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By functionally isolating stem cells (LSCs) from individuals with leukemia and parsing our their gene expression, Dick and his colleagues find that LSCs have heterogeneous surface markers and frequencies and possess a gene expression profile resembling that of normal hematopoietic stem cells. The gene expression program derived from LSCs could be a general predictor of disease outcome, stratifying risk for cytogenetically normal patients, which suggests that stemness underlies leukemia aggressiveness. Xenograft studies indicate that some solid tumors and leukemias are organized as cellular hierarchies sustained by cancer stem cells (CSCs). Despite the promise of the CSC model, its relevance in humans remains uncertain. Here we show that acute myeloid leukemia (AML) follows a CSC model on the basis of sorting multiple populations from each of 16 primary human AML samples and identifying which contain leukemia stem cells (LSCs) using a sensitive xenograft assay. Analysis of gene expression from all functionally validated populations yielded an LSC-specific signature. Similarly, a hematopoietic stem cell (HSC) gene signature was established. Bioinformatic analysis identified a core transcriptional program shared by LSCs and HSCs, revealing the molecular machinery underlying 'stemness' properties. Both stem cell programs were highly significant independent predictors of patient survival and were found in existing prognostic signatures. Thus, determinants of stemness influence the clinical outcome of AML, establishing that LSCs are clinically relevant and not artifacts of xenotransplantation.

An unstable epigenome is implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism. This is important because the epigenome is potentially modifiable. We have previously reported that adult offspring exposed to maternal immune activation (MIA) prenatally have significant global DNA hypomethylation in the hypothalamus. However, what genes had altered methylation state, their functional effects on gene expression and whether these changes can be moderated, have not been addressed. In this study, we used next-generation sequencing (NGS) for methylome profiling in a MIA rodent model of neurodevelopmental disorders. We assessed whether differentially methylated regions (DMRs) affected the chromatin state by mapping known DNase I hypersensitivity sites (DHSs), and selected overlapping genes to confirm a functional effect of MIA on gene expression using qPCR. Finally, we tested whether methylation differences elicited by MIA could be limited by post-natal dietary (omega) n-3 polyunsaturated fatty acid (PUFA) supplementation. These experiments were conducted using hypothalamic brain tissue from 12-week-old offspring of mice injected with viral analogue PolyI:C on gestation day 9 of pregnancy or saline on gestation day 9. Half of the animals from each group were fed a diet enriched with n-3 PUFA from weaning (MIA group, n = 12 units, n = 39 mice; Control group, n = 12 units, n = 38 mice). The results confirmed our previous finding that adult offspring exposed to MIA prenatally had significant global DNA hypomethylation. Furthermore, genes linked to synaptic plasticity were over-represented among differentially methylated genes following MIA. More than 80% of MIA-induced hypomethylated sites, including those affecting chromatin state and MECP2 binding, were stabilised by the n-3 PUFA intervention. MIA resulted in increased expression of two of the ‘top five’ genes identified from an integrated analysis of DMRs, DHSs and MECP2 binding sites, namely Abat (t = 2.46, p < 0.02) and Gnas9 (t = 2.96, p < 0.01), although these changes were not stabilised by dietary intervention. Thus, prenatal MIA exposure impacts upon the epigenomic regulation of gene pathways linked to neurodevelopmental conditions; and many of the changes can be attenuated by a low-cost dietary intervention.

