ABSTRACT
Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. Using isotope tracer analysis, we show that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages is sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. Unexpectedly, mechanistic studies reveal that limiting flux through the cholesterol biosynthetic pathway spontaneously engages a type I IFN response in a STING-dependent manner. The upregulation of type I IFNs was traced to a decrease in the pool size of synthesized cholesterol and could be inhibited by replenishing cells with free cholesterol. Taken together, these studies delineate a metabolic-inflammatory circuit that links perturbations in cholesterol biosynthesis with activation of innate immunity.
Subject(s)
Cholesterol/metabolism , Immunity, Innate , Interferon-gamma/metabolism , Signal Transduction , Animals , Cell Line, Tumor , Humans , Interferon beta-1b , Membrane Proteins/metabolism , Mevalonic Acid/metabolism , Mice , Mice, Inbred C57BL , Sterol Regulatory Element Binding Protein 1/metabolism , Sterol Regulatory Element Binding Protein 2/metabolismABSTRACT
Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DDR-activated APA event occurs in the first intron of CDKN1A, inducing an alternate last exon-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon DNA Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high-throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform under non-stress conditions, and SPUD is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53. The RNA binding protein HuR binds to and promotes the stability of SPUD precursor RNA. SPUD induction increases p21 protein, but not mRNA levels, affecting p21 functions in cell-cycle, CDK2 expression and cell growth. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD alters their association with CDKN1A full-length in a DDR-dependent manner, promoting CDKN1A translation. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cell-cycle.
Subject(s)
RNA, Long Noncoding , Cell Cycle , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Damage , Polyadenylation , Protein Isoforms/genetics , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Humans , Cell Line, TumorABSTRACT
BACKGROUND AND AIMS: Female sex is associated with higher rates of stroke in atrial fibrillation (AF) after adjustment for other CHA2DS2-VASc factors. This study aimed to describe sex differences in age and cardiovascular care to examine their relationship with stroke hazard in AF. METHODS: Population-based cohort study using administrative datasets of people aged ≥66 years diagnosed with AF in Ontario between 2007 and 2019. Cause-specific hazard regression was used to estimate the adjusted hazard ratio (HR) for stroke associated with female sex over a 2-year follow-up. Model 1 included CHA2DS2-VASc factors, with age modelled as 66-74 vs. ≥ 75 years. Model 2 treated age as a continuous variable and included an age-sex interaction term. Model 3 further accounted for multimorbidity and markers of cardiovascular care. RESULTS: The cohort consisted of 354 254 individuals with AF (median age 78 years, 49.2% female). Females were more likely to be diagnosed in emergency departments and less likely to receive cardiologist assessments, statins, or LDL-C testing, with higher LDL-C levels among females than males. In Model 1, the adjusted HR for stroke associated with female sex was 1.27 (95% confidence interval 1.21-1.32). Model 2 revealed a significant age-sex interaction, such that female sex was only associated with increased stroke hazard at age >70 years. Adjusting for markers of cardiovascular care and multimorbidity further decreased the HR, so that female sex was not associated with increased stroke hazard at age ≤80 years. CONCLUSION: Older age and inequities in cardiovascular care may partly explain higher stroke rates in females with AF.
