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Aim: COVID‐19 has had significant mental health impacts internationally and anxiety rates are estimated to have tripled during the pandemic, but the specific causes remain underexplored. This study's purpose was to investigate the associations of sociodemographic factors, COVID‐19‐related policies, and COVID‐19 case/mortality rates with levels of anxiety among Canadians during the pandemic. Methods: This study used linear regression models populated with three integrated sources of data: a repeated cross‐sectional survey (n = 7008), Oxford COVID‐19 Government Response Tracker data, and COVID‐19 case/mortality rates. Sociodemographic factors included were age, gender, race, province, income, education, rurality, household composition, and factors related to employment. Results: Local COVID‐19 case and mortality rates and stay‐at‐home orders were positively associated with anxiety symptom severity. Anxiety was most severe among those who: were female, Indigenous, or Middle Eastern; had postsecondary education; lived with others; and became unemployed or had working hours altered during the pandemic. Anxiety was less severe among: older adults; male, Caucasians, and black individuals; those with high incomes, and; those for whom employment did not change during the pandemic. Conclusion: Anxiety was primarily driven by socioeconomic factors among Canadians during the COVID‐19 pandemic. Policies that alleviate socioeconomic uncertainty for groups that are most vulnerable may reduce the long‐term harm of the pandemic and associated lockdown policies. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to provide clinicians with introductory guidance for interpreting and assessing confidence in on Network meta-analysis (NMA) results. Methods: We reviewed current literature on NMA and summarized key points. Results: Network meta-analysis (NMA) is a statistical method for comparing the efficacy of three or more interventions simultaneously in a single analysis by synthesizing both direct and indirect evidence across a network of randomized clinical trials. It has become increasingly popular in healthcare, since direct evidence (head-to-head randomized clinical trials) are not always available. NMA methods are categorized as either Bayesian or frequentist, and while the two mostly provide similar results, the two approaches are theoretically different and require different interpretations of the results. Conclusions: We recommend a careful approach to interpreting NMA results and the validity of an NMA depends on its underlying statistical assumptions and the quality of the evidence used in the NMA. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that less frequent repositioning of long‐term care residents at moderate to high risk of developing pressure ulcers (PrUs) is noninferior to current repositioning standards in preventing PrUs, but the long‐term health and economic consequences of less frequent repositioning have not been adequately estimated. Our objective was to estimate the cost‐effectiveness of different repositioning strategies (2‐, 3‐, 4‐hour intervals). We conducted a cost‐utility analysis using a lifetime horizon based on data from a randomized clinical trial and the literature. We updated a published PrU decision model with resource usage, unit costs, and epidemiological estimates from the literature and from a small observational study. The Ontario Ministry of Health and Long‐Term Care perspective was taken. We estimated lifetime costs to be CAN$5,425 (95% credible interval (CrI)=$922–12,166) less per resident with 3‐hour repositioning than with 2‐hour repositioning and CAN$3,296 (95% CrI=$483–9,738) less than with 4‐hour repositioning. The gain in expected quality‐adjusted life years from a 3‐ to a 2‐hour repositioning strategy was 0.008, (95% CrI=0.005–0.016) and from a 3‐ to a 4‐hour repositioning strategy was 0.009 (95% CrI=0.007–0.018). Repositioning at 3‐hour intervals was the dominant strategy with respect to the incremental cost‐effectiveness ratio against the 2‐ and 4‐hour strategies. Sensitivity analysis showed a 99% probability that 3‐hour repositioning was a dominant strategy. We concluded that repositioning at 3‐hour intervals for residents at moderate or high risk of PrUs and who were cared for on high‐density foam mattresses appeared to be the most cost‐effective strategy. [ABSTRACT FROM AUTHOR]

Androgen‐deprivation therapy (ADT) is an effective treatment for men with advanced prostate cancer, but loss of bone mineral density (BMD) is a major risk factor for fractures. This review compared the efficacy of available treatments to provide prescribing guidance to healthcare professionals. This is the first review to compare the effectiveness of different osteoporotic treatments (bisphosphonates, denosumab, toremifene, and raloxifene) on BMD in patients with non‐metastatic prostate cancer on ADT using network meta‐analysis. Results suggest that all evaluated treatments are effective in improving BMD compared to placebo. Zoledronic acid (ZA) was found to have a greater improvement in BMD compared to other active treatments at all three studied sites, except for risedronate, which had better BMD improvement compared to ZA at the femoral neck site in one small study. Our study did not identify evidence that one drug is unequivocally more effective than another. All drugs appeared to be effective in reducing the rate of bone loss. Healthcare professionals should also consider patient preference, costs, and local availability as part of the decision process. [ABSTRACT FROM AUTHOR]

Purpose To use patient-level microsimulation models to evaluate the comparative cost-effectiveness of early corneal cross-linking (CXL) and conventional management with penetrating keratoplasty (PKP) when indicated in managing keratoconus in Canada. Design Cost-utility analysis using individual-based, state–transition microsimulation models. Participants Simulated cohorts of 100 000 individuals with keratoconus who entered each treatment arm at 25 years of age. Fellow eyes were modeled separately. Simulated individuals lived up to a maximum of 110 years. Methods We developed 2 state–transition microsimulation models to reflect the natural history of keratoconus progression and the impact of conventional management with PKP versus CXL. We collected data from the published literature to inform model parameters. We used realistic parameters that maximized the potential costs and complications of CXL, while minimizing those associated with PKP. In each treatment arm, we allowed simulated individuals to move through health states in monthly cycles from diagnosis until death. Main Outcome Measures For each treatment strategy, we calculated the total cost and number of quality-adjusted life years (QALYs) gained. Costs were measured in Canadian dollars. Costs and QALYs were discounted at 5%, converting future costs and QALYs into present values. We used an incremental cost-effectiveness ratio (ICER = difference in lifetime costs/difference in lifetime health outcomes) to compare the cost-effectiveness of CXL versus conventional management with PKP. Results Lifetime costs and QALYs for CXL were estimated to be Can$5530 (Can$4512, discounted) and 50.12 QALYs (16.42 QALYs, discounted). Lifetime costs and QALYs for conventional management with PKP were Can$2675 (Can$1508, discounted) and 48.93 QALYs (16.09 QALYs, discounted). The discounted ICER comparing CXL to conventional management was Can$9090/QALY gained. Sensitivity analyses revealed that in general, parameter variations did not influence the cost-effectiveness of CXL. Conclusions CXL is cost-effective compared with conventional management with PKP in the treatment of keratoconus. Our ICER of Can$9090/QALY falls well below the range of Can$20 000 to Can$100 000/QALY and below US$50 000/QALY, thresholds generally used to evaluate the cost-effectiveness of health interventions in Canada and the United States. This study provides strong economic evidence for the cost-effectiveness of early CXL in keratoconus. [ABSTRACT FROM AUTHOR]

Background: Medication reviews have become part of pharmacy practice across developed countries. This study aimed to identify factors affecting the likelihood of eligible Ontario seniors receiving a pharmacy-led medication review called MedsCheck annual (MCA). Methods: We designed a cohort study using a random sample of pharmacy claims for MCA-eligible Ontario seniors using linked administrative data from April 2012 to March 2013. Guided by a conceptual framework, we constructed a generalized-estimating-equations model to estimate the effect of patient, pharmacy and community factors on the likelihood of receiving MCA. Results: Of the 2,878,958 eligible claim-dates, 65,605 included an MCA. Compared to eligible individuals who did not receive an MCA, recipients were more likely to have a prior MCA (OR = 3.03), receive a new medication on the claim-date (OR = 1.78), be hypertensive (OR = 1.18) or have a recent hospitalization (OR = 1.07). MCA recipients had fewer medications (e.g., OR = 0.44 for ≥12 medications versus 0-4 medications), and were less likely to receive an MCA in a rural (OR = 0.74) or high-volume pharmacy (OR = 0.65). Conclusions: The most important determinant of receiving an MCA was having had a prior MCA. Overall, MCA recipients were healthier, younger, urban-dwelling, and taking fewer medications than non-recipients. Policies regarding current and future medication review programs may need to evolve to ensure that those at greatest need receive timely and comprehensive medication reviews. [ABSTRACT FROM AUTHOR]

