Glass-Like Phonon Dynamics and Thermal Transport in a GeTe Nano-Composite at Low Temperature.

In this work, the experimental evidence of glass-like phonon dynamics and thermal conductivity in a nanocomposite made of GeTe and amorphous carbon is reported, which is of interest for microelectronics, and specifically phase change memories. It is shown that, the total thermal conductivity is reduced by a factor of three at room temperature with respect to pure GeTe, due to the reduction of both electronic and phononic contributions. This latter, similarly to glasses, is small and weakly increasing with temperature between 100 and 300 K, indicating a mostly diffusive thermal transport and reaching a value of 0.86(7) Wm-1K-1 at room temperature. A thorough investigation of the nanocomposite's phonon dynamics reveals the appearance of an excess intensity in the low energy vibrational density of states, reminiscent of the Boson peak in glasses. These features can be understood in terms of an enhanced phonon scattering at the interfaces, due to the presence of elastic heterogeneities, at wavelengths in the 2-20 nm range. The findings confirm recent simulation results on crystalline/amorphous nanocomposites and open new perspectives in phonon and thermal engineering through the direct manipulation of elastic heterogeneities.

Opioid-related deaths between 2019 and 2021 across 9 Canadian provinces and territories.

BACKGROUND: The drug toxicity crisis continues to accelerate across Canada, with rapid increases in opioid-related harms following the onset of the COVID-19 pandemic. We sought to describe trends in the burden of opioid-related deaths across Canada throughout the pandemic, comparing these trends by province or territory, age, and sex. METHODS: We conducted a repeated cross-sectional analysis of accidental opioid-related deaths between Jan. 1, 2019, and Dec. 31, 2021, across 9 Canadian provinces and territories using aggregated national data. Our primary measure was the burden of premature opioid-related death, measured by potential years of life lost. Our secondary measure was the proportion of all deaths attributable to opioids; we used the Cochrane-Armitage test for trend to compare proportions. RESULTS: Between 2019 and 2021, the annual number of opioid-related deaths increased from 3007 to 6222 and years of life lost increased from 126 115 to 256 336 (from 3.5 to 7.0 yr of life lost per 1000 population). In 2021, the highest number of years of life lost was among males (181 525 yr) and people aged 30-39 years (87 045 yr). In 2019, we found that 1.7% of all deaths among those younger than 85 years were related to opioids, rising to 3.2% in 2021. Significant increases in the proportion of deaths related to opioids were observed across all age groups (p < 0.001), representing 29.3% and 29.0% of deaths among people aged 20-29 and 30-39 years in 2021, respectively. INTERPRETATION: Across Canada, the burden of premature opioid-related deaths doubled between 2019 and 2021, representing more than one-quarter of deaths among younger adults. The disproportionate loss of life in this demographic group highlights the critical need for targeted prevention efforts.

Public funding for private for-profit centres and access to cataract surgery by patient socioeconomic status: an Ontario population-based study.

BACKGROUND: Public funding of cataract surgery provided in private, for-profit surgical centres increased to help mitigate surgical backlogs during the COVID-19 pandemic in Ontario, Canada. We sought to compare the socioeconomic status of patients who underwent cataract surgery in not-for-profit public hospitals with those who underwent this surgery in private for-profit surgical centres and to evaluate whether differences in access by socioeconomic status decreased after the infusion of public funding for private, for-profit centres. METHODS: We conducted a population-based study of all cataract operations in Ontario, Canada, between January 2017 and March 2022. We analyzed differences in socioeconomic status among patients who accessed surgery at not-for-profit public hospitals versus those who accessed it at private for-profit surgical centres before and during the period of expanded public funding for private for-profit centres. RESULTS: Overall, 935 729 cataract surgeries occurred during the study period. Within private for-profit surgical centres, the rate of cataract surgeries rose 22.0% during the funding change period for patients in the highest socioeconomic status quintile, whereas, for patients in the lowest socioeconomic status quintile, the rate fell 8.5%. In contrast, within public hospitals, the rate of surgery decreased similarly among patients of all quintiles of socioeconomic status. During the funding change period, 92 809 fewer cataract operations were performed than expected. This trend was associated with socioeconomic status, particularly within private for-profit surgical centres, where patients with the highest socioeconomic status were the only group to have an increase in cataract operations. INTERPRETATION: After increased public funding for private, for-profit surgical centres, patient socioeconomic status was associated with access to cataract surgery in these centres, but not in public hospitals. Addressing the factors underlying this incongruity is vital to ensure access to surgery and maintain public confidence in the cataract surgery system.

