Background: Human papillomavirus (HPV) infection is the necessary cause of almost all cervical cancers. HPV vaccination programs have been implemented worldwide, yet real-world evidence on vaccine effectiveness against invasive cervical cancer remains limited. Methods: We conducted a retrospective cohort study using synthetically generated data from a large health provider in Israel, including women who underwent a first Papanicolaou (Pap) test during 2014-2015. Their HPV-vaccination status before an index Pap test was obtained from computerized records. Incident cervical cancer and high-grade cervical pathology (cervical cancer, cervical intraepithelial neoplasia [CIN] 1-3, and carcinoma in situ) occurrence were examined through 2022. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and fitted with propensity score weighting. Results: The cohort included 98,102 women, of whom 9198 (9.4%) were vaccinated against HPV before an index Pap test. While HPV-vaccinated women had a higher risk of cervical pathology compared with unvaccinated women, among women vaccinated before age 18, HPV vaccination was associated with a substantially lower, though not statistically significant, risk of cervical cancer (HR 0.28, 95% CI: 0.07-1.20, p = 0.087). Conclusions: In this large cohort, HPV vaccination was correlated with a higher risk of cervical pathology, likely reflecting residual confounding factors from sexual behavior and differential baseline risks of HPV infection. In contrast, vaccination during adolescence showed a marked trend toward a reduced risk of cervical cancer, consistent with international evidence that early vaccination, prior to HPV exposure, is the most effective preventative treatment.

Purpose:To evaluate the real-world effectiveness of antiresorptive osteoporosis pharmacologic treatments on fracture incidence and survival in patients with type 2 diabetes mellitus (T2DM), with subgroup analysis by treatment route. Methods:We conducted a retrospective cohort study using a national registry of patients with T2DM and osteoporosis. Patients receiving antiresorptive treatments (oral or intravenous/subcutaneous [IV/SC]) were compared to untreated individuals using propensity score matching. The primary outcomes were major osteoporotic fracture (MOF) and all-cause mortality. Cox proportional hazards models were used to assess associations, including subgroup analyses by BMI and HbA1c. Results:Among 8,788 matched patients, treatment was associated with significantly lower mortality (adjusted HR 0.86; 95% CI: 0.78-0.94) but not with reduced fracture incidence (HR 1.11; 95% CI: 0.96-1.29). In the treated subgroup (N = 2,960), IV/SC therapy was associated with reduced fracture risk (HR 0.58; 95% CI: 0.35-0.94) but increased mortality (HR 1.63; 95% CI: 1.35-1.96) compared to oral treatment. Conclusion:In this real-world cohort of patients with type 2 diabetes and obesity, osteoporosis treatment was associated with improved survival but not reduced fracture risk. Injectable therapies offered greater fracture protection but were linked to higher mortality, likely due to confounding by indication. Poor adherence may limit the effectiveness of oral treatments in routine care. These findings underscore the need for individualized osteoporosis management strategies in high-risk diabetic populations and raise important considerations regarding the optimal route of administration in real-world settings.

Screening for gestational diabetes (GDM) is universally recommended for all pregnant women. While abnormal results of this screening are an established risk factor for developing T2DM1,2, few studies opted to assess the risk in women with high-normal Glucose Challenge Test (GCT) values. Using a large nationally representative cohort, we sought to define within the normal GCT range, optimal versus higher-risk levels for incident and early-onset T2DM (<40 years).