Background: There are numerous health-related quality of life (HRQol) measurements used in coronary heart disease (CHD) in the literature. However, only values assessed with preference-based instruments can be directly applied in a cost-utility analysis (CUA). Objective: To summarize and synthesize instrument-specific preference-based values in CHD and the underlying disease-subgroups, stable angina and post-acute coronary syndrome (post-ACS), for developed countries, while accounting for study-level characteristics, and within- and between-study correlation. Methods: A systematic review was conducted to identify studies reporting preference-based values in CHD. A multivariate meta-analysis was applied to synthesize the HRQoL values. Meta-regression analyses examined the effect of study level covariates age, publication year, prevalence of diabetes and gender. Results: A total of 40 studies providing preference-based values were detected. Synthesized estimates of HRQoL in post-ACS ranged from 0.64 (Quality of Well-Being) to 0.92 (EuroQol European”tariff”), while in stable angina they ranged from 0.64 (Short form 6D) to 0.89 (Standard Gamble). Similar findings were observed in estimates applying to general CHD. No significant improvement in model fit was found after adjusting for study-level covariates. Large between-study heterogeneity was observed in all the models investigated. Conclusions: The main finding of our study is the presence of large heterogeneity both within and between instrument-specific HRQoL values. Current economic models in CHD ignore this between-study heterogeneity. Multivariate meta-analysis can quantify this heterogeneity and offers the means for uncertainty around HRQoL values to be translated to uncertainty in CUAs. [ABSTRACT FROM AUTHOR]

Background and Overview. In everyday practice, dentists face clinical decisions for which they need to consider both treatment consequences (that is, benefits and harms) and costs. Economic analysis is a study design in which investigators evaluate and compare the costs and consequences of different treatment alternatives within a defined period. A critical appraisal of such studies includes an assessment of the risk of bias, results, and applicability of the study. The authors provide the concepts and guidelines that dentists can apply to critically appraise economic analyses. Practical Implications. Dentists who wish to inform their clinical decisions regarding questions that involve both treatment consequences and costs can use these guidelines to understand the different types of economic analyses and to decide what type of economic analyses to search for, as well as to critically appraise any economic analyses identified. [ABSTRACT FROM AUTHOR]

Mixed treatment comparison (MTC) models rely on estimates of relative effectiveness from randomized clinical trials so as to respect randomization across treatment arms. This approach could potentially be simplified by an alternative parameterization of the way effectiveness is modeled. We introduce a treatment-based parameterization of the MTC model that estimates outcomes on both the study and treatment levels. We compare the proposed model to the commonly used MTC models using a simulation study as well as three randomized clinical trial datasets from published systematic reviews comparing (i) treatments on bleeding after cirrhosis, (ii) the impact of antihypertensive drugs in diabetes mellitus, and (iii) smoking cessation strategies. The simulation results suggest similar or sometimes better performance of the treatment-based MTC model. Moreover, from the real data analyses, little differences were observed on the inference extracted from both models. Overall, our proposed MTC approach performed as good, or better, than the commonly applied indirect and MTC models and is simpler, fast, and easier to implement in standard statistical software. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objectives Patients receiving therapy for haematological malignancies have a higher risk of invasive fungal infections (IFIs). Antifungal prophylaxis is an effective strategy against IFIs, but relative effectiveness estimates across agents are inconclusive. A mixed treatment comparison (MTC) was conducted to estimate the relative effectiveness of all agents for a number of outcomes of interest. Methods A systematic review was performed to collect evidence from randomized controlled trials (RCTs) on the risk of IFIs and on mortality after antifungal prophylaxis. The agents analysed were no prophylaxis/placebo, fluconazole, itraconazole, micafungin, caspofungin, liposomal amphotericin B and posaconazole. Meta-analyses and MTCs were used to synthesize the evidence. The primary outcome was the risk of proven or probable IFI. Secondary outcomes were risk of candidiasis/aspergillosis, risk of IFI mortality and risk of all-cause mortality. Results Antifungal prophylaxis was more effective than no prophylaxis/placebo in reducing IFI risk. The IFI risk after voriconazole or posaconazole was lower than after fluconazole [relative risk (RR) 0.38, 95% CI 0.14–0.83 and RR 0.34, 95% CI 0.14–0.83] or itraconazole tablets (RR 0.22 95% CI 0.06–0.72 and RR 0.20 95% CI 0.05–0.72). Posaconazole was also found to be more effective than no prophylaxis/placebo in reducing all-cause mortality (RR 0.56, 95% CI 0.30–0.98). Posaconazole had the highest probability of being the most effective agent in reducing IFI risk and all-cause mortality. Conclusions IFI prophylaxis has a positive effect on IFI risk reduction. However, its effect on all-cause mortality is not as pronounced. The analysis has additionally pinpointed posaconazole as potentially the most effective IFI prophylaxis in neutropenic patients. [ABSTRACT FROM PUBLISHER]

Background: New targeted therapeutics for metastatic renal cell carcinoma (mRCC) enable an increment in progression-free survival (PFS) ranging from 2 to 6 months. Compared with best supportive care, everolimus demonstrated an additional PFS of 3 months in patients with mRCC whose disease had progressed on sunitinib and/or sorafenib. The only targeted therapy for mRCC currently reimbursed in Serbia is sunitinib. Objective: The aim of this study was to estimate the cost-effectiveness and the budget impact of the introduction of everolimus in Serbia in comparison to best supportive care, for mRCC patients refractory to sunitinib. Methods: A Markov model was designed corresponding with Serbian treatment protocols. A health care payer perspective was taken, including direct costs only. Treated and untreated cohorts were followed up over 18 cycles, each cycle lasting 8 weeks, which covered the lifetime horizon of mRCC patients refractory to the first-line treatment. Annual discounted rates of 1.5% for effectiveness and 3% for costs were applied. Transitions between health states were modeled by time-dependent probabilities extracted from published Kaplan-Meier curves of PFS and overall survival (OS). Utility values were obtained from the appraisals of other mRCC treatments. One-way and probabilistic sensitivity analyses were done to test the robustness and uncertainty of the base-case estimate. Lastly, the potential impacts of everolimus on the overall health care expenditures on annual and 4-year bases were estimated in the budget-impact analysis. Results: The incremental cost-effectiveness ratio for everolimus was estimated at €86,978 per quality-adjusted life-year. Sensitivity analysis identified the hazard multiplier, a statistical approximator of OS gain, as the main driver of everolimus cost-effectiveness. Furthermore, probabilistic sensitivity analyses revealed a wide 95% CI around the base-case incremental cost-effectiveness ratio estimate (€32,594–€425,258 per quality-adjusted life-year). Finally, an average annual budgetary impact of everolimus in first 4 years after its potential reimbursement would be around €270,000, contributing to <1% of the total budget in Serbian oncology. Conclusions: Everolimus as a second-line treatment of mRCC is not likely to be a cost-effective option under the present conditions in Serbia, with a relatively limited impact on its budget in oncology. A major constraint on the estimation of the cost- effectiveness of everolimus relates to the uncertainty around the everolimus effect on extending OS. How- ever, prior to a final decision on the acceptance/ rejection of everolimus, reassessment of the whole therapeutic group might be needed to construct an economically rational treatment strategy within the mRCC field. [ABSTRACT FROM AUTHOR]

Background: Despite the increase in cancer incidence in the last years in Serbia, no nation-wide, population-based cancer epidemiology data have been reported. In this study cancer incidence and mortality rates for Serbia are presented using nation-wide data from two population-based cancer registries. These rates are additionally compared to European and global cancer epidemiology estimates. Finally, predictions on Serbian cancer incidence and mortality rates are provided. Methods: Cancer incidence and mortality was collected from the cancer registries of Central Serbia and Vojvodina from 1999 to 2009. Using age-specific regression models, we estimated time trends and predictions for cancer incidence and mortality for the following five years (2010-2014). The comparison of Serbian with European and global cancer incidence/mortality rates, adjusted to the world population (ASR-W) was performed using Serbian population-based data and estimates from GLOBOCAN 2008. Results: Increasing trends in both overall cancer incidence and mortality rates were identified for Serbia. In men, lung cancer showed the highest incidence (ASR-W 2009: 70.8/100,000), followed by colorectal (ASR-W 2009: 39.9/100,000), prostate (ASR-W 2009: 29.1/100,000) and bladder cancer (ASR-W 2009: 16.2/100,000). Breast cancer was the most common form of cancer in women (ASR-W 2009: 70.8/100,000) followed by cervical (ASR-W 2009: 25.5/100,000), colorectal (ASR-W 2009: 21.1/100,000) and lung cancer (ASR-W 2009: 19.4/100,000). Prostate and colorectal cancers have been significantly increasing over the last years in men, while this was also observed for breast cancer incidence and lung cancer mortality in women. In 2008 Serbia had the highest mortality rate from breast cancer (ASR-W 2008: 22.7/100,000), among all European countries while incidence and mortality of cervical, lung and colorectal cancer were well above European estimates. Conclusion: Cancer incidence and mortality in Serbia has been generally increasing over the past years. For a number of cancer sites, incidence and mortality is alarmingly higher than in the majority of European regions. For this increasing trend to be controlled, the management of risk factors that are present among the Serbian population is necessary. Additionally, prevention and early diagnosis are areas where significant improvements could still be made. [ABSTRACT FROM AUTHOR]

