Risk of Long-Term Ischemic Stroke in Patients With Traumatic Brain Injury and Incident Hypertension.

Traumatic brain injury (TBI) is independently associated with hypertension and ischemic stroke. The goal of this study was to determine the interplay between TBI and incident hypertension in the occurrence of post-TBI stroke. This prospective study used a hospital-based registry to identify patients without pre-existing comorbidities. TBI patients (n = 3664) were frequency matched on age, sex, and race to non-TBI patients (n = 1848). Follow-up started 6 months post-TBI or study entry and extended up to 10 years. To examine hypertension's role in post-TBI stroke, we used logistic regression models to calculate the effect estimates for stroke in four exposure categories that included TBI or hypertension in isolation and in combination. Second, we calculated the conditional direct effect (CDE) of TBI in models that considered hypertension as intermediary. Third, we examined whether TBI effect was modified by antihypertensive medication use. The 10-year cumulative incidence of stroke was higher in the TBI group (4.7%) than the non-TBI group (1.3%; p < 0.001). TBI patients who developed hypertension had the highest risk of stroke (odds ratio [OR] = 4.83, 95% confidence interval [CI] = 2.53-9.23, p < 0.001). The combined effect estimates were less than additive, suggesting an overlapping biological pathway. The total effect of TBI (OR = 3.16, 95% CI = 1.94-5.16, p < 0.001) was higher than the CDE that accounted for hypertension (OR = 2.45, 95% CI = 0.93-6.47, p = 0.06). Antihypertensives attenuated the TBI effect, suggesting that the TBI effect on stroke is partially mediated through hypertension. TBI is an independent risk factor for long-term stroke, and the underlying biological pathway may partly operate through TBI-precipitated hypertension. These findings suggest that screening for hypertension may mitigate stroke risk in TBI.

Medication use and risk of amyotrophic lateral sclerosis: using machine learning for an exposome-wide screen of a large clinical database.

BACKGROUND: Accumulating evidence suggests that non-genetic factors have important etiologic roles in amyotrophic lateral sclerosis (ALS), yet identification of specific culprit factors has been challenging. Many medications target biological pathways implicated in ALS pathogenesis, and screening large pharmacologic datasets for signals could greatly accelerate the identification of risk-modulating pharmacologic factors for ALS. METHOD: We conducted a high-dimensional screening of patients' history of medication use and ALS risk using an advanced machine learning approach based on gradient-boosted decision trees coupled with Bayesian model optimization and repeated data sampling. Clinical and medication dispensing data were obtained from a large Israeli health fund for 501 ALS cases and 4,998 matched controls using a lag period of 3 or 5 years prior to ALS diagnosis for ascertaining medication exposure. RESULTS: Of over 1,000 different medication classes, we identified 8 classes that were consistently associated with increased ALS risk across independently trained models, where most are indicated for control of symptoms implicated in ALS. Some suggestive protective effects were also observed, notably for vitamin E. DISCUSSION: Our results indicate that use of certain medications well before the typically recognized prodromal period was associated with ALS risk. This could result because these medications increase ALS risk or could indicate that ALS symptoms can manifest well before suggested prodromal periods. The results also provide further evidence that vitamin E may be a protective factor for ALS. Targeted studies should be performed to elucidate the possible pathophysiological mechanisms while providing insights for therapeutics design.

Adolescent Body Mass Index and Early Chronic Kidney Disease in Young Adulthood.