Subject(s)
Atrial Fibrillation , Stroke , Female , Humans , Male , Aged , Aged, 80 and over , Atrial Fibrillation/complications , Atrial Fibrillation/epidemiology , Atrial Fibrillation/diagnosis , Cohort Studies , Cholesterol, LDL , Stroke/etiology , Stroke/complications , Proportional Hazards Models , Risk Factors , Risk AssessmentABSTRACT
BACKGROUND: Interhospital transfer for patients with stroke due to large vessel occlusion for endovascular thrombectomy (EVT) has been associated with treatment delays. METHODS: We analyzed data from Optimizing Patient Treatment in Major Ischemic Stroke With EVT, a quality improvement registry to support EVT implementation in Canada. We assessed for unadjusted differences in baseline characteristics, time metrics, and procedural outcomes between patients with large vessel occlusion transferred for EVT and those directly admitted to an EVT-capable center. RESULTS: Between January 1, 2018, and December 31, 2021, a total of 6803 patients received EVT at 20 participating centers (median age, 73 years; 50% women; and 50% treated with intravenous thrombolysis). Patients transferred for EVT (n=3376) had lower rates of M2 occlusion (22% versus 27%) and higher rates of basilar occlusion (9% versus 5%) compared with those patients presenting directly at an EVT-capable center (n=3373). Door-to-needle times were shorter in patients receiving intravenous thrombolysis before transfer compared with those presenting directly to an EVT center (32 versus 36 minutes). Patients transferred for EVT had shorter door-to-arterial access times (37 versus 87 minutes) but longer last seen normal-to-arterial access times (322 versus 181 minutes) compared with those presenting directly to an EVT-capable center. No differences in arterial access-to-reperfusion times, successful reperfusion rates (85% versus 86%), or adverse periprocedural events were found between the 2 groups. Patients transferred to EVT centers had a similar likelihood for good functional outcome (modified Rankin Scale score, 0-2; 41% versus 43%; risk ratio, 0.95 [95% CI, 0.88-1.01]; adjusted risk ratio, 0.98 [95% CI, 0.91-1.05]) and a higher risk for all-cause mortality at 90 days (29% versus 25%; risk ratio, 1.15 [95% CI, 1.05-1.27]; adjusted risk ratio, 1.14 [95% CI, 1.03-1.28]) compared with patients presenting directly to an EVT center. CONCLUSIONS: Patients transferred for EVT experience significant delays from the time they were last seen normal to the initiation of EVT.
Subject(s)
Endovascular Procedures , Ischemic Stroke , Patient Transfer , Registries , Thrombectomy , Time-to-Treatment , Humans , Female , Male , Aged , Endovascular Procedures/methods , Canada/epidemiology , Middle Aged , Aged, 80 and over , Thrombectomy/methods , Ischemic Stroke/surgery , Ischemic Stroke/therapy , Stroke/therapy , Stroke/surgery , Stroke/epidemiology , Thrombolytic Therapy/methods , Treatment OutcomeABSTRACT
BACKGROUND: Understanding sex differences in stroke care is important in reducing potential disparities. Our objective was to explore sex differences in workflow efficiency, treatment efficacy, and safety in the AcT trial (Alteplase Compared to Tenecteplase). METHODS: AcT was a multicenter, registry-linked randomized noninferiority trial comparing tenecteplase (0.25 mg/kg) with alteplase (0.9 mg/kg) in acute ischemic stroke within 4.5 hours of onset. In this post hoc analysis, baseline characteristics, workflow times, successful reperfusion (extended Thrombolysis in Cerebral Infarction score ≥2b), symptomatic intracerebral hemorrhage, 90-day functional independence (modified Rankin Scale score, 0-1), and 90-day mortality were compared by sex. Mixed-effects regression analysis was used adjusting for age, stroke severity, and occlusion site for outcomes. RESULTS: Of 1577 patients treated with intravenous thrombolysis (2019-2022), 755 (47.9%) were women. Women were older (median, 77 [68-86] years in women versus 70 [59-79] years in men) and had a higher proportion of severe strokes (National Institutes of Health Stroke Scale score >15; 32.4% versus 24.9%) and large vessel occlusions (28.7% versus 21.5%) compared with men. All workflow times were comparable between sexes. Women were less likely to achieve functional independence (31.7% versus 39.8%; unadjusted relative risk, 0.80 [95% CI, 0.70-0.91]) and had higher mortality (17.7% versus 13.3%; unadjusted relative risk, 1.33 [95% CI, 1.06-1.69]). Adjusted analysis showed no difference in outcomes between sexes. CONCLUSIONS: Differences in prognostic factors of age, stroke severity, and occlusion site largely accounted for higher functional dependence and mortality in women. No sex disparities were apparent in workflow quality indicators. Given the integration of the AcT trial into clinical practice, these results provide reassurance that no major sex biases are apparent in acute stroke management throughout participating Canadian centers. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.