There has been a large increase in the incidence of invasive fungal infections (IFIs) over the past decades, largely because of the increasing size of the population at risk. One of the major risk groups for IFIs are patients with haematological malignancies treated with cytotoxic chemotherapy or undergoing haematopoietic stem cell transplantation. These IFIs are associated with high morbidity and mortality rates. Consequently, as the diagnosis of IFIs is difficult, antifungal prophylaxis is desirable in high-risk patients. Furthermore, as the economic impact of IFIs is also significant, it is important to assess the cost benefit and cost effectiveness of each prophylactic agent in order to aid decisions concerning which prophylactic agent provides the best value for limited healthcare resources. This article systematically reviews the available pharmacoeconomic evidence regarding antifungal prophylaxis in immunocompromised patients treated for haematological malignancies. Furthermore, specific points of interest concerning economic analyses of antifungal prophylaxis are briefly discussed. Considering the available evidence, antifungal prophylaxis in immunocompromised patients treated for haematological malignancies seems to be an intervention with favourable cost-benefit, cost-effectiveness and costsaving potential. Furthermore, recently introduced antifungal agents seem to be attractive alternatives to fluconazole from a pharmacoeconomic point of view. However, due to wide heterogeneity in patient characteristics, underlying diseases, hospital settings and study methods in the included economic studies, as well as the lack of 'head-to-head' trials, it is difficult to find clear evidence of the economic advantages of a single prophylactic agent. Furthermore, we show that the results of cost-effectiveness analyses are highly dependent on several crucial factors that influence the baseline IFI incidence rates and, therefore, differ per patient population or region. [ABSTRACT FROM AUTHOR]

Background: As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics. Methods: We utilized a linked prescription dataset originating from a general practitioner (GP) and a pharmacy database, both from the northern Netherlands. We selected specific drugs of interest, containing about 55,000 prescriptions from 15 different classes. We used a crossed generalized linear mixed model to estimate the effects that certain patient and pharmacy characteristics as well as timing have on the likelihood that a prescription will eventually be substituted by the pharmacist. Results: Generic substitution occurred at 25% of the branded prescriptions. Generic substitution was more likely to occur earlier in time after patent expiry and to patients that were older and more experienced in their drug use. Individually owned pharmacies had a lower probability of generic substitution compared to chain pharmacies. Oppositely, branded substitution occurred in 10% of generic prescriptions and was positively related to the patients' experience in branded use. Individually owned pharmacies were more likely to substitute a generic drug to a branded compared to other pharmacies. Antidepressant and PPI prescriptions were less prone to generic and more prone to branded substitution. Conclusion: Analysis of prescription substitution by the pharmacist revealed strong relations between substitution and patient experience on drug use, pharmacy status and timing. These findings can be utilised to design further strategies to enhance generic substitution. [ABSTRACT FROM AUTHOR]

Background: As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics. Methods: We utilized a linked prescription dataset originating from a general practitioner (GP) and a pharmacy database, both from the northern Netherlands. We selected specific drugs of interest, containing about 55,000 prescriptions from 15 different classes. We used a crossed generalized linear mixed model to estimate the effects that certain patient and pharmacy characteristics as well as timing have on the likelihood that a prescription will eventually be substituted by the pharmacist. Results: Generic substitution occurred at 25% of the branded prescriptions. Generic substitution was more likely to occur earlier in time after patent expiry and to patients that were older and more experienced in their drug use. Individually owned pharmacies had a lower probability of generic substitution compared to chain pharmacies. Oppositely, branded substitution occurred in 10% of generic prescriptions and was positively related to the patients' experience in branded use. Individually owned pharmacies were more likely to substitute a generic drug to a branded compared to other pharmacies. Antidepressant and PPI prescriptions were less prone to generic and more prone to branded substitution. Conclusion: Analysis of prescription substitution by the pharmacist revealed strong relations between substitution and patient experience on drug use, pharmacy status and timing. These findings can be utilised to design further strategies to enhance generic substitution. [ABSTRACT FROM AUTHOR]

Objective: The study''s objective was to analyze the adoption and persistence of risperidone long-acting injectable (RLAI) therapy after its introduction in the Netherlands in 2003 compared with the adoption and persistence of existing first-generation antipsychotic (FGA) depot drugs as an example of the diffusion of a new drug in the Netherlands. Methods: Data on antipsychotic use were obtained from the InterAction DataBase (IADB.nl), a database containing pharmacy dispensing records of patients in the northern Netherlands, from May 20, 2003, to December 31, 2006. Treatment complexity for patients prescribed RLAI was analyzed on the basis of psychotropic comedication at baseline and during treatment, as well as on the number of previous antipsychotic therapies. Differences in treatment complexity between patients using RLAI and those using FGA depot drugs were estimated using parametric regressions. To evaluate persistence, survival analysis techniques were applied to estimate the probability of patients continuing the use of RLAI or FGA depot drugs over time. Results: Data on 435 patients who were treated with depot antipsychotics were extracted from the IADB.nl. Patients had a mean (SD) age of 40.7 (13.8) years, and 65% of them were male. The results of this analysis indicated that persistence for patients prescribed RLAI was significantly lower compared with other depot antipsychotics (RLAI vs zuclopenthixol, P = 0.002; RLAI vs all other depot antipsychotics, P = 0.009). At the initiation of treatment, patients prescribed RLAI had more previous psychotropic comedication and had, on average, ~5 and ~1.5 times more prior depot drug therapies compared with zuclopenthixol and any other FGA depot drug, respectively. Conclusions: The findings of this study suggest that RLAI has been prescribed more often for difficult-totreat patients than have other available depot antipsychotics. This may explain the low adoption and poor persistence observed in the first few years after the introduction of RLAI. Further research with more extensive data should be pursued to obtain better understanding of the current diffusion of RLAI in daily clinical practice. [Copyright &y& Elsevier]

Background: Childhood cancer survivors are at increased risk of late mortality (death =5 years after diagnosis) from cancer recurrence and treatment-related late effects. The authors conducted a systematic review and meta-analysis to provide comprehensive estimates of late mortality risk among survivors internationally and to investigate differences in risk across world regions. Methods: Health sciences databases were searched for cohort studies comprised of 5-year childhood cancer survivors in which the risk of mortality was evaluated across multiple cancer types. Eligible studies assessed all-cause mortality risk in survivors relative to the general population using the standardized mortality ratio (SMR). The absolute excess risk (AER) was assessed as a secondary measure to examine excess deaths. Cause-specific mortality risk was also assessed, if reported. SMRs from nonoverlapping cohorts were combined in subgroup meta-analysis, and the effect of world region was tested in univariate meta-regression. Results: Nineteen studies were included, and cohort sizes ranged from 314 to 77,423 survivors. Throughout survivorship, SMRs for all-cause mortality generally declined, whereas AERs increased after 15-20 years from diagnosis in several cohorts. All-cause SMRs were significantly lower overall in North American studies than in European studies (relative SMR, 0.63; 95% confidence interval, 0.49-0.80). SMRs for subsequent malignant neoplasms and for cardiovascular, respiratory, and external causes did not vary significantly between world regions. Conclusions: The current findings suggest that late mortality risk may differ significantly between world regions, but these conclusions are based on a limited number of studies with considerable heterogeneity. Reasons for regional differences remain unclear but may be better elucidated through future analyses of individual-level data. [ABSTRACT FROM AUTHOR]