BACKGROUND:Gestational diabetes mellitus (GDM) is increasingly prevalent and linked with adverse maternal and neonatal outcomes. Low cognitive function in youth has been associated with various adverse metabolic outcomes. This study examined the association between adolescent cognitive function and GDM in the first pregnancy. METHODS:In this retrospective nationwide population-based cohort study, data from the Israel Defense Forces conscription database, including cognitive assessments conducted at approximately age 17 years (1976-2016), were linked with electronic medical records from Maccabi Healthcare Services, documenting prenatal care and gestational diabetes screening data. General intelligence test (GIT) scores were standardized into sex-specific Z-scores and categorized as low, intermediate, or high. GDM during first pregnancy was defined according to the two-step approach. Logistic regression analyses were used to calculate odds ratios (OR) for GDM. RESULTS:Among 189,663 women, 21,979 (11.6%) had low, 130,215 (68.7%) had intermediate, and 37,469 (19.8%) high GIT Z-scores; 10,187 (5.4%) developed GDM. Relative to high scores, low and intermediate scores were associated with higher odds of GDM: OR 1.17 (95% CI 1.08-1.26) and OR 1.09 (1.03-1.15), respectively. CONCLUSIONS:Lower adolescent cognitive function was modestly associated with increased risk of GDM in the first pregnancy, independent of sociodemographic factors and adolescent BMI. Cognitive function may serve as an early marker of maternal metabolic health.

Objectives: The World Health Organization (WHO) goal of eradicating hepatitis C virus (HCV) infection by 2030 has encouraged healthcare providers to implement proactive strategies to improve diagnosis and treatment. The aims of this retrospective cohort study were to assess a program designed to improve the HCV care cascade and facilitate access to treatment, within a national healthcare provider in Israel, Maccabi Healthcare Services (MHS). Methods: Included were adult patients newly diagnosed with HCV infection before and after the implementation of a screening and care optimization program. Patients diagnosed in 2017 served as the reference group (RG), while those diagnosed in 2019 (following the program implementation) comprised the intervention group (IG). Study outcomes included completion of HCV laboratory testing, time to consultation with gastroenterologist/hepatologist (GE), and initiation of treatment with direct-acting antivirals (DAAs). Results: The study sample included 356 HCV Ab+ patients in the RG (median age = 46 years; 41% females), and 328 in the IG (median age = 48 years; 39% females). Compared to RG, IG demonstrated higher rates of patient visiting GE visit (78.1% vs. 63%) and initiating DAA treatment (66.3% vs. 35.5%). Conclusions: Implementation of a restructured HCV care cascade was associated with a greater proportion of patients receiving expert consultation and higher DAA treatment uptake, important steps towards HCV eradication.

OBJECTIVE:The association between autoimmune diseases and type 1 diabetes (T1D) is mostly based on studies among people with T1D at baseline. We assessed the risk of incident T1D among adolescents with other autoimmune diseases. RESEARCH DESIGN AND METHODS:Included were all Israeli adolescents without a history of dysglycemia, aged 16-19 years, undergoing medical evaluation before mandatory military service between January 1996 and December 2016. Data were linked with information on adult-onset T1D from the Israeli National Diabetes Registry. The cohort was dichotomized by the presence of any autoimmune disease. Cox proportional hazards modeling was applied. RESULTS:A total of 1,426,362 people were included, of whom 38,766 (2.7%) had a history of autoimmunity at study entry (10,333 with autoimmune thyroid disease [AITD] and 9,603 with celiac disease). Over 15,810,751 person-years of follow-up, there were 37 and 740 incident cases of T1D among people with and without autoimmunity, respectively, and a crude incident rate of 9.6 and 4.8 cases per 105 person-years, respectively. In a multivariable model adjusted for sex, birth year, and sociodemographic variables, the hazard ratio (HR) for incident T1D among people with autoimmunity was 2.19 (95% CI 1.57-3.04) versus those without. Results persisted when islet autoantibody data were used as mandatory criteria for T1D case definition (HR 2.22, 95% CI 1.13-4.35). The HRs among people with AITD and celiac disease were 3.99 (2.5-6.4) and 2.82 (1.46-5.45), respectively. CONCLUSIONS:Autoimmune diseases in late adolescence were associated with an increased risk of T1D in adulthood in both sexes, especially among those with AITD and celiac disease.