Exposure to Valsartan Products Containing Nitrosamine Impurities in the United States, Canada, and Denmark.

BACKGROUND: Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark. METHODS: We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, the recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status was calculated. RESULTS: We identified 3.3 and 2.8 million (United States) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10 747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167 (±223.1) and 146 (±255.8) days in the United States and Canada respectively. For the recalled products, mean cumulative duration of use was 178 (±249.6), 269 (±397.3) and 166 (±251.0) days in the United States, Canada, and Denmark, respectively. CONCLUSION: In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and probably did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a 6-year period, patients exposed to these products for longer durations could have a potentially different risk of cancer.

Cost Evaluation of the Ontario Virtual Urgent Care Pilot Program: Population-Based, Matched Cohort Study.

BACKGROUND: In 2020, the Ministry of Health (MoH) in Ontario, Canada, introduced a virtual urgent care (VUC) pilot program to provide alternative access to urgent care services and reduce the need for in-person emergency department (ED) visits for patients with low acuity health concerns. OBJECTIVE: This study aims to compare the 30-day costs associated with VUC and in-person ED encounters from an MoH perspective. METHODS: Using administrative data from Ontario (the most populous province of Canada), a population-based, matched cohort study of Ontarians who used VUC services from December 2020 to September 2021 was conducted. As it was expected that VUC and in-person ED users would be different, two cohorts of VUC users were defined: (1) those who were promptly referred to an ED by a VUC provider and subsequently presented to an ED within 72 hours (these patients were matched to in-person ED users with any discharge disposition) and (2) those seen by a VUC provider with no referral to an in-person ED (these patients were matched to patients who presented in-person to the ED and were discharged home by the ED physician). Bootstrap techniques were used to compare the 30-day mean costs of VUC (operational costs to set up the VUC program plus health care expenditures) versus in-person ED care (health care expenditures) from an MoH perspective. All costs are expressed in Canadian dollars (a currency exchange rate of CAD $1=US $0.76 is applicable). RESULTS: We matched 2129 patients who presented to an ED within 72 hours of VUC referral and 14,179 patients seen by a VUC provider without a referral to an ED. Our matched populations represented 99% (2129/2150) of eligible VUC patients referred to the ED by their VUC provider and 98% (14,179/14,498) of eligible VUC patients not referred to the ED by their VUC provider. Compared to matched in-person ED patients, 30-day costs per patient were significantly higher for the cohort of VUC patients who presented to an ED within 72 hours of VUC referral ($2805 vs $2299; difference of $506, 95% CI $139-$885) and significantly lower for the VUC cohort of patients who did not require ED referral ($907 vs $1270; difference of $362, 95% CI 284-$446). Overall, the absolute 30-day costs associated with the 2 VUC cohorts were $18.9 million (ie, $6.0 million + $12.9 million) versus $22.9 million ($4.9 million + $18.0 million) for the 2 in-person ED cohorts. CONCLUSIONS: This costing evaluation supports the use of VUC as most complaints were addressed without referral to ED. Future research should evaluate targeted applications of VUC (eg, VUC models led by nurse practitioners or physician assistants with support from ED physicians) to inform future resource allocation and policy decisions.

Association between immigration status and total knee arthroplasty outcomes in Ontario, Canada: a population-based matched cohort study.