ObjectiveAllogeneic haematopoietic cell transplantation (HCT) is a potentially curative treatment for haematologic and oncologic diseases. There is a perception that the United States of America (USA) offers greater access to expensive therapies such as HCT. Alternatively, Canada is thought to suffer from protracted wait times, but lower spending. Our objective was to compare HCT utilisation and short-term outcomes in Ontario (ON), Canada, and New York State (NY), USA.Design, setting and participantsWe conducted a population-based cohort study using administrative health data to identify all residents of ON and NY who underwent allogeneic HCT between 2012 and 2015.Primary and secondary outcome measuresThe primary outcome measures were age and sex standardised HCT utilisation rates, in-hospital mortality, hospital length of stay (LOS) and readmission rates in ON and NY. Secondary outcomes included comparing ON and NY HCT recipients with respect to demographic characteristics and patient wealth (using neighbourhood income quintile).ResultsWe identified 547 HCT procedures in ON and 1361 HCT procedures performed in NY. HCT recipients in ON were younger than NY (mean age 49.0 vs 51.6 years; p<0.001) and a lower percentage of ON recipients resided in affluent neighbourhoods compared with NY (47.2% vs 52.6%; p=0.026). Utilisation of HCT was 14.4 per 1 million population per year in ON and 26.7 per 1 million per year in NY (p<0.001). The magnitude of the ON–NY difference in utilisation was larger for older patients. In-hospital mortality, LOS and readmission rates were lower in ON than NY in both unadjusted and adjusted analyses.ConclusionsWe found significantly lower utilisation of HCT in ON compared with NY, particularly among older patients. Higher in-hospital mortality in NY relative to ON requires further study. These differences are thought provoking for patients, healthcare providers and policy-makers in both jurisdictions.

We aimed to compare health care utilization of children with pediatric-onset multiple sclerosis to that of age, sex and geographically-matched children without multiple sclerosis. Using population-based administrative data from Ontario, Canada for the period 2003-2014, we applied a validated case definition to identify persons aged ≤18 years with multiple sclerosis. We identified up to 5 children without multiple sclerosis matched on sex, age, and region of residence. In each cohort, we determined annual rates of any hospitalization and physician services use. Using general linear models we compared utilization rates adjusting for age, sex, region, socioeconomic status and year. Subsequently, we limited the analysis to incident cases of multiple sclerosis and their matches, and compared rates of utilization in the year of multiple sclerosis diagnosis, and the three years thereafter. We identified 659 youth with multiple sclerosis (428 incident cases), and 3,294 matched controls. Two-thirds of both cohorts were female. After adjustment for sociodemographic factors and year, the multiple sclerosis cohort was more likely to be hospitalized than the matched cohort (odds ratio 15.2; 95%CI: 12.0, 19.1), and had higher rates of ambulatory physician visits (rate ratio 4.58; 95%CI: 4.26, 4.92). The odds of hospitalization (odds ratio 40.1; 95%CI: 27.1, 59.5) and physician visits (rate ratio 5.14; 95%CI: 4.63, 5.71) were markedly elevated in the year of MS diagnosis, declining thereafter but remaining elevated versus the matched cohort. Children with multiple sclerosis have substantially elevated rates of health care utilization as compared to matched children without multiple sclerosis, over calendar time and throughout the early disease course.

Background Side effects can occur within hours to days of starting antidepressant medications, whereas full therapeutic benefit for mood typically takes up to four weeks. This mismatch between time to harm and lag to benefit often leads to premature discontinuation of antidepressants, a phenomenon that can be partially reversed through early doctor-patient communication and follow-up. We investigated the relationship between relational continuity of care – the number of years family physicians have cared for older adult patients – and early follow-up care for patients prescribed antidepressants. Methods A retrospective cohort study was conducted on residents of Ontario, Canada aged 66 years or older who were dispensed their first antidepressant prescription through the provincial drug insurance program between April 1, 2016, and March 31, 2019. The study utilized multivariable regression to estimate the relationship between relational continuity and 30-day follow-up with the prescribing family physician. Separate estimates were generated for older adults living in urban, non-major urban, and rural communities. Results The study found a small positive relationship between relational continuity of care and follow-up care by the prescribing family physician for patients dispensed a first antidepressant prescription (RRR = 1.005; 95% CI = 1.004, 1.006). The relationship was moderated by the patients’ location of dwelling, where the effect was stronger for older adults residing in non-major urban (RRR = 1.009; 95% CI = 1.007, 1.012) and rural communities (RRR = 1.006; 95% CI = 1.002, 1.011). Conclusions Our findings do not provide strong evidence of a relationship between relational continuity of care and higher quality management of antidepressant prescriptions. However, the relationship is slightly more pronounced in rural communities where access to continuous primary care and specialized mental health services is more limited. This may support the ongoing need for the recruitment and retention of primary care providers in rural communities.

