Non-osteoporotic fractures are associated with increased risk of subsequent major osteoporotic fractures.

We studied the association between non-osteoporotic fractures and future major osteoporotic fractures, using UK health records. Non-osteoporotic fractures were found to increase the risk of major osteoporotic fractures, although to a lesser extent than osteoporotic fractures. This highlights the importance of considering all previous fractures in assessing future fracture risk. PURPOSE: Previous studies demonstrated that osteoporotic fractures-minor and major-increase the risk for future major osteoporotic fractures; we test whether non-osteoporotic fractures are also associated with such increased risk. METHODS: The study is a retrospective cohort study using UK primary care electronic health records. Exposure groups were defined according to fracture location prior to the year 2011 (index date): major, minor, and non-osteoporotic. The outcome of incident major osteoporotic fractures following the index date was compared between the exposure groups and the general population. RESULTS: The general study population included 1,951,388 patients. The exposure groups included 39,931 patients with a prior major osteoporotic fracture, 19,397 with a prior minor osteoporotic fracture, and 50,115 patients with a prior non-osteoporotic fracture. The standardized Incidence Rate Ratio for future major osteoporotic fractures was 2.73 (95% confidence interval: 2.64-2.82), 2.43 (2.32-2.54), and 1.83 (1.74-1.92), respectively. CONCLUSION: Non-osteoporotic fractures are significantly associated with increased risk for future major osteoporotic fractures relative to the general population, yet to a lesser extent compared to major and minor osteoporotic fractures.

A meta-analysis of previous falls and subsequent fracture risk in cohort studies.

The relationship between self-reported falls and fracture risk was estimated in an international meta-analysis of individual-level data from 46 prospective cohorts. Previous falls were associated with an increased fracture risk in women and men and should be considered as an additional risk factor in the FRAX® algorithm. INTRODUCTION: Previous falls are a well-documented risk factor for subsequent fracture but have not yet been incorporated into the FRAX algorithm. The aim of this study was to evaluate, in an international meta-analysis, the association between previous falls and subsequent fracture risk and its relation to sex, age, duration of follow-up, and bone mineral density (BMD). METHODS: The resource comprised 906,359 women and men (66.9% female) from 46 prospective cohorts. Previous falls were uniformly defined as any fall occurring during the previous year in 43 cohorts; the remaining three cohorts had a different question construct. The association between previous falls and fracture risk (any clinical fracture, osteoporotic fracture, major osteoporotic fracture, and hip fracture) was examined using an extension of the Poisson regression model in each cohort and each sex, followed by random-effects meta-analyses of the weighted beta coefficients. RESULTS: Falls in the past year were reported in 21.4% of individuals. During a follow-up of 9,102,207 person-years, 87,352 fractures occurred of which 19,509 were hip fractures. A previous fall was associated with a significantly increased risk of any clinical fracture both in women (hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.33-1.51) and men (HR 1.53, 95% CI 1.41-1.67). The HRs were of similar magnitude for osteoporotic, major osteoporotic fracture, and hip fracture. Sex significantly modified the association between previous fall and fracture risk, with predictive values being higher in men than in women (e.g., for major osteoporotic fracture, HR 1.53 (95% CI 1.27-1.84) in men vs. HR 1.32 (95% CI 1.20-1.45) in women, P for interaction = 0.013). The HRs associated with previous falls decreased with age in women and with duration of follow-up in men and women for most fracture outcomes. There was no evidence of an interaction between falls and BMD for fracture risk. Subsequent risk for a major osteoporotic fracture increased with each additional previous fall in women and men. CONCLUSIONS: A previous self-reported fall confers an increased risk of fracture that is largely independent of BMD. Previous falls should be considered as an additional risk factor in future iterations of FRAX to improve fracture risk prediction.

Trends and Correlates of Early-Life Exposure to Acid-Suppressant Therapy in Israel (2005-2020).