BACKGROUND: Immigrants and refugees face unique challenges navigating the health care system to manage severe arthritis, because of unfamiliarity, lack of awareness of surgical options, or access. The purpose of this study was to assess total knee arthroplasty (TKA) uptake, surgical outcomes, and hospital utilization among immigrants and refugees compared with Canadian-born patients. METHODS: We included all adults undergoing primary TKA from January 2011 to December 2020 in Ontario. Cohorts were defined as Canadian-born or immigrants and refugees. We assessed change in yearly TKA utilization for trend. We compared differences in 1-year revision, infection rates, 30-day venous thromboembolism (VTE), presentation to emergency department, and hospital readmission between matched Canadian-born and immigrant and refugee groups. RESULTS: We included 158 031 TKA procedures. A total of 11 973 (7.6%) patients were in the immigrant and refugee group, and 146 058 (92.4%) patients were in the Canadian-born group. The proportion of TKAs in Ontario performed among immigrants and refugees nearly doubled over the 10-year study period (p < 0.001). After matching, immigrants were at relatively lower risk of 1-year revision (0.9% v. 1.6%, p < 0.001), infection (p < 0.001), death (p = 0.004), and surgical complications (p < 0.001). No differences were observed in rates of 30-day VTE or length of hospital stay. Immigrants were more likely to be discharged to rehabilitation (p < 0.001) and less likely to present to the emergency department (p < 0.001) than Canadian-born patients. CONCLUSION: Compared with Canadian-born patients, immigrants and refugees have favourable surgical outcomes and similar rates of resource utilization after TKA. We observed an underutilization of these procedures in Ontario relative to their proportion of the population. This may reflect differences in perceptions of chronic pain or barriers accessing arthroplasty.

Impact of the coronavirus disease 2019 pandemic on equity of access to hip and knee replacements: a population-level study.

PURPOSE: The COVID-19 pandemic had innumerable impacts on healthcare delivery. In Canada, this included limitations on inpatient capacity, which resulted in an increased focus on outpatient surgery for non-emergent cases such as joint replacements. The objective of this study was to assess whether the pandemic and the shift towards outpatient surgery had an impact on access to joint replacement for marginalized patients. METHODS: Data from Ontario's administrative healthcare databases were obtained for all patients undergoing an elective hip or knee replacement between January 1, 2018 and August 31, 2021. All surgeries performed before March 15, 2020 were classified as "pre-COVID," while all procedures performed after that date were classified as "post-COVID." The Ontario Marginalization Index domains were used to analyze proportion of marginalized patients undergoing surgery pre- and post-COVID. RESULTS: A total of 102,743 patients were included-42,812 hip replacements and 59,931 knee replacements. There was a significant shift towards outpatient surgery during the post-COVID period (1.1% of all cases pre-COVID to 13.2% post-COVID, p < 0.001). In the post-COVID cohort, there were significantly fewer patients from some marginalized groups, as well as fewer patients with certain co-morbidities, such as congestive heart failure and chronic obstructive pulmonary disease. CONCLUSION: The most important finding of this population-level database study is that, compared to before the COVID-19 pandemic, there has been a change in the profile of patients undergoing hip and knee replacements in Ontario, specifically across a range of indicators. Fewer marginalized patients are undergoing joint replacement surgery since the COVID-19 pandemic. Further monitoring of access to joint replacement surgery is required in order to ensure that surgery is provided to those who are most in need.

Characteristics of walk-in clinic physicians and patients in Ontario: Cross-sectional study.