Background Use of fluoroquinolones (FQs), broad-spectrum antibiotics, has been linked to adverse health outcomes and resulted in safety warnings by regulatory agencies worldwide. We tested the effect of Canadian risk mitigation measures (RMMs) introduced in January 2017 on FQ prescription rates. Methods We conducted a retrospective multi-site cohort study using administrative data from six Canadian provinces. The cohort included adults (18 + years) with outpatient prescriptions for four oral systemic FQs (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin) between 2008 and 2022. Overall FQ prescription rates and percentage of FQ prescriptions for three antibiotic indications (acute bacterial sinusitis [ABS], acute exacerbation of chronic obstructive pulmonary disease [AECOPD], urinary tract infection [UTI]) were assessed before and after RMMs were introduced. Segmented generalized linear models were applied to monthly prescription rates and percentages for: (1) pre-RMM (January 2008-December 2016; reference), (2) post-RMM pre-COVID (January 2017-Feburary 2020), and (3) post-RMM within-COVID (March 2020-December 2022) segments. We estimated province-specific relative rates (RR) for the post-RMM segments and slope coefficients for pre- and post-RMM segments and their 95% confidence intervals (CIs) and pooled them using random-effects models. Results Crude annual FQ prescription rates decreased from 107.5 to 45.0 per 1,000 population over the study period; in the pre-RMM segment, age- and sex-adjusted rates decreased an average of 0.30 per 1,000 population per month (95% CI: 0.19–0.41); province-specific estimates of decrease ranged from 0.16 to 0.48. The pooled RR for the post-RMM pre-COVID segment was 0.50 (95% CI: 0.43–0.59); the post-RMM within-COVID segment pooled RR was similar (RR = 0.38; 95% CI: 0.29–0.50). The decline in percentage of FQ prescriptions post-RMM pre-COVID was largest for UTI (pooled RR = 0.32, 95% CI: 0.25–0.41), followed by ABS (RR = 0.41, 95% CI: 0.34–0.51) and AECOPD (RR = 0.51, 95% CI: 0.37–0.69), although there was variation across provinces. Conclusions Canadian RMMs for FQ use were associated with a decrease in prescription rates overall and for three indications, although rates had begun to decline before RMMs were introduced and the magnitude of decrease varied across provinces. Safety warnings tailored to specific indications and regional practices may be needed to address variation in FQ prescribing. Trial registration HMA-EMA catalogue of real-world data studies (Study ID: 108,049).

Background Some jurisdictions restrict primary care physicians’ daily patient volume to safeguard quality of care for complex patients. Our objective was to determine whether people with dementia receive lower-quality care if their primary care physician sees many patients daily. Methods Population-based retrospective cohort study using health administrative data from 100,256 community-living adults with dementia aged 66 years or older, and the 8,368 primary care physicians who cared for them in Ontario, Canada. Multivariable Poisson GEE regression models tested whether physicians’ daily patient volume was associated with the adjusted likelihood of people with dementia receiving vaccinations, prescriptions for cholinesterase inhibitors, benzodiazepines, and antipsychotics from their primary care physician. Results People with dementia whose primary care physicians saw ≥ 30 patients daily were 32% (95% CI: 23% to 41%, p < 0.0001) and 25% (95% CI: 17% to 33%, p < 0.0001) more likely to be prescribed benzodiazepines and antipsychotic medications, respectively, than patients of primary care physicians who saw < 20 patients daily. Patients were 3% (95% CI: 0.4% to 6%, p = 0.02) less likely to receive influenza vaccination and 8% (95% CI: 4% to 13%, p = 0.0001) more likely to be prescribed cholinesterase inhibitors if their primary care physician saw ≥ 30 versus < 20 patients daily. Conclusions People with dementia were more likely to receive both potentially harmful and potentially beneficial medications, and slightly less likely to be vaccinated by high-volume primary care physicians.