Importance: Despite increasing obesity rates in adolescents, data regarding early kidney sequelae are lacking. Objective: To assess the association between adolescent body mass index (BMI) and early chronic kidney disease (CKD) in young adulthood (<45 years of age). Design, Setting, and Participants: This cohort study linked screening data of mandatory medical assessments of Israeli adolescents to data from a CKD registry of a national health care system. Adolescents who were aged 16 to 20 years; born since January 1, 1975; medically evaluated for mandatory military service through December 31, 2019; and insured by Maccabi Healthcare Services were assessed. Individuals with kidney pathology, albuminuria, hypertension, dysglycemia, or missing blood pressure or BMI data were excluded. Body mass index was calculated as weight in kilograms divided by height in meters squared and categorized by age- and sex-matched percentiles according to the US Centers for Disease Control and Prevention. Follow-up started at the time of medical evaluation or January 1, 2000 (whichever came last), and ended at early CKD onset, death, the last day insured, or August 23, 2020 (whichever came first). Data analysis was performed from December 19, 2021, to September 11, 2023. Main Outcomes and Measures: Early CKD, defined as stage 1 to 2 CKD by moderately or severely increased albuminuria, with an estimated glomerular filtration rate of 60 mL/min/1.73 m2 or higher. Results: Of 629 168 adolescents evaluated, 593 660 (mean [SD] age at study entry, 17.2 [0.5] years; 323 293 [54.5%] male, 270 367 [45.5%] female) were included in the analysis. During a mean (SD) follow-up of 13.4 (5.5) years for males and 13.4 (5.6) years for females, 1963 adolescents (0.3%) developed early CKD. Among males, the adjusted hazard ratios were 1.8 (95% CI, 1.5-2.2) for adolescents with high-normal BMI, 4.0 (95% CI, 3.3-5.0) for those with overweight, 6.7 (95% CI, 5.4-8.4) for those with mild obesity, and 9.4 (95% CI, 6.6-13.5) for those with severe obesity. Among females, the hazard ratios were 1.4 (95% CI, 1.2-1.6) for those with high-normal BMI, 2.3 (95% CI, 1.9-2.8) for those with overweight, 2.7 (95% CI, 2.1-3.6) for those with mild obesity, and 4.3 (95% CI, 2.8-6.5) for those with severe obesity. The results were similar when the cohort was limited to individuals who were seemingly healthy as adolescents, individuals surveyed up to 30 years of age, or those free of diabetes and hypertension at the end of the follow-up. Conclusions and Relevance: In this cohort study, high BMI in late adolescence was associated with early CKD in young adulthood. The risk was also present in seemingly healthy individuals with high-normal BMI and before 30 years of age, and a greater risk was seen among those with severe obesity. These findings underscore the importance of mitigating adolescent obesity rates and managing risk factors for kidney disease in adolescents with high BMI.

Safety of GLP-1 Receptor Agonists and Other Second-Line Antidiabetics in Early Pregnancy.

Importance: Increasing use of second-line noninsulin antidiabetic medication (ADM) in pregnant individuals with type 2 diabetes (T2D) may result in fetal exposure, but their teratogenic risk is unknown. Objective: To evaluate periconceptional use of second-line noninsulin ADMs and whether it is associated with increased risk of major congenital malformations (MCMs) in the infant. Design, Setting, and Participants: This observational population-based cohort study used data from 4 Nordic countries (2009-2020), the US MarketScan Database (2012-2021), and the Israeli Maccabi Health Services database (2009-2020). Pregnant women with T2D were identified and their live-born infants were followed until up to 1 year after birth. Exposure: Periconceptional exposure was defined as 1 or more prescription fill of sulfonylureas, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors, or insulin (active comparator) from 90 days before pregnancy to end of first trimester. Main Outcomes and Measures: Relative risks (RRs) and 95% CIs for MCMs were estimated using log-binomial regression models, adjusting for key confounders in each cohort and meta-analyzed. Results: Periconceptional exposure to second-line noninsulin ADMs differed between countries (32, 295, and 73 per 100 000 pregnancies in the Nordics, US, and Israel, respectively), and increased over the study period, especially in the US. The standardized prevalence of MCMs was 3.7% in all infants (n = 3 514 865), 5.3% in the infants born to women with T2D (n = 51 826), and among infants exposed to sulfonylureas was 9.7% (n = 1362); DPP-4 inhibitors, 6.1% (n = 687); GLP-1 receptor agonists, 8.3% (n = 938); SGLT2 inhibitors, 7.0% (n = 335); and insulin, 7.8% (n = 5078). Compared with insulin, adjusted RRs for MCMs were 1.18 (95% CI, 0.94-1.48), 0.83 (95% CI, 0.64-1.06), 0.95 (95% CI, 0.72-1.26), and 0.98 (95% CI, 0.65-1.46) for infants exposed to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT2 inhibitors, respectively. Conclusions and Relevance: Use of second-line noninsulin ADMs is rapidly increasing for treatment of T2D and other indications, resulting in an increasing number of exposed pregnancies. Although some estimates were imprecise, results did not indicate a large increased risk of MCMs above the risk conferred by maternal T2D requiring second-line treatment. Although reassuring, confirmation from other studies is needed, and continuous monitoring will provide more precise estimates as data accumulate.

Pharmaceutical Agents as Potential Drivers in the Development of Early-Onset Colorectal Cancer: Case-Control Study.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used. OBJECTIVE: We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC. METHODS: We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model. RESULTS: Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk. CONCLUSIONS: Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined.

Association between ambient particulate matter and preterm birth stratified by temperature: A population-based pregnancy cohort study.

