The Association of Adverse Pregnancy Outcomes With Overactive Bladder Anticholinergics.

IMPORTANCE: The pregnancy safety and teratogenicity of overactive bladder (OAB) anticholinergic medications in humans are unknown. OBJECTIVE: The aim of this study was to determine if the use of OAB anticholinergics during pregnancy was associated with adverse pregnancy outcomes or congenital malformation. STUDY DESIGN: Using routinely collected health care data from Ontario, Canada, we conducted a retrospective cohort study and identified women aged 18-45 years who gave birth between 2004 and 2022 and were eligible for provincial drug benefits. We used gestational age and birth dates to approximate conception dates. The primary exposure was filling a prescription for an OAB anticholinergic during pregnancy (compared with nonusers). The coprimary outcomes were pregnancy complication (which included preterm birth or low birth weight) and congenital malformation. Poisson regression models with generalized estimating equations and inverse probability of treatment weighting were used to estimate risk ratios (RRs). RESULTS: We identified 138,271 births, of which 479 (0.3%) had exposure to an OAB anticholinergic, for a median of 60 (interquartile range, 30-120) days. The most common OAB anticholinergic was oxybutynin (84%). In the weighted cohort, the risk of a pregnancy complication was significantly elevated (RR, 1.65; 95% confidence interval [CI], 1.40-1.95; P < 0.01; absolute risk difference + 9.9% [95% CI, +5.9, +13.9]), with a dose-response relationship close to statistical significance (P = 0.07). The risk of congenital malformations with OAB anticholinergic use was not significant (RR, 1.24; 95% CI, 0.85-1.80; P = 0.26). CONCLUSIONS: Pregnant women who take OAB anticholinergic medications have a higher risk of pregnancy complications, but not congenital malformations, compared with non-OAB anticholinergic users. This information can be used when counseling women of child-bearing age about these medications.

Comparison of hospitalization events among residents of assisted living and nursing homes during COVID-19: Do settings respond differently during public health crises?

BACKGROUND: COVID-19 and resulting health system and policy decisions led to significant changes in healthcare use by nursing homes (NH) residents. It is unclear whether healthcare outcomes were similarly affected among older adults in assisted living (AL). This study compared hospitalization events in AL and NHs during COVID-19 pandemic waves 1 through 4, relative to historical periods. METHODS: This was a population-based, repeated cross-sectional study using linked clinical and health administrative databases (January 2018 to December 2021) for residents of all publicly subsidized AL and NH settings in Alberta, Canada. Setting-specific monthly cohorts were derived for pandemic (starting March 1, 2020) and comparable historical (2018/2019 combined) periods. Monthly rates (per 100 person-days) of all-cause hospitalization, hospitalization with delayed discharge, and hospitalization with death were plotted and rate ratios (RR) estimated for period (pandemic wave vs historical comparison), setting (AL vs NH) and period-setting interactions, using Poisson regression with generalized estimating equations, adjusting for resident and home characteristics. RESULTS: On March 1, 2020, there were 9,485 AL and 14,319 NH residents, comparable in age (mean 81 years), sex (>60% female) and dementia prevalence (58-62%). All-cause hospitalization rates declined in both settings during waves 1 (AL: adjusted RR 0.60, 95%CI 0.51-0.71; NH: 0.74, 0.64-0.85) and 4 (AL: 0.76, 0.66-0.88; NH: 0.65, 0.56-0.75) but unlike NHs, AL rates were not significantly lower during wave 2 (and increased 27% vs NH, January 2021). Hospitalization with delayed discharge increased in NHs only (during and immediately after wave 1). Both settings showed a significant increase in hospitalization with death in wave 2, this increase was larger and persisted longer for AL. CONCLUSIONS: Pandemic-related changes in hospitalization events differed for AL and NH residents and by wave, suggesting unique system and setting factors driving healthcare use and outcomes in these settings in response to this external stress.

Assessment of serum tumor markers CEA, CA-125, and CA19-9 as adjuncts in non-small cell lung cancer management.

Conventional tumor markers may serve as adjuncts in non-small cell lung cancer (NSCLC) management. This study analyzed whether three tumor markers (CEA, CA19-9, and CA-125) held associations with radiographic and clinical outcomes in NSCLC. It constituted a single-center study of NSCLC patients treated with systemic therapy at the London Regional Cancer Program. Serum tumor markers were analyzed for differences in radiographic responses (RECIST v1.1 or iRECIST), associations with clinical characteristics, and all-cause mortality. A total of 533 NSCLC patients were screened, of which 165 met inclusion criteria. A subset of 92 patients had paired tumor markers and radiographic scans. From the latter population, median (IQR) fold-change from nadir to progression was 2.13 (IQR 1.24-3.02; p < 0.001) for CEA, 1.46 (IQR 1.13-2.18; p < 0.001) for CA19-9, and 1.53 (IQR 0.96-2.12; p < 0.001) for CA-125. Median (IQR) fold-change from baseline to radiographic response was 0.50 (IQR 0.27, 0.95; p < 0.001) for CEA, 1.08 (IQR 0.74, 1.61; p = 0.99) for CA19-9, and 0.47 (IQR 0.18, 1.26; p = 0.008) for CA-125. In conclusion, tumor markers are positioned to be used as adjunct tools in clinical decision making, especially for their associations with radiographic response (CEA/CA-125) or progression (CEA/CA-125/CA-19-9).

