An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries.

Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of nine different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

Stent-assisted Woven EndoBridge embolization for the treatment of pulsatile tinnitus caused by an ipsilateral high-riding jugular bulb.

PURPOSE: Pulsatile tinnitus can be caused by a high-riding jugular bulb (HRJB), characterized by the superior position of the jugular bulb in the petrous temporal bone. The anatomical position and morphology of this entity make it challenging for endovascular treatment. We report our experience with two patients successfully treated with a stent-assisted Woven EndoBridge (WEB; Microvention, Tustin, CA, USA) device. MATERIALS AND METHODS: We describe two cases of HRJB in patients presenting with disabling pulsatile tinnitus. Temporary balloon occlusion of the jugular bulb prior to the intervention reduced tinnitus intensity. Both patients were subsequently treated under general anesthesia with the WEB device deployed in the HRJB which was held by a stent deployed in the sigmoid sinus. RESULTS: Both procedures were successful with good positioning of the WEB device and no procedural complications. Both patients had complete resolution of pulsatile tinnitus immediately after the procedure. Follow-up imaging showed successful occlusion of the venous cavity with a widely patent stent. CONCLUSION: Among patients with pulsatile tinnitus caused by an ipsilateral HRJB, a stent-assisted WEB device seems to be a viable endovascular option with angiographic and clinical success.

Ascertaining the Francophone population in Ontario: validating the language variable in health data.

BACKGROUND: Language barriers can impact health care and outcomes. Valid and reliable language data is central to studying health inequalities in linguistic minorities. In Canada, language variables are available in administrative health databases; however, the validity of these variables has not been studied. This study assessed concordance between language variables from administrative health databases and language variables from the Canadian Community Health Survey (CCHS) to identify Francophones in Ontario. METHODS: An Ontario combined sample of CCHS cycles from 2000 to 2012 (from participants who consented to link their data) was individually linked to three administrative databases (home care, long-term care [LTC], and mental health admissions). In total, 27,111 respondents had at least one encounter in one of the three databases. Language spoken at home (LOSH) and first official language spoken (FOLS) from CCHS were used as reference standards to assess their concordance with the language variables in administrative health databases, using the Cohen kappa, sensitivity, specificity, positive predictive value (PPV), and negative predictive values (NPV). RESULTS: Language variables from home care and LTC databases had the highest agreement with LOSH (kappa = 0.76 [95%CI, 0.735-0.793] and 0.75 [95%CI, 0.70-0.80], respectively) and FOLS (kappa = 0.66 for both). Sensitivity was higher with LOSH as the reference standard (75.5% [95%CI, 71.6-79.0] and 74.2% [95%CI, 67.3-80.1] for home care and LTC, respectively). With FOLS as the reference standard, the language variables in both data sources had modest sensitivity (53.1% [95%CI, 49.8-56.4] and 54.1% [95%CI, 48.3-59.7] in home care and LTC, respectively) but very high specificity (99.8% [95%CI, 99.7-99.9] and 99.6% [95%CI, 99.4-99.8]) and predictive values. The language variable from mental health admissions had poor agreement with all language variables in the CCHS. CONCLUSIONS: Language variables in home care and LTC health databases were most consistent with the language often spoken at home. Studies using language variables from administrative data can use the sensitivity and specificity reported from this study to gauge the level of mis-ascertainment error and the resulting bias.

An integrated technology for quantitative wide mutational scanning of human antibody Fab libraries.

Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of ten different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

Place of Death and Place of Care at the End of Life: Are They Correlated? A Retrospective Cohort Study of Ontario Decedents.

Background: Dying in nonpalliative acute care is generally considered inappropriate and avoidable. Place of death, a commonly reported big-dot indicator of end-of-life care quality, is often used as a proxy for place of care despite no empirical evidence for their correlations. Thus, we examined the correlations between place of death and place of care in the last month of life. We also investigated anecdotal claims that individuals cared in acute care often get discharged to die at home, and vice versa. Methods: We conducted a retrospective cohort study of Ontario decedents (18+) who died between January 1, 2015 and December 31, 2017. We identified individuals who died in nonpalliative acute care, palliative care unit, subacute care, long-term care (LTC), and the community. We calculated the number of days decedents spent in each setting in their last month of life, and used descriptive analyses to investigate their correlations. Results: Decedent's place of death generally correlated with their place of care in the last month of life-individuals who died in a particular setting spent more time in that setting than individuals who died elsewhere. Furthermore, 75.0% of individuals who spent more than two weeks of their last month in acute care died in acute care. Among individuals who died in the community and in LTC, 65.4% and 75.0%, respectively, spent zero days in acute care. Interpretation: We showed that place of death can be a useful high-level performance indicator, by itself and as a proxy for place of care, to gauge end-of-life quality and service provision/implementation.