OBJECTIVES: To describe trends and correlates of acid-suppressant therapy usage during the first year of life. STUDY DESIGN: A population-based cohort in a large state-mandated health fund in Israel, including members born between 2005 and 2020, was conducted. Acid-suppressant therapy initiation was defined by any purchase within the first year of life. The association between acid-suppressant therapy initiation with medical and sociodemographic characteristics was assessed via logistic regression. RESULTS: Among 595 860 children, acid-suppressant therapy was initiated in 22 412 (37.6 per 1000). The incidence rate increased by 2.8-fold from 18.2 per 1000 in 2005 to 51.0 per 1000 in 2020, furthermore the median age at initiation decreased. Primary care providers accounted for 74.8% of prescribing physicians in 2005 vs 96.1% in 2020, whereas the prevalence of prescribing gastroenterologists decreased from 18.8% to 2.8%. Preterm birth and small weight per gestational age were associated with acid-suppressant therapy usage, with an aOR of 4.23 (95% CI 3.59-4.99), 3.05 (95% CI 2.72-3.42), and 1.65 (95% CI 1.58-1.74) for extreme, very, and moderate preterm vs term birth and aOR 1.22 (95% CI 1.16-1.28) for small weight per gestational age. Birth order was inversely associated with acid-suppressant therapy initiation, with aOR 0.62 (95% CI 0.60-0.65) for third born vs firstborns. High socioeconomic status was linearly associated with initiation, with aOR 1.12 (95% CI 1.11-1.12) per 1-point increase on a 10-point score. CONCLUSIONS: Our analysis demonstrates a substantial increase in early life exposure to acid-suppressant therapy during recent years in Israel. Correlates for initiation in early life were identified to define a population for intervention to reduce potential unnecessary use.

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.

Long-Term Follow-Up of Denosumab Discontinuers with Multiple Vertebral Fractures in the Real-World: A Case Series.

Denosumab discontinuation is associated with rapid reversal of bone turnover suppression and with a considerable increase in fracture risk, including a risk for multiple vertebral fractures (MVF). Long-term follow-up of patients who sustained MVF after denosumab discontinuation has not been reported. This case-series was aimed to provide a long-term follow-up on the management and outcome of denosumab discontinuers who initially presented with multiple vertebral fractures. Denosumab discontinuers were identified from a computerized database of a large healthcare provider. Baseline and follow-up clinical, laboratory, and imaging data were obtained from the computerized database and electronic medical records. The post-denosumab discontinuers MVF patients consisted of 12 women aged 71±12. Osteoporotic fractures were prevalent before denosumab discontinuation in 6 of the patients. The majority received bisphosphonates before denosumab. MVF occurred 134±76 days after denosumab discontinuation. The patients were followed for a median of 36.5 (IQR 28.2, 42.5) months after MVF. Two patients passed-away. Two patients suffered recurrent vertebral fractures. Following MVF, patients were treated inconsistently with denosumab, teriparatide, oral, and intravenous bisphosphonates, in various sequences. Two patients underwent vertebroplasty/kyphoplasty. This long-term follow-up of real-world patients with MVF following denosumab discontinuation reveals that management is inconsistent, and recurrent fractures are not uncommon. It calls for clear management guidelines for patients with MVF after denosumab discontinuation and for special attention to this high-risk group.

Bone Mineral Density of the 1/3 Radius Refines Osteoporosis Diagnosis, Correlates With Prevalent Fractures, and Enhances Fracture Risk Estimates.