Thirty-day risk of digoxin toxicity among older adults co-prescribed trimethoprim-sulfamethoxazole versus amoxicillin: A population-based cohort study.

IMPORTANCE: Trimethoprim-sulfamethoxazole (TMP-SMX) may increase digoxin concentration, a medication with a narrow therapeutic index. Small changes in digoxin concentration could predispose individuals to the risk of toxicity. OBJECTIVE: To characterize the risk of digoxin toxicity in older adults taking digoxin following co-prescription of TMP-SMX compared with co-prescription of amoxicillin. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective population-based cohort study in Ontario, Canada (2002-2020) using linked health care data. Participants comprised 47,961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74-86]) who were newly treated with TMP-SMX (n = 10,273) compared with those newly treated with amoxicillin (n = 37,688). EXPOSURE: Co-prescription of TMP-SMX versus amoxicillin in older adults concurrently taking digoxin. MAIN OUTCOME AND MEASURE: The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD. RESULTS: A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted RR, 5.71 [95% confidence interval (CI), 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]). CONCLUSION AND RELEVANCE: In older adults taking digoxin, the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co-prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Physicians should prescribe an alternative antibiotic when clinically appropriate. If TMP-SMX must be co-prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose-reduced on an individual basis.

COVID-19 vaccine uptake among Ontario physicians: a descriptive population-based retrospective cohort study.

OBJECTIVES: To determine COVID-19 vaccine uptake among physicians in Ontario, Canada from 14 December 2020 to 13 February 2022. DESIGN: Population-based retrospective cohort study. SETTING: All registered physicians in Ontario, Canada using data from linked provincial administrative healthcare databases. PARTICIPANTS: 41 267 physicians (including postgraduate trainees) who were Ontario residents and registered with the College of Physicians and Surgeons of Ontario were included. Physicians who were out of province, had not accessed Ontario Health Insurance Plan-insured services for their own care for ≥5 years and those with missing identifiers were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were the proportions of physicians who were recorded to have received at least one, at least two and three doses of a Health Canada-approved COVID-19 vaccine by study end date. Secondary outcomes were how uptake varied by physician characteristics (including age, sex, specialty and residential location) and time elapsed between doses. RESULTS: Of 41 267 physicians, (56% male, mean age 47 years), 39 359 (95.4%) received at least one dose, 39 148 (94.9%) received at least two doses and 35 834 (86.8%) received three doses of a COVID-19 vaccine. Of those who received three doses, the proportions were 90.4% among those aged ≥60 years and 81.2-89.5% among other age groups; 88.7% among family physicians and 89% among specialists. 1908 physicians (4.6%) had no record of vaccination, and this included 3.4% of family physicians and 4.1% of specialists; however, 28% of this group had missing specialty information. CONCLUSIONS: In Ontario, within 14 months of COVID-19 vaccine availability, 86.8% of physicians had three doses of a COVID-19 vaccine, compared with 45.6% of the general population. Findings may signify physicians' confidence in the safety and effectiveness of COVID-19 vaccines.

Association Between the Dialysate Bicarbonate and the Pre-dialysis Serum Bicarbonate Concentration in Maintenance Hemodialysis: A Retrospective Cohort Study.

Background: It is unclear whether the use of higher dialysate bicarbonate concentrations is associated with clinically relevant changes in the pre-dialysis serum bicarbonate concentration. Objective: The objective is to examine the association between the dialysate bicarbonate prescription and the pre-dialysis serum bicarbonate concentration. Design: This is a retrospective cohort study. Setting: The study was performed using linked administrative health care databases in Ontario, Canada. Patients: Prevalent adults receiving maintenance in-center hemodialysis as of April 1, 2020 (n = 5414) were included. Measurements: Patients were grouped into the following dialysate bicarbonate categories at the dialysis center-level: individualized (adjustment based on pre-dialysis serum bicarbonate concentration) or standardized (>90% of patients received the same dialysate bicarbonate concentration). The standardized category was stratified by concentration: 35, 36 to 37, and ≥38 mmol/L. The primary outcome was the mean outpatient pre-dialysis serum bicarbonate concentration at the patient level. Methods: We examined the association between dialysate bicarbonate category and pre-dialysis serum bicarbonate using an adjusted linear mixed model. Results: All dialysate bicarbonate categories had a mean pre-dialysis serum bicarbonate concentration within the normal range. In the individualized category, 91% achieved a pre-dialysis serum bicarbonate ≥22 mmol/L, compared to 87% in the standardized category. Patients in the standardized category tended to have a serum bicarbonate that was 0.25 (95% confidence interval [CI] = -0.93, 0.43) mmol/L lower than patients in the individualized category. Relative to patients in the 35 mmol/L category, patients in the 36 to 37 and ≥38 mmol/L categories tended to have a serum bicarbonate that was 0.70 (95% CI = -0.30, 1.70) mmol/L and 0.87 (95% CI = 0.14, 1.60) mmol/L higher, respectively. There was no effect modification by age, sex, or history of chronic lung disease. Limitations: We could not directly confirm that all laboratory measurements were pre-dialysis. Data on prescribed dialysate bicarbonate concentrations for individual dialysis sessions were not available, which may have led to some misclassification, and adherence to a practice of individualization could not be measured. Residual confounding is possible. Conclusions: We found no significant difference in the pre-dialysis serum bicarbonate concentration irrespective of whether an individualized or standardized dialysate bicarbonate was used. Dialysate bicarbonate concentrations ≥38 mmol/L (vs 35 mmol/L) may increase the pre-dialysis serum bicarbonate concentration by 0.9 mmol/L.