Few studies have compared surgical utilization between countries or how rates may differ according to patients' socioeconomic status. To compare population-level utilization of 3 common nonemergent surgical procedures in New York State (US), Ontario (Canada), and New South Wales (Australia) and how utilization differs for residents of lower- and higher-income neighborhoods. This cohort study included all adults aged 18 years and older who were hospitalized for pancreatectomy, radical prostatectomy, or nephrectomy between 2011 and 2016 in New York, between 2011 and 2018 in Ontario, and between 2013 and 2018 in New South Wales. Each patient's address of residence was linked to 2016 census data to ascertain neighborhood income. Data were analyzed from August 2019 to November 2020. Primary outcomes were (1) each jurisdiction's per capita age- and sex-standardized utilization rates (procedures per 100 000 residents per year) for each surgery and (2) utilization rates among residents of lower- and higher-income neighborhoods. This study included 115 428 surgical patients (25 780 [22.3%] women); 5717, 21 752, and 24 617 patients in New York were hospitalized for pancreatectomy, radical prostatectomy, and nephrectomy, respectively; 4929, 19 125, and 16 916 patients in Ontario, respectively; and 2069, 13 499, and 6804 patients in New South Wales, respectively. Patients in New South Wales were older for all procedures (eg, radical prostatectomy, mean [SD] age in New South Wales, 64.8 [7.3] years; in New York, 62.7 [8.4] years; in Ontario, 62.8 [6.7] years; P < .001); patients in New York were more likely than those in other locations to be women for pancreatectomy (New York: 2926 [51.2%]; Ontario: 2372 [48.1%]; New South Wales, 1003 [48.5%]; P = .004) and nephrectomy (New York: 10 645 [43.2%]; Ontario: 6529 [38.6%]; 2605 [38.3%]; P < .001). With the exception of nephrectomy in Ontario, there was a higher annual utilization rate for all procedures in all jurisdictions among patients residing in affluent neighborhoods (quintile 5) compared with poorer neighborhoods (quintile 1). This difference was largest in New South Wales for pancreatectomy (4.65 additional procedures per 100 000 residents [SE, 0.28]; P < .001) and radical prostatectomy (73.46 additional procedures per 100 000 residents [SE, 1.20]; P < .001); largest in New York for nephrectomy (8.43 additional procedures per 100 000 residents [SE, 0.85]; P < .001) and smallest in New York for radical prostatectomy (19.70 additional procedures per 100 000 residents [SE, 2.63]; P < .001); and smallest in Ontario for pancreatectomy (1.15 additional procedures per 100 000 residents [SE, 0.28]; P < .001) and nephrectomy (-1.10 additional procedures per 100 000 residents [SE, 0.52]; P < .001). New York had the highest utilization of nephrectomy (28.93 procedures per 100 000 residents per year [SE, 0.18]) and New South Wales for had the highest utilization of pancreatectomy and radical prostatectomy (6.94 procedures per 100 000 residents per year [SE, 0.15] and 94.37 procedures per 100 000 residents per year [SE, 0.81], respectively; all P < .001). Utilization was lowest in Ontario for all procedures (pancreatectomy, 6.18 procedures per 100 000 residents per year [SE, 0.09]; radical prostatectomy, 49.24 procedures per 100 000 residents per year [SE, 0.36]; nephrectomy, 21.40 procedures per 100 000 residents per year [SE, 0.16]; all P < .001). In this study, New York and New South Wales had higher per capita surgical utilization and larger neighborhood income-utilization gradients than Ontario. These findings suggest that income-based disparities are larger in the United States and Australia and smaller in Canada and highlight trade-offs inherent in the health care systems of different countries.