AIMS:Gestational diabetes (GDM) is the strongest known risk factor for maternal type 2 diabetes. However, little is known about type 2 diabetes risk in women with normal glucose challenge test (GCT) results during pregnancy. We investigated the association between GCT results in the normal range and type 2 diabetes risk, both overall and across pre-pregnancy BMI categories. MATERIALS AND METHODS:This retrospective cohort study identified pregnant women aged 20-50 who had normal (< 140 mg/dL) GCT results between 2004 and 2022. Follow-up for type 2 diabetes extended from the date of the last documented GCT until 31 September 2024. Survival analyses examine GCT and combine BMI-GCT exposures. RESULTS:Among 249 190 eligible women (mean age 32.7 years), 1354 developed type 2 diabetes during a median follow-up of 7 years. GCT results within the normal range were associated with the risk of type 2 diabetes, in a graded manner, without a clear threshold. Compared to women with normal pre-pregnancy BMI and GCT of 70-89 mg/dL, women with a GCT of 130-140 mg/dL had adjusted hazard ratios for type 2 diabetes ranging from 14.7 (95% CI: 6.2-33.3) among women with normal BMI to 145 (95% CI: 67.7-309) among women with obesity. CONCLUSIONS:Pre-pregnancy BMI and GCT values within the normal range can be used for further type 2 diabetes risk stratification, ranging from minimal risk among women with a GCT < 90 mg/dL and normal weight to substantially increased risk among women with pre-pregnancy overweight or obesity.

BACKGROUND:Adherence to screening following a pregnancy with gestational diabetes mellitus (GDM) remains low. OBJECTIVE:To assess the risk of future type 2 diabetes (T2D) based on the number and type of abnormal results of a 100-gram oral glucose tolerance test (OGTT) performed during pregnancy. METHODS:This retrospective study used data from a major Israeli healthcare provider. Women aged 20 to 50 years without a prior diagnosis of T2D who had a complete 100-gram OGTT during their last pregnancy between January 2000 and December 2022 were included. The primary outcome was the development of T2D by September 2024. Risk was assessed using Cox proportional hazards models based on the number and type of abnormal OGTT values. RESULTS:The study included 107 889 women (age 34.1 ± 5.2 years; BMI 27.6 ± 5.3 kg/m2). Median follow-up was 6.7 years (IQR 3.3-12.4), totaling 900 000 person-years. T2D developed in 4500 women (0.5%). When compared to women with all OGTT values normal, the risk of T2D rose with each additional abnormal value: hazard ratio (HR) 3.45 (95% CI: 3.15-3.77) for 1 abnormal value, 4.03 (3.69-4.41) for 2 abnormal values, 7.15 (6.49-7.88) for 3, and 10.60 (9.28-12.20) for 4. Abnormal fasting glucose was associated with a higher risk (HR 5.28; 95% CI: 4.83-5.76) than abnormal nonfasting values (HR 3.03; 95% CI: 2.78-3.29). A previous diagnosis of GDM was significantly associated with future T2D risk, even in patients with no current abnormal OGTT values. CONCLUSION:The number and type of abnormal OGTT results strongly predict future T2D. These findings can inform targeted postpartum interventions and predictive tools for early prevention in high-risk women.

Evidence supporting osteoporosis screening in older men remains limited. In a large real-world cohort of 29,906 men aged ≥ 70 undergoing DXA screening, osteoporosis was identified in 16.5