Subject(s)
Ischemic Stroke , Tenecteplase , Tissue Plasminogen Activator , Female , Humans , Male , Canada , Ischemic Stroke/drug therapy , Tenecteplase/adverse effects , Tissue Plasminogen Activator/adverse effects , Treatment Outcome , Workflow , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Equivalence Trials as TopicABSTRACT
BACKGROUND: Although many Medicare beneficiaries with heart failure (HF) are discharged with home health services, little is known about mortality rates and hospice use in this group. OBJECTIVES: To identify risk factors for 6-month mortality and hospice use among patients hospitalized due to HF who receive home health care, which could inform efforts to improve palliative and hospice use for these patients. METHODS: A retrospective cohort analysis was conducted in a 100% national sample of Medicare fee-for-service beneficiaries with HF who were discharged to home health care between 2017 and 2018. Multivariable Cox regression models examined factors associated with 6-month mortality, and multivariable logistic regression models examined factors associated with hospice use at the time of death. RESULTS: A total of 285,359 Medicare beneficiaries were hospitalized with HF and discharged with home health care; 15.5% (44,174) died within 6 months. Variables most strongly associated with mortality included: age > 85 years (hazard ratio [HR] 1.66, 95% CI 1.61-1.71), urgent/emergency hospital admission (HR 1.68, 1.61-1.76), and "serious" condition compared to "stable" condition (HR 1.64, CI 1.52-1.78). Among 44,174 decedents, 48.2% (21,284) received hospice care at the time of death. Those with lower odds of hospice use at death included patients who were: < 65 years (odds ratio [OR] 0.65, CI 0.59-0.72); of Black (OR 0.64, CI 0.59-0.68) or Hispanic race/ethnicity (OR 0.79, CI 0.72-0.88); and Medicaid-eligible (OR 0.80, CI 0.76-0.85). CONCLUSIONS: Although many patients hospitalized for HF are at risk of 6-month mortality and may benefit from palliative and/or hospice services, our findings indicate under-use of hospice care and important disparities in hospice use by race/ethnicity and socioeconomic status.
Subject(s)
Heart Failure , Home Care Services , Hospice Care , Medicare , Humans , United States/epidemiology , Heart Failure/mortality , Heart Failure/therapy , Male , Female , Home Care Services/statistics & numerical data , Home Care Services/trends , Medicare/statistics & numerical data , Aged, 80 and over , Retrospective Studies , Aged , Hospice Care/statistics & numerical data , Hospitalization/statistics & numerical data , Risk FactorsABSTRACT
PURPOSE: Oxaliplatin-containing adjuvant chemotherapy yields a significant survival benefit in stage III colon cancer and is the standard of care. Simultaneously, it causes dose-dependent peripheral neuropathy that may increase the risk of fall-related injury (FRI) such as fracture and laceration. Because these events carry significant morbidity and the global burden of colon cancer is on the rise, we examined the association between treatment with a full versus shortened course of adjuvant chemotherapy and post-treatment FRI and fracture. METHODS: In this overlap propensity score weighted, retrospective cohort study, we included patients aged ≥ 18 years with resected stage III colon cancer diagnosed 2007-2019 and treated with oxaliplatin-containing adjuvant chemotherapy (oxaliplatin plus a fluoropyrimidine; capecitabine [CAPOX] or 5-fluorouracil and leucovorin [FOLFOX]). Propensity score methods facilitate the separation of design from analysis and comparison of baseline characteristics across the weighted groups. Treatment groups were defined as 50% (4 cycles CAPOX/6 cycles FOLFOX) and > 85% (7-8 cycles CAPOX/11-12 cycles FOLFOX) of a maximal course of adjuvant chemotherapy to approximate the treatment durations received in the IDEA collaboration. The main outcomes were time to any FRI and time to fracture. We determined the subdistribution hazard ratios (sHR) estimating the association between FRI/fracture and treatment group, accounting for the competing risk of death. RESULTS: We included 3,461 patients; 473 (13.7%) received 50% and 2,988 (86.3%) received > 85% of a maximal course of adjuvant therapy. For post-treatment FRI, median follow-up was 4.6 years and total follow-up was 17,968 person-years. There were 508 FRI, 301 fractures, and 692 deaths. Treatment with > 85% of a maximal course of therapy conferred a sHR of 0.84 (95% CI 0.62-1.13) for post-treatment FRI and a sHR of 0.72 (95% CI 0.49-1.06) for post-treatment fracture. CONCLUSION: For patients with stage III colon cancer undergoing treatment with oxaliplatin-containing adjuvant chemotherapy, any potential neuropathy associated with longer durations of treatment was not found to result in greater rates of FRI and fracture. Within the limits of this retrospective study, our findings suggest concern about FRI, while mechanistically plausible, ought not to determine treatment duration.