Multi-criteria decision analysis (MCDA) is a value assessment tool designed to help support complex decision-making by incorporating multiple factors and perspectives in a transparent, structured approach. We developed an MCDA rating tool, consisting of seven criteria evaluating the importance and feasibility of conducting potential real-world evidence (RWE) studies aimed at addressing uncertainties stemming from initial cancer drug funding recommendations. In collaboration with the Canadian Agency for Drugs and Technologies in Health's Provincial Advisory Group, a validation exercise was conducted to further evaluate the application of the rating tool using RWE proposals varying in complexity. Through this exercise, we aimed to gain insight into consensus building and deliberation processes and to identify efficiencies in the application of the rating tool. An experienced facilitator led a multidisciplinary committee, consisting of 11 Canadian experts, through consensus building, deliberation, and prioritization. A total of nine RWE proposals were evaluated and prioritized as low (n = 4), medium (n = 3), or high (n = 2) priority. Through an iterative process, efficiencies and recommendations to improve the rating tool and associated procedures were identified. The refined MCDA rating tool can help decision-makers prioritize important and feasible RWE studies for research and can enable the use of RWE for the life-cycle evaluation of cancer drugs. [ABSTRACT FROM AUTHOR]

Background and Objective: Decision models for health technology assessment (HTA) are largely submitted to HTA agencies using commercial software, which has known limitations. The use of the open-source programming language R has been suggested because of its efficiency, transparency, reproducibility, and ability to consider complex analyses. However, its use in HTA remains limited. This qualitative study aimed to explore the main reasons for this slow uptake of R in HTA and identify tangible facilitators. Methods: We undertook two semi-structured focus group discussions with 24 key stakeholders from government agencies, consultancy, pharmaceutical companies, and academia. Two 1.5-hour discussions reflected on barriers identified in a previous study and highlighted additional barriers. Discussions were recorded and semi-transcribed, and data were organized and summarized into key themes. Results: Human resources constraints were identified as a key barrier, including a lack of training, prioritization and collaboration, and resistance to change. Another key barrier was the lack of acceptance, or clear guidance, around submissions in R by HTA agencies. Participants also highlighted a lack of communication around accepted packages and decision model structures, and between HTA agencies on standard decision modeling structures. Conclusions: There is a need for standardization, which can facilitate decision model sharing, coding homogeneity, and improved country adaptations. The creation of training materials and tailored workshops was identified as a key short-term facilitator. Increased communication and engagement of stakeholders could also facilitate the use of R by identifying needs and opportunities, encouraging HTA agencies to address structural barriers, and increasing incentives to use R. [ABSTRACT FROM AUTHOR]

A response from the author of the article "A Practical Approach to Evidence-Based Dentistry: IX: How to Appraise and Use an Article About Economic Analysis" in the 2015 issue is presented.

The use of open-source programming languages, such as R, in health decision sciences is growing and has the potential to facilitate model transparency, reproducibility, and shareability. However, realizing this potential can be challenging. Models are complex and primarily built to answer a research question, with model sharing and transparency relegated to being secondary goals. Consequently, code is often neither well documented nor systematically organized in a comprehensible and shareable approach. Moreover, many decision modelers are not formally trained in computer programming and may lack good coding practices, further compounding the problem of model transparency. To address these challenges, we propose a high-level framework for model-based decision and cost-effectiveness analyses (CEA) in R. The proposed framework consists of a conceptual, modular structure and coding recommendations for the implementation of model-based decision analyses in R. This framework defines a set of common decision model elements divided into five components: (1) model inputs, (2) decision model implementation, (3) model calibration, (4) model validation, and (5) analysis. The first four components form the model development phase. The analysis component is the application of the fully developed decision model to answer the policy or the research question of interest, assess decision uncertainty, and/or to determine the value of future research through value of information (VOI) analysis. In this framework, we also make recommendations for good coding practices specific to decision modeling, such as file organization and variable naming conventions. We showcase the framework through a fully functional, testbed decision model, which is hosted on GitHub for free download and easy adaptation to other applications. The use of this framework in decision modeling will improve code readability and model sharing, paving the way to an ideal, open-source world. [ABSTRACT FROM AUTHOR]

The volume and technical complexity of both academic and commercial research using decision analytic modelling has increased rapidly over the last two decades. The range of software programs used for their implementation has also increased, but it remains true that a small number of programs account for the vast majority of cost-effectiveness modelling work. We report a comparison of four software programs: TreeAge Pro, Microsoft Excel, R and MATLAB. Our focus is on software commonly used for building Markov models and decision trees to conduct cohort simulations, given their predominance in the published literature around cost-effectiveness modelling. Our comparison uses three qualitative criteria as proposed by Eddy et al.: "transparency and validation", "learning curve" and "capability". In addition, we introduce the quantitative criterion of processing speed. We also consider the cost of each program to academic users and commercial users. We rank the programs based on each of these criteria. We find that, whilst Microsoft Excel and TreeAge Pro are good programs for educational purposes and for producing the types of analyses typically required by health technology assessment agencies, the efficiency and transparency advantages of programming languages such as MATLAB and R become increasingly valuable when more complex analyses are required. [ABSTRACT FROM AUTHOR]

Investigating for mismatch repair protein deficiency (MMRd), microsatellite instability (MSI), and Lynch syndrome (LS) is widely accepted in endometrial cancer, but knowledge is limited on its value in epithelial ovarian cancer (EOC). The primary objective was to evaluate the prevalence of mismatch repair protein deficiency (MMRd), microsatellite instability (MSI)-high, and Lynch syndrome (LS) in epithelial ovarian cancer (EOC), as well as the diagnostic accuracy of LS screening tests. The secondary objective was to determine the prevalence of MMRd, MSI-high, and LS in synchronous ovarian endometrial cancer and in histological subtypes. We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process and Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, and Embase databases. We included studies analysing MMR, MSI, and/or LS by sequencing. A total of 55 studies were included. The prevalence of MMRd, MSI-high, and LS in EOC was 6% (95% confidence interval (CI) 5–8%), 13% (95% CI 12–15%), and 2% (95% CI 1–3%) respectively. Hypermethylation was present in 76% of patients with MLH1 deficiency (95% CI 64–84%). The MMRd prevalence was highest in endometrioid (12%) followed by non-serous non-mucinous (9%) and lowest in serous (1%) histological subtypes. MSI-high prevalence was highest in endometrioid (12%) and non-serous non-mucinous (12%) and lowest in serous (9%) histological subtypes. Synchronous and endometrioid EOC had the highest prevalence of LS pathogenic variants at 7% and 3% respectively, with serous having lowest prevalence (1%). Synchronous ovarian and endometrial cancers had highest rates of MMRd (28%) and MSI-high (28%). Sensitivity was highest for IHC (91.1%) and IHC with MSI (92.8%), while specificity was highest for IHC with methylation (92.3%). MMRd and germline LS testing should be considered for non-serous non-mucinous EOC, particularly for endometrioid. The rates of mismatch repair deficiency, microsatellite instability high, and mismatch repair germline mutations are highest in endometrioid subtype and non-serous non-mucinous ovarian cancer. The rates are lowest in serous histologic subtype. • Prevalence of MMRd, MSI-high, and LS is highest in endometrioid histological subtype, followed by non-serous non-mucinous histology • Serous histology has the lowest prevalence of MMRd, MSI-high, and LS • IHC with hypermethylation has high specificity (92.3%) and positive predictive value (67%) as a screening test for LS in EOC, however this is based on limited data [ABSTRACT FROM AUTHOR]

Background: Despite the increase in cancer incidence in the last years in Serbia, no nation-wide, population-based cancer epidemiology data have been reported. In this study cancer incidence and mortality rates for Serbia are presented using nation-wide data from two population-based cancer registries. These rates are additionally compared to European and global cancer epidemiology estimates. Finally, predictions on Serbian cancer incidence and mortality rates are provided.Methods: Cancer incidence and mortality was collected from the cancer registries of Central Serbia and Vojvodina from 1999 to 2009. Using age-specific regression models, we estimated time trends and predictions for cancer incidence and mortality for the following five years (2010-2014). The comparison of Serbian with European and global cancer incidence/mortality rates, adjusted to the world population (ASR-W) was performed using Serbian population-based data and estimates from GLOBOCAN 2008.Results: Increasing trends in both overall cancer incidence and mortality rates were identified for Serbia. In men, lung cancer showed the highest incidence (ASR-W 2009: 70.8/100,000), followed by colorectal (ASR-W 2009: 39.9/100,000), prostate (ASR-W 2009: 29.1/100,000) and bladder cancer (ASR-W 2009: 16.2/100,000). Breast cancer was the most common form of cancer in women (ASR-W 2009: 70.8/100,000) followed by cervical (ASR-W 2009: 25.5/100,000), colorectal (ASR-W 2009: 21.1/100,000) and lung cancer (ASR-W 2009: 19.4/100,000). Prostate and colorectal cancers have been significantly increasing over the last years in men, while this was also observed for breast cancer incidence and lung cancer mortality in women. In 2008 Serbia had the highest mortality rate from breast cancer (ASR-W 2008: 22.7/100,000), among all European countries while incidence and mortality of cervical, lung and colorectal cancer were well above European estimates.Conclusion: Cancer incidence and mortality in Serbia has been generally increasing over the past years. For a number of cancer sites, incidence and mortality is alarmingly higher than in the majority of European regions. For this increasing trend to be controlled, the management of risk factors that are present among the Serbian population is necessary. Additionally, prevention and early diagnosis are areas where significant improvements could still be made. [ABSTRACT FROM AUTHOR]

