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Background: The efficacy-effectiveness gap between randomized trial and real-world evidence regarding the clinical benefit of ipilimumab for metastatic melanoma (MM) has been well characterized by previous literature, consistent with initial concerns raised by health technology assessment agencies (HTAs). As these differences can significantly impact cost-effectiveness, it is critical to assess the real-world cost-effectiveness of second-line ipilimumab versus non-ipilimumab treatments for MM. Methods: This was a population-based retrospective cohort study of patients who received second-line non-ipilimumab therapies between 2008 and 2012 versus ipilimumab treatment between 2012 and 2015 (after public reimbursement) for MM in Ontario. Using a 5-year time horizon, censor-adjusted and discounted (1.5%) costs (from the public payer's perspective in Canadian dollars) and effectiveness were used to calculate incremental cost-effectiveness ratios (ICERs) in life-years gained (LYGs) and quality-adjusted life years (QALYs), with bootstrapping to capture uncertainty. Varying the discount rate and reducing the price of ipilimumab were done as sensitivity analyses. Results: In total, 329 MM were identified (Treated: 189; Controls: 140). Ipilimumab was associated with an incremental effectiveness of 0.59 LYG, incremental cost of $91,233, and ICER of $153,778/LYG. ICERs were not sensitive to discounting rate. Adjusting for quality of life using utility weights resulted in an ICER of $225,885/QALY, confirming the original HTA estimate prior to public reimbursement. Reducing the price of ipilimumab by 100% resulted in an ICER of $111,728/QALY. Conclusion: Despite its clinical benefit, ipilimumab as second-line monotherapy for MM patients is not cost-effective in the real world as projected by HTA under conventional willingness-to-pay thresholds. [ABSTRACT FROM AUTHOR]

Objective: To investigate the incidence of and factors associated with SARS–CoV‐2 testing and infection in immune‐mediated inflammatory disease (IMID) patients versus matched non‐IMID comparators from the general population. Methods: We conducted a population‐based, matched cohort study among adult residents from Ontario, Canada, from January 2020 to December 2020. We created cohorts for the following IMIDs: rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, ankylosing spondylitis, systemic autoimmune rheumatic diseases, multiple sclerosis (MS), iritis, inflammatory bowel disease (IBD), polymyalgia rheumatica, and vasculitis. Each patient was matched with 5 patients without IMIDs based on sociodemographic factors. We estimated the incidence of SARS–CoV‐2 testing and infection in IMID patients and non‐IMID patients. Multivariable logistic regressions assessed odds of SARS–CoV‐2 infection. Results: We studied 493,499 patients with IMIDs and 2,466,946 patients without IMIDs. Patients with IMIDs were more likely to have at least 1 SARS–CoV‐2 test versus patients without IMIDs (27.4% versus 22.7%), but the proportion testing positive for SARS–CoV‐2 was identical (0.9% in both groups). Overall, IMID patients had 20% higher odds of being tested for SARS–CoV‐2 (odds ratio 1.20 [95% confidence interval 1.19–1.21]). The odds of SARS–CoV‐2 infection varied across IMID groups but was not significantly elevated for most IMID groups compared with non‐IMID comparators. The odds of SARS–CoV‐2 infection was lower in IBD and MS and marginally higher in RA and iritis. Conclusion: Patients across all IMIDs were more likely to be tested for SARS–CoV‐2 versus those without IMIDs. The risk of SARS–CoV‐2 infection varied across disease subgroups. [ABSTRACT FROM AUTHOR]

Intracellular folate homeostasis is essential for the 1-carbon transfer reactions necessary for DNA synthesis and biological methylation reactions in colonic epithelial cells. Perturbed 1-carbon transfer reactions resulting from folate depletion predispose normal colonic epithelial cells to neoplastic transformation while inhibiting the growth of colon cancer cells. Using an in vitro model of folate deficiency, we determined the effects of folate deficiency on the steady-state transcript levels of genes involved in intracellular folate metabolism and 1-carbon transfer reactions in HCT116 and Caco2 human colon adenocarcinoma cells. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring increased folate uptake and intracellular folate retention, the provision of metabolically more effective substrates for folate-dependent enzymes, and reduced folate hydrolysis and efflux. In HCT116 cells, folate depletion was associated with changes in transcript levels of genes favoring the preferential shuttling of the flux of 1-carbon units to the methionine cycle over the nucleotide synthesis pathway. In Caco2 cells, some adaptive responses in response to folate depletion were not as apparent as in HCT116 cells, and in some cases, the direction of change was counterintuitive. In Caco2 cells, the metabolic priority in response to folate depletion was to shuttle the available folate pools to the nucleotide biosynthesis pathway at the expense of biological methylation reactions. In both HCT116 and Caco2 cells, folate depletion was associated with the conservation of the existing pattern and extent of DNA methylation.