Contexte: On ignore si des concentrations plus élevées de bicarbonate dans le dialysat sont associées à des changements cliniquement significatifs dans le taux de bicarbonate sérique prédialyse. Objectif: Examiner l'association entre la prescription de bicarbonate du dialysat et le taux de bicarbonate sérique prédialyse. Conception: Étude de cohorte rétrospective. Cadre: Étude réalisée en Ontario (Canada) à partir des données administratives de santé. Sujets: Ont été inclus les adultes prévalents qui recevaient une hémodialyse chronique en centre le 1er avril 2020 (n=5 414). Mesures: Les sujets ont été regroupés dans les catégories suivantes de concentration en bicarbonate dans le dialysat utilisée dans leur unité de dialyse: individualisée (ajustée selon le taux de bicarbonate sérique prédialyse) ou normalisée (même concentration pour >90% des sujets). La catégorie « standardisée ¼ a été stratifiée selon la concentration: 35 mmol/L, 36 à 37 mmol/L et ≥38 mmol/L. Le principal critère d'évaluation était le taux moyen de bicarbonate sérique prédialyse en ambulatoire au niveau du patient. Méthodologie: Nous avons examiné l'association entre la catégorie de concentration en bicarbonate du dialysat et le taux de bicarbonate sérique prédialyse à l'aide d'un modèle linéaire mixte corrigé. Résultats: Pour toutes les catégories de concentration en bicarbonate du dialysat, le taux moyen de bicarbonate sérique prédialyse était dans la plage normale. Dans la catégorie « individualisée ¼, 91% des sujets avaient un taux de bicarbonate sérique prédialyse de ≥22 mmol/L, comparativement à 87% dans la catégorie « standardisée ¼. Les patients de la catégorie « standardisée ¼ tendaient à avoir un taux de bicarbonate sérique de 0,25 mmol/L (IC 95%: -0,93 à 0,43) inférieur à celui des patients de la catégorie « individualisée ¼. Comparé aux patients de la catégorie 35 mmol/L, les patients des catégories 36 à 37 mmol/L et ≥38 mmol/L tendaient respectivement à avoir un taux de bicarbonate sérique de 0,70 mmol/L (IC 95%: -0,30 à 1,70) et de 0,87 mmol/L (IC 95%: 0,14 à 1,60) plus élevé. L'âge, le sexe ou les antécédents de maladie pulmonaire chronique n'ont pas semblé modifier l'effet. Limites: Il n'a pas été possible de confirmer directement que toutes les mesures de laboratoire avaient été effectuées avant la dialyse. Les données sur les concentrations de bicarbonate prescrites pour les séances de dialyse individuelles n'étaient pas disponibles, ce qui peut avoir conduit à une classification erronée. De plus, l'observance d'une pratique d'individualisation n'a pas pu être mesurée. Une confusion résiduelle est possible. Conclusion: Nous n'avons observé aucune différence significative dans les taux de bicarbonate sériques prédialyse, qu'on ait utilisé une concentration individualisée ou standardisée de bicarbonate dans le dialysat. L'utilisation d'un dialysat à ≥38 mmol/L (c. 35 mmol/L) de bicarbonate peut entraîner une hausse de 0,9 mmol/L du taux de bicarbonate sérique prédialyse.

Impact of the 2021 CKD-EPI eGFR Equation on Kidney Care Referral Criteria in Ontario, Canada: A Population-based Cross-sectional Study.

Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care. Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR. Design: Population-based, cross-sectional study. Setting: Ontario, Canada's most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario's residents self-identify as being of Black race. Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021. Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario's provincial renal agency. Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population. Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population. Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable. Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation.