Background: As in other societies, pharmaceutical expenditures in the Netherlands are rising every year. As a consequence, needs for cost control are often expressed. One possible solution for cost control could come through increasing generic substitution by pharmacists. We aim to analyse the extent and nature of substitution in recent years and estimate the likelihood of generic or branded substitution in Dutch pharmacies in relation to various characteristics.Methods: We utilized a linked prescription dataset originating from a general practitioner (GP) and a pharmacy database, both from the northern Netherlands. We selected specific drugs of interest, containing about 55,000 prescriptions from 15 different classes. We used a crossed generalized linear mixed model to estimate the effects that certain patient and pharmacy characteristics as well as timing have on the likelihood that a prescription will eventually be substituted by the pharmacist.Results: Generic substitution occurred at 25% of the branded prescriptions. Generic substitution was more likely to occur earlier in time after patent expiry and to patients that were older and more experienced in their drug use. Individually owned pharmacies had a lower probability of generic substitution compared to chain pharmacies. Oppositely, branded substitution occurred in 10% of generic prescriptions and was positively related to the patients' experience in branded use. Individually owned pharmacies were more likely to substitute a generic drug to a branded compared to other pharmacies. Antidepressant and PPI prescriptions were less prone to generic and more prone to branded substitution.Conclusion: Analysis of prescription substitution by the pharmacist revealed strong relations between substitution and patient experience on drug use, pharmacy status and timing. These findings can be utilised to design further strategies to enhance generic substitution. [ABSTRACT FROM AUTHOR]

Background: We sought to determine the cost‐effectiveness of noninvasive fetal RhD blood group genotyping in nonalloimmunized and alloimmunized pregnancies in Canada. Study design and methods: We developed two probabilistic state‐transition (Markov) microsimulation models to compare fetal genotyping followed by targeted management versus usual care (i.e., universal Rh immunoglobulin [RhIG] prophylaxis in nonalloimmunized RhD‐negative pregnancies, or universal intensive monitoring in alloimmunized pregnancies). The reference case considered a healthcare payer perspective and a 10‐year time horizon. Sensitivity analysis examined assumptions related to test cost, paternal screening, subsequent pregnancies, other alloantibodies (e.g., K, Rh c/C/E), societal perspective, and lifetime horizon. Results: Fetal genotyping in nonalloimmunized pregnancies (at per‐sample test cost of C$247/US$311) was associated with a slightly higher probability of maternal alloimmunization (22 vs. 21 per 10,000) and a reduced number of RhIG injections (1.427 vs. 1.795) than usual care. It was more expensive (C$154/US$194, 95% Credible Interval [CrI]: C$139/US$175‐C$169/US$213) and had little impact on QALYs (0.0007, 95%CrI: −0.01–0.01). These results were sensitive to the test cost (threshold achieved at C$88/US$111), and inclusion of paternal screening. Fetal genotyping in alloimmunized pregnancies (at test cost of C$328/US$413) was less expensive (‐C$6280/US$7903, 95% CrI: ‐C$6325/US$7959 to ‐C$6229/US$7838) and more effective (0.19 QALYs, 95% CrI 0.17–0.20) than usual care. These cost savings remained robust in sensitivity analyses. Discussion: Noninvasive fetal RhD genotyping saves resources and represents good value for the management of alloimmunized pregnancies. If the cost of genotyping is substantially decreased, the targeted intervention can become a viable option for nonalloimmunized pregnancies. [ABSTRACT FROM AUTHOR]

Nearly half of patients transferred from non-trauma to trauma centres have minor injuries. The transfer of patients with minor injuries to trauma centres is not associated with any known patient benefit and represents an opportunity to reduce healthcare costs and improve patient experience. In this study, we evaluated the relationship between hospital resources and overtriage, with the objective of identifying targets for system-level intervention. We conducted a population-based cohort study of adults, age ≥ 16, presenting with minor injuries to non-trauma centres in Ontario, Canada (2009–2020). The primary outcome was overtriage, defined as transfer to a trauma centre. Hierarchical logistic regression was used to evaluate the association between hospital resources and a patient's likelihood of being overtriaged, adjusting for case-mix. amongst 165,302 patients with minor injuries, 15,641 (9.5 %) were transferred to a trauma centre (overtriage). Presence of a CT scanner, surgical support, or intensive care unit had no impact on a patient's likelihood of overtriage. Relative to community hospitals, presentation to a teaching hospital was independently associated with greater odds of overtriage (OR 2.97, 95 % CI: 1.26–7.00). Accounting for case-mix and resources, the median difference in a patient's odds of overtriage varied 3.7-fold across non-trauma centres (MOR 3.76). There is significant variability in overtriage across non-trauma centres, even after adjusting for case-mix and hospital resources. These finding suggests that some centres have developed processes to minimize overtriage independent of available resources. Broad implementation of these processes may represent an opportunity for system-wide quality improvement. [ABSTRACT FROM AUTHOR]

Introduction: Extrapolation of time-to-event data from clinical trials is commonly used in decision models for health technology assessment (HTA). The objective of this study was to assess performance of standard parametric survival analysis techniques for extrapolation of time-to-event data for a single event from clinical trials with limited data due to small samples or short follow-up.Methods: Simulated populations with 50,000 individuals were generated with an exponential hazard rate for the event of interest. A scenario consisted of 5000 repetitions with six sample size groups (30-500 patients) artificially censored after every 10% of events observed. Goodness-of-fit statistics (AIC, BIC) were used to determine the best-fitting among standard parametric distributions (exponential, Weibull, log-normal, log-logistic, generalized gamma, Gompertz). Median survival, one-year survival probability, time horizon (1% survival time, or 99th percentile of survival distribution) and restricted mean survival time (RMST) were compared to population values to assess coverage and error (e.g., mean absolute percentage error).Results: The true exponential distribution was correctly identified using goodness-of-fit according to BIC more frequently compared to AIC (average 92% vs 68%). Under-coverage and large errors were observed for all outcomes when distributions were specified by AIC and for time horizon and RMST with BIC. Error in point estimates were found to be strongly associated with sample size and completeness of follow-up. Small samples produced larger average error, even with complete follow-up, than large samples with short follow-up. Correctly specifying the event distribution reduced magnitude of error in larger samples but not in smaller samples.Conclusions: Limited clinical data from small samples, or short follow-up of large samples, produce large error in estimates relevant to HTA regardless of whether the correct distribution is specified. The associated uncertainty in estimated parameters may not capture the true population values. Decision models that base lifetime time horizon on the model's extrapolated output are not likely to reliably estimate mean survival or its uncertainty. For data with an exponential event distribution, BIC more reliably identified the true distribution than AIC. These findings have important implications for health decision modelling and HTA of novel therapies seeking approval with limited evidence. [ABSTRACT FROM AUTHOR]

Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time. Prospero registration CRD42019094101. [ABSTRACT FROM AUTHOR]

