Restrictive or Liberal Transfusion Strategy in Myocardial Infarction and Anemia.

BACKGROUND: A strategy of administering a transfusion only when the hemoglobin level falls below 7 or 8 g per deciliter has been widely adopted. However, patients with acute myocardial infarction may benefit from a higher hemoglobin level. METHODS: In this phase 3, interventional trial, we randomly assigned patients with myocardial infarction and a hemoglobin level of less than 10 g per deciliter to a restrictive transfusion strategy (hemoglobin cutoff for transfusion, 7 or 8 g per deciliter) or a liberal transfusion strategy (hemoglobin cutoff, <10 g per deciliter). The primary outcome was a composite of myocardial infarction or death at 30 days. RESULTS: A total of 3504 patients were included in the primary analysis. The mean (±SD) number of red-cell units that were transfused was 0.7±1.6 in the restrictive-strategy group and 2.5±2.3 in the liberal-strategy group. The mean hemoglobin level was 1.3 to 1.6 g per deciliter lower in the restrictive-strategy group than in the liberal-strategy group on days 1 to 3 after randomization. A primary-outcome event occurred in 295 of 1749 patients (16.9%) in the restrictive-strategy group and in 255 of 1755 patients (14.5%) in the liberal-strategy group (risk ratio modeled with multiple imputation for incomplete follow-up, 1.15; 95% confidence interval [CI], 0.99 to 1.34; P = 0.07). Death occurred in 9.9% of the patients with the restrictive strategy and in 8.3% of the patients with the liberal strategy (risk ratio, 1.19; 95% CI, 0.96 to 1.47); myocardial infarction occurred in 8.5% and 7.2% of the patients, respectively (risk ratio, 1.19; 95% CI, 0.94 to 1.49). CONCLUSIONS: In patients with acute myocardial infarction and anemia, a liberal transfusion strategy did not significantly reduce the risk of recurrent myocardial infarction or death at 30 days. However, potential harms of a restrictive transfusion strategy cannot be excluded. (Funded by the National Heart, Lung, and Blood Institute and others; MINT ClinicalTrials.gov number, NCT02981407.).

Empirically derived profiles of neurocognitive functioning in youth and young adults with sickle cell disease.

OBJECTIVE: Sickle cell disease (SCD) is an inherited blood disorder associated with neurocognitive deficits. In contrast to variable-centered approaches, no known research has utilized person-centered strategies to identify multidimensional patterns of neurocognitive functioning of an individual with SCD. The purpose of the present study was to create empirically derived profiles and identify predictors of neurocognitive functioning subgroups among youth and young adults with SCD. METHODS: Individuals with SCD (N = 393, mean age 14.05 years, age range 8-24, 50.4% female/49.6% male) completed neurocognitive assessments. Latent profile analysis derived subgroups/classes of neurocognitive functioning and determined relations with demographic and medical variables. RESULTS: Three latent classes emerged: average functioning (n = 102, 27%), low average functioning (n = 225, 60%), and exceptionally low functioning (n = 46, 12%). Older age was associated with membership in the low average and exceptionally low functioning groups (relative to the average group). Being prescribed hydroxyurea was associated with membership in the average functioning group (relative to the low average group) and absence of hydroxyurea use was associated with membership in the exceptionally low group (relative to the low average group). Lower social vulnerability was associated with membership in the average functioning group compared to the low average and exceptionally low groups. CONCLUSIONS: Clinicians can help reduce disparities in cognitive development for individuals with SCD by promoting early treatment with hydroxyurea and implementing methods to reduce social vulnerabilities that can interfere with access to evidence-based care.

Examining the influence of pain and fatigue on neurocognitive functioning in adolescents and young adults with sickle cell disease.

Pain and fatigue are among the most common and impactful complications of sickle cell disease (SCD). Individuals with SCD are also more likely to have neurocognitive deficits. Previous studies have suggested that pain and fatigue might influence neurocognitive functioning in patients with SCD. However, these studies are limited by small sample sizes and inadequate measurement of cognitive performance. The present study aimed to investigate the relationship between pain and fatigue with neurocognitive functioning using performance-based measures of neurocognition. Pain and fatigue were not associated with neurocognitive performance. Implications and directions for future research are discussed.

