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Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews. We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07-1.24) to 1.06 (95% CI 0.99-1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 (95% CI 0.97-1.18) to 1.14 (95% CI 1.03-1.26). The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies; we cannot assume our findings extend to a broader range of interventions and settings. The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited reviews and had the potential to change the conclusions of the reviews. Systematic reviews that incorporate non-randomized studies of medical interventions should include a detailed assessment of RoB for each included study.

Background Health care spending is overwhelmingly concentrated within a very small proportion of the population, referred to as the high-cost users (HCU). To date, research on HCU has been limited in scope, focusing mostly on those characteristics available through administrative databases, which have been largely clinical in nature, or have relied on ecological measures of socio-demographics. This study links population health surveys to administrative data, allowing for the investigation of a broad range of individual-level characteristics and provides a more thorough characterization of community-dwelling HCU across demographic, social, behavioral and clinical characteristics. Methods We linked three cycles of the Canadian Community Health Survey (CCHS) to medical claim data for the years 2003-2008 for Ontario, Canada. Participants were ranked according to gradients of cost (Top 1%, Top 2-5%, Top 6-50% and Bottom 50%) and multinomial logistic regression was used to investigate a wide range of factors, including health behaviors and socio-demographics, likely associated with HCU status. Results Using a total sample of 91,223 adults (18 and older), we found that HCU status was strongly associated with being older, having multiple chronic conditions, and reporting poorer self-perceived health. Specifically, in the fully-adjusted model, poor self-rated health (vs. good) was associated with a 26-fold increase in odds of becoming a Top 1% HCU (vs. Bottom 50% user) [95% CI: (18.9, 36.9)]. Further, HCU tended to be of lower socio-economic status, former daily smokers, physically inactive, current non-drinkers, and obese. Conclusions The results of this study have provided valuable insights into the broader characteristics of community-dwelling HCU, including unique demographic and behavioral characteristics. Additionally, strong associations with self-reported clinical variables, such as self-rated general and mental health, highlight the importance of the patient perspective for HCU. These findings have the potential to inform policies for health care and public health, particularly in light of increasing decision-maker attention in the sustainability of the health care system, improving patient outcomes and, more generally, in order to achieve the common goal of improving population health outcomes.

Obesity induced low-grade chronic inflammation disrupts proper immune and metabolic function. Vitamin D deficiency increases inflammation, which is associated with cardiometabolic risk. This systematic review examines the association between oral vitamin D (VD) supplementation and circulating inflammatory biomarkers and glycemic outcomes from randomized controlled trials (RCTs) of overweight and/or obese adults. MEDLINE OVID, EMBASE and the Cochrane Central Register of Controlled Trials were searched according to a predefined protocol. Eligible RCTs included adults randomized to receive either oral VD or placebo. Two reviewers independently assessed RCTs for inclusion. Bias was assessed using the Cochrane Collaboration risk of bias tool. Mean differences were calculated comparing end-of-study sample means between the independent VD and placebo groups. Eleven unique RCTs met inclusion criteria from a total of 3,383 identified citations, including 79 screened articles and 14 full text data extractions. Inflammatory and glycemic measures were reported in 7 and 10 RCTs, respectively. Most trial findings were non-significant with considerable heterogeneity in design, participants and outcomes. All but one trial was rated as either high or unclear risk of bias. Two RCTs reported significant changes in inflammatory biomarkers; however, the mean difference between groups was not statistically significant: C-reactive protein 0.19 mg/L (p = 0.88); Tumor Necrosis Factor -0.54 pg/ml (p = 0.20). Two other trials found significant mean differences in fasting plasma glucose -0.32 mmol/L (p = 0.03), Hemoglobin A1c -0.13% (p = 0.04), and Homeostatic Model Assessment -0.86 (p = 0.02) following VD supplementation. Overall, there is no clear established benefit of VD supplementation on inflammatory biomarkers among overweight/obese adults. Baseline serum VD possibly influences the effect of VD repletion on inflammatory markers. Risk of bias was present in most studies, thus supporting the need for higher quality studies in this area to more conclusively understand the role VD supplementation has on inflammatory pathways.