BACKGROUND: Despite expert recommendations for use, limited evidence identifies effectiveness of mechanical insufflation-exsufflation (MI-E) in addressing respiratory morbidity and resultant health care utilization and costs for individuals with neuromuscular disorders. We examined the impact of provision of publicly funded MI-E devices on health care utilization, health care costs, and survival trajectory. METHODS: This is a retrospective pre/post cohort study linking data on prospectively recruited participants using MI-E to health administrative databases to quantify outcomes. RESULTS: We linked data from 106 participants (8 age < 15 y) and determined annualized health care use pre/post device. We found no difference in emergency department (ED) visit or hospital admission rates. Following MI-E approval, participants required fewer hospital days (median [interquartile range] [IQR]) 0 [0-9] vs 0 [0-4], P = .03). Rates of physician specialist visits also decreased (median IQR 7 [4-11] vs 4 [2-7], P < .001). Conversely, rates of home care nursing and homemaking/personal support visits increased. Following MI-E, total costs were lower for 59.4%, not different for 13.2%, and higher for 27.4%. Physician billing costs decreased whereas home care costs increased. Regression modeling identified pre-MI-E costs were the most important predictor of costs after approval. At 12 months, 23 (21.7%) participants had died. Risk of death was higher for those using more medical devices (hazard ratio 1.12, [95% CI 1.02-1.22]) in the home. CONCLUSIONS: Provision of publicly funded MI-E devices did not influence rates of ED visits or hospital admission but did shift health care utilization and costs from the acute care to community sector. Although increased community costs negated cost savings from physician billings, evidence suggests costs savings from reduced hospital days and fewer specialist visits. Risk of death was highest in individuals requiring multiple medical technologies. [ABSTRACT FROM AUTHOR]

Abstract Background Comorbid depression is common among adults with painful osteoarthritis (OA). We evaluated the relationship between depressed mood and receipt of mental health (MH) care services. Methods In a cohort with OA, annual interviews assessed comorbidity, arthritis severity, and MH (SF-36 mental health score). Surveys were linked to administrative health databases to identify mental health-related visits to physicians in the two years following the baseline interview (1996-98). Prescriptions for anti-depressants were ascertained for participants aged 65+ years (eligible for drug benefits). The relationship between MH scores and MH-related physician visits was assessed using zero-inflated negative binomial regression, adjusting for confounders. For those aged 65+ years, logistic regression examined the probability of receiving any MH-related care (physician visit or anti-depressant prescription). Results Analyses were based on 2,005 (90.1%) individuals (mean age 70.8 years). Of 576 (28.7%) with probable depression (MH score < 60/100), 42.5% experienced one or more MH-related physician visits during follow-up. The likelihood of a physician visit was associated with sex (adjusted OR women vs. men = 5.87, p = 0.005) and MH score (adjusted OR per 10-point decrease in MH score = 1.63, p = 0.003). Among those aged 65+, 56.7% with probable depression received any MH care. The likelihood of receiving any MH care exhibited a significant interaction between MH score and self-reported health status (p = 0.0009); with good general health, worsening MH was associated with increased likelihood of MH care; as general health declined, this effect was attenuated. Conclusions Among older adults with painful OA, more than one-quarter had depressed mood, but almost half received no mental health care, suggesting a care gap.

Abstract Background There are gaps between what family practitioners do in clinical practice and the evidence-based ideal. The most commonly used strategy to narrow these gaps is the printed educational message (PEM); however, the attributes of successful printed educational messages and their overall effectiveness in changing physician practice are not clear. The current endeavor aims to determine whether such messages change prescribing quality in primary care practice, and whether these effects differ with the format of the message. Methods/design The design is a large, simple, factorial, unblinded cluster-randomized controlled trial. PEMs will be distributed with informed, a quarterly evidence-based synopsis of current clinical information produced by the Institute for Clinical Evaluative Sciences, Toronto, Canada, and will be sent to all eligible general and family practitioners in Ontario. There will be three replicates of the trial, with three different educational messages, each aimed at narrowing a specific evidence-practice gap as follows: 1) angiotensin-converting enzyme inhibitors, hypertension treatment, and cholesterol lowering agents for diabetes; 2) retinal screening for diabetes; and 3) diuretics for hypertension. For each of the three replicates there will be three intervention groups. The first group will receive informed with an attached postcard-sized, short, directive "outsert." The second intervention group will receive informed with a two-page explanatory "insert" on the same topic. The third intervention group will receive informed, with both the above-mentioned outsert and insert. The control group will receive informed only, without either an outsert or insert. Routinely collected physician billing, prescription, and hospital data found in Ontario's administrative databases will be used to monitor pre-defined prescribing changes relevant and specific to each replicate, following delivery of the educational messages. Multi-level modeling will be used to study patterns in physician-prescribing quality over four quarters, before and after each of the three interventions. Subgroup analyses will be performed to assess the association between the characteristics of the physician's place of practice and target behaviours. A further analysis of the immediate and delayed impacts of the PEMs will be performed using time-series analysis and interventional, auto-regressive, integrated moving average modeling. Trial registration number Current controlled trial ISRCTN72772651.