OBJECTIVE: To describe family physicians who primarily practise in a walk-in clinic setting and compare them with family physicians who provide longitudinal care. DESIGN: A cross-sectional study that linked results from a 2019 physician survey to provincial administrative health care data in Ontario. The characteristics, practice patterns, and patients of physicians primarily working in a walk-in clinic setting were compared with those of family physicians providing longitudinal care. SETTING: Ontario. PARTICIPANTS: Physicians who primarily worked in a walk-in clinic setting in 2019, as indicated by an annual physician survey. MAIN OUTCOME MEASURES: Physician demographic and practice characteristics, as well as their patients' demographic and health care utilization characteristics, were reported according to whether the physician was a walk-in clinic physician or a family physician who provided longitudinal care. RESULTS: Compared with the 9137 family physicians providing longitudinal care, the 597 physicians who self-identified as practising primarily in walk-in clinics were more frequently male (67% vs 49%) and more likely to speak a language other than English or French (43% vs 32%). Walk-in clinic physicians tended to have more encounters with patients who were younger (mean 37 vs 47 years), who had lower levels of prior health care utilization (15% vs 19% in highest band), who resided in large urban areas (87% vs 77%), and who lived in highly ethnically diverse neighbourhoods (45% vs 35%). Walk-in clinic physicians tended to have more encounters with unattached patients (33% vs 17%) and with patients attached to another physician outside their group (54% vs 18%). CONCLUSION: Physicians who primarily work in walk-in clinics saw many patients from historically underserved groups and many patients who were attached to another family physician.

Association of surgeon volume with complications following direct anterior approach (DAA) total hip arthroplasty: a population-based study.

BACKGROUND AND PURPOSE:  Total hip arthroplasty (THA) can be performed through various surgical approaches, including direct anterior (DAA). DAA-THA may offer faster recovery but carries a higher risk of complications, which may be mitigated by surgeon volume and experience. We examined the association of surgeons' annual surgical volume with major complications after DAA-THA in a population-based sample. METHODS:  A population-based retrospective cohort study was carried out on primary DAA-THA patients in Ontario between April 2016 and March 2021. We used restricted cubic splines to visually define the association between annual DAA surgeon volume and the risk of major surgical complications (fractures, dislocations, infections, and revisions) within 1 year of surgery. We further compared the complication rates amongst different DAA volume categories (< 30, 30-60, and > 60 cases/year). RESULTS: The study encompassed 9,672 DAA-THA patients (52% female, median age 67 years). We showed a sharp decline in the probability of complications as the surgical volume of DAA-THA increased within the lower range of 0-30 cases/year; the probability slightly increased after the surgical volume exceeded 60 cases/year. The overall complication rates were 3.09%, 2.24%, and 2.18% for the surgical experience group of < 30 cases/year, 30-60 cases/year, and > 60 cases/year, respectively. CONCLUSION:  There was an inverse relationship between surgical volume and complication rates in DAA-THA within the lower volume ranges. Maintaining a surgical volume of at least 30 DAA-THA cases/year can minimize complications, emphasizing the importance of surgical volume in this approach.

MRI use leading up to total knee arthroplasty: a retrospective cohort study.

BACKGROUND: Demand for total knee arthroplasty (TKA) is increasing as it remains the gold-standard treatment for end-stage osteoarthritis (OA) of the knee. Magnetic resonance imaging (MRI) scans of the knee are not indicated for diagnosing knee OA and represent a possible delay to orthopaedic surgeon referral and unnecessary expenditure. The purpose of this study was to determine the proportion of patients who underwent an MRI in the two years prior to their primary TKA for OA and determine patient and physician associations with increased MRI usage. METHODS: This is a population-based cohort study using administrative data from Ontario, Canada. All patients over 40 years old who underwent their first primary TKA between April 1, 2008, and March 31, 2019, were included. Statistical analyses were performed using SAS and included the Cochran-Armitage test for trend of MRI prior to surgery. A predictive multivariable regression model was used to determine features correlated to receiving an MRI. RESULTS: There were 194,989 eligible first-time TKA recipients, of which 38,244 (19.6%) received an MRI in the two years prior to their surgery. The majority of these (69.6%) were ordered by primary care physicians. Patients who received an MRI were younger, had fewer comorbidities and were more affluent than patients who did not (p < 0.001). MRI use prior to TKA increased from 2008 to 2018 (p < 0.001). CONCLUSION: Despite MRIs rarely being indicated for the work-up of end-stage OA, nearly one in five patients have an MRI in the two years prior to their TKA. This may be increasing healthcare expenditure and surgical wait-times.

Evaluating the importance of individual heterogeneity in reproduction to Weddell seal population dynamics using integral projection models.