Prevalence and patterns of multimorbidity among linguistic groups of patients receiving home care in Ontario: a retrospective cohort study.

BACKGROUND: Prior studies have demonstrated the negative impact of language barriers on access, quality, and safety of healthcare, which can lead to health disparities in linguistic minorities. As the population ages, those with multiple chronic diseases will require increasing levels of home care and long-term services. This study described the levels of multimorbidity among recipients of home care in Ontario, Canada by linguistic group. METHODS: Population-based retrospective cohort of 510,685 adults receiving home care between April 1, 2010, to March 31, 2018, in Ontario, Canada. We estimated and compared prevalence and characteristics of multimorbidity (2 or more chronic diseases) across linguistic groups (Francophones, Anglophones, Allophones). The most common combinations and clustering of chronic diseases were examined. Logistic regression models were used to explore the main predictors of 'severe' multimorbidity (defined as the presence of five or more chronic diseases). RESULTS: The proportion of home care recipients with multimorbidity and severe multimorbidity was 92% and 44%, respectively. The prevalence of multimorbidity was slightly higher among Allophones (93.6%) than among Anglophones (91.8%) and Francophones (92.4%). However, Francophones had higher rates of cardiovascular and respiratory disease (64.9%) when compared to Anglophones (60.2%) and Allophones (61.5%), while Anglophones had higher rates of cancer (34.2%) when compared to Francophones (25.2%) and Allophones (24.3%). Relative to Anglophones, Allophones were more likely to have severe multimorbidity (adjusted OR = 1.04, [95% CI: 1.02-1.06]). CONCLUSIONS: The prevalence of multimorbidity among Ontarians receiving home care services is high; especially for whose primary language is a language other than English or French (i.e., Allophones). Understanding differences in the prevalence and characteristics of multimorbidity across linguistic groups will help tailor healthcare services to the unique needs of patients living in minority linguistic situations.

Race, Poverty, and Foster Care Placement in the United States: Longitudinal and Cross-Sectional Perspectives.

Although the connections between race, poverty, and foster care placement seem obvious, the link has not in fact been studied extensively. To address this gap, we view poverty and placement through longitudinal and cross-sectional lenses to more accurately capture how changes in poverty rates relate to changes in placement frequency. The longitudinal study examines the relationship between poverty rate changes and changes in the placement of Black and White children between 2000 and 2015. The cross-sectional study extends the longitudinal analysis by using a richer measure of socio-ecological diversity and more recent foster care data. Using Poisson regression models, we assess the extent to which changes in race-differentiated child poverty rates are correlated with Black and White child placement frequencies and placement disparities. Regardless of whether one looks longitudinally or cross-sectionally, we find that Black children are placed in foster care more often than White children. Higher White child poverty rates are associated with substantially reduced placement differences; however, higher Black child poverty rates are associated with relatively small changes in placement disparity. Black and White child placement rates are more similar in counties with the fewest socio-ecological assets.

Development and Validation of a Predictive Risk Algorithm for Bleeding in Individuals on Long-term Hemodialysis: An International Prospective Cohort Study (BLEED-HD).

Background: Individuals with kidney disease are at a high risk of bleeding and as such tools that identify those at highest risk may aid mitigation strategies. Objective: We set out to develop and validate a prediction equation (BLEED-HD) to identify patients on maintenance hemodialysis at high risk of bleeding. Design: International prospective cohort study (development); retrospective cohort study (validation). Settings: Development: 15 countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018); Validation: Ontario, Canada. Patients: Development: 53 147 patients; Validation: 19 318 patients. Measurements: Hospitalization for a bleeding event. Methods: Cox proportional hazards models. Results: Among the DOPPS cohort (mean age, 63.7 years; female, 39.7%), a bleeding event occurred in 2773 patients (5.2%, event rate 32 per 1000 person-years), with a median follow-up of 1.6 (interquartile range [IQR], 0.9-2.1) years. BLEED-HD included 6 variables: age, sex, country, previous gastrointestinal bleeding, prosthetic heart valve, and vitamin K antagonist use. The observed 3-year probability of bleeding by deciles of risk ranged from 2.2% to 10.8%. Model discrimination was low to moderate (c-statistic = 0.65) with excellent calibration (Brier score range = 0.036-0.095). Discrimination and calibration of BLEED-HD were similar in an external validation of 19 318 patients from Ontario, Canada. Compared to existing bleeding scores, BLEED-HD demonstrated better discrimination and calibration (c-statistic: HEMORRHAGE = 0.59, HAS-BLED = 0.59, and ATRIA = 0.57, c-stat difference, net reclassification index [NRI], and integrated discrimination index [IDI] all P value <.0001). Limitations: Dialysis procedure anticoagulation was not available; validation cohort was considerably older than the development cohort. Conclusion: In patients on maintenance hemodialysis, BLEED-HD is a simple risk equation that may be more applicable than existing risk tools in predicting the risk of bleeding in this high-risk population.