A growing body of literature reports associations between exposure to particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5) and 2.5-10 µm (PM10-2.5) during pregnancy and preterm birth (PTB). However, the role of ambient temperature in PM-PTB associations was rarely investigated. In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM and ambient temperature predictions from a satellite-based spatiotemporal model, at a 1 × 1 km spatial resolution, were linked to the date of birth and maternal residence. Mixed effects Cox regression models, adjusted for covariates, with a random intercept at the mother level were used to assess associations between mean exposure during pregnancy and PTB. We found that exposure to PM2.5 was positively associated with PTB when the average exposure during pregnancy was either low (first quintile) or high (fifth quintile), compared to exposure in the 2nd-4th quintiles, with hazard ratios (HRs) 1.18 (95% confidence interval [CI], 1.13-1.24) and 1.07 (95% CI, 1.02-1.12), respectively. The results revealed effect modification of temperature. For mothers exposed to low (below median) average temperature during pregnancy, HRs of PTB were 0.93 (95% CI, 0.87-1.00) and 1.21 (95% CI, 1.14-1.29) for the first and fifth PM2.5 quintiles, respectively, when compared to the 2nd-4th quintiles. However, a reverse trend was indicated for high-temperature pregnancies, where the corresponding HRs were 1.48 (95% CI, 1.39-1.58) and 0.92, (95% CI, 0.96-0.98). In conclusion, consideration of climatic factors can provide new insights into the risk of PTB as a result of exposure to PM2.5 during pregnancy.

Glucose intolerance in pregnancy and risk of early-onset type 2 diabetes: a population-based cohort study.

BACKGROUND: The risk of type 2 diabetes among women with glucose intolerance during pregnancy that does not meet gestational diabetes criteria requires further investigation. We aimed to explore the associations between various degrees of gestational glucose intolerance and the risk of type 2 diabetes in young adulthood. METHODS: For this population-based cohort study, the national Israeli conscription database was linked to Maccabi Healthcare Services (MHS), the second-largest state-mandated health provider in Israel. We included 177 241 women who underwent a pre-recruitment evaluation at adolescence (age 16-20 years), 1 year before mandatory military service, and later underwent, from Jan 1, 2001, to Dec 31, 2019, two-step gestational diabetes screening with a 50 g glucose challenge test (GCT) based on a threshold of 140 mg/dL (7·8 mmol/L), followed as needed by a 100 g oral glucose tolerance test (OGTT). Abnormal OGTT values were defined according to the Carpenter-Coustan thresholds: 95 mg/dL (5·3 mmol/L) or higher in the fasting state; 180 mg/dL (10·0 mmol/L) or higher at 1 h; 155 mg/dL (8·6 mmol/L) or higher at 2 h; and 140 mg/dL (7·8 mmol/L) or higher at 3 h. The primary outcome was incident type 2 diabetes in the MHS diabetes registry. Cox proportional hazards models were applied to estimate adjusted hazard ratios (HRs) with 95% CIs for incident type 2 diabetes. FINDINGS: During a cumulative follow-up of 1 882 647 person-years, and with a median follow-up of 10·8 (IQR 5·2-16·4) years, 1262 women were diagnosed with type 2 diabetes. Crude incidence rates of type 2 diabetes were 2·6 (95% CI 2·4-2·9) per 10 000 person-years in women with gestational normoglycaemia, 8·9 (7·4-10·6) per 10 000 person-years in women with an abnormal GCT and normal OGTT, 26·1 (22·4-30·1) per 10 000 person-years in women with one abnormal OGTT value (in the fasting state or 1 h, 2 h, or 3 h post-challenge), and 71·9 (66·0-78·3) per 10 000 person-years in women with gestational diabetes. After adjustment for sociodemographic characteristics, adolescent BMI, and age at gestational screening, the risk of type 2 diabetes was higher, compared to the gestational normoglycaemia group, in women with an abnormal GCT and normal OGTT (adjusted hazard ratio [HR] 3·39 [95% CI 2·77-4·16]; p<0·0001), in women with one abnormal OGTT value (9·11 [7·64-10·86]; p<0·0001), and in women with gestational diabetes (24·84 [21·78-28·34]; p<0·0001). The risk of type 2 diabetes was modestly increased in women with isolated elevated fasting glucose (adjusted HR 11·81 [95% CI 8·58-16·25]; p<0·0001), and in women with gestational diabetes and an abnormal fasting glucose (38·02 [32·41-44·61]; p<0·0001). INTERPRETATION: Gestational glucose intolerance, including conditions not meeting gestational diabetes criteria of the two-step strategy, confers a high risk of type 2 diabetes in young adulthood. These conditions should be recognised as risk factors for type 2 diabetes, especially among women with abnormal fasting glucose concentrations during pregnancy. FUNDING: None.