Contexte: Dans certaines régions, les individus sont dirigés vers différents types de soins rénaux, ou y deviennent admissibles, selon des critères fondés sur le débit de filtration glomérulaire estimé (DFGe). Historiquement, le DFG était estimé avec une équation développée en 2009 comportant un terme qui tenait compte du fait d'être une personne de race noire. Une nouvelle équation sans mention de la race a été développée en 2021. Il est difficile de savoir comment l'adoption de l'équation de 2021 influencera le nombre de personnes qui répondront aux critères pour recevoir divers types de soins rénaux. Objectifs: Établir des estimations populationnelles de la variation du nombre de personnes qui répondent aux critères d'orientation fondés sur le DFGe pour recevoir trois différents types de soins rénaux (consultation avec un néphrologue, soins dans une clinique multidisciplinaire spécialisée, évaluation pour une transplantation rénale) selon que le DFGe est calculé avec l'équation de 2021 ou de 2009. Conception: Étude populationnelle transversale rétrospective. Cadre: L'Ontario, la province la plus peuplée du Canada avec 14,2 millions d'habitants en 2021. Moins de 5 % des résidents de l'Ontario s'identifient comme étant de race noire. Sujets: Des adultes avec au moins une mesure de la créatinine sérique en ambulatoire au cours des deux ans précédant le 31 décembre 2021. Mesures: Les critères d'orientation vers trois différents types de soins rénaux : consultation avec un néphrologue, soins en clinique multidisciplinaire spécialisée et évaluation pour une transplantation rénale. Les seuils de DFGe utilisés pour définir l'admissibilité à ­ ou l'orientation vers ­ ces services de santé rénale étaient fondés sur les lignes directrices de l'agence provinciale de soins rénaux de l'Ontario. Méthodologie: On a comparé les nombres d'individus répondant aux critères d'orientation pour les trois différents services de santé, calculés avec les équations de 2009 et de 2021, en se limitant aux personnes qui ne recevaient pas encore de tels soins. Les données individuelles sur la race n'étant pas disponibles, les estimations ont été répétées en attribuant aléatoirement un statut de race noire à 1 %, à 5 % et à 10 % de la population étudiée. Résultats: Une mesure de la créatinine sérique en ambulatoire était disponible pour un total de 1 048 110 adultes. Avec l'équation de 2009, 37 345 personnes répondaient aux critères pour être dirigées vers un néphrologue, 10 019 répondaient aux critères pour recevoir des soins dans une clinique multidisciplinaire spécialisée et 10 178 répondaient aux critères pour être évaluées pour une transplantation rénale. Avec l'équation de 2021, ces mêmes nombres de personnes (pourcentage par rapport à l'équation de 2009) étaient respectivement 26 645 (71,3 %), 9 009 (89,9 %) et 8 615 (84,6 %). Des chiffres qui sont demeurés majoritairement inchangés même en assumant une proportion de jusqu'à 10 % de personnes de race noire dans la population. Limites: Les critères d'orientation fondés uniquement sur le rapport albumine/créatinine urinaire n'ont pas été évalués. Les données autodéclarées sur la race n'étaient pas disponibles. Conclusion: Pour la planification des soins de santé, dans les régions où une minorité de la population est noire, un nombre important de personnes pourraient ne plus répondre aux critères d'orientation vers différents types de soins rénaux après l'adoption de l'équation de 2021 pour le calcul du DFGe.

Presentation and Outcome of Patients with Multiple Myeloma (MM), Single Centre Experience from Windsor Essex Regional Cancer Centre.

Introduction: Outcomes for patients with multiple myeloma has significantly improved through the years. This is mainly related to the use of novel agents. Methods: This is a retrospective study that reviewed presentation and outcome of 139 patients with multiple myeloma at the Windsor Essex Regional Cancer Centre from Jan. 1, 2015 to Dec. 31, 2019. Median age was 71 years and most patients had higher risk disease (65.5% either R ISS stage II or III). 30% had high risk FISH for myeloma including del.17P, t (4:14), t (14:16) and Gain (1q21). In terms of presentation, 38.8% had anemia (hemoglobin <100g/L), 18.7% had hypercalcemia, 74.1% had skeletal lytic lesions, 38.8% had pathologic fracture and 17.3% had plasmacytoma. Results: Almost all (92%) of the patients were treated using at least one novel agent (proteasome inhibitor or immunomodulators [ImiDs]). Cyclophosphamide, bortezomib, and dexamethasone (CyBorD) was the most used treatment regimen (48.9%) followed by bortezomib, melphalan and prednisone (BMP) at 28.8% and lenalidomide, dexamethasone (LenDex) at 14.4%. With respect to response to therapy, 51.8% had at least Very good partial response (VGPR), while 9.4% had progressive disease. 33% had autologous stem cell transplant. After a median follow up of 2.4 years, median overall survival was 3.7 years. 2 years overall survival and relapse-free survival were 70% and 83%, respectively. Discussion: Our study showed comparable outcome for patients with multiple myeloma despite older age and higher risk disease. Outcome is expected to improve with the introduction of more novel agents.

Social factors associated with self-reported changes in mental health symptoms among youth in the COVID-19 pandemic: a cross-sectional survey.

BACKGROUND: Children and youth experienced marked impacts on day-to-day life in the COVID-19 pandemic that were associated with poorer familial and friend relationships, and greater mental health challenges. Few studies provide self-report data on mental health symptoms from children and youth themselves. We sought to examine the associations between social factors and child and youth self-reported symptoms of worsened mood, anxiety, and irritability during the COVID-19 pandemic. METHODS: A nationally representative cross-sectional survey was administered online to collect self-report data across 10 Canadian provinces among children (11-14 years) and youth (15-18 years), April-May 2022. Age-appropriate questions were based on The Partnership for Maternal, Newborn & Child Health and the World Health Organization of the United Nations H6 + Technical Working Group on Adolescent Health and Well-Being consensus framework and the Coronavirus Health and Impact Survey. Associations between a priori defined social factors (e.g., relationship quality) and respondent self-reported mental health were evaluated using ordinal logistic regression models adjusted for age, sex, and geographic location. RESULTS: We analyzed data from 483 (51.7%) children (11-14 years; 227, 47.0% girls) and 450 (48.3%) youth (15-18 years; 204, 45.3% girls). The parents of most children and youth had resided in Canada for over 20 years (678, 72.7%). Over one-quarter of children and youth self-identified as Black, Indigenous, or a Person of Color (134, 27.7%; 134, 29.8%, respectively). Over one-third of children and youth self-reported symptoms of worsened mood (149, 30.9%; 125, 27.8%, respectively), anxiety (181, 37.5%; 167, 37.1%, respectively), or irritability (160, 33.1%; 160, 35.6%, respectively) during, compared to pre-pandemic. In descending order of odds ratios (OR), for children and youth, worsened familial relationships (during compared to pre-pandemic) was associated with the self-reported symptoms of worsened mood (child: OR 4.22, 95%CI 2.51-6.88; youth: OR 6.65 95%CI 3.98-11.23), anxiety (child: OR 4.24, 95%CI2.69-6.75; youth: OR 5.28, 95%CI 3.17-8.86), and irritability (child: OR 2.83, 95%CI 1.76-4.56; youth: OR 6.46, 95%CI 3.88-10.90). CONCLUSIONS: Self-reported data from a nationally representative sample of children and youth suggest strong associations between social factors and mental health during the COVID-19 pandemic. Interventions targeting child and youth familial relationships may positively impact child and youth mental health.