Social determinants of neurocognitive and academic performance in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is associated with poor neurocognitive outcomes due to biomedical and psychosocial factors. The aims of this study were to investigate associations between household and neighborhood socioeconomic status (SES) with cognitive and academic outcomes in SCD and to determine if these relationships were modified by sickle genotype, fetal hemoglobin, or age. PROCEDURE: We prospectively recruited patients to complete a battery of neurocognitive and academic measures. Household SES was measured using the Barratt Simplified Measure of Social Status, a composite index of parent education and occupation. The Social Vulnerability Index was used to classify individuals based on social vulnerabilities at the neighborhood level. RESULTS: Overall, 299 patients between the ages of 4 and 18 (mean = 11.4, standard deviation = 4.3) years diagnosed with SCD (57% SS/SB0 -thalassemia) completed testing. Stepwise multivariate models demonstrated that patients with low social vulnerability (i.e., high SES) at the neighborhood level displayed intelligence and math scores that were 4.70 and 7.64 points higher than those living in areas with moderate social vulnerability, respectively (p < .05). Reading performance did not differ based on neighborhood SES; however, the effect of neighborhood SES was dependent on age, such that older participants living in neighborhoods with moderate or high levels of social vulnerability displayed poorer reading scores than those with low social vulnerability (p < .05). CONCLUSIONS: This study identified patients with SCD at higher risk of poor academic performance based on SES. Interventions addressing academic difficulties should be offered to all children with SCD, but should be emergently offered to this subpopulation.

Internalizing Symptoms in Adolescents With Sickle Cell Disease.

OBJECTIVE: Sickle cell disease (SCD) is a genetic blood disorder that may affect patients' mood and behavior. However, measuring the prevalence of internalizing symptoms (anxiety and depression) in patients with SCD has been elusive. We assessed internalizing symptoms in adolescents with SCD to evaluate prevalence and to test whether neurocognitive performance and frequency of pain-related episodes were associated with internalizing concerns. METHODS: One hundred eighty-five patients (57% HbSS/HbSß0-thalassemia, 43% HbSC/HbSß+-thalassemia), ages 12-18 years, received a neuropsychological evaluation as a part of a larger cohort study. Internalizing symptoms were measured using the Behavior Assessment System for Children, Second or Third Edition. Scores on the depression and anxiety scales were compared to normative values using Wilcoxon signed rank test. Spearman correlations examined associations between neurocognitive performances and internalizing symptoms. Robust multivariable regression models measured associations between internalizing symptoms and age, sex, sickle genotype, total hemoglobin, fetal hemoglobin, socioeconomic status, and frequency of pain episodes. RESULTS: Parent- and self-reported ratings of internalizing symptoms were not elevated compared to normative expectations. Overall, 1.8% and 6.3% of the sample displayed clinically elevated symptoms of anxiety and depression based on self-report, respectively. There were no associations between internalizing symptoms and neurocognitive performance (all p > .05). In multivariable analyses, the frequency of pain episodes was positively associated with self-reported anxiety (p = .006) and parent-reported depressive symptoms (p = .017). CONCLUSIONS: Adolescents with SCD do not report elevated internalizing symptoms compared to normative expectations. Further research is needed to examine the trajectory of internalizing symptoms and the bidirectional relationship between pain and psychosocial functioning in SCD.

Association of Initial Pulseless Electrical Activity Heart Rate and Clinical Outcomes following Adult Non-Traumatic Out-of-Hospital Cardiac Arrest.