Maternal exposure to particulate matter early in pregnancy and congenital anomalies in offspring: Analysis of concentration-response relationships in a population-based cohort with follow-up throughout childhood.

Studies have suggested an association between particulate matter (PM) air pollution and certain congenital anomalies (CAs). However, most studies assumed a linear concentration-response relation and were based on anomalies that were ascertained at birth or up to 1 year of age. We investigated associations between exposures to PM during the first trimester of pregnancy and CAs in 9 organ systems using birth and childhood follow-up data from a leading health care provider in Israel. We conducted a retrospective population-based cohort study among 396,334 births, 2004-2015. Daily PM data at a 1 × 1 km spatial grid were obtained from a satellite-derived prediction models and were linked to the mothers' residential addresses at birth. Adjusted odds ratios (ORs) were estimated with logistic regression models using exposure levels as either continuous or categorical variables. We captured 57,638 isolated CAs with estimated prevalence of 96 and 136 anomalies per 1000 births in the first year of life and by age 6 years, respectively. Analysis of continuous PM with diameter < 2.5 µm (PM2.5) indicated a supra-linear relation with anomalies in the circulatory, respiratory, digestive, genital and integument systems (79 % of CAs). The slope of the concentration-response function was positive and steepest for PM2.5 lower than the median concentration (21.5 µg/m3) and had a less steep or negative slope at higher levels. Similar trends were observed for PM2.5 quartiles. For example, for cardiac anomalies, the ORs were 1.09 (95 % confidence interval: 1.02, 1.15), 1.04 (0.98, 1.10) and 1.00 (0.94, 1.07) for births in the second, third and fourth quartiles, respectively, when compared to the first quartile. In sum, this study adds new evidence for adverse effects of air pollution on neonatal health even with low-level air pollution. Information on late diagnosis of children with anomalies is important in evaluating the burden of disease.

Late diagnosis of autism spectrum disorder-Journey, parents' concerns, and sex influences.

Despite increasing awareness for diagnosing autism spectrum disorder (ASD) and initiating treatments early in life, many children and adolescents continue to be diagnosed at a relatively older age. Focusing on children who first received an ASD diagnosis at age six or older, this study aimed to describe the symptoms that parents reported when ASD was diagnosed, follow the patients' clinical trajectory prior to receiving the diagnosis, and describe differences in symptoms and prior diagnoses between males and females cases. We included 258 children (205 males and 53 females) who were first diagnosed with autism at age 6-18 in 2017-2018. We retrieved demographic information, neurologic and developmental symptoms, diagnoses, and medications dispensing history from the children's electronic medical charts. The data indicated that prior diagnoses of language delays and attention deficit hyperactivity disorder were common among children with a late ASD diagnosis. Two thirds of the children were prescribed one or more medications to treat psychosocial and behavioral conditions before receiving a late ASD diagnosis. Difficulties in social relationships with peers were the leading reported symptoms by parents at the time of ASD diagnosis. Across these different domains, some differences were found between males and females, including a somewhat higher cognitive level in males, who were also more likely to present aggressive behavior.

Glucose Intolerance in Pregnancy and Offspring Obesity in Late Adolescence.

OBJECTIVE: Gestational hyperglycemia is associated with deleterious neonatal outcomes, but long-term risks for offspring obesity are less clear. We estimated the odds for offspring adolescent overweight and obesity among mothers with gestational glucose intolerance. RESEARCH DESIGN AND METHODS: In a mother-offspring historical cohort, the Israel military conscription data set was linked to a large health maintenance organization. Included were women who were evaluated at adolescence and underwent two-step gestational diabetes screening (mean age, 31 years) with a 50-g glucose challenge test (GCT), followed by a 100-g oral glucose tolerance test (OGTT) if the result was abnormal. Glucose tolerance categories included gestational normoglycemia, abnormal GCT with normal OGTT, impaired glucose tolerance (IGT; one abnormal OGTT value), and gestational diabetes. The primary outcome was offspring overweight/obesity (BMI ≥85th percentile) at adolescence, measured prior to military conscription. Logistic regression models were applied. RESULTS: Of 33,482 mother-offspring pairs, overweight and obesity were observed in 6,516 offspring. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25% (P < 0.0001). Corresponding odds ratios after adjustment for the mother's late adolescent characteristics (sociodemographic confounders and BMI) and pregnancy age were 1.2 (95% CI 1.1-1.4), 1.3 (1.2-1.5), and 1.4 (1.3-1.6), respectively. Further adjustment for offspring birth weight percentile and sociodemographic variables did not materially change results. Associations were more pronounced with increasing obesity severity. CONCLUSIONS: Gestational glucose intolerance, including categories not meeting the gestational diabetes threshold, was associated with increased odds for offspring overweight/obesity at late adolescence.