Subject(s)
Accidental Falls , Antineoplastic Combined Chemotherapy Protocols , Colonic Neoplasms , Fluorouracil , Leucovorin , Neoplasm Staging , Oxaliplatin , Humans , Retrospective Studies , Female , Male , Chemotherapy, Adjuvant/methods , Chemotherapy, Adjuvant/adverse effects , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Colonic Neoplasms/mortality , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Oxaliplatin/administration & dosage , Oxaliplatin/adverse effects , Oxaliplatin/therapeutic use , Aged , Accidental Falls/statistics & numerical data , Leucovorin/therapeutic use , Leucovorin/adverse effects , Leucovorin/administration & dosage , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Fractures, Bone/etiology , Fractures, Bone/epidemiology , Capecitabine/administration & dosage , Propensity Score , Adult , Organoplatinum CompoundsABSTRACT
Women face a disproportionate burden of stroke mortality and disability. Biologic sex and sociocultural gender both contribute to differences in stroke risk factors, assessment, treatment, and outcomes. There are substantial differences in the strength of association of stroke risk factors, as well as female-specific risk factors. Moreover, there are differences in presentation, response to treatment, and stroke outcomes in women. This review outlines current knowledge of impact of sex and gender on stroke, as well as delineates research gaps and areas for future inquiry.
Subject(s)
Sex Characteristics , Stroke/epidemiology , Stroke/physiopathology , Diabetes Mellitus/blood , Diabetes Mellitus/epidemiology , Diabetes Mellitus/physiopathology , Estrogens/blood , Female , Humans , Hypertension/blood , Hypertension/epidemiology , Hypertension/physiopathology , Pregnancy , Pregnancy Complications, Cardiovascular/blood , Pregnancy Complications, Cardiovascular/epidemiology , Pregnancy Complications, Cardiovascular/physiopathology , Risk Factors , Sex Factors , Stroke/bloodABSTRACT
OBJECTIVE: To examine the association of co-morbidity with home-time after acute stroke and whether the association is influenced by age. METHODS: We conducted a province-wide study using linked administrative databases to identify all admissions for first acute ischemic stroke or intracerebral hemorrhage between 2007 and 2018 in Alberta, Canada. We used ischemic stroke-weighted Charlson Co-morbidity Index of 3 or more to identify those with severe co-morbidity. We used zero-inflated negative binomial models to determine the association of severe co-morbidity with 90-day and 1-year home-time, and logistic models for achieving ≥ 80 out of 90 days of home-time, assessing for effect modification by age and adjusting for sex, stroke type, comprehensive stroke center care, hypertension, atrial fibrillation, year of study, and separately adjusting for estimated stroke severity. We also evaluated individual co-morbidities. RESULTS: Among 28,672 patients in our final cohort, severe co-morbidity was present in 27.7% and was associated with lower home-time, with a greater number of days lost at younger age (-13 days at age < 60 compared to -7 days at age 80+ years for 90-day home-time; -69 days at age < 60 compared to -51 days at age 80+ years for 1-year home-time). The reduction in probability of achieving ≥ 80 days of home-time was also greater at younger age (-22.7% at age < 60 years compared to -9.0% at age 80+ years). Results were attenuated but remained significant after adjusting for estimated stroke severity and excluding those who died. Myocardial infarction, diabetes, and cancer/metastases had a greater association with lower home-time at younger age, and those with dementia had the greatest reduction in home time. CONCLUSION: Severe co-morbidity in acute stroke is associated with lower home-time, more strongly at younger age.
ABSTRACT
BACKGROUND: Stroke outcomes research requires risk-adjustment for stroke severity, but this measure is often unavailable. The Passive Surveillance Stroke SeVerity (PaSSV) score is an administrative data-based stroke severity measure that was developed in Ontario, Canada. We assessed the geographical and temporal external validity of PaSSV in British Columbia (BC), Nova Scotia (NS) and Ontario, Canada. METHODS: We used linked administrative data in each province to identify adult patients with ischemic stroke or intracerebral hemorrhage between 2014-2019 and calculated their PaSSV score. We used Cox proportional hazards models to evaluate the association between the PaSSV score and the hazard of death over 30 days and the cause-specific hazard of admission to long-term care over 365 days. We assessed the models' discriminative values using Uno's c-statistic, comparing models with versus without PaSSV. RESULTS: We included 86,142 patients (n = 18,387 in BC, n = 65,082 in Ontario, n = 2,673 in NS). The mean and median PaSSV were similar across provinces. A higher PaSSV score, representing lower stroke severity, was associated with a lower hazard of death (hazard ratio and 95% confidence intervals 0.70 [0.68, 0.71] in BC, 0.69 [0.68, 0.69] in Ontario, 0.72 [0.68, 0.75] in NS) and admission to long-term care (0.77 [0.76, 0.79] in BC, 0.84 [0.83, 0.85] in Ontario, 0.86 [0.79, 0.93] in NS). Including PaSSV in the multivariable models increased the c-statistics compared to models without this variable. CONCLUSION: PaSSV has geographical and temporal validity, making it useful for risk-adjustment in stroke outcomes research, including in multi-jurisdiction analyses.