OBJECTIVE: Studies evaluating the prognostic value of the pulseless electrical activity (PEA) heart rate in out-of-hospital cardiac arrest (OHCA) patients have reported conflicting results. The objective of this study was to evaluate the association between the initial PEA heart rate and favorable clinical outcomes for OHCA patients. METHODS: The present post-hoc cohort study used the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry Version 3, which included OHCA patients in seven US and three Canadian sites from April 2011 to June 2015. The primary outcome was survival to hospital discharge and the secondary outcome was survival with a good functional outcome. For the primary analysis, the patients were separated into eight groups according to their first rhythms and PEA heart rates: (1) initial PEA heart rate of 1-20 beats per minute (bpm); (2) 21-40 bpm; (3) 41-60 bpm; (4) 61-80 bpm; (5) 81-100 bpm; (6) 101-120 bpm; (7) over 120 bpm; (8) initial shockable rhythm (reference category). Multivariable logistic regression models were used to assess the associations of interest. RESULTS: We identified 17,675 patients (PEA: 7,089 [40.1%]; initial shockable rhythm: 10,797 [59.9%]). Patients with initial PEA electrical frequencies ≤100 bpm were less likely to survive to hospital discharge than patients with initial shockable rhythms (1-20 bpm: adjusted odds ratio [AOR] = 0.15 [95%CI 0.11-0.21]; 21-40 bpm: AOR = 0.21 [0.18-0.25]; 41-60 bpm: AOR = 0.30 [0.25-0.36]; 61-80 bpm: AOR = 0.37 [0.28-0.49]; 81-100 bpm: AOR = 0.55 [0.41-0.65]). However, there were no statistical outcome differences between PEA patients with initial electrical frequencies of >100 bpm and patients with initial shockable rhythms (101-120 bpm: AOR = 0.65 [95%CI 0.42-1.01]; >120 bpm: AOR = 0.72 [95%CI 0.37-1.39]). Similar results were observed for survival with good functional outcomes (101-120 bpm: AOR = 0.60 [95%CI 0.31-1.15]; >120 bpm: AOR = 1.08 [95%CI 0.50-2.28]). CONCLUSIONS: We observed a good association between higher initial PEA electrical frequency and favorable clinical outcomes for OHCA patients. As there is no significant difference in outcomes between patients with initial PEA heart rates of more than 100 bpm and those with initial shockable rhythms, we can hypothesize that these patients could be considered in the same prognostic category.

Accuracy of the Initial Rhythm to Predict a Short No-Flow Time in Out-of-Hospital Cardiac Arrest.

OBJECTIVES: The no-flow time (NFT) can help establish prognosis in out-of-hospital cardiac arrest (OHCA) patients. It is often used as a selection criterion for extracorporeal resuscitation. In patients with an unwitnessed OHCA for whom the NFT is unknown, the initial rhythm has been proposed to identify those more likely to have had a short NFT. Our objective was to determine the predictive accuracy of an initial shockable rhythm for an NFT of 5 minutes or less (NFT ≤ 5). DESIGN: Retrospective analysis of prospectively collected data. SETTING: Prehospital OHCA in eight U.S. and three Canadian sites. PATIENTS: A total of 28,139 adult patients with a witnessed nontraumatic OHCA were included, of whom 11,228 (39.9%) experienced an emergency medical service-witnessed OHCA (NFT = 0), 695 (2.7%) had a bystander-witnessed OHCA, and an NFT less than or equal to 5, and 16,216 (57.6%) with a bystander-witnessed OHCA and an NFT greater than 5. INTERVENTIONS: Sensitivity, specificity, and likelihood ratios of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 minutes. MEASUREMENTS AND MAIN RESULTS: The sensitivity of an initial shockable rhythm to identify patients with an NFT less than or equal to 5 was poor (25% [95% CI, 25-26]), but specificity was moderate (70% [95% CI, 69-71]). The positive and likelihood ratios were inverted (negative accuracy) (positive likelihood ratio, 0.76 [95% CI, 0.74-0.79]; negative likelihood ratio, 1.12 [95% CI, 1.10-1.12]). Including only patients with a bystander-witnessed OHCA improved the sensitivity to 48% (95% CI, 45-52), the positive likelihood ratio to 1.45 (95% CI, 1.33-1.58), and the negative likelihood ratio to 0.77 (95% CI, 0.72-0.83), while slightly lowering the specificity to 67% (95% CI, 66-67). CONCLUSIONS: Our analysis demonstrated that the presence of a shockable rhythm at the time of initial assessment was poorly sensitive and only moderately specific for OHCA patients with a short NFT. The initial rhythm, therefore, should not be used as a surrogate for NFT in clinical decision-making.