Adolescent Blood Pressure and the Risk for Early Kidney Damage in Young Adulthood.

BACKGROUND: Recent guidelines classified blood pressure above 130/80 mm Hg as hypertension. However, outcome data were lacking. OBJECTIVE: To determine the association between blood pressure in adolescence and the risk for early kidney damage in young adulthood. METHODS: In this nationwide cohort study, we included 629 168 adolescents aged 16 to 20 who underwent medical examinations before mandatory military service in Israel. We excluded 30 466 adolescents with kidney pathology, hypertension, or missing blood pressure or anthropometric data at study entry. Blood pressure measurements at study entry were categorized according to the Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents: group A (<120/<80 mm Hg; Reference group), group B (120/<80-129/<80 mm Hg), group C (130/80-139/89 mm Hg), and group D (≥140/90 mm Hg). Early kidney damage in young adulthood was defined as albuminuria of ≥30 mg/g with an estimated glomerular filtration rate of 60 mL/(min·1.73 m2) or over. RESULTS: Of 598 702 adolescents (54% men), 2004 (0.3%) developed early kidney damage during a mean follow-up of 15.1 (7.2) years. The adjusted hazard ratios for early kidney damage in blood pressure group C were 1.17 (1.03-1.32) and 1.51 (1.22-1.86) among adolescents with lean (body mass index <85th percentile) and high body mass index (body mass index ≥85th percentile), respectively. Corresponding hazard ratios for kidney disease in group D were 1.49 (1.15-1.93) and 1.79 (1.35-2.38) among adolescents with lean and high body mass index, respectively. CONCLUSIONS: Blood pressure of ≥130/80 mm Hg was associated with early kidney damage in young adulthood, especially in adolescents with overweight and obesity.

Mother-level random effect in the association between PM2.5 and fetal growth: A population-based pregnancy cohort.

BACKGROUND: A growing body of literature reports associations between exposure to particulate matter with diameter ≤2.5 µm (PM2.5) during pregnancy and birth outcomes. However, findings are inconsistent across studies. OBJECTIVES: To assess the association between PM2.5 and birth outcomes of fetal growth in a cohort with high prevalence of siblings by multilevel models accounting for geographical- and mother-level correlations. METHODS: In Israel, we used Maccabi Healthcare Services data to establish a population-based cohort of 381,265 singleton births reaching 24-42 weeks' gestation and birth weight of 500-5000 g (2004-2015). Daily PM2.5 predictions from a satellite-based spatiotemporal model were linked to the date of birth and maternal residence. We generated mean PM2.5 values for the entire pregnancy and for exposure periods during pregnancy. Associations between exposure and birth outcomes were modeled by using multilevel logistic regression with random effects for maternal locality of residence, administrative census area (ACA) and mother. RESULTS: In fully adjusted models with a mother-level random intercept only, a 10-µg/m3 increase in PM2.5 over the entire pregnancy was positively associated with term low birth weight (TLBW) (Odds ratio, OR = 1.25, 95% confidence interval, CI: 1.09,1.43) and small for gestational age (SGA) (OR = 1.15, 95% CI: 1.06,1.26). Locality- and ACA-level effects accounted for <0.4% of the variance while mother-level effects explained ∼50% of the variability. Associations varied by exposure period, infants' sex, birth order, and maternal pre-pregnancy BMI. CONCLUSIONS: Consideration of mother-level variability in a region with high fertility rates provides new insights on the strength of associations between PM2.5 and birth outcomes.

The Effectiveness of the Two-Dose BNT162b2 Vaccine: Analysis of Real-World Data.