High-Throughput Computing to Automate Population-Based Studies to Detect the 30-Day Risk of Adverse Outcomes After New Outpatient Medication Use in Older Adults with Chronic Kidney Disease: A Clinical Research Protocol.

Background: Safety issues are detected in about one third of prescription drugs in the years following regulatory agency approval. Older adults, especially those with chronic kidney disease, are at particular risk of adverse reactions to prescription drugs. This protocol describes a new approach that may identify credible drug-safety signals more efficiently using administrative health care data. Objective: To use high-throughput computing and automation to conduct 700+ drug-safety cohort studies in older adults in Ontario, Canada. Each study will compare 74 acute (30-day) outcomes in patients who start a new prescription drug (new users) to a group of nonusers with similar baseline health characteristics. Risks will be assessed within strata of baseline kidney function. Design and setting: The studies will be population-based, new-user cohort studies conducted using linked administrative health care databases in Ontario, Canada (January 1, 2008, to March 1, 2020). The source population for these studies will be residents of Ontario aged 66 years or older who filled at least one outpatient prescription through the Ontario Drug Benefit (ODB) program during the study period (all residents have universal health care, and those aged 65+ have universal prescription drug coverage through the ODB). Patients: We identified 3.2 million older adults in the source population during the study period and built 700+ initial medication cohorts, each containing mutually exclusive groups of new users and nonusers. Nonusers were randomly assigned cohort entry dates that followed the same distribution of prescription start dates as new users. Eligibility criteria included a baseline estimated glomerular filtration rate (eGFR) measurement within 12 months before the cohort entry date (median time was 71 days before cohort entry in the new user group), no prior receipt of maintenance dialysis or a kidney transplant, and no prior prescriptions for drugs in the same subclass as the study drug. New users and nonusers will be balanced on ~400 baseline health characteristics using inverse probability of treatment weighting on propensity scores within 3 strata of baseline eGFR: ≥60, 45 to <60, <45 mL/min per 1.73 m2. Outcomes: We will compare new user and nonuser groups on 74 clinically relevant outcomes (17 composites and 57 individual outcomes) in the 30 days after cohort entry. We used a prespecified approach to identify these 74 outcomes. Statistical analysis plan: In each cohort, we will obtain eGFR-stratum-specific weighted risk ratios and risk differences using modified Poisson regression and binomial regression, respectively. Additive and multiplicative interaction by eGFR category will be examined. Drug-outcome associations that meet prespecified criteria (identified signals) will be further examined in additional analyses (including survival, negative-control exposure, and E-value analyses) and visualizations. Results: The initial medication cohorts had a median of 6120 new users per cohort (interquartile range: 1469-38 839) and a median of 1 088 301 nonusers (interquartile range: 751 697-1 267 009). Medications with the largest number of new users were amoxicillin trihydrate (n = 1 000 032), cephalexin (n = 571 566), prescription acetaminophen (n = 571 563), and ciprofloxacin (n = 504,374); 19% to 29% of new users in these cohorts had an eGFR <60 mL/min per 1.73 m2. Limitations: Despite our use of robust techniques to balance baseline indicators and to control for confounding by indication, residual confounding will remain a possibility. Only acute (30-day) outcomes will be examined. Our data sources do not include nonprescription (over-the-counter) drugs or drugs prescribed in hospitals and do not include outpatient prescription drug use in children or adults <65 years. Conclusion: This accelerated approach to conducting postmarket drug-safety studies has the potential to more efficiently detect drug-safety signals in a vulnerable population. The results of this protocol may ultimately help improve medication safety.

