and a needs assessment survey. The data collected from the environmental scan, ethnography, and interviews were used to develop the items in the survey. The survey was developed around four domains: (1) Medical Procedures and Tests, (2) Understanding the Rapid Diagnostic Process, (3) Breast Cancer and Other Breast Conditions, and (4) Support and Coping. A total of 101 patients completed the survey. Mean importance scores were significantly different between domains of information need (p < .0001) and significantly higher for the 'Medical Procedures and Tests' domain compared with all others. Multivariate analysis suggested that participants with higher levels of education (p = .02) and a preference to speak English at home (p = .009) tended to rate the importance of 'Support and Coping' information lower than other participants. Information about medical procedures and tests are most important for the patients undergoing rapid diagnostic testing in our sample. Education materials that are tailored to patient needs should be provided to patients during this stage of the cancer journey to help meet informational needs.

Anti-vascular endothelial growth factor therapy for age-related macular degeneration: a systematic review and network meta-analysis.

BACKGROUND: The comparative safety and efficacy between anti-vascular endothelial growth factor agents (anti-VEGFs) and between combined therapies for patients with neovascular age-related macular degeneration (nAMD) is unclear. We conducted a systematic review to examine the comparative safety and efficacy anti-VEGFs for adults with nAMD. METHODS: Studies were identified through MEDLINE, EMBASE, and Cochrane CENTRAL (inception to June 3, 2019), grey literature, and scanning reference lists. Two reviewers independently screened citations and full-text articles to identify randomized controlled trials (RCTs), extracted data, and appraised risk of bias. Pairwise random-effects meta-analysis and Bayesian network meta-analysis (NMA) were conducted. The primary outcomes were the proportion of patients experiencing moderate vision gain (≥ 15 letters on the Early Treatment Diabetic Retinopathy Study chart) and the proportion of patients experiencing moderate vision loss (≤ 15 letters). RESULTS: After screening 3647 citations and 485 potentially relevant full-text articles, 92 RCTs with 24,717 patients were included. NMA (34 RCTs, 8809 patients, 12 treatments) showed small differences among anti-VEGFs in improving the proportion of patients with moderate vision gain, with the largest for conbercept versus broluczumab (OR 0.15, 95% CrI: 0.05-0.56), conbercept versus ranibizumab (OR 0.17, 95% CrI: 0.05-0.59), conbercept versus aflibercept (OR 0.19, 95% CrI: 0.06-0.65), and conbercept versus bevacizumab (OR 0.2, 95% CrI: 0.06-0.69). In NMA (36 RCTs, 9081 patients, 13 treatments) for the proportion of patients with moderate vision loss, small differences were observed among anti-VEGFs, with the largest being for conbercept versus aflibercept (OR 0.24, 95% CrI: 0-4.29), conbercept versus brolucizumab (OR 0.24, 95% CrI: 0-4.71), conbercept versus bevacizumab (OR 0.26, 95% CrI: 0-4.65), and conbercept versus ranibizumab (OR 0.27, 95% CrI: 0-4.67). CONCLUSION: The only observed differences were that ranibizumab, bevacizumab, aflibercept, and brolucizumab were statistically superior to conbercept in terms of the proportion of patients with nAMD who experienced moderate vision gain. However, this finding is based on indirect evidence through one small trial comparing conbercept with placebo. This does not account for drug-specific differences when assessing anatomic and functional treatment efficacy in variable dosing regimens. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42015022041.

In healthy older adults, daily aspirin increased cancer mortality.

SOURCE CITATION: McNeil JJ, Gibbs P, Orchard SG, et al. Effect of aspirin on cancer incidence and mortality in older adults. J Natl Cancer Inst. 2021;113:258-65. 32778876.

Prophylaxis against covid-19: living systematic review and network meta-analysis.

UPDATES: This is the second version (first update) of the living systematic review, replacing the previous version (available as a data supplement). When citing this paper please consider adding the version number and date of access for clarity. OBJECTIVE: To determine and compare the effects of drug prophylaxis on severe acute respiratory syndrome coronavirus virus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (covid-19). DESIGN: Living systematic review and network meta-analysis (NMA). DATA SOURCES: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature to 4 March 2022. STUDY SELECTION: Randomised trials in which people at risk of covid-19 were allocated to prophylaxis or no prophylaxis (standard care or placebo). Pairs of reviewers independently screened potentially eligible articles. METHODS: After duplicate data abstraction, we conducted random-effects bayesian network meta-analysis. We assessed risk of bias of the included studies using a modification of the Cochrane risk of bias 2.0 tool and assessed the certainty of the evidence using the grading of recommendations assessment, development and evaluation (GRADE) approach. RESULTS: The second iteration of this living NMA includes 32 randomised trials which enrolled 25 147 participants and addressed 21 different prophylactic drugs; adding 21 trials (66%), 18 162 participants (75%) and 16 (76%) prophylactic drugs. Of the 16 prophylactic drugs analysed, none provided convincing evidence of a reduction in the risk of laboratory confirmed SARS-CoV-2 infection. For admission to hospital and mortality outcomes, no prophylactic drug proved different than standard care or placebo. Hydroxychloroquine and vitamin C combined with zinc probably increase the risk of adverse effects leading to drug discontinuation­risk difference for hydroxychloroquine (RD) 6 more per 1000 (95% credible interval (CrI) 2 more to 10 more); for vitamin C combined with zinc, RD 69 more per 1000 (47 more to 90 more), moderate certainty evidence. CONCLUSIONS: Much of the evidence remains very low certainty and we therefore anticipate future studies evaluating drugs for prophylaxis may change the results for SARS-CoV-2 infection, admission to hospital and mortality outcomes. Both hydroxychloroquine and vitamin C combined with zinc probably increase adverse effects. SYSTEMATIC REVIEW REGISTRATION: This review was not registered. The protocol established a priori is included as a supplement. FUNDING: This study was supported by the Canadian Institutes of Health Research (grant CIHR-IRSC:0579001321).