BACKGROUND: Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were shown to be highly efficacious in preventing the disease in randomized controlled trials; nonetheless, evidence on the real-world effectiveness of this vaccine is limited. Study objective was to evaluate the effectiveness of BNT162b2 vaccine in preventing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19-related hospitalization and mortality. METHODS: This historical cohort study included members of a large health provider in Israel that were vaccinated with at least 1 dose of BNT162b2. The primary outcome was incidence rate of a SARS-CoV-2 infection confirmed with real-time polymerase chain reaction (rt-PCR), between 7 and 27 days after second dose (protection-period), as compared to days 1-7 after the first dose, where no protection by the vaccine is assumed (reference-period). RESULTS: Data of 1 178 597 individuals vaccinated with BNT162b2 were analyzed (mean age 47.7 years [SD = 18.1], 48.4% males) of whom 872 454 (74.0%) reached the protection period. Overall, 4514 infections occurred during the reference period compared to 728 during the protection period, yielding a weighted mean daily incidence of 54.8 per 100 000 (95% confidence interval [CI]: 26.1-115.0 per 100 000) and 5.4 per 100 000 (95% CI: 3.5-8.4 per 100 000), respectively. The vaccine effectiveness in preventing infection was 90% (95% CI: 79%-95%) and 94% (95% CI: 88%-97%) against COVID-19. Among immunosuppressed patients, vaccine effectiveness against infection was 71% (95% CI: 37%-87%). The adjusted hazard ratios for hospitalization in those infected were 0.82 (95% CI: .36-1.88), 0.45 (95% CI: .23-.90), and 0.56 (95% CI: .36-.89) in the age groups 16-44, 45-64. and ≥75 years, respectively. CONCLUSIONS: The effectiveness of the BNT162b2 vaccine is comparable to the one reported in the phase III clinical trial.

On the Nature of Informative Presence Bias in Analyses of Electronic Health Records.

Electronic health records (EHRs) offer unprecedented opportunities to answer epidemiologic questions. However, unlike in ordinary cohort studies or randomized trials, EHR data are collected somewhat idiosyncratically. In particular, patients who have more contact with the medical system have more opportunities to receive diagnoses, which are then recorded in their EHRs. The goal of this article is to shed light on the nature and scope of this phenomenon, known as informative presence, which can bias estimates of associations. We show how this can be characterized as an instance of misclassification bias. As a consequence, we show that informative presence bias can occur in a broader range of settings than previously thought, and that simple adjustment for the number of visits as a confounder may not fully correct for bias. Additionally, where previous work has considered only underdiagnosis, investigators are often concerned about overdiagnosis; we show how this changes the settings in which bias manifests. We report on a comprehensive series of simulations to shed light on when to expect informative presence bias, how it can be mitigated in some cases, and cases in which new methods need to be developed.

Maternal Thyroid Anomalies and Attention-Deficit Hyperactivity Disorder in Progeny.

Previous epidemiologic investigations suggested that maternal thyroid anomalies are a possible causal factor in attention-deficit hyperactivity disorder (ADHD) in progeny, yet clinical trials indicated that levothyroxine treatment was ineffective in preventing neurodevelopmental impairments. We used an Israeli cohort of 385,542 singleton births from 1999-2012 to explore the interrelated roles of maternal thyroid conditions, laboratory gestational thyroid hormone measurements, use of thyroid medications, and offspring ADHD. Analyses were performed using Cox proportional hazards models. Results indicated that maternal hypothyroidism diagnosis was associated with an elevated progeny ADHD hazard (adjusted hazard ratio = 1.14, 95% confidence interval = 1.10, 1.18). However, this association was unmitigated by gestational use of levothyroxine and was unexplained by maternal gestational thyroid hormone levels. Associations with gestational thyrotropin values and hypothyroxinemia were also observed but were robust only in mothers without other records indicative of a thyroid problem. Results indicated that maternal thyroid hypofunction was associated with progeny ADHD but possibly not due to a direct causal relationship. Instead, maternal thyroid hypofunction may serve as a proxy indicator for other factors that affect neurodevelopment through thyroid hormone independent pathways, which are thus unaffected by pharmaceutical treatments for thyroid hypofunction. Factors known to disrupt thyroid functioning should be examined for their independent ADHD-related effects.

Adolescent body mass index and changes in pre-pregnancy body mass index in relation to risk of gestational diabetes.