Identifying and accounting for unobserved individual heterogeneity in vital rates in demographic models is important for estimating population-level vital rates and identifying diverse life-history strategies, but much less is known about how this individual heterogeneity influences population dynamics. We aimed to understand how the distribution of individual heterogeneity in reproductive and survival rates influenced population dynamics using vital rates from a Weddell seal population by altering the distribution of individual heterogeneity in reproduction, which also altered the distribution of individual survival rates through the incorporation of our estimate of the correlation between the two rates and assessing resulting changes in population growth. We constructed an integral projection model (IPM) structured by age and reproductive state using estimates of vital rates for a long-lived mammal that has recently been shown to exhibit large individual heterogeneity in reproduction. Using output from the IPM, we evaluated how population dynamics changed with different underlying distributions of unobserved individual heterogeneity in reproduction. Results indicate that the changes to the underlying distribution of individual heterogeneity in reproduction cause very small changes in the population growth rate and other population metrics. The largest difference in the estimated population growth rate resulting from changes to the underlying distribution of individual heterogeneity was less than 1%. Our work highlights the differing importance of individual heterogeneity at the population level compared to the individual level. Although individual heterogeneity in reproduction may result in large differences in the lifetime fitness of individuals, changing the proportion of above- or below-average breeders in the population results in much smaller differences in annual population growth rate. For a long-lived mammal with stable and high adult-survival that gives birth to a single offspring, individual heterogeneity in reproduction has a limited effect on population dynamics. We posit that the limited effect of individual heterogeneity on population dynamics may be due to canalization of life-history traits.

Up-to-date on cancer screening among Ontario patients seen by walk-in clinic physicians: A retrospective cohort study.

Walk-in clinics are typically viewed as high-volume locations for managing acute issues but also may serve as a location for primary care, including cancer screening, for patients without a family physician. In this population-based cohort study, we compared breast, cervical and colorectal cancer screening up-to-date status for people living in the Canadian province of Ontario who were formally enrolled to a family physician versus those not enrolled but who had at least one encounter with a walk-in clinic physician in the previous year. Using provincial administrative databases, we created two mutually exclusive groups: i) those who were formally enrolled to a family physician, ii) those who were not enrolled but had at least one visit with a walk-in clinic physician from April 1, 2019 to March 31, 2020. We compared up to date status for three cancer screenings as of April 1, 2020 among screen-eligible people. We found that people who were not enrolled and had seen a walk-in clinic physician in the previous year consistently were less likely to be up to date on cancer screening than Ontarians who were formally enrolled with a family physician (46.1% vs. 67.4% for breast, 45.8% vs. 67.4% for cervical, 49.5% vs. 73.1% for colorectal). They were also more likely to be foreign-born and to live in structurally marginalized neighbourhoods. New methods are needed to enable screening for people who are reliant on walk-in clinics and to address the urgent need in Ontario for more primary care providers who deliver comprehensive, longitudinal care.

Prescription of oxycodone versus codeine after childbirth and risk of persistent opioid use: a population-based cohort study.

BACKGROUND: Oxycodone is increasingly prescribed for postpartum analgesia in lieu of codeine owing to concerns regarding the neonatal safety of codeine during lactation. We examined whether initiation of oxycodone after delivery was associated with an increased risk of persistent opioid use relative to initiation of codeine. METHODS: We conducted a population-based cohort study of people who filled a prescription for either codeine or oxycodone within 7 days of discharge from hospital after delivery between Sept. 1, 2012, and June 30, 2020. The primary outcome was persistent opioid use, defined as 1 or more additional prescriptions for an opioid within 90 days of the first postpartum prescription and 1 or more additional prescriptions in the 91 to 365 days thereafter. We used inverse probability of treatment weighting to assess the risk of persistent postpartum opioid use, comparing people who initiated oxycodone with those who initiated codeine. RESULTS: Over the 8-year study period, we identified 70 607 people who filled an opioid prescription within 7 days of discharge from hospital: 21 308 (30.2%) received codeine and 49 299 (69.8%) oxycodone. Compared with people who filled a prescription for codeine, receipt of oxycodone was not associated with persistent opioid use (relative risk [RR] 1.04, 95% confidence interval [CI] 0.91-1.20). We found an association between a prescription for oxycodone and persistent use after vaginal delivery (RR 1.63, 95% CI 1.31-2.03), but not after cesarean delivery (RR 0.85, 95% CI 0.73-1.00). INTERPRETATION: Initiation of oxycodone (v. codeine) was not associated with an increased risk of persistent opioid use, except after vaginal delivery.