Granulomatosis with polyangiitis presenting as pancreatic disease.

Granulomatosis with polyangiitis (GPA) is a rare necrotising small vessel vasculitis typically associated with oronasal, pulmonary and renal manifestations. Pancreatic disease is an exceedingly rare initial presentation and is associated with delayed diagnosis and rapid progression. We discuss a 66-year-old woman presenting with epigastric pain, elevated lipase and radiographic evidence of focal pancreatitis. She had no relevant medical history and no lithiasis seen on imaging. Pertinent findings include strawberry gingivitis, positive proteinase-antineutrophil cytoplasm antibody (98% specificity) and focal nodular parenchymal lung lesions on CT chest-all of which are consistent with a diagnosis of GPA. She was promptly started on high-dose steroids which resulted in significant clinical and biochemical improvement. Cyclophosphamide was added once biopsy confirmed the absence of malignancy. In order to optimise the clinical outcomes of GPA, physicians must keep a wide differential and high index of suspicion in the setting of unexplained pancreatitis with systemic features.

A living WHO guideline on drugs to prevent covid-19.

CLINICAL QUESTION: What is the role of drugs in preventing covid-19? WHY DOES THIS MATTER?: There is widespread interest in whether drug interventions can be used for the prevention of covid-19, but there is uncertainty about which drugs, if any, are effective. The first version of this living guideline focuses on the evidence for hydroxychloroquine. Subsequent updates will cover other drugs being investigated for their role in the prevention of covid-19. RECOMMENDATION: The guideline development panel made a strong recommendation against the use of hydroxychloroquine for individuals who do not have covid-19 (high certainty). HOW THIS GUIDELINE WAS CREATED: This living guideline is from the World Health Organization (WHO) and provides up to date covid-19 guidance to inform policy and practice worldwide. Magic Evidence Ecosystem Foundation (MAGIC) provided methodological support. A living systematic review with network analysis informed the recommendations. An international guideline development panel of content experts, clinicians, patients, an ethicist and methodologists produced recommendations following standards for trustworthy guideline development using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. UNDERSTANDING THE NEW RECOMMENDATION: The linked systematic review and network meta-analysis (6 trials and 6059 participants) found that hydroxychloroquine had a small or no effect on mortality and admission to hospital (high certainty evidence). There was a small or no effect on laboratory confirmed SARS-CoV-2 infection (moderate certainty evidence) but probably increased adverse events leading to discontinuation (moderate certainty evidence). The panel judged that almost all people would not consider this drug worthwhile. In addition, the panel decided that contextual factors such as resources, feasibility, acceptability, and equity for countries and healthcare systems were unlikely to alter the recommendation. The panel considers that this drug is no longer a research priority and that resources should rather be oriented to evaluate other more promising drugs to prevent covid-19. UPDATES: This is a living guideline. New recommendations will be published in this article and signposted by update notices to this guideline. READERS NOTE: This is the first version of the living guideline for drugs to prevent covid-19. It complements the WHO living guideline on drugs to treat covid-19. When citing this article, please consider adding the update number and date of access for clarity.

Blastomycosis with rapid-onset acute respiratory distress syndrome in an urban setting.

While blastomycosis is endemic to eastern USA and northwestern Ontario, acquisition is an anomaly in urban settings. We present a 54-year-old immunocompetent man from the greater Toronto area with no travel, who presented with a 3-week history of chest pain and dyspnoea. Initial radiographic workup revealed a mass-like opacification in the right apical mediastinum. Extensive investigations including bronchoscopy with bronchoalveolar lavage, mediastinal mass biopsy with fungal and mycobacterial cultures and multiple stains, and CT were unrevealing. The patient progressed to respiratory failure over 4 months. Ultimately, sputum and bone marrow cultures confirmed a diagnosis of disseminated blastomycosis. The patient required prolonged extracorporeal membrane oxygenation and ongoing ventilation postdecannulation. Our case highlights diagnostic challenges with blastomycosis, particularly in immunocompetent individuals with no travel to recreational areas, and emphasises the importance of maintaining a high index of suspicion and sending fungal cultures of appropriate specimens and/or cytopathology in clinically compatible cases.