Contexte: Des problèmes d'innocuité sont détectés dans environ un tiers des médicaments d'ordonnance au cours des années qui suivent leur approbation par l'organisme de réglementation. Les personnes âgées, en particulier celles qui sont atteintes d'insuffisance rénale chronique, sont particulièrement exposées aux effets indésirables des médicaments d'ordonnance. Ce protocole décrit une nouvelle approche qui, à partir des données administratives du système de santé, pourrait permettre d'identifier plus efficacement les signaux crédibles sur la sécurité des médicaments. Objectif: Utiliser l'informatique à haut débit et l'automatisation pour mener plus de 700 études de cohorte sur l'innocuité des médicaments chez les adultes âgés résidant en Ontario (Canada). Chaque étude comparera 74 résultats aigus (30 jours) chez des patients qui commencent un nouveau médicament sur ordonnance (nouveaux utilisateurs) à ceux d'un groupe de non-utilisateurs avec des caractéristiques de santé initiales similaires. Les risques seront évalués par strates de la fonction rénale initiale. Cadre et type d'étude: Études populationnelles de cohortes de nouveaux utilisateurs de médicaments menées à l'aide des bases de données administratives couplées du système de santé ontarien (Canada). Période étudiée: du 1er janvier 2008 au 1er mars 2020. Population source: les Ontariens de 66 ans ou plus ayant rempli au moins une ordonnance pour patient non hospitalisé par l'entremise du Program de médicaments de l'Ontario (PMO) pendant la période de l'étude (tous les résidents de la province bénéficient d'un système de soins de santé universel; les personnes âgées de 65 ans et plus bénéficient d'une couverture universelle des médicaments d'ordonnance par l'intermédiaire du PMO). Sujets: Nous avons identifié 3,2 millions d'adultes âgés dans la population source au cours de la période d'étude et constitué plus de 700 cohortes de médicaments, chacune contenant des groupes mutuellement exclusifs de nouveaux utilisateurs et de non-utilisateurs. Les non-utilisateurs se sont vu attribuer au hasard des dates d'entrée dans la cohorte qui suivaient les dates de début d'ordonnance des nouveaux utilisateurs. Les critères d'admissibilité étaient d'avoir une mesure initiale du débit de filtration glomérulaire estimé [DFGe] dans les 12 mois précédant la date d'entrée dans la cohorte (dans le groupe des nouveaux utilisateurs, le délai médian était de 71 jours avant l'entrée dans la cohorte), ne pas suivre de dialyze chronique, ne pas avoir eu de greffe rénale et n'avoir jamais eu de prescription d'un médicament de la même sous-classe que le médicament à l'étude. Les nouveaux utilisateurs et les non-utilisateurs seront jumelés selon environ 400 caractéristiques de santé initiales à l'aide de la probabilité inverse de traitement pondérée selon les scores de propension dans les trois strates de mesure du DFGe initial: ≥60 ml/min/1,73 m2; 45 à <60 ml/min/1,73 m2 et <45 ml/min/1,73 m2. Résultats: Nous comparerons les groupes de nouveaux utilisateurs et de non-utilisateurs selon 74 critères de jugement cliniquement pertinents (17 critères composites et 57 critères individuels) pendant les 30 jours suivant l'entrée dans la cohorte. Une approche prédéfinie a permis de déterminer ces 74 résultats. Plan d'analyze statistique: Dans chaque cohorte, nous calculerons les différences de risque (par régression de Poisson) et les rapports de risque (par régression binomiale) pondérés pour chaque strate de DFGe. Les interactions additives et multiplicatives par catégorie de DFGe seront examinées. Les associations médicaments-résultats répondant à des critères prédéfinis (signaux identifiés) seront examinées plus avant dans des analyses supplémentaires (survie, exposition à des témoins négatifs, analyses de la valeur E, etc.) et des visualizations. Résultats: Dans les cohortes initiales de médicaments, les médianes sont de 6 120 nouveaux utilisateurs (intervalle interquartile de 1 469 à 38 839) et de 1 088 301 non-utilisateurs (intervalle interquartile de 751 697 à 1 267 009). Les médicaments comptant le plus grand nombre de nouveaux utilisateurs sont le trihydrate d'amoxicilline (n = 1 000 032), la céfalexine (n = 571 566), l'acétaminophène sur ordonnance (n = 571 563) et la ciprofloxacine (n = 504 374). De 19 à 29 % des nouveaux utilisateurs dans ces cohortes présentaient un DFGe < 60 ml/min/1.73 m2. Limites: Malgré l'utilization de techniques robustes pour équilibrer les indicateurs de base et pour contrôler le risque de confusion par indication, il pourrait subsister des facteurs de confusion résiduels. Seuls les résultats aigus (30 jours) seront examinés. Nos sources de données ne comprennent pas les médicaments sans ordonnance (en vente libre) ni les médicaments prescrits dans les hôpitaux, et n'incluent pas l'utilization de médicaments sur ordonnance en ambulatoire chez les enfants ou les adultes de moins de 65 ans. Conclusion: Cette approche accélérée pour la réalisation d'études d'innocuité des médicaments après leur mise en marché a le potentiel de détecter efficacement les effets indésirables de ces médicaments dans une population vulnérable. Les résultats de ce protocole serviront à améliorer l'innocuité des médicaments.