BACKGROUND: Pregestational excessive body mass index (BMI) is linked to an increased risk for gestational diabetes mellitus (GDM), but less is known on the effect of adolescent BMI on GDM occurrence. The study aimed to investigate possible associations of adolescent BMI and changes in BMI experienced before first pregnancy, with gestational diabetes risk. METHODS: This retrospective study was based on linkage of a military screening database of adolescent health status (Israel Defence Forces) including measured height and weight, with medical records (Maccabi Healthcare Services, MHS) of a state-mandated health provider. The latter covers about 25% of the Israeli population; about 90% of pregnant women undergo screening by the two-step Carpenter-Coustan method. Adolescent BMI was categorized according to Center of Disease Control and Prevention percentiles. Only first documented pregnanies were analyzed and GDM was the outcome. FINDINGS: Of 190,905 nulliparous women, 10,265 (5.4%) developed GDM. Incidence proportions of GDM were 5.1%, 6.1%, 7.3%, and 8.9% among women with adolescent normal BMI, underweight, overweight, and obesity (p<0.001), respectively. In models that accounted for age at pregnancy, birth year, and sociodemographic variables, the adjusted odd ratios (aORs) for developing GDM were: 1.2 (95%CI, 1.1-1.3), 1.5 (1.4-1.6), and 1.9 (1.7-2.1) for adolescent underweight, overweight, and obesity (reference group, normal BMI). Adolescent BMI tracked with BMI notes in the pre-pregnancy period (r=63%). Resuming normal pre-pregnancy BMI from overweight or obesity in adolescence diminished GDM risk, but this diminished risk was not observed among those who returned to a normal per-pre-pregnancy BMI from being underweight in adolescence. Sustained overweight or obesity conferred an aOR for developing GDM of 2.5 (2.2-2.7); weight gain from adolescent underweight and normal BMI to pre-pregnancy excessive BMI conferred aORs of 3.1 (1.6-6.2) and 2.6 (2.2-2.7), respectively. INTERPRETATION: Change in BMI status from adolescence to pre-pregnancy may contribute to GDM risk. Identifying at-risk populations is important for early preventive interventions. FUNDING: None.

Association Between BNT162b2 Vaccination and Incidence of SARS-CoV-2 Infection in Pregnant Women.

Importance: Data on BNT162b2 messenger RNA (mRNA) vaccine (Pfizer-BioNTech) effectiveness and safety in pregnancy are currently lacking because pregnant women were excluded from the phase 3 trial. Objective: To assess the association between receipt of BNT162b2 mRNA vaccine and risk of SARS-CoV-2 infection among pregnant women. Design, Setting, and Participants: This was a retrospective cohort study within the pregnancy registry of a large state-mandated health care organization in Israel. Pregnant women vaccinated with a first dose from December 19, 2020, through February 28, 2021, were 1:1 matched to unvaccinated women by age, gestational age, residential area, population subgroup, parity, and influenza immunization status. Follow-up ended on April 11, 2021. Exposures: Exposure was defined by receipt of the BNT162b2 mRNA vaccine. To maintain comparability, nonexposed women who were subsequently vaccinated were censored 10 days after their exposure, along with their matched pair. Main Outcomes and Measures: The primary outcome was polymerase chain reaction-validated SARS-CoV-2 infection at 28 days or more after the first vaccine dose. Results: The cohort included 7530 vaccinated and 7530 matched unvaccinated women, 46% and 33% in the second and third trimester, respectively, with a mean age of 31.1 years (SD, 4.9 years). The median follow-up for the primary outcome was 37 days (interquartile range, 21-54 days; range, 0-70). There were 118 SARS-CoV-2 infections in the vaccinated group and 202 in the unvaccinated group. Among infected women, 88 of 105 (83.8%) were symptomatic in the vaccinated group vs 149 of 179 (83.2%) in the unvaccinated group (P ≥ .99). During 28 to 70 days of follow-up, there were 10 infections in the vaccinated group and 46 in the unvaccinated group. The hazards of infection were 0.33% vs 1.64% in the vaccinated and unvaccinated groups, respectively, representing an absolute difference of 1.31% (95% CI, 0.89%-1.74%), with an adjusted hazard ratio of 0.22 (95% CI, 0.11-0.43). Vaccine-related adverse events were reported by 68 patients; none was severe. The most commonly reported symptoms were headache (n = 10, 0.1%), general weakness (n = 8, 0.1%), nonspecified pain (n = 6, <0.1%), and stomachache (n = 5, <0.1%). Conclusions and Relevance: In this retrospective cohort study of pregnant women, BNT162b2 mRNA vaccination compared with no vaccination was associated with a significantly lower risk of SARS-CoV-2 infection. Interpretation of study findings is limited by the observational design.

Body Mass Index in 1.9 Million Adolescents and Stroke in Young Adulthood.