Background: Albuminuria is a marker for renal and cardiovascular (CV) risk, allowing early diagnosis of subjects with elevated renal and CV risk. Objective: This study aimed to estimate the costeffectiveness and budget impact of various population-based screen-and-treat scenarios for elevated albuminuria levels (ie, microalbuminuria) in the Netherlands. Methods: A multistate transition Markov model was developed to simulate the natural course of albuminuria-based disease progression to dialysis and occurrence of CV events. Several population-based strategies directed at screening for elevated albuminuria were evaluated. These strategies depended on urinary albumin concentration (UAC), urinary albumin excretion (UAE), and age. Transition probabilities were derived from the observational community-based Prevention of Renal and Vascular End Stage Disease (PREVEND) cohort study. Health care costs (in year-2008 euros) and life-years gained were calculated over an 8-year period. In the base-case analysis, we analyzed screening for and treatment of microalbuminuria. Screening for microal-buminuria involved prescreening for UAC ≥20 mg/L, followed by a confirmation test for UAE ≥30 mg/d. Other options based on combinations of albuminuria for UAC prescreening (no prescreening, and ≥10, ≥20, ≥100, and ≥200 mg/L) and UAE confirmation test (≥15, ≥30, and ≥300 mg/d) for treatment were investigated in scenario analyses. Furthermore, these various strategies based on UAC and UAE values were analyzed in different subgroups based on age (all ages, aged ≥50 years, and aged ≥60 years). Results: The PREVEND study included 8592 Dutch residents aged 28 to 75 years at the time of initial screening. Among a hypothetical cohort of 1000 subjects identified and treated in the base-case analysis, it was estimated (based on PREVEND follow-up data) that, in the screening/treatment and no-screening scenarios, 76 versus 124 CV events occurred, 16 versus 27 CV deaths, and 3 versus 5 dialysis cases, respectively. The per-person difference in net costs for screening was calculated at €926 (€2003 vs €1077), and prevention of CV deaths was estimated to gain 0.0421 discounted life-year per person. Correspondingly, the cost-effectiveness was estimated at €22,000 per life-year gained. In the base-case analysis, probabilistic sensitivity analysis indicated that the likelihood of cost-effectiveness of a screen-and-treat strategy was 54%, 90%, and 95% for a maximum acceptable cost-effectiveness threshold of €20,000, €50,000, and €80,000 per life-year gained, respectively. Higher albuminuria thresholds for screening and start of treatment further improved the cost-effectiveness but reduced the overall health gains achieved. Limiting screening to those subjects aged ≥50 and ≥60 years resulted in more favorable cost-effectiveness compared with population-based screening without age restriction. Conclusions: Our analyses suggest the potentially favorable cost-effectiveness of population-based screening for albuminuria in the general Dutch population. The results offer health care decision-makers new tools for considering actual implementation of such screening. [Copyright &y& Elsevier]

Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002–2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1–1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5–1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5–1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase–treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. C17 Research Network. • Few studies compare health care use or cost of different paediatric acute lymphoblastic leukaemia protocols. • We compared population-based patient cohorts treated with Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI) protocols. • We found more emergency department visits with COG but more outpatient visits with DFCI. • During the study period, cost intensity was higher among DFCI patients. • Strategies minimising burden of both protocols are warranted. [ABSTRACT FROM AUTHOR]

Aim: To assess the sensitivity and specificity of automated movement recognition in predicting motor impairment in high-risk infants.Method: We searched MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, and Scopus databases and identified additional studies from the references of relevant studies. We included studies that evaluated automated movement recognition in high-risk infants to predict motor impairment, including cerebral palsy (CP) and non-CP motor impairments. Two authors independently assessed studies for inclusion, extracted data, and assessed methodological quality using the Quality Assessment of Diagnostic Accuracy Studies-2. Meta-analyses were performed using hierarchical summary receiver operating characteristic models.Results: Of 6536 articles, 13 articles assessing 59 movement variables in 1248 infants under 5 months corrected age were included. Of these, 143 infants had CP. The overall sensitivity and specificity for motor impairment were 0.73 (95% confidence interval [CI] 0.68-0.77) and 0.70 (95% CI 0.65-0.75) respectively. Comparatively, clinical General Movements Assessment (GMA) was found to have sensitivity and specificity of 98% (95% CI 74-100) and 91% (95% CI 83-93) respectively. Sensor-based technologies had higher specificity (0.88, 95% CI 0.80-0.93).Interpretation: Automated movement recognition technology remains inferior to clinical GMA. The strength of this study is its meta-analysis to summarize performance, although generalizability of these results is limited by study heterogeneity. [ABSTRACT FROM AUTHOR]

Background: Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present.Methods: In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries.Conclusions: PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences. [ABSTRACT FROM AUTHOR]

Background: Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present. Methods: In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries. Conclusions: PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences. [ABSTRACT FROM AUTHOR]

Background: Procedural sedation and analgesia (PSA) is frequently required to perform closed reductions for fractures and dislocations in children. Intravenous (IV) ketamine is the most commonly used sedative agent for closed reductions. However, as children find IV insertion a distressing and painful procedure, there is need to identify a feasible alternative route of administration. There is evidence that a combination of dexmedetomidine and ketamine (ketodex), administered intranasally (IN), could provide adequate sedation for closed reductions while avoiding the need for IV insertion. However, there is uncertainty about the optimal combination dose for the two agents and whether it can provide adequate sedation for closed reductions. The Intranasal Dexmedetomidine Plus Ketamine for Procedural Sedation (Ketodex) study is a Bayesian phase II/III, non-inferiority trial in children undergoing PSA for closed reductions that aims to address both these research questions. This article presents in detail the statistical analysis plan for the Ketodex trial and was submitted before the outcomes of the trial were available for analysis.Methods/design: The Ketodex trial is a multicenter, four-armed, randomized, double-dummy controlled, Bayesian response adaptive dose finding, non-inferiority, phase II/III trial designed to determine (i) whether IN ketodex is non-inferior to IV ketamine for adequate sedation in children undergoing a closed reduction of a fracture or dislocation in a pediatric emergency department and (ii) the combination dose for IN ketodex that provides optimal sedation. Adequate sedation will be primarily measured using the Pediatric Sedation State Scale. As secondary outcomes, the Ketodex trial will compare the length of stay in the emergency department, time to wakening, and adverse events between study arms.Discussion: The Ketodex trial will provide evidence on the optimal dose for, and effectiveness of, IN ketodex as an alternative to IV ketamine providing sedation for patients undergoing a closed reduction. The data from the Ketodex trial will be analyzed from a Bayesian perspective according to this statistical analysis plan. This will reduce the risk of producing data-driven results introducing bias in our reported outcomes.Trial Registration: ClinicalTrials.gov NCT04195256 . Registered on December 11, 2019. [ABSTRACT FROM AUTHOR]

Introduction: continuous assessment of healthcare resources during the COVID-19 pandemic will help in proper planning and to prevent an overwhelming of the Nigerian healthcare system. In this study, we aim to predict the effect of COVID-19 on hospital resources in Nigeria. Methods: we adopted a previously published discrete-time, individual-level, health-state transition model of symptomatic COVID-19 patients to the Nigerian healthcare system and COVID-19 epidemiology in Nigeria by September 2020. We simulated different combined scenarios of epidemic trajectories and acute care capacity. Primary outcomes included the expected cumulative number of cases, days until depletion resources and the number of deaths associated with resource constraints. Outcomes were predicted over a 60-day time horizon. Results: in our best-case epidemic trajectory, which implies successful implementation of public health measures to control COVID-19 spread, assuming all three resource scenarios, hospital resources would not be expended within the 60-days time horizon. In our worst-case epidemic trajectory, assuming conservative resource scenario, only ventilated ICU beds would be depleted after 39 days and 16 patients were projected to die while waiting for ventilated ICU bed. Acute care resources were only sufficient in the three epidemic trajectory scenarios when combined with a substantial increase in healthcare resources. Conclusion: substantial increase in hospital resources is required to manage the COVID-19 pandemic in Nigeria, even as the infection growth rate declines. Given Nigeria's limited health resources, it is imperative to focus on maintaining aggressive public health measures as well as increasing hospital resources to reduce COVID-19 transmission further. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) poses a significant but heterogeneous burden to individuals and healthcare systems. Policymakers develop targeted policies to minimize this burden but need personalized tools to evaluate novel interventions and target them to subpopulations most likely to benefit. We developed a platform to identify subgroups that are at increased risk of emergency department visits, hospitalizations and mortality and to provide stratified patient input in economic evaluations of COPD interventions. We relied on administrative and survey data from Ontario, Canada and applied a combination of microsimulation and multi-state modeling methods. We illustrated the functionality of the platform by quantifying outcomes across smoking status (current, former, never smokers) and by estimating the effect of smoking cessation on resource use and survival, by comparing outcomes of hypothetical cohorts of smokers who quit at diagnosis and smokers that continued to smoke post diagnosis. The cumulative incidence of all-cause mortality was 37.9% (95% CI: 34.9, 41.4) for never smokers, 34.7% (95% CI: 32.1, 36.9) for current smokers, and 46.4% (95% CI: 43.6, 49.0) for former smokers, at 14 years. Over 14 years, smokers who did not quit at diagnosis had 16.3% (95% CI: 9.6, 38.4%) more COPD-related emergency department visits than smokers who quit at diagnosis. In summary, we combined methods from clinical and economic modeling to create a novel tool that policymakers and health economists can use to inform future COPD policy decisions and quantify the effect of modifying COPD risk factors on resource utilization and morality. [ABSTRACT FROM AUTHOR]