OBJECTIVE: To investigate the added value of 1/3 radius (1/3R) for the diagnosis of osteoporosis by spine and hip sites and its correlation with prevalent fractures and predicted fracture risk. METHODS: Fracture Risk Assessment Tool (FRAX) scores for hip and major osteoporotic fractures (MOF) with/without trabecular bone score were considered proxy for fracture risk. The contribution of 1/3R to risk prediction was depicted via linear regression models with FRAX score as the dependent variable-first only with central and then with radius T-score as an additional covariate. Significance of change in the explained variance was compared by F-test. RESULTS: The study included 1453 patients, 86% women, aged 66 ± 10 years. A total of 32% (n = 471) were osteoporotic by spine/hip and 8% (n = 115) by radius only, constituting a 24.4% increase in the number of subjects defined as osteoporotic (n = 586, 40%). Prior fracture prevalence was similar among patients with osteoporosis by spine/hip (17.4%) and radius only (19.1%) (P = .77). FRAX prediction by a regression model using spine/hip T-score yielded explained variance of 51.8% and 49.9% for MOF and 39.8% and 36.4% for hip (with/without trabecular bone score adjustment, respectively). The contribution of 1/3R was statistically significant (P < .001) and slightly increased the explained variance to 52.3% and 50.4% for MOF and 40.9% and 37.4% for hip, respectively. CONCLUSION: Reclassification of BMD results according to radius measurements results in higher diagnostic output. Prior fractures were equally prevalent among patients with radius-only and classic-site osteoporosis. FRAX tool performance slightly improved by incorporating radius BMD. Whether this approach may lead to a better fracture prediction warrants further prospective evaluation.

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.

Identification and Characterization of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by substantial diagnostic and evaluation gaps with no systematic screening. Even recognized cases are undercoded because of the perceived benign nature of disease and current absence of approved pharmacologic treatment. NAFLD is often detected incidentally, particularly in the asymptomatic early phase. We doubled NAFLD detection via natural language processing of 1 million imaging reports combined with laboratory data from an unselected population. We describe NAFLD comorbidities and health care utilization as compared with age, sex, and body mass index matched control subjects.

Fracture Risk Assessment With FRAX Using Real-World Data in a Population-Based Cohort From Israel.

The predictive value of the World Health Organization's Fracture Risk Assessment Tool (FRAX) was evaluated using real-world community data. A population-based cohort of 141,320 women aged 50-90 years (median age, 58 years; interquartile range, 54-67) in 2004 was extracted from the central database of a large Israeli health-care services provider and insurer. Retrospective FRAX scores were calculated using computerized health records and compared with actual incidence of major osteoporotic fractures (MOFs) during the following 10 years. Fracture proportions of 6.9% for MOFs and 2.2% for hip fractures were expected, as opposed to 13.5% and 2.9% observed. The area under the receiver operating characteristic curve (AUC) of FRAX scores calculated without the inclusion of bone mineral density (BMD) data was 0.65 (95% confidence interval: 0.65, 0.66) for MOF and 0.82 (95% confidence interval: 0.81, 0.82) for hip fracture. A total of 16,578 subjects had BMD data at the index date, and their risk estimates based solely on BMD exhibited lower predictive performance for both MOFs (AUC = 0.62 vs. 0.65; P = 0.003) and hip fractures (AUC = 0.78 vs. 0.84; P < 0.001) as compared with FRAX. FRAX scores based on electronic health records provided reasonable discrimination despite some underestimation of the absolute risk of nonhip fractures. Integration of FRAX with routine clinical systems could increase implementation in daily practice and improve risk detection, especially for patients without BMD data.

Adherence With Bisphosphonates and Long-Term Risk of Hip Fractures: A Nested Case-Control Study Using Real-World Data.