The toll of transition: Caregiver perceptions of family adjustment during the transition off pediatric cancer therapy.

OBJECTIVE: The role of transition-focused psychology appointments in managing the transition off therapy is unclear. The objective of this research was to explore caregiver perceived familial distress and the role of psychology in preparing families for transition. METHODS: Fifty-seven caregivers of youth, who finished treatment, completed an online questionnaire through a quality improvement project on experiences of families at transition. Twenty-two percent of caregivers had children who completed a transition-focused psychology consult and 63% completed a cognitive assessment at transition. Retrospective analyses were conducted assessing the association of psychology visits on caregiver perceptions of being informed of and prepared to manage transition-related challenges. RESULTS: Most caregivers reported experiencing adjustment concerns for family members. Caregivers of children completing a transition-focused psychology consult or cognitive assessment reported feeling more informed and greater preparedness to manage difficulties. Although decreased distress was not associated with the visit, those who felt more informed and prepared reported lower distress. CONCLUSIONS: Caregivers perceive transitioning off therapy as stressful for their family, though they experience decreased familial distress when informed of and prepared to manage transition-related challenges. These findings highlight the importance of psychosocial support at transition.

Neurocognitive functioning in preschool children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. PROCEDURE: Sixty-two patients with SCD (60% HbSS/HbSß0 -thalassemia; 40% HbSC/HbSß+ -thalassemia) between the ages of 3 and 6 years (mean = 4.77 years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSß0 -thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45) years of age. The average dose was 28.8 mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. RESULTS: Patients with HbSS/HbSß0 -thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR ] < .05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR  > .05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR  < .05). Greater household socioeconomic status was positively associated with academic readiness. CONCLUSIONS: Preschoolers with severe SCD (HbSS/HbSß0 -thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed.

A comparison of confounder selection and adjustment methods for estimating causal effects using large healthcare databases.

PURPOSE: Confounding adjustment is required to estimate the effect of an exposure on an outcome in observational studies. However, variable selection and unmeasured confounding are particularly challenging when analyzing large healthcare data. Machine learning methods may help address these challenges. The objective was to evaluate the capacity of such methods to select confounders and reduce unmeasured confounding bias. METHODS: A simulation study with known true effects was conducted. Completely synthetic and partially synthetic data incorporating real large healthcare data were generated. We compared Bayesian adjustment for confounding (BAC), generalized Bayesian causal effect estimation (GBCEE), Group Lasso and Doubly robust estimation, high-dimensional propensity score (hdPS), and scalable collaborative targeted maximum likelihood algorithms. For the hdPS, two adjustment approaches targeting the effect in the whole population were considered: Full matching and inverse probability weighting. RESULTS: In scenarios without hidden confounders, most methods were essentially unbiased. The bias and variance of the hdPS varied considerably according to the number of variables selected by the algorithm. In scenarios with hidden confounders, substantial bias reduction was achieved by using machine-learning methods to identify proxies as compared to adjusting only by observed confounders. hdPS and Group Lasso performed poorly in the partially synthetic simulation. BAC, GBCEE, and scalable collaborative-targeted maximum likelihood algorithms performed particularly well. CONCLUSIONS: Machine learning can help to identify measured confounders in large healthcare databases. They can also capitalize on proxies of unmeasured confounders to substantially reduce residual confounding bias.

Adaptive Functioning in Children and Adolescents With Sickle Cell Disease.