Background: There are limited treatment options that clinicians can provide to children presenting to emergency departments with vomiting secondary to acute gastroenteritis. Based on evidence of effectiveness and safety, clinicians now routinely administer ondansetron in the emergency department to promote oral rehydration therapy success. However, clinicians are also increasingly providing multiple doses of ondansetron for home use, creating unquantified cost and health system resource use implications without any evidence to support this expanding practice.Methods/design: DOSE-AGE is a randomized, placebo-controlled, double-blinded, six-center, pragmatic clinical trial being conducted in six Canadian pediatric emergency departments (EDs). In September 2019 the study began recruiting children aged 6 months to 18 years with a minimum of three episodes of vomiting in the 24 h preceding enrollment, <72 h of gastroenteritis symptoms and who were administered a dose of ondansetron during their ED visit. We are recruiting 1030 children (1:1 allocation via an internet-based, third-party, randomization service) to receive a 48-h supply (i.e., six doses) of ondansetron oral solution or placebo, administered on an as-needed basis. All participants, caregivers and outcome assessors will be blinded to group assignment. Outcome data will be collected by surveys administered to caregivers 24, 48 and 168 h following enrollment. The primary outcome is the development of moderate-to-severe gastroenteritis in the 7 days following the ED visit as measured by a validated clinical score (the Modified Vesikari Scale). Secondary outcomes include duration and frequency of vomiting and diarrhea, proportions of children experiencing unscheduled health care visits and intravenous rehydration, caregiver satisfaction with treatment and safety. A preplanned economic evaluation will be conducted alongside the trial.Discussion: Definitive data are lacking to guide the clinical use of post-ED visit multidose ondansetron in children with acute gastroenteritis. Usage is increasing, despite the absence of supportive evidence. The incumbent additional costs associated with use, and potential side effects such as diarrhea and repeat visits, create an urgent need to evaluate the effect and safety of multiple doses of ondansetron in children focusing on post-emergency department visit and patient-centered outcomes.Trial Registration: ClinicalTrials.gov: NCT03851835. Registered on 22 February 2019. [ABSTRACT FROM AUTHOR]

Background: Current guidelines for the management of adhesive small bowel obstruction suggest a limited trial of non-operative management, often of 3-5 days. A longer delay to operation may worsen post-operative outcomes in patients who ultimately require operation. Our objective was to evaluate the impact of time to operation on post-operative outcomes in patients who undergo operation following a trial of non-operative management for adhesive small bowel obstruction.Methods: We used health administrative data to identify patients with adhesive small bowel obstruction who underwent operative management following a trial of non-operative management from 2005 to 2014 in the province of Ontario, Canada. We used multivariable logistic regression to examine the relationship between the time from admission to operation with rates of 30-day mortality, serious complication, and bowel resection.Results: Three thousand five hundred sixty-three patients underwent operation after a trial of non-operative management for adhesive small bowel obstruction. Older patients, patients with a high comorbidity burden, and patients with a lower socioeconomic status were more likely to experience a longer pre-operative period. After adjusting for covariates, each additional day from admission to operation increased odds of serious complication (OR = 1.07, 95% CI = 1.03-1.11) and bowel resection (OR = 1.06, 95% CI = 1.03-1.98). Longer times to operation were not associated with greater adjusted odds of 30-day mortality.Conclusion: Each additional day from admission to operation is associated with greater odds of adverse outcomes. Clinical practice guidelines should emphasize strategies that identify patients who will ultimately require operation. [ABSTRACT FROM AUTHOR]

Background: Adolescent women treated for Hodgkin lymphoma (HL) are at increased risk of breast cancer (BC). We evaluate the cost-utility of eight high-risk BC surveillance strategies for this population, including the Children's Oncology Group guideline of same-day annual mammography and magnetic resonance imaging (MRI) beginning at age 25 years.Methods: A discrete event simulation model was used to simulate the life histories of a cohort of 500 000 25-year-old women treated for HL at age 15 years. We estimated BC incidence and mortality, life expectancy, quality-adjusted life-years (QALYs), health-care costs, and the relative cost-utility (incremental cost-utility ratio [ICUR]) under the eight assessed surveillance strategies. One-way sensitivity analysis enabled modeling of uncertainty evaluation. A publicly funded health-care payer perspective was adopted.Results: Costs across the eight screening strategies ranged from $32 643 to $43 739, whereas QALYs ranged from 24.419 to 24.480. In an incremental cost-effectiveness analysis, annual mammography beginning at age 25 years was associated with an ICUR of $43 000/QALY gained, annual MRI beginning at age 25 years with a switch to annual mammography at age 50 years had an ICUR of $148 000/QALY, and annual MRI beginning at age 25 years had an ICUR of $227 222/QALY. Among all assessed surveillance strategies, the differences in life expectancy were small.Conclusions: Current high-risk BC surveillance guidelines do not reflect the most cost-effective strategy in survivors of adolescent HL. The results suggest that groups at high risk of BC may require high-risk surveillance guidelines that reflect their specific risk profile. [ABSTRACT FROM AUTHOR]

Study Objectives: The objectives of this study were to evaluate (1) the accuracy of the clinical diagnosis of obstructive sleep apnea (OSA) informed by the home sleep study with a Type 4 portable monitor BresoDx® versus Type 1 polysomnography (PSG); and (2) agreement of the apnea-hypopnea index (AHI) compared between BresoDx and PSG.Material and Methods: This was a randomized, parallel, multicentre, single-blind, pragmatic controlled trial enrolling adults referred to three Ontario sleep clinics for suspected OSA. Participants were randomized to BresoDx followed by PSG (one-night apart) or PSG followed by BresoDx sleep testing sequence arms. The primary outcomes included the accuracy of clinical diagnosis and OSA severity measured by AHI between tests.Results: In sum, 233 participants completed both sleep studies and 206 completed physician consultation visits. The agreement between clinical diagnosis informed by PSG versus BresoDx was fair (Cohen's kappa coefficient = 0.28). The sensitivity of BresoDx-informed clinical diagnosis against PSG was between 0.86 and 0.89, and the specificity between 0.38 and 0.44. For AHI cut-off of ≥5 events/hour the sensitivity, specificity and positive and negative predictive values were 0.85, 0.48, 0.81 and 0.54.Conclusions: Home sleep apnea testing with BresoDx can be used in a referral population with a high pretest probability of OSA similar to other Type IV devices. This study complements the existing body of evidence suggesting that home testing with portable devices plays a valuable role for diagnosing of OSA in a variety of settings. SIESTA TRIAL REGISTRATION: www.clinicaltrials.gov (Identifier: NCT02003729). [ABSTRACT FROM AUTHOR]

Background: Chronic hepatitis C (CHC) is among the most burdensome infectious diseases in the world. Health utilities are a valuable tool for quantifying this burden and conducting cost-utility analysis.Objective: Our study summarizes the available data on utilities in CHC patients. This will facilitate analyses of CHC treatment and elimination strategies.Methods: We searched MEDLINE, Embase, and the Cochrane Library for studies measuring utilities in CHC patients. Utilities were pooled by health state and utility instrument using meta-analysis. A further analysis used meta-regression to adjust for the effects of clinical status and methodological variation.Results: Fifty-one clinical studies comprising 15 053 patients were included. Based on the meta-regression, patients' utilities were lower for more severe health states (predicted mean EuroQol-5D-3L utility for mild/moderate CHC: 0.751; compensated cirrhosis: 0.671; hepatocellular carcinoma: 0.662; decompensated cirrhosis: 0.602). Patients receiving interferon-based treatment had lower utilities than those on interferon-free treatment (0.647 vs 0.733). Patients who achieved sustained virologic response (0.786) had higher utilities than those with mild to moderate CHC. Utilities were substantially higher for patients in experimental studies compared to observational studies (coefficient: +0.074, P < .05). The time tradeoff instrument was associated with the highest utilities, and the Health Utilities Index 3 was associated with the lowest utilities.Conclusion: Chronic hepatitis C is associated with a significant impairment in global health status, as measured by health utility instruments. Impairment is greater in advanced disease. Experimental study designs yield higher utilities-an effect not previously documented. Curative therapy can alleviate the burden of CHC, although further research is needed in certain areas, such as the long-term impacts of treatment on utilities. [ABSTRACT FROM AUTHOR]