Background Vancomycin-resistant enterococci (VRE) are a serious antimicrobial resistant threat in the healthcare setting. We assessed the cost-effectiveness of VRE screening and isolation for patients at high-risk for colonisation on a general medicine ward compared to no VRE screening and isolation from the healthcare payer perspective. Methods We developed a microsimulation model using local data and VRE literature, to simulate a 20-bed general medicine ward at a tertiary-care hospital with up to 1000 admissions, approximating 1 year. Primary outcomes were accrued over the patient’s lifetime, discounted at 1.5%, and included expected health outcomes (VRE colonisations, VRE infections, VRE-related bacteremia, and deaths subsequent to VRE infection), quality-adjusted life years (QALYs), healthcare costs, and incremental cost-effectiveness ratio (ICER). Probabilistic sensitivity analysis (PSA) and scenario analyses were conducted to assess parameter uncertainty. Results In our base-case analysis, VRE screening and isolation prevented six healthcare-associated VRE colonisations per 1000 admissions (6/1000), 0.6/1000 VRE-related infections, 0.2/1000 VRE-related bacteremia, and 0.1/1000 deaths subsequent to VRE infection. VRE screening and isolation accrued 0.0142 incremental QALYs at an incremental cost of $112, affording an ICER of $7850 per QALY. VRE screening and isolation practice was more likely to be cost-effective (> 50%) at a cost-effectiveness threshold of $50,000/QALY. Stochasticity (randomness) had a significant impact on the cost-effectiveness. Conclusion VRE screening and isolation can be cost-effective in majority of model simulations at commonly used cost-effectiveness thresholds, and is likely economically attractive in general medicine settings. Our findings strengthen the understanding of VRE prevention strategies and are of importance to hospital program planners and infection prevention and control.

Liberated trial data have enduring potential to benefit patients, prevent harm, and correct misleading research

In December 2020, Ontario, Canada, entered a provincewide shutdown to mitigate COVID-19 transmission. A regionalized approach was taken to reopen schools throughout early 2021 without any other opening of the economy, offering a unique natural experiment to estimate the impact of school reopening on community transmission. Estimated increases of 0.07, 0.08, 0.07, and 0.13 percentage points in community COVID-19 case growth rates occurred 11-15, 16-20, 21-25, and 26-30 days, respectively, after schools reopened. Although small, these changes were particularly evident among children younger than age fourteen, increased over time, and were greater when lag periods were considered, which points to a likely causal effect between in-person classes and a small increase in transmission. These findings suggest that although additional COVID-19 cases are to be expected after the reopening of schools, these risks may be manageable with sufficient, layered mitigation policies.

Background The potential benefits of coordinating infectious disease eradication programs that use campaigns such as supplementary immunization activities (SIAs) should not be over-looked. One example of a coordinated approach is an adaptive \"sequential strategy\": first, all annual SIA budget is dedicated to the eradication of a single infectious disease; once that disease is eradicated, the annual SIA budget is re-focussed on eradicating a second disease, etc . Herd immunity suggests that a sequential strategy may eradicate several infectious diseases faster than a non-adaptive \"simultaneous strategy\" of dividing annual budget equally among eradication programs for those diseases. However, mathematical modeling is required to understand the potential extent of this effect. Methods Our objective was to illustrate how budget allocation strategies can interact with the nonlinear nature of disease transmission to determine time to eradication of several infectious diseases under different budget allocation strategies. Using a mathematical transmission model, we analyzed three hypothetical vaccine-preventable infectious diseases in three different countries. A central decision-maker can distribute funding among SIA programs for these three diseases according to either a sequential strategy or a simultaneous strategy. We explored the time to eradication under these two strategies under a range of scenarios. Results For a certain range of annual budgets, all three diseases can be eradicated relatively quickly under the sequential strategy, whereas eradication never occurs under the simultaneous strategy. However, moderate changes to total SIA budget, SIA frequency, order of eradication, or funding disruptions can create disproportionately large differences in the time and budget required for eradication under the sequential strategy. We find that the predicted time to eradication can be very sensitive to small differences in the rate of case importation between the countries. We also find that the time to eradication of all three diseases is not necessarily lowest when the least transmissible disease is targeted first. Conclusions Relatively modest differences in budget allocation strategies in the near-term can result in surprisingly large long-term differences in time required to eradicate, as a result of the amplifying effects of herd immunity and the nonlinearities of disease transmission. More sophisticated versions of such models may be useful to large international donors or other organizations as a planning or portfolio optimization tool, where choices must be made regarding how much funding to dedicate to different infectious disease eradication efforts.

Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.