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BACKGROUND AND PURPOSE: To assess cost-effectiveness of late time-window endovascular treatment (EVT) in a clinical trial setting and a "real-world" setting. METHODS: Data are from the randomized ESCAPE trial and a prospective cohort study (ESCAPE-LATE). Anterior circulation large vessel occlusion patients presenting > 6 hours from last-known-well were included, whereby collateral status was an inclusion criterion for ESCAPE but not ESCAPE-LATE. A Markov state transition model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) for EVT in addition to best medical care vs. best medical care only in a clinical trial setting (comparing ESCAPE-EVT to ESCAPE control arm patients) and a "real-world" setting (comparing ESCAPE-LATE to ESCAPE control arm patients). We performed an unadjusted analysis, using 90-day modified Rankin Scale(mRS) scores as model input and analysis adjusted for baseline factors. Acceptability of EVT was calculated using upper/lower willingness-to-pay thresholds of 100,000 USD/50,000 USD/QALY. RESULTS: Two-hundred and forty-nine patients were included (ESCAPE-LATE:n = 200, ESCAPE EVT-arm:n = 29, ESCAPE control-arm:n = 20). Late EVT in addition to best medical care was cost effective in the unadjusted analysis both in the clinical trial and real-world setting, with acceptability 96.6%-99.0%. After adjusting for differences in baseline variables between the groups, late EVT was marginally cost effective in the clinical trial setting (acceptability:49.9%-61.6%), but not the "real-world" setting (acceptability:32.9%-42.6%). CONCLUSION: EVT for LVO-patients presenting beyond 6 hours was cost effective in the clinical trial setting and "real-world" setting, although this was largely related to baseline patient differences favoring the "real-world" EVT group. After adjusting for these, EVT benefit was reduced in the trial setting, and absent in the real-world setting.
ABSTRACT
PURPOSE: A well-known limitation of multi-leaf collimators is that they cannot easily form island blocks. This can be important in mantle region therapy. Cerrobend photon blocks, currently used for supplementary shielding, are labor-intensive and error-prone. To address this, an innovative, non-toxic, automatically manufactured photon block using 3D-printing technology is proposed, offering a patient-specific and accurate alternative. METHODS AND MATERIALS: The study investigates the development of patient-specific photon shielding blocks using 3D-printing for three different patient cases. A 3D-printed photon block shell filled with tungsten ball bearings (BBs) was designed to have similar dosimetric properties to Cerrobend standards. The generation of the blocks was automated using the Eclipse Scripting API and Python. Quality assurance was performed by comparing the expected and actual weight of the tungsten BBs used for shielding. Dosimetric and field geometry comparisons were conducted between 3D-printed and Cerrobend blocks, utilizing ionization chambers, imaging, and field geometry analysis. RESULTS: The quality assurance assessment revealed a -1.3% average difference in the mass of tungsten ball bearings for different patients. Relative dose output measurements for three patient-specific blocks in the blocked region agreed within 2% of each other. Against the Treatment Planning System (TPS), both 3D-printed and Cerrobend blocks agreed within 2%. For each patient, 6 MV image profiles taken through the 3D-printed and Cerrobend blocks agreed within 1% outside high gradient regions. Jaccard distance analysis of the MV images against the TPS planned images, found Cerrobend blocks to have 15.7% dissimilarity to the TPS, while that of the 3D-printed blocks was 6.7%. CONCLUSIONS: This study validates a novel, efficient 3D-printing method for photon block creation in clinical settings. Despite potential limitations, the benefits include reduced manual labor, automated processes, and greater precision. It holds potential for widespread adoption in radiation therapy, furthering non-toxic radiation shielding.