Contexte: Les personnes atteintes d'insuffisance rénale présentent un risque élevé d'hémorragie. Des outils permettant de déceler les personnes les plus exposées au risque pourrait aider à mettre en œuvre des stratégies d'atténuation. Objectifs: Nous avons mis au point et validé une équation prédictive (BLEED-HD) afin d'identifier les patients sous hémodialyse d'entretien qui présentent un risque élevé d'hémorragie. Type d'étude: Étude de cohorte prospective internationale (développement); étude de cohorte rétrospective (validation). Cadre: Développement: dans 15 pays (étude DOPPS phases 2 à 6 entre 2002 et 2018); validation: en Ontario (Canada). Sujets: Développement: 53 147 patients; validation: 19 318 patients. Mesures: Hospitalisation pour un événement hémorragique. Méthodologie: Modèles à risques proportionnels de Cox. Résultats: Dans la cohorte DOPPS (âge moyen: 63,7 ans; 39,7 % de femmes), 2 773 patients avaient subi un événement hémorragique (5,2 %; taux d'événements: 32 pour 1 000 années-personnes) avec un suivi médian de 1,6 an (ÉIQ: 0,9 à 2,1). BLEED-HD prend six variables en compte: âge, sexe, pays d'origine, saignement gastro-intestinal antérieur, présence d'une valve cardiaque prothétique et utilisation d'un antagoniste de la vitamine K. La probabilité observée de saignements dans les 3 ans par déciles de risque allait de 2,2 à 10,8 %. La discrimination du modèle variait de faible à modérée (statistique c: 0,65) avec un excellent étalonnage (plage de score de Brier: 0,036-0,095). La discrimination et l'étalonnage de se sont avérés semblables lors de la validation externe auprès de 19 318 patients de l'Ontario (Canada). Par rapport aux scores d'hémorragie existants, l'équation BLEED-HD a démontré une meilleure discrimination et un meilleur étalonnage (statistique c: HEMORRHAGE 0,59; HAS-BLED 0,59 et ATRIA 0,57; différence dans les c-stat, indices NRI et IDI toutes valeurs de p < 0,0001). Limites: L'information sur l'anticoagulant utilisé dans la procédure de dialyse n'était pas disponible; la cohorte de validation était beaucoup plus âgée que la cohorte de développement. Conclusion: Pour les patients sous hémodialyse d'entretien, BLEED-HD est une équation simple de calcul du risque qui peut être plus facilement applicable que les outils existants pour prédire le risque d'hémorragie dans cette population à haut risque.

Adverse Gastrointestinal Events With Sodium Polystyrene Sulfonate Use in Patients on Maintenance Hemodialysis: An International Cohort Study.

Background: There are concerns regarding the gastrointestinal (GI) safety of sodium polystyrene sulfonate (SPS), a medication commonly used in the management of hyperkalemia. Objective: To compare the risk of GI adverse events among users versus non-users of SPS in patients on maintenance hemodialysis. Design: International prospective cohort study. Setting: Seventeen countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018). Patients: 50 147 adults on maintenance hemodialysis. Measurements: An adverse GI event defined by a GI hospitalization or GI fatality with SPS prescription compared with no SPS prescription. Methods: Overlap propensity score-weighted Cox models. Results: Sodium polystyrene sulfonate prescription was present in 13.4% of patients and ranged from 0.42% (Turkey) to 20.6% (Sweden) with 12.5% use in Canada. A total of 935 (1.9%) adverse GI events (140 [2.1%] with SPS, 795 [1.9%] with no SPS; absolute risk difference 0.2%) occurred. The weighted hazard ratio (HR) of a GI event was not elevated with SPS use compared with non-use (HR = 0.93, 95% confidence interval = 0.83-1.6). The results were consistent when examining fatal GI events and/or GI hospitalization separately. Limitations: Sodium polystyrene sulfonate dose and duration were unknown. Conclusions: Sodium polystyrene sulfonate use in patients on hemodialysis was not associated with a higher risk of an adverse GI event. Our findings suggest that SPS use is safe in an international cohort of maintenance hemodialysis patients.