BACKGROUND: Hip fracture is a major complication of osteoporosis. Bisphosphonate medication is the mainstay of treatment for osteoporosis. However, concerns have been raised regarding the effectiveness of bisphosphonates in reducing hip fracture risk after long-term use, particularly among patients with suboptimal adherence. OBJECTIVE: To examine the association between adherence with bisphosphonate therapy and long-term risk of hip fracture. METHODS: Included in the present nested case-control study were osteoporotic women (n = 14 357) who initiated bisphosphonate therapy in 2000-2010 and were retrospectively followed for incident hip fracture through November 2014. Within this cohort, each case of primary hip fractures was individually matched to 3 controls without a primary hip fracture. Proportion of follow-up days covered (PDC) with bisphosphonates was calculated from bisphosphonate purchases. Adherence was categorized into the following groups: purchase of 1 or 2 months' supply (reference group), at least 3 months' supply to PDC ≤20%, PDC >20% to ≤80%, PDC >80% to ≤100%. RESULTS: Included in the analysis were 426 case-control groups with a mean age (SD) of 73.7 years (7.9). Compared with the reference group, PDC of 80% to 100% with bisphosphonates was associated with a significant reduction in hip fracture risk for patients with 8 to 15 years of follow-up (OR = 0.39; 95% CI = 0.18-0.87). Among patients with a follow-up of up to 3 years, OR was 0.58 (95% CI = 0.31-1.06). CONCLUSIONS: Adherence with bisphosphonates among osteoporotic patients is associated with lower risk of hip fracture, with no indication of diminished effectiveness with long-term use.

Cost and Consequences of Nonadherence With Oral Bisphosphonate Therapy: Findings From a Real-World Data Analysis.

BACKGROUND: Adherence to osteoporosis treatment remains poor despite available treatments and physician and patient education. This study aims to determine the effect of low adherence in real-world data. OBJECTIVE: To examine the association between adherence with oral bisphosphonate therapy and fracture risk as well as health care resource utilization. METHODS: Women included in this retrospective analysis were 55 years or older and had started oral bisphosphonate therapy between 2005 and 2011 in a large not-for-profit health care center in Israel. Adherence to therapy was measured by the medication possession ratio (MPR) during the first year from therapy initiation. Patients with MPR lower than 70% were considered nonadherent. Study outcomes were osteoporotic fracture events and health care utilization (including physician visits and hospitalizations) during the second year from therapy initiation. RESULTS: Among the 17 770 women included in the analysis (mean age = 66.5 years; SD = ±8.3 years), 48.9% were nonadherent to therapy during the first year of treatment. Osteoporotic fracture risks during the second year among adherent and nonadherent patients were 2.1% and 2.5%, respectively (P = 0.1). When analysis was limited to patients 75 years or older, nonadherence with bisphosphonates was associated with an adjusted odds ratio of 1.49 (95% CI = 1.08-2.04) for osteoporotic fractures compared with adherent patients. Nonadherent patients had 13.4% higher medical costs than their adherent counterparts among patients 75 years and older (P = 0.002). CONCLUSIONS: In patients 75 years and older, nonadherence with oral bisphosphonates can be associated with significantly greater short-term risk of osteoporotic fractures and higher utilization of health care services.

Trends in statin therapy initiation during the period 2000-2010 in Israel.

PURPOSE: The aim of this population-based study is to describe trends in the characteristics and treatment patterns of statin initiators over the first decade of the 21st century. METHODS: New statin use was studied retrospectively using the database of Maccabi Healthcare Services (MHS), a large Israeli health maintenance organization. Statin initiators were defined as MHS members aged ≥ 30 years who first purchased statins between 2000 and 2010. The starting dose was calculated in simvastatin equivalents based on the World Health Organization's daily defined dose index. Persistence was calculated as the percentage of days covered (PDC) with statins during the first year of therapy. RESULTS: Statin initiation peaked in 2005 and decreased from 38.6 to 18.6 per 1,000 in the period 2005-2010. The average age at therapy initiation decreased from 58.9 (± 12.0) to 54.5 (± 11.7) years, and the average (SD) baseline low-density lipoprotein cholesterol (LDL-C) decreased from 4.2 (± 1.1) to 4.0 (± 0.9) mmol/l during the study period. Women were on average 3 years older than men at treatment initiation, with a higher baseline LDL-C. Among statin initiators, the prevalence of ischemic heart disease (IHD) decreased from 17.8 to 6.7 %, and diabetes prevalence increased from 8.6 to 15.7 %, peaking in 2008 (18.0 %). The PDC with statins ranged between 52.9 and 57.7 %. Simvastatin use at initiation increased from 27.5 % in 2000 to >90 % since 2002. Starting dose increased from 18.5 (± 8.9) to 24.3 (± 13.7) mg simvastatin equivalent. CONCLUSIONS: Among the study population, statin initiators were increasingly characterized by a lower cardiovascular risk-namely, younger individuals without IHD and with a lower baseline LDL-C. These trends underscore the important shift towards statin initiation for primary prevention, as well as the need to balance between benefits and the potential side effect of statins.