Hospital funding reforms for prostate cancer surgery may have altered management of localized prostate cancer in the province of Ontario, Canada. To determine whether changes in hospital funding policy aimed at improving health care quality and value were associated with changes in the management of localized prostate cancer or the characteristics of patients receiving radical prostatectomy (RP) for localized prostate cancer. This population-based, interrupted time series study used linked population-based administrative data regarding adults in Ontario with incidental localized prostate cancer and those who underwent RP for localized prostate cancer. Patients who underwent RP were compared with patients who underwent surgical procedures for localized renal cell carcinoma, which was not included in the policy change but was subjected to similar secular trends and potential confounders. Monthly outcomes were analyzed using interventional autoregressive integrated moving average models. Data were collected from January 2011 to November 2017 and analyzed in January 2019. Funding policy change in April 2015 from flexible block funding for all hospital-based care to prespecified payment amounts per procedure for treatment of localized prostate cancer, coupled with the dissemination of a diagnosis-specific handbook outlining best practices. Initial management (RP vs radiation therapy vs active surveillance) and tumor risk profiles per management strategy among incident cases of localized prostate cancer. Additional outcomes were case volume, mean length of stay, proportion of patients returning to hospital or emergency department within 30 days, proportion of patients older than 65 years, mean Charlson Comorbidity Index, and proportion of minimally invasive surgical procedures among patients undergoing RP for localized prostate cancer. A total of 33 128 patients with incident localized prostate cancer (median [interquartile range (IQR)] age, 67 [61-73] years; median [IQR] cases per monthly observation interval, 466 [420-516]), 17 159 patients who received radical prostatectomy (median [IQR] age, 63 [58-68] years; median [IQR] cases per monthly observation interval, 209 [183-225]), and 5762 individuals who underwent surgery for renal cell carcinoma (median [IQR] age, 62 [53-70] years; median [IQR] cases per monthly observation interval, 71 [61-77]) were identified. By the end of the observation period, radical prostatectomy and radiation therapy were used in comparable proportions (30.3% and 28.9%, respectively) and included only a small fraction of low-risk patients (6.4% and 2.9%, respectively). No statistically significant association of the funding policy change with most outcomes was found. The implementation of funding reform for hospitals offering RP was not associated with changes in the management of localized prostate cancer, although it may have encouraged more appropriate selection of patients for RP. Mostly preexisting trends toward guideline-conforming practice were observed. Co-occurring policy changes and/or guideline revisions may have weakened signals from the policy change.

Conventional construction materials which rely on a fossil-based, nonrenewable extractive economy are typically associated with an entrenched linear economic approach to production. Current research indicates the clear interrelationships between the production and use of construction materials and anthropogenic climate change. This paper investigates the potential for emerging high-performance biobased construction materials, produced sustainably and/or using waste byproducts, to enable a more environmentally sustainable approach to the built environment. Life-cycle assessment (LCA) is employed to compare three wall assemblies using local biobased materials in Montreal (Canada), Nairobi (Kenya), and Accra (Ghana) vs. a traditional construction using gypsum boards and rockwool insulation. Global warming potential, nonrenewable cumulative energy demand, acidification potential, eutrophication potential, and freshwater consumption (FWC) are considered. Scenarios include options for design for disassembly (DfD), as well as potential future alternatives for electricity supply in Kenya and Ghana. Results indicate that all biobased alternatives have lower (often significantly so) life-cycle impacts per functional unit, compared to the traditional construction. DfD strategies are also shown to result in −10% to −50% impact reductions. The results for both African countries exhibit a large dependence on the electricity source used for manufacturing, with significant potential for future decarbonization, but also some associated tradeoffs in terms of acidification and eutrophication.