Contexte: Des préoccupations sont soulevées quant à l'innocuité gastro-intestinale (GI) du sulfonate de polystyrène sodique (SPS), un médicament couramment utilisé dans la gestion de l'hyperkaliémie. Objectif: Comparer dans une population de patients sous hémodialyse d'entretien le risque d'effets indésirables gastro-intestinaux chez les utilisateurs du SPS par rapport aux patients non-utilisateurs. Conception: Étude de cohorte prospective internationale. Cadre: 17 pays (phases 2 à 6 de l'essai DOPPS [de 2002 à 2018]). Sujets: 50 147 adultes sous hémodialyse d'entretien. Mesures: La comparaison entre les événements gastro-intestinaux indésirables, définis par une hospitalisation ou un décès en lien avec un problème gastro-intestinal, selon que les patients avaient ou non une prescription de SPS. Méthodologie: Modèles de Cox pondérés par le score de propension au chevauchement. Résultats: Dans l'ensemble de la cohorte, 13,4 % des patients avaient une prescription de SPS; l'usage de SPS variait selon les pays entre 0,42 % (Turquie) et 20,6 % (Suède) avec 12,5 % au Canada. En tout, 935 (1,9 %) événements GI indésirables sont survenus dans l'ensemble de la cohorte, soit 140 (2,1 %) chez les patients avec prescription de SPS et 795 (1,9 %) chez les patients sans prescription de SPS (différence de risque absolue: 0,2 %). Le rapport de risque (RR) pondéré d'un événement GI n'était pas plus élevé avec l'utilisation de SPS (RR = 0,93; IC 95 %: 0,83-1,6). Les résultats étaient cohérents lorsque l'on a examiné séparément les événements gastro-intestinaux (hospitalisation et/ou décès). Limites: La dose et la durée du traitement par SPS étaient inconnues. Conclusion: L'utilisation de SPS chez les patients sous hémodialyse n'a pas été associée à un risque plus élevé d'événements indésirables d'origine gastro-intestinale. Nos résultats suggèrent que l'utilisation du SPS est sans danger dans la cohorte internationale de patients sous hémodialyse d'entretien étudiée.

Common framework mutations impact antibody interfacial dynamics and flexibility.

Introduction: With the flood of engineered antibodies, there is a heightened need to elucidate the structural features of antibodies that contribute to specificity, stability, and breadth. While antibody flexibility and interface angle have begun to be explored, design rules have yet to emerge, as their impact on the metrics above remains unclear. Furthermore, the purpose of framework mutations in mature antibodies is highly convoluted. Methods: To this end, a case study utilizing molecular dynamics simulations was undertaken to determine the impact framework mutations have on the VH-VL interface. We further sought to elucidate the governing mechanisms by which changes in the VH-VL interface angle impact structural elements of mature antibodies by looking at root mean squared deviations, root mean squared fluctuations, and solvent accessible surface area. Results and discussion: Overall, our results suggest framework mutations can significantly shift the distribution of VH-VL interface angles, which leads to local changes in antibody flexibility through local changes in the solvent accessible surface area. The data presented herein highlights the need to reject the dogma of static antibody crystal structures and exemplifies the dynamic nature of these proteins in solution. Findings from this work further demonstrate the importance of framework mutations on antibody structure and lay the foundation for establishing design principles to create antibodies with increased specificity, stability, and breadth.

A Health Survey-Based Prediction Equation for Incident CKD.

BACKGROUND: Prediction tools that incorporate self-reported health information could increase CKD awareness, identify modifiable lifestyle risk factors, and prevent disease. We developed and validated a survey-based prediction equation to identify individuals at risk for incident CKD (eGFR <60 ml/min per 1.73 m2), with and without a baseline eGFR. METHODS: A cohort of adults with an eGFR ≥70 ml/min per 1.73 m2 from Ontario, Canada, who completed a comprehensive general population health survey between 2000 and 2015 were included (n=22,200). Prediction equations included demographics (age, sex), comorbidities, lifestyle factors, diet, and mood. Models with and without baseline eGFR were derived and externally validated in the UK Biobank (n=15,522). New-onset CKD (eGFR <60 ml/min per 1.73 m2) with ≤8 years of follow-up was the primary outcome. RESULTS: Among Ontario individuals (mean age, 55 years; 58% women; baseline eGFR, 95 (SD 15) ml/min per 1.73 m2), new-onset CKD occurred in 1981 (9%) during a median follow-up time of 4.2 years. The final models included lifestyle factors (smoking, alcohol, physical activity) and comorbid illnesses (diabetes, hypertension, cancer). The model was discriminating in individuals with and without a baseline eGFR measure (5-year c-statistic with baseline eGFR: 83.5, 95% confidence interval [CI], 82.2 to 84.9; without: 81.0, 95% CI, 79.8 to 82.4) and well calibrated. In external validation, the 5-year c-statistic was 78.1 (95% CI, 74.2 to 82.0) and 66.0 (95% CI, 61.6 to 70.4), with and without baseline eGFR, respectively, and maintained calibration. CONCLUSIONS: Self-reported lifestyle and health behavior information from health surveys may aid in predicting incident CKD. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN05650522.mp3.