DXA assessment and fracture prevention in hormone positive breast cancer patients after treatment initiation with aromatase inhibitors: A registry-based cohort study.

Background: Several guidelines have been proposed to prevent aromatase inhibitors induced bone loss (AIBL), but there is scarce data on their endorsement in clinical practice. Aim: To assess bone health evaluation and fracture prevention in postmenopausal women with estrogen receptor (ER)-positive breast cancer after aromatase inhibitors (AI) initiation. Methods: An historical cohort analysis based on data from the cancer and osteoporosis Maccabi Health Services (MHS) registries from Jan 1st 2009 to Dec 31st 2020. Cases of estrogen receptor (ER)-positive breast cancer were extracted. Index date was set as the first aromatase inhibitors (AI) purchase. Variables such as age, BMI, smoking history, alcohol use, rheumatoid arthritis, diabetes, glucocorticosteroid use, previous fractures, BMD T-scores and purchases of AI and anti-resorptive agents were collected. Age under 50, previous cancer, prior major osteoporotic fractures and prior anti-resorptive treatment were exclusion criteria. Kaplan-Meier curves were generated to assess the time to outcomes. Multivariable Cox's proportional hazards survival model was performed. Results: A total of 8617 women initiating AI were eligible. The median follow up was 6.1 years. The mean (SD) age at index was 62.8 (9.2), the mean (SD) BMI was 29.1 (5.6). The mean (SD) T-score was -1.3 (1.2) at the lumbar spine, -1.5 (0.9) at the femoral neck and -1.0 (1.0) at the total hip. Twenty percent had type 2 diabetes, 8.1 % were active smokers, 3.8% had rheumatoid arthritis and 1.2% were exposed to glucocorticoids.A total of 37% and 53% underwent a DXA scan at 1 and 2 years from AI initiation, and 12% and 17% were prescribed an anti-resorptive agent at 1 and 2 years from index. Advanced age was associated with a higher rate of evaluation and treatment, while obesity and diabetes were associated with a lower rate. The cumulative incidence of a major osteoporotic fracture was 8.8 and 15.8 % at 5 and 10 years, respectively. Conclusions: Despite the excess risk of fractures, bone health assessment and preventive treatment are still partial and postponed in breast cancer AI treated patients. Strategies to ensure appropriate care are needed.

Youth Mental Health Outcomes up to Two Years After SARS-CoV-2 Infection Long-COVID or Long-Pandemic Syndrome: A Retrospective Cohort Study.