Health care utilization and outcomes of patients seen by virtual urgent care versus in-person emergency department care.

BACKGROUND: Virtual urgent care (VUC) is intended to support diversion of patients with low-acuity complaints and reduce the need for in-person emergency department visits. We aimed to describe subsequent health care utilization and outcomes of patients who used VUC compared with similar patients who had an in-person emergency department visit. METHODS: We used patient-level encounter data that were prospectively collected for patients using VUC services provided by 14 pilot programs in Ontario, Canada. We linked the data to provincial administrative databases to identify subsequent 30-day health care utilization and outcomes. We defined 2 subgroups of VUC users; those with a documented prompt referral to an emergency department by a VUC provider, and those without. We matched patients in each cohort to an equal number of patients presenting to an emergency department in person, based on encounter date, medical concern and the logit of a propensity score. For the subgroup of patients not promptly referred to an emergency department, we matched patients to those who were seen in an emergency department and then discharged home. RESULTS: Of the 19 595 patient VUC visits linked to administrative data, we matched 2129 patients promptly referred to the emergency department by a VUC provider to patients presenting to the emergency department in person. Index visit hospital admissions (9.4% v. 8.7%), 30-day emergency department visits (17.0% v. 17.5%), and hospital admissions (12.9% v. 11.0%) were similar between the groups. We matched 14 179 patients who were seen by a VUC provider with no documented referral to the emergency department. Patients seen by VUC were more likely to have a subsequent in-person emergency department visit within 72 hours (13.7% v. 7.0%), 7 days (16.5% v. 10.3%) and 30 days (21.9% v. 17.9%), but hospital admissions were similar within 72 hours (1.1% v. 1.3%), and higher within 30 days for patients who were discharged home from the emergency department (2.6% v. 3.4%). INTERPRETATION: The impact of the provincial VUC pilot program on subsequent health care utilization was limited. There is a need to better understand the inherent limitations of virtual care and ensure future virtual providers have timely access to in-person outpatient resources, to prevent subsequent emergency department visits.

Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study.

BACKGROUND: The association between hydrochlorothiazide (HCTZ) and skin cancer remains controversial. OBJECTIVE: To determine whether HCTZ is associated with an increased risk of skin cancer compared with angiotensin-converting enzyme inhibitors and calcium channel blockers. METHODS: Two new-user, active comparator cohorts were assembled using 6 Canadian databases. Site-specific hazard ratios (HRs) with 95% CIs were estimated using standardized morbidity ratio weighted Cox proportional hazard models and pooled using random-effects meta-analysis. RESULTS: HCTZ was not associated with an overall increased risk of keratinocyte carcinoma compared with angiotensin-converting enzyme inhibitors or calcium channel blockers, although increased risks were observed with longer durations (≥10 years; HR: 1.12; 95% CI: 1.03-1.21) and higher cumulative doses (≥100,000 mg; HR: 1.49; 95% CI: 1.27-1.76). For melanoma, there was no association with angiotensin-converting enzyme inhibitors, but a 32% increased risk with calcium channel blockers (crude incidence rates: 64.2 vs 58.4 per 100,000 person-years; HR: 1.32; 95% CI: 1.19-1.46; estimated number needed to harm at 5 years of follow-up: 1627 patients), with increased risks with longer durations and cumulative doses. LIMITATIONS: Residual confounding due to the observational design. CONCLUSIONS: Increased risks of keratinocyte carcinoma and melanoma were observed with longer durations of use and higher cumulative doses of HCTZ.