Primary Care Physician Use and Frequency of Visits Among Physicians in Ontario, Canada.

Importance: Maintaining a healthy physician workforce includes the routine use of primary care physician (PCP) services; however, physicians may face barriers to attaining formal care. Objective: To analyze access to and frequency of visits to PCPs among physicians compared with nonphysicians. Design, Setting, and Participants: This population-based, retrospective cohort study used registration data from the College of Physicians and Surgeons of Ontario, Canada, from January 1, 1990, to March 31, 2018. Data for all newly practicing physicians as of March 31, 2018, were linked to Ontario health administrative databases. Data were analyzed from August 25, 2020, to August 6, 2021. Main Outcomes and Measures: The main outcomes were enrollment in a PCP practice and visits with a PCP. Generalized estimating equations compared primary care visits between physicians and nonphysicians, matched 1:5 based on age, sex, neighborhood income quintile, and health region. Results: Among 19 581 physicians (mean [SD] age, 43.99 [8.94] years; 53.27% male) matched to 97 905 nonphysicians, physicians were less likely to be enrolled with a PCP than were nonphysicians (81.8% vs 86.4%; absolute difference, 4.6%; adjusted odds ratio [OR], 0.75; 95% CI, 0.72-0.79) and had fewer primary care visits during the preceding 2 years (median [IQR], 2 [0-4] vs 4 [1-7]; adjusted relative rate ratio [RRR], 0.59; 95% CI, 0.58-0.60). Physicians aged 40 years or older and male physicians were less likely to be rostered (ages 40-44 years: OR, 0.70 [95% CI, 0.64-0.77]; male: OR, 0.60 [95% CI, 0.57-0.63]) and more likely to have a lower frequency of PCP visits (ages 40-44 years: RRR, 0.53 [95% CI, 0.51-0.56]; male: RRR, 0.50 [95% CI, 0.50-0.51]) compared with nonphysicians. Conclusions and Relevance: In this retrospective cohort study, enrollment with a PCP practice and frequency of visits were lower among physicians compared with a matched general population of nonphysicians. Individual, system, and medical cultural factors associated with these results need to be better understood so that physicians can take better care of themselves and their patients.

Patient-physician language concordance and quality and safety outcomes among frail home care recipients admitted to hospital in Ontario, Canada.

BACKGROUND: When patients and physicians speak the same language, it may improve the quality and safety of care delivered. We sought to determine whether patient-physician language concordance is associated with in-hospital and postdischarge outcomes among home care recipients who were admitted to hospital. METHODS: We conducted a population-based study of a retrospective cohort of 189 690 home care recipients who were admitted to hospital in Ontario, Canada, between 2010 and 2018. We defined patient language (obtained from home care assessments) as English (Anglophone), French (Francophone) or other (allophone). We obtained physician language from the College of Physicians and Surgeons of Ontario. We defined hospital admissions as language concordant when patients received more than 50% of their care from physicians who spoke the patients' primary language. We identified in-hospital (adverse events, length of stay, death) and post-discharge outcomes (emergency department visits, readmissions, death within 30 days of discharge). We used regression analyses to estimate the adjusted rate of mean and the adjusted odds ratio (OR) of each outcome, stratified by patient language, to assess the impact of language-concordant care within each linguistic group. RESULTS: Allophone patients who received language-concordant care had lower risk of adverse events (adjusted OR 0.25, 95% confidence interval [CI] 0.15-0.43) and in-hospital death (adjusted OR 0.44, 95% CI 0.29-0.66), as well as shorter stays in hospital (adjusted rate of mean 0.74, 95% CI 0.66-0.83) than allophone patients who received language-discordant care. Results were similar for Francophone patients, although the magnitude of the effect was smaller than for allophone patients. Language concordance or discordance of the hospital admission was not associated with significant differences in postdischarge outcomes. INTERPRETATION: Patients who received most of their care from physicians who spoke the patients' primary language had better in-hospital outcomes, suggesting that disparities across linguistic groups could be mitigated by providing patients with language-concordant care.

Suicide and Self-Harm Among Physicians in Ontario, Canada.