In 2021, Maccabi Healthcare Services (MHS) introduced "UTI Smart-Set" (UTIS), an AI-driven decision support system (DSS) based on a machine-learning (ML) algorithm, to optimize antibiotic treatments for UTIs. UTIS reduced antibiotic mismatch-defined as pathogen resistance to prescribed empiric antibiotic based on culture-by ~ 30%, yet ~ 33% of physicians did not follow its recommendations. We aimed to characterize physicians according to UTIS implementation. We conducted a retrospective cohort study using MHS data of UTI encounters between 9/2023 and 3/2024. Analysis included 626 physicians and 15,033 encounters. We examined correlations between physicians' characteristics and implementing UTIS recommendations, accounting for patient- and encounter-level variables. Results indicted that physicians with younger patients population (odds ratio [OR], 0.952 per year, 95% CI 0.922-0.983), diagnose more UTIs (OR 1.021 per case, 95% CI 1.007-1.035), and work within group practices (OR 1.542, 95% CI 1.02-2.333), were more likely to follow UTIS recommendations. Conversely, older physicians (OR 1.034 per year, 95% CI 1.012-1.056), Arabic sector (OR 3.474, 95% CI 1.709-7.062), and a higher volume of patients (OR 1.027 per 100 patients, 95% CI 1.003-1.052) were less likely to implement UTIS recommendations. Addressing these physicians' characteristics is important to improve the integration of DSS.

[This corrects the article DOI: 10.3389/fendo.2026.1688669.].

Background:High body mass index (BMI) is a modifiable cancer risk factor, projected to surpass smoking as the leading preventable risk factor. The impact of weight change from late adolescence to adulthood on cancer risk remains unclear. We aimed to assess the association between adolescence-to-adulthood BMI trajectories and obesity-related cancer risk. Methods:A population-based cohort study of 800,024 people (45.1% women) insured by a large state-mandated health provider. BMI was measured during military pre-recruitment evaluations during 1967-2018 in adolescence and in subsequent clinic visits in adulthood during 1998-2020. Follow-up began one year after an adult BMI measurement until cancer diagnosis, death, transfer to another health provider, or December 16, 2021. BMI trajectories from adolescence to adulthood were classified as lean-to-lean, lean-to-high, high-to-lean, and high-to-high (cutoff: sex-specific and age-specific 85th percentile in adolescence, defined according to the United States Centers for Disease Control and Prevention growth charts, and 25 kg/m2 in adulthood). Weight change was also assessed per 5% increments. The primary outcome was obesity-related cancers including esophagus, postmenopausal breast, liver and gallbladder, stomach, pancreas, colon and rectum, kidney, multiple myeloma, thyroid, uterus and ovary. The secondary outcome was obesity-related cancers diagnosed before age 50 years (early-onset cancers). Cox proportional hazards models were applied. Findings:During 7,610,263 person-years, 6,376 people were diagnosed with obesity-related cancers, at a mean age of 53.3 ± 9.8 years. Adjusted hazard ratios (HRs) were 1.31 (95% confidence interval [CI], 1.24-1.39) for lean-to-high, 1.01 (95% CI, 0.78-1.31) for high-to-lean, and 1.47 (95% CI, 1.34-1.61) for high-to-high groups, compared to the lean-to-lean group. Respective HRs for early-onset obesity-related cancers were 1.33 (95% CI, 1.20-1.47), 0.88 (95% CI, 0.60-1.31), and 1.39 (95% CI, 1.20-1.61). Each 5% weight gain conferred a 3% increased hazard (95% CI, 1.02-1.03), with a similar 3% increase for early-onset cancers (95% CI, 1.02-1.04). Cancer-specific risks included 3% (95% CI, 1.02-1.04) for postmenopausal breast cancer, 3% (95% CI, 1.01-1.04) for colorectal cancer, 4% (95% CI, 1.02-1.05) for thyroid cancer, 5% (95% CI, 1.04-1.07) for kidney cancer, and 8% (95% CI, 1.06-1.09) for uterine cancer. Some cancers, including leukemia and non-Hodgkin's lymphoma, were not associated with weight gain but were positively associated with high adolescent BMI. Interpretation:Maintaining a healthy BMI from adolescence to adulthood may reduce obesity-related cancer risk, including early-onset, highlighting the importance of early weight management strategies. Funding:Novo Nordisk, Israel.