OBJECTIVE: Risk for neurocognitive deficits in sickle cell disease (SCD) is well established, yet minimal research has evaluated the risk for deficits in adaptive functioning. We assessed adaptive functioning in pediatric patients with SCD to test the hypothesis that disease, treatment, and demographic factors were associated with adaptive outcomes. METHODS: Two hundred fifty-six patients (57% HbSS/HbSß0-thalassemia and 43% HbSC/HbSß+-thalassemia), ages 8-18, received routine neuropsychological assessments as part of a larger prospective lifetime cohort study. Adaptive functioning was measured using the Behavior Assessment System for Children, Second or Third Edition. Adaptive scores were compared with normative values using t-test or Wilcoxon signed rank test and linear regression models were used to measure associations between adaptive functioning and age, hydroxyurea (HU) use, sickle genotype, and socioeconomic status. Furthermore, we examined the influence of intellectual and executive functioning on adaptive behavior using hierarchical linear regression analyses. RESULTS: Parent ratings of adaptive functioning skills did not differ from normative expectations (all false discovery rate [FDR] adjusted p-value [pFDR] > 0.05). Social vulnerability was negatively associated with adaptive scores on most adaptive scales in both genotypes (pFDR < 0.05). HU treatment was not significantly associated with any adaptive scale. Overall IQ was positively associated with Functional Communication and Leadership only for those with HbSS/HbSß0-thalassemia. Higher parent ratings of executive difficulties were correlated with lower adaptive scores (estimate = -0.64, standard error = 0.051, p < .001). CONCLUSIONS: Poorer parent-rated adaptive skills were associated with increased social vulnerability, lower Full-Scale IQ, and parent-rated executive difficulties. Most adaptive scores were in the normal range; however, parent ratings may not fully capture the impact of disease complications and neurocognitive deficits on daily functioning.

Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood.

Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross-sectional analysis, we examined the association between hydroxyurea (HU) treatment and neurocognitive functioning from school-age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSß0 -thalassaemia (71% HU treated) and 149 patients with HbSC/HbSß+ -thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school-age (age 8-9 years), early adolescence (age 12-13 years), late adolescence (age 16-17 years) and young adulthood (ages 19-24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life [standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01] for patients with HbSS/HbSß0 -thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSß0 -thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ [estimate (SE) 0·77 (0·25)/year, PFDR = 0·01], after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration.

Use of antithrombotic therapy for secondary prevention in patients with stable atherosclerotic cardiovascular disease: Insights from the COordinated National Network to Engage Cardiologists in the antithrombotic Treatment of patients with CardioVascular Disease (CONNECT-CVD) study.

BACKGROUND: Although acetylsalicylic acid is the most commonly used antithrombotic agent for the secondary prevention of cardiovascular events, residual atherothrombotic risk has prompted a guideline recommendation for the addition of dual antiplatelet therapy (DAPT) or dual pathway inhibition (DPI) in high vascular risk patients. Accordingly, the CONNECT CVD quality enhancement initiative provides a contemporary "snapshot" of the clinical features and antithrombotic management of atherosclerotic cardiovascular disease (ASCVD) patients in Canada. METHODS: Canadian cardiologists (49 cardiologists from six provinces) undertook a retrospective chart audit of 10 ASCVD patients in their outpatient practice who met the Cardiovascular Outcomes for People Using Anticoagulation Strategy-like criteria from May 2018 to April 2019. RESULTS: Of the 492 (two cardiologists provided 11 patients) enroled, average age was 70 years, 25% were female, 39% had diabetes and 20% had atrial fibrillation. Prior revascularisation was common (percutaneous coronary artery intervention 61%, coronary artery bypass graft 39%), with 31% having multivessel disease. A total of 47% of patients had a Reduction of Atherothrombosis for Continued Health bleeding score of ≥11 (~2.8% risk of serious bleeding at 2 years). Single antiplatelet therapy (SAPT) alone was most commonly used (62%), while 22% were on DAPT alone. In total, 22% were on oral anticoagulation (OAC), with 16% being on non-vitamin K oral anticoagulant alone, 5% on DPI and 1% received triple therapy. CONCLUSIONS: In contemporary Canadian clinical practice of stable ASCVD patients, a large number of patients receive antithrombotic therapy other than SAPT. Further efforts are required to guide the appropriate selection of patients in whom more potent antithrombotic therapies may safely reduce residual risk.

Cardiovascular disease and cancer in women with accreta and retained placenta: a longitudinal cohort study.