Subject(s)
Radiation Protection , Tungsten , Humans , Photons , Radiometry , Printing, Three-Dimensional , Radiotherapy Planning, Computer-Assisted , Radiotherapy DosageABSTRACT
BACKGROUND: Studying the baseline incidence of cerebral venous thrombosis (CVT) prior to COVID-19 and the limitations of how this has been previously reported in the literature will help improve understanding of this disease and how risks may have changed in the post-COVID era. METHODS: We examined CVT incidence using linked administrative data in British Columbia, Canada (population 5.2 million). To contextualize our findings, we also examined CVT incidence in the published literature and searched MEDLINE and EMBASE for article titles and abstracts up to Nov 2, 2021 on CVT incidence in adults. We performed abstract screening and full-text review prior to data extraction and explored associations between CVT incidence and year of study, geographic location, and study quality with meta-analyses and meta-regression. A random-effects restricted maximum likelihood model was used. Publication bias was assessed using the Egger tests and using visual inspection of the funnel plot for symmetry. RESULTS: There were 554 unique CVT cases (mean age 50.9 years, 55.4% women) in British Columbia from 2000 to 2017; overall annual incidence was 8.7 (95%CI' 8.0-9.4) per million. Incidence increased over time in men across the entire study period, and from 2011 to 2017 in women. We identified 22 other studies on CVT incidence before 2020 (21/23 total studies included in meta-analysis). Annual incidence overall was 12.1 (95% CI' 9.9-14.3) per million with significant between-study heterogeneity (I2 98.8%, Qp-value<0.001). There were no significant associations on meta-regression between incidence and study year, study quality score, or gross national income per capita of the study country. Visual inspection of the funnel plot and a significant Egger test (z=2.8, P<0.01) suggested possible publication bias. CONCLUSIONS: Incidence of CVT in Canadian data increased over time but remained lower than in other population-based studies. Significant heterogeneity exists in the literature, which may be subject to publication bias.
Subject(s)
COVID-19 , Intracranial Thrombosis , Venous Thrombosis , Male , Adult , Humans , Female , Middle Aged , Incidence , Intracranial Thrombosis/epidemiology , Venous Thrombosis/epidemiology , Venous Thrombosis/diagnosis , British Columbia/epidemiologyABSTRACT
BACKGROUND: Estimates of attributable costs of stroke are scarce, as most prior studies do not account for the baseline health care costs in people at risk of stroke. We estimated the attributable costs of stroke in a universal health care setting and their variation across stroke types and several social determinants of health. METHODS: We undertook a population-based administrative database-derived matched retrospective cohort study in Ontario, Canada. Community-dwelling adults aged ≥40 years with a stroke between 2003 and 2018 were matched (1:1) on demographics and comorbidities with controls without stroke. Using a difference-in-differences approach, we estimated the mean 1-year direct health care costs attributable to stroke from a public health care payer perspective, accounting for censoring with a weighted available sample estimator. We described health sector-specific costs and reported variation across stroke type and social determinants of health. RESULTS: The mean 1-year attributable costs of stroke were Canadian dollars 33â 522 (95% CI, $33â 231-$33â 813), with higher costs for intracerebral hemorrhage ($40â 244; $39â 193-$41â 294) than ischemic stroke ($32â 547; $32â 252-$32â 843). Most of these costs were incurred in acute care hospitals ($15â 693) and rehabilitation facilities ($7215). Compared with all patients with stroke, the mean attributable costs were higher among immigrants ($40â 554; $39â 316-$41â 793), those aged <65 years ($35â 175; $34â 533-$35â 818), and those residing in low-income neighborhoods ($34â 687; $34â 054-$35â 320) and lower among rural residents ($29â 047; $28â 362-$29â 731). CONCLUSIONS: Our findings of high attributable costs of stroke, especially in immigrants, younger patients, and residents of low-income neighborhoods, can be used to evaluate potential health care cost savings associated with different primary stroke prevention strategies.