BACKGROUND: Studies of occupation-associated suicide suggest physicians may be at a higher risk of suicide compared to nonphysicians. We set out to assess the risk of suicide and self-harm among physicians and compare it to nonphysicians. METHODS: We conducted a population-based, retrospective cohort study using registration data from the College of Physicians and Surgeons of Ontario from 1990 to 2016 with a follow-up to 2017, linked to Ontario health administrative databases. Using age- and sex-standardized rates and inverse probability-weighted, cause-specific hazards regression models, we compared rates of suicide, self-harm, and a composite of either event among all newly registered physicians to nonphysician controls. RESULTS: Among 35,989 physicians and 6,585,197 nonphysicians, unadjusted suicide events (0.07% vs. 0.11%) and rates (9.44 vs. 11.55 per 100,000 person-years) were similar. Weighted analyses found a hazard ratio of 1.05 (95% confidence interval: 0.69 to 1.60). Self-harm requiring health care was lower among physicians (0.22% vs. 0.46%; hazard ratio: 0.65, 95% confidence interval: 0.52 to 0.82), as was the composite of suicide or self-harm (hazard ratio: 0.70, 95% confidence interval: 0.57 to 0.86). The composite of suicide or self-harm was associated with a history of a mood or anxiety disorder (odds ratio: 2.84, 95% confidence interval: 1.17 to 6.87), an outpatient mental health visit in the past year (odds ratio: 3.08, 95% confidence interval: 1.34 to 7.10) and psychiatry visit in the preceding year (odds ratio: 3.87, 95% confidence interval: 1.67 to 8.95). INTERPRETATION: Physicians in Ontario are at a similar risk of suicide deaths and a lower risk of self-harm requiring health care relative to nonphysicians. Risk factors associated with suicide or self-harm may help inform prevention programs.

Amiodarone, Verapamil, or Diltiazem Use With Direct Oral Anticoagulants and the Risk of Hemorrhage in Older Adults.

Background: Routinely used cardiac medications, based on pharmacokinetics, are hypothesized to increase drug levels of direct oral anticoagulants (DOACs), with the potential to increase the risk of hemorrhage. We set out to compare the risk for hemorrhage following initiation of amiodarone, verapamil, or diltiazem (moderate cytochrome P450 3A4 and/or P-glycoprotein activity) vs metoprolol or amlodipine (weak or no activity), among older adults prescribed DOACs. Methods: We conducted a population-based, retrospective cohort study of all adults (aged ≥ 66 years) on a DOAC (dabigatran, apixaban, rivaroxaban; n = 295,038) who were newly prescribed amiodarone (n = 4872), verapamil (n = 1284), or diltiazem (n = 14,638), compared with metoprolol or amlodipine, from Ontario, Canada (2009-2016). The outcome was hospital admission or emergency room visit with a major hemorrhage (upper or lower gastrointestinal tract, intracranial), examined using weighted models. Results: A total of 1737 hemorrhage events occurred (amiodarone, 80 [1.6%] vs metoprolol 503 [2.3%]; verapamil, 32 [2.5%] vs amlodipine, 406 [1.6%]; diltiazem, 312 [2.1%] vs amlodipine, 404 [1.5%]). The weighted risk of major hemorrhage was not elevated with amiodarone, verapamil, or diltiazem initiation in DOAC users, compared to metoprolol or amlodipine, during the full follow-up period (hazard ratio [HR; 95% confidence interval]: amiodarone HR 0.77 [0.61-0.97]; verapamil HR 1.32 [0.88-1.98]; diltiazem HR 0.99 [0.85-1.15]). This finding was consistent with a broader definition of bleeding, adjusting for kidney function, by DOAC type or dosage. Conclusions: Hemorrhage risk with amiodarone, verapamil, and diltiazem was similar to that with comparators, among DOAC users aged > 66 years.