PURPOSE: The association between placental detachment disorders and risk of chronic disease is unclear. We determined the association of placenta accreta and retained placenta with risk of future maternal cardiovascular disease and cancer. METHODS: We tracked a longitudinal cohort of 541,051 pregnant women over a period of 13 years (2006-2019) in Quebec, Canada. The main exposure measures were placenta accreta and retained placenta in any pregnancy. Outcomes included future hospitalizations for cardiovascular disease and cancer. Using Cox regression models adjusted for maternal characteristics, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of accreta and retained placenta with cardiovascular disease and cancer at 13 years. RESULTS: The incidence of cardiovascular hospitalization was 21.2 per 10,000 person-years for accreta and 23.4 per 10,000 for retained placenta with postpartum hemorrhage, compared with 20.3 per 10,000 for neither placental disorder. Cancer incidence followed a similar pattern, with rates highest for retained placenta with hemorrhage. Retained placenta with hemorrhage was associated with 1.19 times the risk of cardiovascular disease (95% CI 1.03-1.38) and 1.27 times the risk of cancer (95% CI 1.06-1.53). Retained placenta with hemorrhage was associated with heart failure (HR 1.84, 95% CI 1.04-3.27), cardiomyopathy (HR 1.88, 95% CI 1.03-3.43), and cervical cancer (HR 2.03, 95% CI 1.17-3.52). Accreta and retained placenta without hemorrhage were not associated with these outcomes. CONCLUSION: Retained placenta with hemorrhage may be a risk marker for cardiovascular disease and certain cancers later in life.

Cannabis use disorder and the future risk of cardiovascular disease in parous women: a longitudinal cohort study.

BACKGROUND: Cannabis use is increasing in women of reproductive age, but whether cannabis use disorders increase the long-term risk of cardiovascular disease in this population is not known. Cannabis may cause tachycardia, hypertension, cerebral vasoconstriction, and other adverse cardiovascular effects and has been associated with acute myocardial infarction and stroke. Data on the long-term effects of cannabis on the cardiovascular system are more limited. We assessed the relationship between cannabis use disorders early in life and the future risk of cardiovascular disease in women. METHODS: We analyzed a longitudinal cohort of 1,247,035 pregnant women in Quebec, Canada, between 1989 and 2019. The main exposure was current or past history of cannabis use disorders at cohort entry. The main outcome measure included future hospital admission for any cardiovascular disorder during 18,998,986 person years of follow-up. We used Cox proportional hazards regression models adjusted for patient characteristics to compute hazard ratios (HR) and 95% confidence intervals (CI) for the association of cannabis use disorder with the later risk of cardiovascular hospitalization. RESULTS: Women with cannabis use disorders had a higher incidence of cardiovascular hospitalization than unexposed women (58.4 vs. 33.6 per 10,000 person years). Cannabis use disorder was associated with 1.48 times the risk of cardiovascular hospitalization (95% CI 1.27-1.72), compared with no cannabis use disorder. The association was greater for cannabis with concomitant use of other substances (HR 1.84, 95% CI 1.53-2.21) than for cannabis alone (HR 1.30, 95% CI 0.99-1.72). Cannabis use disorder was strongly associated with hemorrhagic stroke, even with adjustment for other substance use (HR 2.08, CI 1.07-4.05). CONCLUSIONS: Cannabis use disorders may increase the long-term risk of cardiovascular disease in women, particularly hemorrhagic stroke. However, some of the excess risk may be due to concomitant use of other substances.

Maternal Autoimmune Disorders and Risk of Kawasaki Disease in Offspring.

We assessed the association between maternal autoimmune disorders and offspring risk of Kawasaki disease in a longitudinal cohort of 792 108 newborns. We found that maternal autoimmune disorders, especially autoimmune thyroiditis, may be risk factors for Kawasaki disease in children, particularly young children.

Clinical impact of hypothalamic-pituitary disorders after conformal radiation therapy for pediatric low-grade glioma or ependymoma.