Subject(s)
Social Determinants of Health , Stroke , Adult , Humans , Ontario/epidemiology , Retrospective Studies , Stroke/epidemiology , Stroke/therapy , Health Care CostsABSTRACT
BACKGROUND: Pregnancy-associated stroke carries high short-term morbidity and mortality, but data on subsequent maternal outcomes are limited. We evaluated long-term maternal health outcomes after pregnancy-associated stroke. METHODS: In this retrospective cohort study, we used administrative data to identify pregnant adults aged ≤49 years with stroke between 2002-2020 in Ontario, Canada and 2 comparison groups: (1) non-pregnant female patients with stroke and (2) pregnant patients without stroke. Patients who survived the index admission were followed until 2021. After propensity score matching, we used Cox regression with a robust variance estimator to compare pregnant patients with stroke and the 2 comparison groups for the composite outcome of death and all-cause non-pregnancy readmission. Where proportional hazard assumption was not met, we reported time-varying hazard ratios (HR) with 95% CIs by modeling the log-hazard ratio as a function of time using restricted cubic splines. RESULTS: We identified 217 pregnant patients with stroke, 7604 non-pregnant patients with stroke, and 1 496 256 pregnant patients without stroke. Of the 202 pregnant patients with stroke who survived the index stroke admission, 41.6% (6.8 per 100 person-years) subsequently died or were readmitted during follow-up. Median follow-up times were 5 years (pregnancy-associated stroke), 3 years (non-pregnant stroke), and 8 years (pregnant without stroke). Pregnant patients with stroke had a lower hazard of death and all-cause readmission compared with non-pregnant patients with stroke at 1-year follow-up (HR, 0.64 [95% CI, 0.44-0.94]), but this association did not persist during longer-term follow-up. Conversely, pregnant patients with stroke had higher hazard of death and readmission compared with pregnant patients without stroke at 1-year follow-up (HR, 5.70 [95% CI, 3.04-10.66]), and this association persisted for a decade. CONCLUSIONS: Stroke during pregnancy is associated with long-term health consequences. It is essential to transition care postpartum to primary or specialty care to optimize vascular health.
Subject(s)
Stroke , Adult , Humans , Female , Retrospective Studies , Follow-Up Studies , Stroke/etiology , Ontario , Outcome Assessment, Health CareABSTRACT
BACKGROUND & AIMS: Tofacitinib is associated with sustained steroid-free remission in patients with ulcerative colitis (UC), with the lowest effective dose recommended for maintenance therapy. However, there are limited real-world data to guide decisions on the optimal maintenance regimen. We aimed to evaluate predictors and outcomes of disease activity after tofacitinib dose de-escalation in this population. METHODS: Included were adults with moderate-severe UC treated with tofacitinib between June 2012 and January 2022. The primary outcome was evidence of UC disease activity-related events: hospitalization/surgery, corticosteroid initiation, tofacitinib dose increase, or therapy switch. RESULTS: Among 162 patients, 52% continued 10 mg twice daily while 48% underwent dose de-escalation to 5 mg twice daily. Cumulative incidence rates of UC events at 12 months were similar in patients with and without dose de-escalation (56% vs 58%; P = .81). In univariable Cox regression among patients with dose de-escalation, an induction course with 10 mg twice daily for more than 16 weeks was protective of UC events (hazard ratio [HR], 0.37; 95% CI, 0.16-0.85) while ongoing severe disease (Mayo 3) was associated with UC events (HR, 6.41; 95% 95% CI, 2.23-18.44), which remained significant after adjusting for age, sex, duration of induction course, and corticosteroid use at dose de-escalation (HR, 6.05; 95% CI, 2.00-18.35). Twenty-nine percent of patients with UC events had their dose re-escalated to 10 mg twice daily, with only 63% able to recapture clinical response at 12 months. CONCLUSIONS: In this real-world cohort, we observed a 56% cumulative incidence of UC events at 12 months in patients with tofacitinib dose de-escalation. Observed factors associated with UC events after dose de-escalation included induction course for fewer than 16 weeks and active endoscopic disease 6 months after initiation.