PURPOSE: Youth mental distress has substantially increased during the COVID-19 pandemic. However, it is unclear if mental symptoms are directly related to SARS-CoV-2 infection or to social restrictions. We aimed to investigate mental health outcomes in infected versus uninfected adolescents, for up to two years after an index polymerase chain reaction (PCR) test. METHODS: A retrospective cohort study, based on electronic health records from a large nationally representative Israeli health fund, among adolescents aged 12-17 years with a PCR test for SARS-CoV-2 between March 1, 2020 and March 1, 2021. Infected and uninfected individuals were matched by age, sex, test date, sector, and socioeconomic status. Cox regression was used to derive hazard ratios (HRs) for mental health outcomes within two years from PCR test for infected versus uninfected individuals, while accounting for pre-existing psychiatric history. External validation was performed on UK primary care data. RESULTS: Among 146,067 PCR-tested adolescents, 24,009 were positive and 22,354 were matched with negative adolescents. SARS-CoV-2 infection was significantly associated with reduced risks for dispensation of antidepressants (HR 0.74, 95% confidence interval [CI] 0.66-0.83), diagnoses of anxiety (HR 0.82, 95% CI 0.71-0.95), depression (HR 0.65, 95% CI 0.53-0.80), and stress (HR 0.80, 95% CI 0.69-0.92). Similar results were obtained in the validation dataset. DISCUSSION: This large, population-based study suggests that SARS-CoV-2 infection is not associated with elevated risk for mental distress in adolescents. Our findings highlight the importance of taking a holistic view on adolescents' mental health during the pandemic, with consideration of both SARS-CoV-2 infection and response measures.

Association of early-life exposure to acid-suppressive therapy and fractures during childhood: a retrospective cohort study.

OBJECTIVES: Increased acid-suppressive therapy (AST) usage during infancy is seen worldwide, while the data on the risk for paediatric fractures associated with these drugs are scarce. We aimed to evaluate the risk for fractures associated with early-life usage of AST. METHODS: This population-based retrospective propensity-matched cohort study included children born between 2005 and 2016 who used AST during the first year of life, and a 3:1 matched unexposed group. Study subjects were followed from the end of the first year of life until the earliest of the following: an outcome event (either fracture or non-fracture injury, separately), age of 10 or August 2022. The cumulative incidence of fractures and the HR of AST for fracture and non-fracture injury as negative control were calculated. RESULTS: A total of 13 894 eligible AST users and 41 418 propensity score-matched non-users were included in the analysis. The cumulative incidence of fracture among children with AST (23.7%) was significantly (p<0.001) higher than non-users (21.7%) corresponding to an HR of 1.11 (95% CI 1.06 to 1.16). The HR for one to two AST purchases versus none was 1.09 (95% CI 1.04 to 1.14) and the HR for 3+ AST purchases versus none was 1.25 (95% CI 1.13 to 1.39). AST was also associated with injuries by an HR of 1.09 (95% CI 1.04 to 1.13). CONCLUSIONS: AST was associated with a small but statistically significant increased incidence of fractures. We cannot exclude reporting bias or residual confounders. The clinical inference is currently unclear.

Bone mineral density of the ultra-distal radius: are we ignoring valuable information?

The current study explored the possible utilization in dual-X-ray-absorptiometry scanning (DXA) of the ultra-distal radius (UDR). This region of interest is currently unused and mostly unstudied in this context. The study findings suggest UDR as potential useful region of interest in DXA scanning and warrant further study of the site. PURPOSE: Bone mineral density (BMD) measurement of a non-dominant arm is not routinely performed during dual-X-ray-absorptiometry (DXA) test, and the possible utility of ultra-distal (UDR) radius BMD is not well-studied. We evaluated in women, correlations of UDR BMD with fracture prevalence, fracture risk prediction by the fracture risk assessment tool (FRAX), and osteoporosis diagnosed by traditional sites. METHODS: Women who underwent a routine DXA (including their non-dominant forearm and including UDR BMD) in a tertiary medical center were included. Risk factors relevant to FRAX calculation were assessed via a self-administered questionnaire. Spearman correlations of UDR BMD to 10-year risks of major osteoporotic and hip fractures (assessed by FRAX) were explored. The possible added value of UDR BMD in explaining prevalent osteoporotic fractures was assessed using a multivariable regression model incorporating age and traditional osteoporosis diagnosis. RESULTS: The study included 1245 women with a median age of 66 years (interquartile range: 59-73), of whom 298 (24%) had UDR T-score ≤ - 2.5 and 154 (12%) reported prior fractures. UDR BMD was significantly negatively correlated with FRAX risk score for hip and major osteoporotic fractures (R = - 0.5 and R = - 0.41, respectively; P < 0.001). UDR T-score ≤ - 2.5 was associated with higher fracture prevalence (19% vs 10%; P < 0.001) and remained significant after adjusting for traditional BMD and age (OR 1.49, 1.01-2.19; P = 0.043). CONCLUSION: UDR BMD correlates both with prior fractures and with predicted fracture risks and might pose added value over traditional DXA sites.