Background and Purpose: There is a continuous rise in the prevalence of adolescent obesity and incidence of stroke among young adults in many Western countries, but the association between them is unclear. Methods: A nationwide population-based study of 1 900 384 Israeli adolescents (58% men; mean age, 17.3 years) who were evaluated before mandatory military service during 1985 and 2013. Body mass index was classified according to the US Center for Disease Control and Prevention percentiles. Primary outcome was a first stroke event as recorded by the Israeli National Stroke Registry between 2014 and 2018. Cox proportional hazard models were applied. Results: There were 1088 first stroke events (921 ischemic and 167 hemorrhagic; mean diagnosis age, 41.0 years). Adolescent body mass index was significantly associated with a graded increase in the risk for any stroke, ischemic stroke, but less so with hemorrhagic stroke. The hazard ratios for the first ischemic stroke event were 1.4 (95% CI, 1.2­1.6), 2.0 (95% CI, 1.6­2.4), and 3.4 (95% CI, 2.7­4.3) for the 50th to 84th percentile, overweight and obese groups, respectively, after adjustment for sex, age, and sociodemographic confounders with the 5th to 49th body mass index percentile group as the reference. The respective hazard ratios after further adjustment for diabetes status were 1.3 (1.1­1.5), 1.6 (1.3­2.0), and 2.4 (1.9­3.1). Results persisted when the cohort was divided by diabetes status and when ischemic stroke before age 30 was the outcome. Conclusions: High adolescent body mass index was associated with ischemic stroke in young adults with or without diabetes. The rising prevalence of adolescent obesity may increase the future burden of stroke in young adults.

Diagnosis despite clinical ambiguity: physicians' perspectives on the rise in Autism Spectrum disorder incidence.

BACKGROUND: To provide insight on physicians' perspectives concerning recent changes in the incidence and diagnostic process of Autism Spectrum Disorder (ASD) compared to other mental and neurodevelopmental disorders. METHOD: A questionnaire was sent to 191 specialists in child neurology and child development, and 200 child psychiatrists in Israel. Information was collected on professional background, as well as on physicians' opinions concerning the accuracy and rate of ASD diagnosis compared to that of cerebral palsy (CP), mental illness, and Attention Deficit Hyperactivity Disorder (ADHD). For each closed-ended question, a global chi-square test for categorical variables was performed. RESULTS: 115 (60.2%) of specialists in child neurology and development, and 59 (29.5%) of child psychiatrists responded. Most physicians (67.2%) indicated that there was a moderate/significant increase in the incidence of ASD, which was higher than similar responses provided for CP (2.9%, p < 0.01) and mental illnesses (14.4%, p < 0.01), and similar to responses provided for ADHD (70.1%, p = 0.56). 52.8% of physicians believed that in more than 10% of clinical assessments, an ASD diagnosis was given despite an inconclusive evaluation (CP: 8.6%, p < 0.01; mental illnesses: 25.8%, p = 0.03; ADHD: 68.4%, p = 0.03). CONCLUSION: The clinicians perceive both ASD and ADHD as over-diagnosed disorders. The shared symptomology between ASD and other disorders, coupled with heightened awareness and public de-stigmatization of ASD and with the availability of ASD-specific services that are not accessible to children diagnosed with other conditions, might lead clinicians to over-diagnose ASD. It is advisable to adopt an approach in which eligibility for treatments is conditional on function, rather than solely on a diagnosis. The medical community should strive for accurate diagnoses and a continuous review of diagnostic criteria.

Associations of Maternal Androgen-Related Conditions With Risk of Autism Spectrum Disorder in Progeny and Mediation by Cardiovascular, Metabolic, and Fertility Factors.

Fetal exposure to elevated androgens is thought to contribute to autism spectrum disorder (ASD) risk. However, data rely heavily on in utero androgens measurements, which also reflect fetal secretions. Thus, in utero hyperandrogenemia might indicate adverse autism-related neurogenesis that has already occurred affecting fetal androgen homeostasis, rather than being a cause of the disorder. Associations between maternal androgen-related conditions and ASD could more directly implicate androgens' etiological role. We examined the association between maternal hyperandrogenemia-related conditions, focusing primarily on polycystic ovarian syndrome (PCOS), and progeny ASD, in an Israeli cohort of 437,222 children born in 1999-2013. Odds ratios and 95% confidence intervals were estimated using generalized estimating equations. Multiple mediation analyses using natural effect models were conducted to evaluate combined mediation of the PCOS effect by androgen-related cardiovascular, metabolic, and fertility factors. Results indicated that children of mothers with PCOS had higher ASD odds compared with children of mothers without PCOS (odds ratio = 1.42, 95% confidence interval: 1.24,1.64), and this effect was only partly mediated by the factors considered. Elevated odds were also observed for other hyperandrogenemia-related conditions. Findings provide support for direct involvement of maternal hyperandrogenemia in ASD etiology. Alternatively, findings might reflect shared genetic and/or environmental factors independently affecting maternal androgen homeostasis and fetal neurodevelopment.