Contexte: Les médicaments cardiaques couramment utilisés, selon la pharmacocinétique, devraient théoriquement augmenter les taux d'anticoagulants oraux directs (AOD), ce qui s'accompagne d'un risque accru d'hémorragie. Nous avons entrepris de comparer le risque d'hémorragie après l'instauration de l'amiodarone, du vérapamil ou du diltiazem (activité modérée du cytochrome P450 3A4 ou de la P-glycoprotéine) par rapport au métoprolol ou à l'amlodipine (activité faible ou nulle), chez des personnes âgées à qui l'on avait prescrit des AOD. Méthodologie: Nous avons mené une étude de cohortes rétrospective en population auprès de tous les adultes (âgés de 66 ans et plus) prenant un AOD (dabigatran, apixaban, rivaroxaban; n = 295 038) à qui l'on venait de prescrire de l'amiodarone (n = 4872), du vérapamil (n = 1284) ou du diltiazem (n = 14 638), comparativement au métoprolol ou à l'amlodipine, en Ontario, au Canada (2009-2016). Le critère d'évaluation était une admission à l'hôpital ou une consultation à l'urgence pour une hémorragie grave (voie gastro-intestinale supérieure ou inférieure, intracrânienne), examiné à l'aide de mo-dèles pondérés. Résultats: Au total, 1 737 événements hémorragiques sont survenus (amiodarone, 80 [1,6 %] contre métoprolol, 503 [2,3 %]; vérapamil, 32 [2,5 %] contre amlodipine, 406 [1,6 %]; diltiazem, 312 [2,1 %] contre amlodipine, 404 [1,5 %]). Le risque pondéré d'hémorragie grave ne s'est pas accru avec l'instauration de l'amiodarone, du vérapamil ou du diltiazem chez les utilisateurs d'AOD, comparativement au métoprolol ou à l'amlodipine, pendant toute la période de suivi (rapport des risques instantanés [RRI; intervalle de confiance à 95 %] : amiodarone : RRI 0,77 [0,61-0,97]; vérapamil : RRI 1,32 [0,88-1,98]; diltiazem : RRI 0,99 [0,85-1,15]). Ce résultat concorde avec une définition plus large du saignement, après ajustement pour la fonction rénale, par type ou posologie d'AOD. Conclusions: Le risque d'hémorragie associé à l'amiodarone, au vérapamil et au diltiazem était semblable à celui des médicaments de comparaison chez les utilisateurs d'AOD âgés de plus de 66 ans.

The association between recreational cannabis legalization, commercialization and cannabis-attributable emergency department visits in Ontario, Canada: an interrupted time-series analysis.

BACKGROUND AND AIMS: Recreational cannabis was legalized in Canada in October 2018. Initially, the Government of Ontario (Canada's largest province) placed strict limits on the number of cannabis retail stores before later removing these limits. This study measured changes in cannabis-attributable emergency department (ED) visits over time, corresponding to different regulatory periods. DESIGN: Interrupted time-series design using population-level data. Two policy periods were considered; recreational cannabis legalization with strict store restrictions (RCL, 17 months) and legalization with no store restrictions [recreational cannabis commercialization (RCC), 15 months] which coincided with the COVID-19 pandemic. Segmented Poisson regression models were used to examine immediate and gradual effects in each policy period. SETTING: Ontario, Canada. PARTICIPANTS: All individuals aged 15-105 years (n = 13.8 million) between January 2016 and May 2021. MEASUREMENTS: Monthly counts of cannabis-attributable ED visits per capita and per all-cause ED visits in individuals aged 15+ (adults) and 15-24 (young adults) years. FINDINGS: We observed a significant trend of increasing cannabis-attributable ED visits pre-legalization. RCL was associated with a significant immediate increase of 12% [incident rate ratio (IRR) = 1.12, 95% confidence interval (CI) = 1.02-1.23] in rates of cannabis-attributable ED visits followed by significant attenuation of the pre-legalization slope (monthly slope change IRR = 0.98, 95% CI = 0.97-0.99). RCC and COVID-19 were associated with immediate significant increases of 22% (IRR = 1.22, 95% CI = 1.09-1.37) and 17% (IRR = 1.17, 95% CI = 1.00-1.37) in rates of cannabis-attributable visits and the proportion of all-cause ED visits attributable to cannabis, respectively, with insignificant increases in monthly slopes. Similar patterns were observed in young adults. CONCLUSIONS: In Ontario, Canada, cannabis-attributable emergency department visits stopped increasing over time following recreational cannabis legalization with strict retail controls but then increased during a period coinciding with cannabis commercialization and the COVID-19 pandemic.

Physician Health Care Visits for Mental Health and Substance Use During the COVID-19 Pandemic in Ontario, Canada.