Incidence of cardiovascular disease and mortality in childhood solid organ transplant recipients: a population-based study.

BACKGROUND: With improved survival among children after transplantation, our understanding of the risk for developing other comorbidities is improving, yet little is known about the long-term risk of cardiovascular events and mortality after solid organ transplantation. METHODS: In a cohort study using health administrative data, we compared cardiovascular events in children (n = 615) with liver, lung, kidney, small bowel, or multi-organ transplant at the Hospital for Sick Children, Toronto, Canada, with asthmatic children (n = 481,697) between 1996 and 2014. Outcomes included non-fatal cardiovascular events, cardiovascular death, all-cause mortality, and a composite of non-fatal and fatal cardiovascular events. Time-stratified Cox proportional hazards models were used. RESULTS: Among 615 children, 317 (52%) were recipients of kidneys, 253 (41%) of livers, and the remaining 45 (7%) had lung, small bowel, or multi-organ transplants. Median follow-up was 12.1 [7.2, 16.7] years. Non-fatal incident cardiovascular events were 34 times higher among solid organ transplant recipients than non-transplanted children (incidence rate ratio (IRR) 34.4, 95% CI: 25.5, 46.4). Among transplant recipients, the cumulative incidence of non-fatal and fatal cardiovascular events was 2.3% and 13.0%, 5 and 15 years after transplantation, respectively. CONCLUSIONS: Increased rate of cardiovascular events in children after transplantation highlights the need for surveillance during transition into adulthood and beyond. A higher resolution version of the Graphical abstract is available as Supplementary information.

Bariatric Surgery and Cardiovascular Outcomes in Patients With Obesity and Cardiovascular Disease:: A Population-Based Retrospective Cohort Study.

BACKGROUND: Bariatric surgery has been shown to significantly reduce cardiovascular risk factors. However, whether surgery can reduce major adverse cardiovascular events (MACE), especially in patients with established cardiovascular disease, remains poorly understood. The present study aims to determine the association between bariatric surgery and MACE among patients with cardiovascular disease and severe obesity. METHODS: This was a propensity score-matched cohort study using province-wide multiple-linked administrative databases in Ontario, Canada. Patients with previous ischemic heart disease or heart failure who received bariatric surgery were matched on age, sex, heart failure history, and a propensity score to similar controls from a primary care medical record database in a 1:1 ratio. The primary outcome was the incidence of extended MACE (first occurrence of all-cause mortality, myocardial infarction, coronary revascularization, cerebrovascular events, and heart failure hospitalization). Secondary outcome included 3-component MACE (myocardial infarction, ischemic stroke, and all-cause mortality). Outcomes were evaluated through a combination of matching via propensity score and subsequent multivariable adjustment. RESULTS: A total of 2638 patients (n=1319 in each group) were included, with a median follow-up time of 4.6 years. The primary outcome occurred in 11.5% (151/1319) of the surgery group and 19.6% (259/1319) of the controls (adjusted hazard ratio [HR], 0.58 [95% CI, 0.48-0.71]; P<0.001). The association was notable for those with heart failure (HR, 0.44 [95% CI, 0.31-0.62]; P<0.001; absolute risk difference, 19.3% [95% CI, 12.0%-26.7%]) and in those with ischemic heart disease (HR, 0.60 [95% CI, 0.48-0.74]; P<0.001; absolute risk difference, 7.5% [95% CI, 4.7%-10.5%]). Surgery was also associated with a lower incidence of the secondary outcome (HR, 0.66 [95% CI, 0.52-0.84]; P=0.001) and cardiovascular mortality (HR, 0.35 [95% CI, 0.15-0.80]; P=0.001). CONCLUSIONS: Bariatric surgery was associated with a lower incidence of MACE in patients with cardiovascular disease and obesity. These findings require confirmation by a large-scale randomized trial.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Survival after surgery for spinal metastases: a population-based study.