BACKGROUND: To determine the impact of hypothalamic-pituitary (HP) disorders on health outcomes in children and adolescents who received conformal radiation therapy (RT) for central nervous system tumors. PROCEDURE: Cohort study including 355 patients (age ≤25 years at diagnosis) treated with high-dose (50.4-59.4 Gy) RT using photons for low-grade glioma or ependymoma. Patients (median age, 6.4 years at RT) received systematic endocrine follow-up (median duration, 10.1 years; range, 0.1-19.6). Associations between HP disorders and adverse health outcomes were determined by multivariable analysis. RESULTS: Prevalence was 37.2% for growth hormone deficiency (GHD), 17.7% for gonadotropin deficiency (LH/FSHD), 14.9% for thyroid-stimulating hormone deficiency (TSHD), 10.3% for adrenocorticotropic hormone deficiency (ACTHD), and 12.6% for central precocious puberty (CPP). Hypothalamus mean dose ≥ 36 Gy was associated with higher odds of any deficiency. GHD was associated with short stature (OR 2.77; 95% CI 1.34-5.70), low bone mineral density (OR 3.47; 95% CI 1.16-10.40), and TSHD with dyslipidemia (OR 5.54; 95% CI 1.66-18.52). Patients with ACTHD and CPP had lower intelligence quotient scores, and memory scores were impaired in patients with GHD (P = 0.02). Treatment of GHD was not associated with increased risk for tumor recurrence, secondary tumors, or mortality. CONCLUSIONS: HP disorders occur frequently in patients receiving high-dose RT and are related to physical and neurocognitive well-being. Future studies are needed to assess whether further optimization of endocrine management yields better health outcomes.

A theoretical exploration of therapeutic monomania as a physician-based instrumental variable.

PURPOSE: To explore the utility of physician prescribing preference as an instrumental variable. METHODS: Expert (non-systematic) review of relevant literature on the appropriate selection of instrumental variables and theoretical exploration of individual physician and physician group prescriber preference. RESULTS: An instrumental variable must satisfy three criteria: (1) It must predict the treatment received (strength of the instrument); (2) it cannot influence the outcome other that through the treatment received (exclusion restriction); and (3) it cannot be influenced by any factor that also influences the outcome (independence assumption). Arguments in favor of prescriber preference as an instrumental variable and suggestions for how to approach specific scenarios that may be encountered are offered. CONCLUSIONS: Prescriber preference, be it of individual physicians or groups of physicians, may, under the right conditions, be powerful instrumental variables. Empiric experimental data are required to determine the appropriateness of combining propensity matching and instrumental variable analysis.

Long-Term Risk of Cardiovascular Disease in Women Who Have Had Infants With Heart Defects.

BACKGROUND: The possibility that congenital heart defects signal a familial predisposition to cardiovascular disease has not been investigated. We aimed to determine whether the risk of cardiovascular disorders later in life was higher for women who have had newborns with congenital heart defects. METHODS: We studied a cohort of 1 084 251 women who had delivered infants between 1989 and 2013 in Quebec, Canada. We identified women whose infants had critical, noncritical, or no heart defects, and tracked the women over time for future hospitalizations for cardiovascular disease, with follow-up extending up to 25 years past pregnancy. We calculated the incidence of cardiovascular hospitalization per 1000 person-years, and used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) for the association between infant heart defects and risk of maternal cardiovascular hospitalization. Models were adjusted for age, parity, preeclampsia, comorbidity, material deprivation, and time period. RESULTS: Women whose infants had heart defects had a higher overall incidence of cardiovascular hospitalization. There were 3.38 cardiovascular hospitalizations per 1000 person-years for those with critical defects (95% CI, 2.67-4.27), 3.19 for noncritical defects (95% CI, 2.96-3.45), and 2.42 for no heart defects (95% CI, 2.39-2.44). In comparison with no heart defects, women whose infants had critical defects had a hazard ratio of 1.43 (95% CI, 1.13-1.82) for any cardiovascular hospitalization, and women whose infants had noncritical defects had a hazard ratio of 1.24 (95% CI, 1.15-1.34), in adjusted models. Risks of specific causes of cardiovascular hospitalization, including myocardial infarction, heart failure, and other atherosclerotic disorders, were also greater for mothers of infants with congenital heart defects than with no defects. CONCLUSIONS: Women whose infants have congenital heart defects have a greater risk of cardiovascular hospitalization later in life. Congenital heart defects in offspring may be an early marker of predisposition to cardiovascular disease.