Increased rates of unattained developmental milestones among Israeli children between 2016 and 2020: a national report.

BACKGROUND: The early years of children's lives are critical for their healthy development. Although children's growth and development rates may vary, a significant delay during early childhood could indicate a medical or a developmental disorder. Developmental surveillance is used worldwide by healthcare providers in routine encounters, as well as by educators and parents, to elicit concerns about child development. In this work, we used a national dataset of developmental assessments to describe temporal trends of milestone attainment rates and associations between milestone attainment and various sociodemographic factors. METHODS: The study included 1,002,700 children ages birth until 6 years with 4,441,689 developmental visits between the years 2016 and 2020. We used the Israeli developmental scale to assess the annual rates of failure to attain language, social and motoric milestones by the entire population, as well as by subgroups stratified by sociodemographic factors. In addition, we evaluated the rates of parental concern for child development and of the nurse's report of development inadequate for age. We used multivariable logistic regression to analyze the impact of different sociodemographic factors on the odds of failure to attain milestones, while controlling for confounding. RESULTS: Milestone failure rates progressively increased over the examined years in all developmental domains, and most prominently in the language domain. Conversely, the rates of parental concern for developmental delay remained constant. In multivariable analysis, higher risk of milestone attainment failure was observed in children whose mothers were divorced, unemployed, immigrant, had lower education, of Bedouin origin or were over 40 years old when giving birth. CONCLUSIONS: This report describes national trends of child development in the gross motor, fine motor, language, and social domains. A periodic report of these trends should be published to objectively evaluate subgroups in need for intervention, and to assess the effectiveness of intervention programs in attempt to maximize the developmental potential of children in Israel.

Epidemiology and comorbidity of severe mental illnesses in the community: findings from a computerized mental health registry in a large Israeli health organization.

PURPOSE: Maccabi Healthcare Services, a large health maintenance organization (HMO) operating in Israel, has recently constructed a computerized registry of patients with severe mental illnesses (SMI). In the present study, we aimed to use this registry to investigate the epidemiology of schizophrenia and bipolar affective disorder among adults, and to assess their comorbidity and mortality compared to the general population. METHODS: In this historical cohort study, we investigated the age- and sex-specific prevalence and incidence rates of HMO members diagnosed with schizophrenia or bipolar affective disorder between 2003 and 2009. We compared their medical comorbidity and mortality to the general HMO population. RESULTS: A total of 8,848 and 5,732 patients were diagnosed with bipolar (crude prevalence rate of 5 per 1,000) and schizophrenia (3 per 1,000), respectively. The annual incidence rates were 4.2 and 2.4 per 1,000 for schizophrenia and bipolar disorder, respectively. On average, schizophrenic men were diagnosed 4-5 years earlier than schizophrenic women. Compared to the general population, schizophrenia and bipolar disorder patients had a 12- and 9-year shorter life expectancy, respectively. They were also more likely to be diagnosed with diabetes mellitus (odds ratio of 1.9 and 1.6, respectively). CONCLUSIONS: The current study demonstrates the potential use of automated medical databases to characterize the epidemiology of SMI in the community. The increased comorbidity and mortality among these patients has important implication for health authorities for prevention and delivery of health-care services.

Pregnancy outcomes after SARS-CoV-2 infection by trimester: A large, population-based cohort study.