Importance: Physicians self-report high levels of symptoms of anxiety and depression, and surveys suggest these symptoms have been exacerbated by the COVID-19 pandemic. However, it is not known whether pandemic-related stressors have led to increases in health care visits related to mental health or substance use among physicians. Objective: To evaluate the association between the COVID-19 pandemic and changes in outpatient health care visits by physicians related to mental health and substance use and explore differences across physician subgroups of interest. Design, Setting, and Participants: A population-based cohort study was conducted using health administrative data collected from the universal health system (Ontario Health Insurance Plan) of Ontario, Canada, from March 1, 2017, to March 10, 2021. Participants included 34 055 physicians, residents, and fellows who registered with the College of Physicians and Surgeons of Ontario between 1990 and 2018 and were eligible for the Ontario Health Insurance Plan during the study period. Autoregressive integrated moving average models and generalized estimating equations were used in analyses. Exposures: The period during the COVID-19 pandemic (March 11, 2020, to March 10, 2021) compared with the period before the pandemic. Main Outcomes and Measures: The primary outcome was in-person, telemedicine, and virtual care outpatient visits to a psychiatrist or family medicine and general practice clinicians related to mental health and substance use. Results: In the 34 055 practicing physicians (mean [SD] age, 41.7 [10.0] years, 17 918 [52.6%] male), the annual crude number of visits per 1000 physicians increased by 27%, from 816.8 before the COVID-19 pandemic to 1037.5 during the pandemic (adjusted incident rate ratio per physician, 1.13; 95% CI, 1.07-1.19). The absolute proportion of physicians with 1 or more mental health and substance use visits within a year increased from 12.3% before to 13.4% during the pandemic (adjusted odds ratio, 1.08; 95% CI, 1.03-1.14). The relative increase was significantly greater in physicians without a prior mental health and substance use history (adjusted incident rate ratio, 1.72; 95% CI, 1.60-1.85) than in physicians with a prior mental health and substance use history. Conclusions and Relevance: In this study, the COVID-19 pandemic was associated with a substantial increase in mental health and substance use visits among physicians. Physician mental health may have worsened during the pandemic, highlighting a potential greater requirement for access to mental health services and system level change.

Children's Health Care Utilization and Cost in the Last Year of Life: A Cohort Comparison with and without Regional Specialist Pediatric Palliative Care.

Background: Research remains inconclusive regarding the impact of specialist pediatric palliative care (SPPC) on health care utilization and cost. Objective: To better understand and quantify the impact of regional SPPC services on children's health care utilization and cost near end of life. Design: A retrospective cohort study used administrative databases to compare outcomes for child decedents (age 31 days to 19 years) from two similar regions in Ontario, Canada between 2010 and 2014, wherein one region had SPPC services (SPPC+) and the other did not (SPPC-). Measurements: Administrative databases provided demographics, health care utilization (days), and costs Canadian dollars) across settings in the last year of life, and location of death. Multivariable analyses produced relative rates (RRs) of health care days (acute and home care), intensive care unit (ICU) days, and health care costs (inpatient, outpatient, home, and physician) as well as the odds ratio (OR) of in-hospital death. Counterfactual analysis quantified the differences in utilization and costs. Results: A total of 807 children were included. On multivariable analysis, residence in the SPPC+ region (n = 363) was associated with fewer mean health care days (RR = 0.73; 95% confidence interval [CI]: 0.59-0.90); fewer mean ICU days (RR = 0.64; 95% CI: 0.44-0.94); lower mean health care costs (RR = 0.71; 95% CI: 0.56-0.91); and lower likelihood of in-hospital death (OR = 0.67; 95% CI: 0.49-0.92). The counterfactual analysis estimated mean reductions of 16.2 days (95% CI: 14.4-18.0) and $24,940 (95% CI: $21,703-$28,177) per child in the SPPC+ region. Conclusions: Although not a causal study, these results support an association between regional SPPC services and decreased health care utilization, intensity, and cost for children near end of life.

In-Hospital Patient Harm Across Linguistic Groups: A Retrospective Cohort Study of Home Care Recipients.

OBJECTIVE: Research examining the impact of language barriers on patient safety is limited. We conducted a population-based study to determine whether patients whose primary language is not English are more likely to experience harm when admitted to hospitals in Ontario, Canada. METHODS: We used linked administrative health records to establish a retrospective cohort of home care recipients (from 2010 to 2015) who were subsequently admitted to hospital. Patient language (obtained from home care assessments) was coded as English, French, or other. Harmful events were identified using the Hospital Harm Indicator developed by the Canadian Institute for Health Information. RESULTS: We included 190,724 patients (156,186 Anglophones, 5,110 Francophones, and 29,428 Allophones). There was no significant difference in the unadjusted risk of harm for Francophones compared with Anglophones (relative risk [RR], 0.94; 95% confidence interval [CI], 0.87-1.02). However, Allophones were more likely to experience harm when compared with Anglophones (RR, 1.14; 95% CI, 1.10-1.18). The risk of harm was even greater for Allophones with low English proficiency (RR, 1.18; 95% CI, 1.13-1.24). After adjusting for potential confounders, Anglophones and Allophones were equally likely to experience harm of any type, but Allophones more likely to experience harm from infections and procedures. CONCLUSIONS: Patients whose primary language was not English or French were more likely to experience harm after admission to hospital, especially if they had low English proficiency. For these patients, the risk of harm from infections and procedures persisted in the adjusted analysis, but the overall risk of harm did not.