Using multiparametric Magnetic Resonance Imaging and Prostate Specific Membrane Antigen Positron Emission Tomography to detect and delineate the gross tumour volume of intraprostatic lesions - A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Radiation therapy is used frequently for patients with prostate cancer. Dose escalation to intraprostatic lesions (IPLs) has been shown to improve oncologic outcomes, without increasing toxicity. Both multiparametric MRI (mpMRI) and PSMA PET can be used to identify IPLs. MATERIALS AND METHODS: A systematic review was conducted to determine the ability of mpMRI, PSMA PET and their combination to detect IPLs prior to radical prostatectomy (RP) as correlated with the histology. Trials included patients that had mpMRI, PSMA PET, or both, prior to RP. The quality of the histopathological-radiological co-registration was assessed as high or low for each study. Recorded outcomes include sensitivity, specificity, and area under the receiver operating characteristic curve (AUROC). A meta-analysis was conducted using a bivariate model to determine the pooled sensitivity and specificity for each imaging modality. This systematic review was registered through PROSPERO (CRD42023389092). RESULTS: Altogether, 42 studies were included in the systematic review. Of these, 20 could be included in the meta-analysis. The pooled sensitivity (95 % CI), specificity (95 % CI) and AUROC for mpMRI (n = 13 studies) were 64.7 % (50.2 % - 76.9 %), 86.4 % (79.7 % - 91.1 %), and 0.852; the pooled outcomes for PSMA PET (n = 12) were 75.7 % (64.0 % - 84.5 %), 87.1 % (80.2 % - 91.9 %), and 0.889; for their combination (n = 5), the pooled outcomes were 70.3 % (64.1 % - 75.9 %), 81.9 % (71.9 % - 88.8 %), and 0.796. When reviewing studies with a high-quality histopathological-radiological co-registration, IPL delineation recommendations varied by study and the imaging modality used. CONCLUSION: All of mpMRI, PSMA PET or their combination were found to have very good diagnostic outcomes for detecting IPLs. Recommendations for delineating IPLs varied based on the imaging modalities used and between research groups. Consensus guidelines for IPL delineation would help with creating consistency for focal boost radiation treatments in future studies.

External Validation of the BACES Score in Canadian Patients With Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: The clinical course of nontuberculous mycobacterial pulmonary disease (NTM-PD) can be variable and difficult to predict. Recently, the BACES score was developed as a tool to predict all-cause mortality in patients with NTM-PD. This score is calculated based on five patient characteristics (BMI, age, cavity, erythrocyte sedimentation rate, and sex), and higher scores portend worse prognosis. Although the BACES score has been validated in a cohort of South Korean patients, it has not yet been validated in other settings or ethnic groups. RESEARCH QUESTION: How well does the BACES mortality score perform in a cohort of Canadian patients with NTM-PD? STUDY DESIGN AND METHODS: We performed a single-center retrospective chart review. Patients who were seen between July 2003 and June 2021 were eligible for inclusion if they met guideline-based diagnostic criteria for NTM-PD and were excluded if any component of the BACES score was missing. To assess the model's discriminatory performance, we compared Kaplan-Meier curves between risk groups and calculated Harrell's C index. To assess calibration, we used a graphical calibration curve. RESULTS: The cohort included 435 patients with a median follow-up of 5.8 years. The median age was 64 years and 74% were female. Based on the BACES scores, patients were classified into three risk groups: low, moderate, or high. Survival curves showed clear separation of the risk groups. Harrell's C index was 0.733 in the study cohort, indicating moderate to good discriminatory performance, although this was lower than the value reported in the derivation cohort (0.812). The graphical calibration curve showed a tendency of the BACES model to underpredict mortality. INTERPRETATION: The BACES model was evaluated in a multicultural cohort of Canadian patients and demonstrated good discriminatory performance but suboptimal calibration, which may be due to population differences, the use of dichotomized variables in model construction, or both.

Psychotropic, Anticonvulsant, and Opioid Use in Assisted Living Residents Before and During the COVID-19 Pandemic.

OBJECTIVES: To examine the associations between COVID-19 pandemic waves (1-4) and prevalent antipsychotic, antidepressant, benzodiazepine, anticonvulsant, and opioid use among assisted living (AL) residents, by setting (dementia care vs other). DESIGN: Population-based, repeated cross-sectional study. SETTING AND PARTICIPANTS: Linked clinical and health administrative databases for residents of all publicly subsidized AL homes (N = 256) in Alberta, Canada, examined from January 2018 to December 2021. Setting-specific quarterly cohorts of residents were derived for pandemic (starting March 1, 2020) and comparable historical (2018/2019 combined) periods. METHODS: The quarterly proportion of residents dispensed an antipsychotic, antidepressant, benzodiazepine, anticonvulsant, or opioid was examined for each setting and period. Log-binomial generalized estimating equations models estimated prevalence ratios (PR) for period (pandemic vs historical quarterly periods), setting (dementia care vs other AL), and period-setting interactions. RESULTS: On March 1, 2020, there were 2874 dementia care and 6611 other AL residents (mean age 82.4 vs 79.9 years, 68.2% vs 66.1% female, 93.5% vs 42.6% with dementia, respectively). Antipsychotic use increased during waves 2 to 4 for residents of both settings, but this increase was significantly greater for dementia care than other AL residents during waves 3 and 4 (eg, wave 3, PR 1.21, 95% CI 1.14-1.27 vs PR 1.12, 95% CI 1.07-1.17, interaction term P = .029). In both settings, there was a significant but modest increase in antidepressant use and a significant decrease in benzodiazepine use during several pandemic waves. For other AL residents only, there was a small statistically significant increase in anticonvulsant use during waves 2 to 4. No significant pandemic effect was observed for prevalent opioid use in either setting. CONCLUSIONS AND IMPLICATIONS: The persistence of the pandemic-associated increase in antipsychotic, antidepressant, and anticonvulsant use in AL residents, and greater increase in antipsychotic use for dementia care settings, raises concerns about the attendant risks for residents, especially those with dementia.

Does prescribing apixaban or rivaroxaban versus warfarin for patients diagnosed with atrial fibrillation save health system costs? A multivalued treatment effects analysis.