BACKGROUND: There are limited published data on population estimates of survival after spinal surgery for metastatic disease. We performed a population-based study to evaluate survival and complications among patients with cancer who underwent surgery for spinal metastases in Ontario, Canada, between 2006 and 2016. METHODS: We used health administrative databases to identify all patients who underwent surgery for spinal metastases in Ontario between Jan. 1, 2006, and Dec. 31, 2016. We assessed overall survival, mortality rates according to primary cancer lesion and complications after surgery. We contrast the results to those for a comparable cohort from 1991 to 1998. RESULTS: A total of 2646 patients (1194 women [45.1%]; mean age 62.5 yr [standard deviation 12.2 yr]) were identified. The median survival time was 236 (interquartile range 84-740) days. Mortality was highest for patients with melanoma, upper gastrointestinal cancer and lung cancer, with 50% dying within 90 days of surgery. The longest median survival times were observed for primary cancers of the thyroid (906 d) and breast (644 d), and myeloma (830 d). Overall 90-day and 1-year mortality rates were 29% and 59%, respectively. CONCLUSION: We identified differential survivorship based on primary tumour type and a shift in the distribution of operations performed for specific primary cancers over the past 2 decades in Ontario. Overall reductions in mortality associated with this shift in treatment may reflect the use of adjuvant therapies and more personalized treatment approaches.

Inequities in access to primary care among opioid recipients in Ontario, Canada: A population-based cohort study.

BACKGROUND: Stigma and high-care needs can present barriers to the provision of high-quality primary care for people with opioid use disorder (OUD) and those prescribed opioids for chronic pain. We explored the likelihood of securing a new primary care provider (PCP) among people with varying histories of opioid use who had recently lost access to their PCP. METHODS AND FINDINGS: We conducted a retrospective cohort study using linked administrative data among residents of Ontario, Canada whose enrolment with a physician practicing in a primary care enrolment model (PEM) was terminated between January 2016 and December 2017. We assigned individuals to 3 groups based upon their opioid use on the date enrolment ended: long-term opioid pain therapy (OPT), opioid agonist therapy (OAT), or no opioid. We fit multivariable models assessing the primary outcome of primary care reattachment within 1 year, adjusting for demographic characteristics, clinical comorbidities, and health services utilization. Secondary outcomes included rates of emergency department (ED) visits and opioid toxicity events. Among 154,970 Ontarians who lost their PCP, 1,727 (1.1%) were OAT recipients, 3,644 (2.4%) were receiving long-term OPT, and 149,599 (96.5%) had no recent prescription opioid exposure. In general, OAT recipients were younger (median age 36) than those receiving long-term OPT (59 years) and those with no recent prescription opioid exposure (44 years). In all exposure groups, the majority of individuals had their enrolment terminated by their physician (range 78.1% to 88.8%). In the primary analysis, as compared to those not receiving opioids, OAT recipients were significantly less likely to find a PCP within 1 year (adjusted hazard ratio [aHR] 0.55, 95% confidence interval [CI] 0.50 to 0.61, p < 0.0001). We observed no significant difference between long-term OPT and opioid unexposed individuals (aHR 0.96; 95% CI 0.92 to 1.01, p = 0.12). In our secondary analysis comparing the period of PCP loss to the year prior, we found that rates of ED visits were elevated among people not receiving opioids (adjusted rate ratio (aRR) 1.20, 95% CI 1.18 to 1.22, p < 0.0001) and people receiving long-term OPT (aRR 1.37, 95% CI 1.28 to 1.48, p < 0.0001). We found no such increase among OAT recipients, and no significant increase in opioid toxicity events in the period following provider loss for any exposure group. The main limitation of our findings relates to their generalizability outside of PEMs and in jurisdictions with different financial incentives incorporated into primary care provision. CONCLUSIONS: In this study, we observed gaps in access to primary care among people who receive prescription opioids, particularly among OAT recipients. Ongoing efforts are needed to address the stigma, discrimination, and financial disincentives that may introduce barriers to the healthcare system, and to facilitate access to high-quality, consistent primary care services for chronic pain patients and those with OUD.