Background: MRI-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive treatment for temporal lobe epilepsy (TLE), with limited effectiveness data. It is unknown if the cost savings associated with shorter hospitalization could offset the high equipment cost of MRgLITT. We examined the cost-utility of MRgLITT versus surgery for TLE from healthcare payer perspective, and the value of additional research to inform policy decision on MRgLITT. Methods: We developed a microsimulation model to evaluate quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) of MRgLITT versus surgery in TLE, assuming life-time horizon and 1.5% discount rate. Model inputs were derived from the literature. We conducted threshold and sensitivity analyses to examine parameter uncertainties, and expected value of partial perfect information analyses to evaluate the expected monetary benefit of eliminating uncertainty on probabilities associated with MRgLITT. Results: MRgLITT yielded 0.08 more QALYs and cost $7,821 higher than surgery, with ICER of $94,350/QALY. Influential parameters that could change model outcomes include probabilities of becoming seizure-free from disabling seizures state and returning to disabling seizures from seizure-free state 5 years after surgery and MRgLITT, cost of MRgLITT disposable equipment, and utilities of disabling seizures and seizure-free states of surgery and MRgLITT. The cost-effectiveness acceptability curve showed surgery was preferred in more than 50% of iterations. The expected monetary benefit of eliminating uncertainty for probabilities associated with MRgLITT was higher than for utilities associated with MRgLITT. Conclusions: MRgLITT resulted in more QALYs gained and higher costs compared to surgery in the base-case. The model was sensitive to variations in the cost of MRgLITT disposable equipment. There is value in conducting more research to reduce uncertainty on the probabilities and utilities of MRgLITT, but priority should be given to research focusing on improving the precision of estimates on effectiveness of MRgLITT. [ABSTRACT FROM AUTHOR]

The epidemiology of prostate cancer (PC) continues to change. We evaluated the changes in incidence, in average age at diagnosis, and in survival from 1992 to 2015 in Ontario. We compared the cumulative incidence of PC-specific and non PC-specific mortality using two algorithms for cause of death: Method 1 assigned deaths from "other cancers" to non PC-specific causes, and Method 2 assigned these cases to PC-specific mortality. There were 188,714 cases diagnosed with PC between 1992 and 2015 in Ontario. The average age at diagnosis declined from 1992 to 2008 by 0.26 year (3.1 months) annually (p < 0.001) and increased by 0.15 year (1.8 months) thereafter (p > 0.05). Between 2010 and 2015, the proportion of patients diagnosed at stage IV increased, and the proportion diagnosed at stage I decreased (p-values for trends <0.001). Overall survival significantly improved over the years. The cumulative incidence of PC-specific mortality at 5 and 10 years was 6.8 and 9.8% using Method 1, and 10.2 and 16.8% using Method 2. We observed trends toward older age and more advanced stage at PC diagnosis in Ontario. Further studies are needed to validate algorithms for estimating PC-specific mortality from administrative databases. [ABSTRACT FROM AUTHOR]

Background: In patients with adhesive small bowel obstruction (aSBO), the decision to operate as well as the timing and technique of surgery have significant impacts on clinical outcomes. Trends in the management of aSBO have not been described at the population level and guideline adherence is unknown. We sought to evaluate the secular trends in the management of aSBO in a large North American population.Methods: We used administrative data to identify patients admitted to hospital for their first episode of aSBO over 2005-2014. We evaluated temporal trends in admission for aSBO and in management practices using Cochran-Armitage tests. Multivariable logistic regressions were used to assess trends when controlling for potential confounders.Results: Patients (40,800) were admitted with their first episode of aSBO. The mean age was 68.5 years and 55% of patients were female. The population-based rate of admission for aSBO decreased over the study period, from 39.1 to 38.1 per 100,000 persons per year. There was a significant increase in the proportion of patients who underwent surgery for aSBO (19 to 23%, p < 0.0001). Among those who underwent surgery, there were significant increases in the proportions of patients who underwent laparoscopic procedures (4 to 14%, p < 0.0001) and who underwent surgery within 1 day of admission (51 to 60%, p < 0.0001).Conclusion: Between 2005 and 2014, there was a decrease in the population-based rate of aSBO, which may reflect increased utilization of minimally invasive techniques. There were significant trends towards increased operative intervention, with surgery occurring earlier and increasingly using laparoscopic approach. [ABSTRACT FROM AUTHOR]

Background The objective of this study was to investigate the changes in blood pressure among patients enrolled in the Telehomecare programme in Ontario, Canada. Methods This observational study utilised a prospective longitudinal cohort design, including patients with heart failure and chronic obstructive pulmonary disease enrolled in the Ontario Telehomecare programme from July 2012 to July 2015. The outcome of interest was change in mean (biweekly) systolic and diastolic blood pressure levels over a six-month period. Patient data were extracted from the Ontario Telemedicine Network database, and analysed using generalised linear mixed model procedures. Results Overall, we analysed data for 3513 patients. Patients were on average 74.1 ± 11.4 years of age; almost half were men, 62% had heart failure, 55% chronic obstructive pulmonary disease and 29% diabetes. At baseline, the mean systolic and diastolic blood pressure levels were 130.4 ± 19.1 mmHg and 72.2 ± 12.5 mmHg for the total sample. At six months, the adjusted reduction in systolic and diastolic blood pressure values were 4.0 mmHg (95% confidence interval: -4.5 to -3.5) and 2.7 mmHg (95% confidence interval: -3.1 to -2.4), respectively. In a subgroup of 1220 patients with uncontrolled blood pressure at baseline (systolic/diastolic blood pressure of 150.7 ± 10.2 mmHg/80.2 ± 13.5 mmHg) the adjusted reduction in systolic blood pressure was 12.5 mmHg (95% confidence interval: -13.4 to -11.6) and in diastolic blood pressure was 7.1 mmHg (95% confidence interval: -7.8 to -6.5) over the six-month period. Conclusions Blood pressure levels were significantly reduced in patients enrolled in the Telehomecare programme, with changes being more pronounced in patients with uncontrolled blood pressure. The sustainability of decreased blood pressure on other clinical outcomes needs further evaluation. [ABSTRACT FROM AUTHOR]

Background: Preterm birth (birth before 37 wk of gestation) occurs in about 8% of pregnancies in Canada and is associated with high mortality and morbidity rates that substantially affect infants, their families and the health care system. Our overall goal is to create a transdisciplinary platform, the Canadian Preterm Birth Network (CPTBN), where investigators, stakeholders and families will work together to improve childhood outcomes of preterm neonates. Methods: Our national cohort will include 24 maternal--fetal/obstetrical units, 31 neonatal intensive care units and 26 neonatal follow-up programs across Canada with planned linkages to provincial health information systems. Three broad clusters of projects will be undertaken. Cluster 1 will focus on quality-improvement efforts that use the Evidence-based Practice for Improving Quality method to evaluate information from the CPTBN database and review the current literature, then identify potentially better health care practices and implement identified strategies. Cluster 2 will assess the impact of current practices and practice changes in maternal, perinatal and neonatal care on maternal, neonatal and neurodevelopmental outcomes. Cluster 3 will evaluate the effect of preterm birth on babies, their families and the health care system by integrating CPTBN data, parent feedback, and national and provincial database information in order to identify areas where more parental support is needed, and also generate robust estimates of resource use, cost and cost-effectiveness around preterm neonatal care. Interpretation: These collaborative efforts will create a flexible, transdisciplinary, evaluable and informative research and quality-improvement platform that supports programs, projects and partnerships focused on improving outcomes of preterm neonates. [ABSTRACT FROM AUTHOR]

To identify, evaluate and summarize the evidence on educational attainment, employment status and income of AYAs surviving cancer. A search of six databases for articles published between 01/01/2010 and 03/31/2022 was performed. Articles with an AYA survivorship population, quantitative design and a cancer-free comparator group were included. Data extraction was conducted, and quality appraisal was completed using ROBINS-I. Results were summarized using a narrative synthesis. A total of 2801 articles were identified, of which 12 were included. Among the limited evidence, educational attainment did not differ from cancer-free peers. Survivors were more likely to be unemployed, have lower incomes and require social security for income supplementation. Evidence suggested that females, diagnosis of brain cancer and the presence of late-effects were among the risk factors for severe outcomes. Limited socioeconomic evidence exists for AYAs surviving cancer. Long-lasting financial toxicities occur and highlights a need for further investigation. [Display omitted] • We found 12 studies which demonstrated AYAs surviving cancer experience financial toxicity compared to cancer-free peers. • Survivors are more likely to be unemployed or remain out of the labour force. • A lower income and need to utilize social security benefits for income supplementation persists throughout survivorship. • Limited socioeconomic evidence exists for this survivorship population and highlights a need for further investigation. [ABSTRACT FROM AUTHOR]