BACKGROUND: Non-valvular atrial fibrillation (AF) is a common heart arrhythmia in the elderly population. AF patients are at high-risk of ischemic strokes, but oral anticoagulant (OAC) therapy reduces such risks. Warfarin had been the standard OAC for AF patients, however its effectiveness is highly variable and dependent on close monitoring of the anticoagulant response. Newer OACs such as rivaroxaban and apixaban address these drawbacks but are more costly. It is uncertain which OAC therapy for AF is cost-saving from the healthcare system perspective. METHODS: We followed a cohort of patients in Ontario, Canada, aged ≥ 66 who were newly diagnosed with AF and prescribed OACs between 2012 and 2017. We used a two-stage estimation procedure. First, we account for the patient selection into OACs using a multinomial logit regression model and estimated propensity scores. Second, we used an inverse probability weighted regression adjustment approach to determine cost-saving OAC options. We also examined component-specific costs (i.e., drug, hospitalization, emergency department and physician) to understand the drivers of cost-saving OACs. RESULTS: We found that compared to warfarin, rivaroxaban and apixaban treatments were cost-saving options, with per-patient 1-year healthcare cost savings at $2436 and $1764, respectively. These savings were driven by cost-savings in hospitalization, emergency department visits, and physician visits, outweighing higher drug costs. These results were robust to alternative model specifications and estimation procedures. CONCLUSIONS: Treating AF patients with rivaroxaban and apixaban than warfarin reduces healthcare costs. OAC reimbursement policies for AF patients should consider rivaroxaban or apixaban over warfarin as the first-line treatment.

Effectiveness of a Fourth COVID-19 mRNA Vaccine Dose Against the Omicron Variant in Solid Organ Transplant Recipients.

BACKGROUND: The effectiveness of booster doses of COVID-19 vaccines in solid organ transplant recipients is unclear. We conducted a population-based matched cohort study using linked administrative healthcare databases from Ontario, Canada to estimate the marginal vaccine effectiveness of a fourth versus third dose of the BNT162b2 and mRNA-1273 vaccines against clinically important outcomes (ie, hospitalization or death) and infection during the era of the Omicron variant. METHODS: We matched 3120 solid organ transplant recipients with a third COVID-19 vaccine dose (reference) to 3120 recipients with a fourth dose. Recipients were matched on the third dose date (±7 d). We used a multivariable Cox proportional hazards model to estimate the marginal vaccine effectiveness with outcomes occurring between December 21, 2021 and April 30, 2022. RESULTS: The cumulative incidence of COVID-19-related hospitalization or death was 2.8% (95% confidence interval [CI], 2.0-3.7) in the third dose group compared with 1.1% (95% CI, 0.59-1.8) in the fourth dose group after 84 d of follow-up (P < 0.001). The adjusted marginal vaccine effectiveness was 70% (95% CI, 47-83) against clinically important outcomes and 39% (95% CI, 21-52) against SARS-CoV-2 infection. CONCLUSIONS: Compared with a third dose, a fourth dose of the COVID-19 vaccine was associated with improved protection against hospitalization, death, and SARS-CoV-2 infection during the Omicron era. Results highlight the importance of a booster COVID-19 vaccine dose in solid organ transplant recipients.

Low-Dose Methotrexate and Serious Adverse Events Among Older Adults With Chronic Kidney Disease.

Importance: Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD). Objectives: To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine. Design, Setting, and Participants: This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine. Exposure: Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d). Main Outcome and Measure: The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression. Results: In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome. Conclusions and Relevance: In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.

Mental health and addiction service utilization among people living with chronic kidney disease.

BACKGROUND: Mental health problems, particularly anxiety and depression, are common in patients with chronic kidney disease (CKD), and negatively impact quality of life, treatment adherence, and mortality. However, the degree to which mental health and addictions services are utilized by those with CKD is unknown. We examined the history of mental health and addictions service use of individuals across levels of kidney function. METHODS: We performed a population-based cross-sectional study using linked healthcare databases from Ontario, Canada from 2009 to 2017. We abstracted the prevalence of individuals with mental health and addictions service use within the previous 3 years across levels of kidney function (eGFR$\ \ge $60, 45 to < 60, 30 to < 45, 15 to < 30, <15 mL/min per 1.73m2 and maintenance dialysis). We calculated prevalence ratios (PR) to compare prevalence across kidney function strata, while adjusting for age, sex, year of cohort entry, urban versus rural location, area-level marginalization, and Charlson comorbidity scores. RESULTS: Of 5 956 589 adults, 9% (n = 534 605) had an eGFR<60 mL/min per 1.73m2 or were receiving maintenance dialysis. Fewer individuals with eGFR < 60 had a history of any mental health and addictions service utilization (crude prevalence range 28% to 31%), compared to individuals with eGFR ≥ 60 (35%). Compared to eGFR ≥ 60, the lowest prevalence of individuals with any mental health and addictions service utilization was among those with eGFR 15 to < 30 (adjusted PR 0.86, 95% CI 0.85 to 0.88), eGFR < 15 (adjusted PR 0.81, 95% CI 0.76 to 0.86) and those receiving maintenance dialysis (adjusted PR 0.83, 95% CI 0.81 to 0.84). Less use of outpatient services accounted for differences in service utilization. CONCLUSIONS: Mental health and addictions service utilization is common but less so in individuals with advanced CKD in Ontario, Canada.