Subject(s)
Adrenal Cortex Hormones , Colitis, Ulcerative , Janus Kinase Inhibitors , Piperidines , Adult , Humans , Adrenal Cortex Hormones/therapeutic use , Colitis, Ulcerative/drug therapy , Piperidines/therapeutic use , Treatment Outcome , Janus Kinase Inhibitors/therapeutic useABSTRACT
BACKGROUND: Adjustment for baseline stroke severity is necessary for accurate assessment of hospital performance. We evaluated whether adjusting for the Passive Surveillance Stroke SeVerity (PaSSV) score, a measure of stroke severity derived using administrative data, changed hospital-specific estimated 30-day risk-standardized mortality rate (RSMR) after stroke. METHODS: We used linked administrative data to identify adults who were hospitalized with ischemic stroke or intracerebral hemorrhage across 157 hospitals in Ontario, Canada between 2014 and 2019. We fitted a random effects logistic regression model using Markov Chain Monte Carlo methods to estimate hospital-specific 30-day RSMR and 95% credible intervals with adjustment for age, sex, Charlson comorbidity index, and stroke type. In a separate model, we additionally adjusted for stroke severity using PaSSV. Hospitals were defined as low-performing, average-performing, or high-performing depending on whether the RSMR and 95% credible interval were above, overlapping, or below the cohort's crude mortality rate. RESULTS: We identified 65,082 patients [48.0% were female, the median age (25th,75th percentiles) was 76 years (65,84), and 86.4% had an ischemic stroke]. The crude 30-day all-cause mortality rate was 14.1%. The inclusion of PaSSV in the model reclassified 18.5% (n=29) of the hospitals. Of the 143 hospitals initially classified as average-performing, after adjustment for PaSSV, 20 were reclassified as high-performing and 8 were reclassified as low-performing. Of the 4 hospitals initially classified as low-performing, 1 was reclassified as high-performing. All 10 hospitals initially classified as high-performing remained unchanged. CONCLUSION: PaSSV may be useful for risk-adjusting mortality when comparing hospital performance. External validation of our findings in other jurisdictions is needed.
ABSTRACT
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease primarily affecting the optic nerves and spinal cord, which is usually associated with anti-aquaporin-4 antibodies. Here, we present two individuals who were negative for anti-aquaporin-4 antibodies and were initially diagnosed with seronegative NMOSD. Each patient's clinical course and radiographic features raised suspicion for an alternative disease process. Both individuals were found to have pathogenic variants of MT-ND5, encoding subunit 5 of mitochondrial complex I, ultimately leading to a revised diagnosis of a primary mitochondrial disorder. These cases illustrate the importance of biochemical and genetic testing in atypical cases of NMOSD.
Subject(s)
Mitochondrial Diseases , Neuromyelitis Optica , Humans , Aquaporin 4 , Autoantibodies , Magnetic Resonance Imaging , Mitochondrial Diseases/diagnosis , Mitochondrial Diseases/genetics , Diagnostic ErrorsABSTRACT
BACKGROUND: Although age-standardized stroke occurrence has been decreasing, the absolute number of stroke events globally, and in Canada, is increasing. Stroke surveillance is necessary for health services planning, informing research design, and public health messaging. We used administrative data to estimate the number of stroke events resulting in hospital or emergency department presentation across Canada in the 2017-18 fiscal year. METHODS: Hospitalization data were obtained from the Canadian Institute for Health Information (CIHI) Discharge Abstract Database and the Ministry of Health and Social Services in Quebec. Emergency department data were obtained from the CIHI National Ambulatory Care Reporting System (Alberta and Ontario). Stroke events were identified using ICD-10 coding. Data were linked into episodes of care to account for readmissions and interfacility transfers. Projections for emergency department visits for provinces/territories outside of Alberta and Ontario were generated based upon age and sex-standardized estimates from Alberta and Ontario. RESULTS: In the 2017-18 fiscal year, there were 108,707 stroke events resulting in hospital or emergency department presentation across the country. This was made up of 54,357 events resulting in hospital admission and 54,350 events resulting in only emergency department presentation. The events resulting in only emergency department presentation consisted of 25,941 events observed in Alberta and Ontario and a projection of 28,409 events across the rest of the country. CONCLUSIONS: We estimate a stroke event resulting in hospital or emergency department presentation occurs every 5 minutes in Canada.
ABSTRACT
We provide an updated estimate of adult stroke event rates by age group, sex, and stroke type using Canadian administrative data. In the 2017-2018 fiscal year, there were an estimated 81,781 hospital or emergency department visits for stroke events in Canada, excluding Quebec. Our findings show that overall, the event rate of stroke is similar between women and men. There were slight differences in stroke event rate at various ages by sex and stroke type and emerging patterns warrant attention in future studies. Our findings emphasize the importance of continuous surveillance to monitor the epidemiology of stroke in Canada.