An International Survey on the Use of Thromboprophylaxis in Urological Surgery.

BACKGROUND: The use of perioperative thromboprophylaxis in urological surgery is common but not standardized. OBJECTIVE: To characterize international practice variation in thromboprophylaxis use in urological surgery. DESIGN, SETTING, AND PARTICIPANTS: We conducted a scenario-based survey addressing the use of mechanical and pharmacological thromboprophylaxis in urological cancer procedures (radical cystectomy [RC], radical prostatectomy [RP], and radical nephrectomy [RN]) among practicing urologists in Canada, Finland, and Japan. The survey presented patient profiles reflecting a spectrum of risk for venous thromboembolism; the respondents described their clinical practice. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The proportion of respondents who routinely used (1) mechanical, (2) pharmacological, and (3) extended pharmacological prophylaxis was stratified by procedure. A logistic regression identified characteristics associated with thromboprophylaxis use. RESULTS AND LIMITATIONS: Of 1051 urologists contacted, 570 (54%) participated in the survey. Japanese urologists were less likely to prescribe pharmacological prophylaxis than Canadian or Finnish urologists (p < 0.001 for all procedures). Canadian and Finnish urologists exhibited large variation for extended pharmacological prophylaxis for RP and RN. Finnish urologists were most likely to prescribe extended prophylaxis versus Canadian and Japanese urologists (RC 98%, 84%, and 26%; Open RP 25%, 8%, and 3%; robotic RP 11%, 9%, and 0%; and RN 43%, 7%, and 1%, respectively; p < 0.001 for each procedure). Less variation was found regarding the prescription of mechanical prophylaxis, which was most commonly used until ambulation or discharge. The length of hospital stay was longer in Japan and may bias estimates of extended prophylaxis in Japan. CONCLUSIONS: We found large variation in clinical practice regarding pharmacological thromboprophylaxis within and between countries. Knowledge translation of evidence-based guidelines may reduce problematic international variation in practice. PATIENT SUMMARY: Use of medications to decrease blood clots after urological cancer surgery differs within and between countries. Closer adherence to urology guidelines addressing the prevention of blood clots may decrease this variation and improve patient outcomes.

Prognostic factors for severity and mortality in patients infected with COVID-19: A systematic review.

BACKGROUND AND PURPOSE: The objective of our systematic review is to identify prognostic factors that may be used in decision-making related to the care of patients infected with COVID-19. DATA SOURCES: We conducted highly sensitive searches in PubMed/MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase. The searches covered the period from the inception date of each database until April 28, 2020. No study design, publication status or language restriction were applied. STUDY SELECTION AND DATA EXTRACTION: We included studies that assessed patients with confirmed or suspected SARS-CoV-2 infectious disease and examined one or more prognostic factors for mortality or disease severity. Reviewers working in pairs independently screened studies for eligibility, extracted data and assessed the risk of bias. We performed meta-analyses and used GRADE to assess the certainty of the evidence for each prognostic factor and outcome. RESULTS: We included 207 studies and found high or moderate certainty that the following 49 variables provide valuable prognostic information on mortality and/or severe disease in patients with COVID-19 infectious disease: Demographic factors (age, male sex, smoking), patient history factors (comorbidities, cerebrovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, cardiovascular disease, cardiac arrhythmia, arterial hypertension, diabetes, dementia, cancer and dyslipidemia), physical examination factors (respiratory failure, low blood pressure, hypoxemia, tachycardia, dyspnea, anorexia, tachypnea, haemoptysis, abdominal pain, fatigue, fever and myalgia or arthralgia), laboratory factors (high blood procalcitonin, myocardial injury markers, high blood White Blood Cell count (WBC), high blood lactate, low blood platelet count, plasma creatinine increase, high blood D-dimer, high blood lactate dehydrogenase (LDH), high blood C-reactive protein (CRP), decrease in lymphocyte count, high blood aspartate aminotransferase (AST), decrease in blood albumin, high blood interleukin-6 (IL-6), high blood neutrophil count, high blood B-type natriuretic peptide (BNP), high blood urea nitrogen (BUN), high blood creatine kinase (CK), high blood bilirubin and high erythrocyte sedimentation rate (ESR)), radiological factors (consolidative infiltrate and pleural effusion) and high SOFA score (sequential organ failure assessment score). CONCLUSION: Identified prognostic factors can help clinicians and policy makers in tailoring management strategies for patients with COVID-19 infectious disease while researchers can utilise our findings to develop multivariable prognostic models that could eventually facilitate decision-making and improve patient important outcomes. SYSTEMATIC REVIEW REGISTRATION: Prospero registration number: CRD42020178802. Protocol available at: https://www.medrxiv.org/content/10.1101/2020.04.08.20056598v1.