OBJECTIVES: Data regarding women infected with SARS-CoV-2 during early trimesters are scarce. We aimed to assess preterm birth (PTB) and small-for-gestational-age (SGA) rates in a large and unselected cohort by trimester at infection and overall. DESIGN: A retrospective cohort study including all women with a positive SARS-CoV-2 RT-PCR test during a non-ectopic singleton pregnancy between February 21st 2020 and July 2nd 2021 (N = 2753). Each infected woman was matched to a non-infected pregnant woman by age, last menstruation date, sector, and socioeconomic status. METHODS: Logistic regression was conducted to assess the risks of PTB and SGA including an interaction between group and trimester of infection. Multivariable models included underlying diseases, previous abortions and null parity. Subgroup analyses were conducted on symptomatic infected women and matched non-infected women. RESULTS: A total of 2753 /2789 (98.7%) eligible women that were infected during pregnancy could be matched, among them, 17.4% and 48.4% were infected during the first and third trimesters, respectively. While first and second trimester infections were not associated with PTB (p>0.8), third trimester infections and in particular after 34 weeks of gestation had a greater risk of PTB with adjusted ORs of 2.76 (95% CI 1.63-4.67) and 7.10 (95% CI 2.44-20.61), respectively. PTB risk was further heightened in symptomatic third trimester infections (OR = 4.28, 95% CI 1.94-9.25). SGA risk was comparable between study groups across all trimesters of infection. Pregnancy loss incidence was similar in both groups (adjusted OR = 1.16; 95% CI 0.90-1.50). CONCLUSION: SARS-CoV-2 infection was associated with increased risk of PTB only among women infected during late pregnancy, particularly among symptomatic women.

Association of BNT162b2 COVID-19 Vaccination During Pregnancy With Neonatal and Early Infant Outcomes.

Importance: Pregnant women were excluded from the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer-BioNTech) preauthorization trial. Therefore, observational data on vaccine safety for prenatally exposed newborns are critical to inform recommendations on maternal immunization. Objective: To examine whether BNT162b2 mRNA vaccination during pregnancy is associated with adverse neonatal and early infant outcomes among the newborns. Design, Setting, and Participants: Population-based cohort study comprising all singleton live births in March through September 2021, within a large state-mandated health care organization in Israel, followed up until October 31, 2021. Exposure: Maternal BNT162b2 mRNA vaccination during pregnancy. Main Outcomes and Measures: Risk ratios (RR) of preterm birth, small birth weight for gestational age (SGA), congenital malformations, all-cause hospitalizations, and infant death. Stabilized inverse probability weighting was used to adjust for maternal age, timing of conception, parity, socioeconomic status, population subgroup, and maternal influenza immunization status. Results: The cohort included 24 288 eligible newborns (49% female, 96% born at ≥37 weeks' gestation), of whom 16 697 were exposed (n = 2134 and n = 9364 in the first and second trimesters, respectively) to maternal vaccination in utero. Median (IQR) follow-up after birth was 126 days (76-179) among exposed and 152 days (88-209) among unexposed newborns. No substantial differences were observed in preterm birth rates between exposed and unexposed newborns (RR = 0.95; 95% CI, 0.83-1.10) or SGA (RR = 0.97; 95% CI, 0.87-1.08). No significant differences were observed in the incidence of all-cause neonatal hospitalizations (RR = 0.99; 95% CI, 0.88-1.12), postneonatal hospitalizations after birth (RR = 0.95; 95% CI, 0.84-1.07), congenital anomalies (RR = 0.69; 95% CI, 0.44-1.04), or infant mortality over the study period (RR = 0.84; 95% CI, 0.43-1.72). Conclusions and Relevance: This large population-based study found no evident differences between newborns of women who received BNT162b2 mRNA vaccination during pregnancy, vs those of women who were not vaccinated, and contributes to current evidence in establishing the safety of prenatal vaccine exposure to the newborns. Interpretation of study findings is limited by the observational design.