AIMS/HYPOTHESIS:Gestational diabetes and abnormal 100-g oral glucose tolerance test (OGTT) results in pregnancy are associated with type 2 diabetes, but their relationship with cardiovascular disease (CVD) is less clear. We evaluated the risk of CVD according to the number of abnormal OGTT values during pregnancy. METHODS:This retrospective cohort study used data from a major Israeli healthcare provider. Pregnant individuals aged 20-50 years without a prior diagnosis of type 2 diabetes and CVD who had a complete 100-g OGTT during their last pregnancy between January 2000 and December 2022 were included. The primary outcome was the development of a composite of CVD by September 2024. Risk was assessed using Cox proportional hazards models based on the number of abnormal OGTT values. RESULTS:The study included 103 389 individuals with a mean age of 34 ± 5.2 years. Overall, the median follow-up was 6.8 years (IQR, 3.4-12.9), totalling 886 955 person-years. A composite of CVD developed in 641 individuals (a cumulative incidence of 0.62%). When compared to individuals with all OGTT values normal, individuals with one to three abnormal values had an adjusted hazard ratio (HR) of 1.2 (95% CI: 1.02-1.4) for CVD, reaching 2.41 (95% CI 1.44-4.05) in those with four abnormal OGTT values. CONCLUSIONS:A history of abnormal 100-gram OGTT results during pregnancy, and specifically having four abnormal values, is associated with an elevated risk of CVD. These results underscore the need for early post-partum identification and prevention strategies in this high-risk population.

BACKGROUND:Nonprimary maternal cytomegalovirus (CMV) infections, resulting from reactivation or reinfection in seropositive women, are increasingly recognized as contributors to congenital CMV (cCMV) disease. However, their clinical impact compared with primary infections remains insufficiently characterized. METHODS:We conducted a retrospective cohort study of symptomatic cCMV identified from a single-center series (2005-2022) and a multicenter registry (2023-2025). Infants were included if they had a positive urine CMV polymerase chain reaction within the first 3 weeks of life and met criteria for symptomatic infection based on central nervous system involvement. Maternal infection type (primary vs. nonprimary) was determined by serologic testing. Clinical characteristics, neuroimaging findings and auditory outcomes were compared between groups. RESULTS:We identified 360 symptomatic infants; maternal infection type was unknown in 55, leaving 305 for analysis [243 (79.7%) primary; 62 (20.3%) nonprimary]. The proportion of nonprimary infections among symptomatic cases increased from 11.4% in 2005-2009 to 37.3% in 2020-2025 (odds ratio: 4.77; 95% confidence interval: 1.63-13.92; P = 0.004). Absolute counts mirrored these trends: nonprimary 5 of 44 in 2005-2009 to 22 of 59 in 2020-2025. Clinical manifestations, including neuroimaging and hearing outcomes, were broadly similar between groups. CONCLUSIONS:In the era of maternal screening and interventions focused on primary CMV infection, nonprimary infections represent a rising share of symptomatic cCMV and a relevant clinical burden. These findings highlight the importance of recognizing nonprimary infections in clinical care and public health planning and support the need to reassess current strategies for maternal counseling and neonatal care.

Importance:Optimizing ADHD stimulant therapy in children is difficult due to individual variability and lack of reliable response predictors, forcing a trial-and-error approach that burdens both patients and families. Objective:To identify factors associated with treatment success based on real-world patterns of ADHD stimulant use. Design:Setting and participants: In this retrospective cohort study we used the comprehensive electronic health records of Maccabi Healthcare Services. We included children aged 6-18 years diagnosed with ADHD between 2015-2023 who had purchased at least one ADHD stimulant and had at least 1 year of follow-up. Patients were classified as persistent users once they purchased at least eight prescriptions over a fixed 12-month period, with each purchase covering a 30-day period, and there were no gaps of 90 days or more; others were defined as non-persistent. Data was stratified by stimulant type using the WHO Anatomical Therapeutic Chemical classification. Demographic and clinical covariates were analyzed to identify factors associated with sustained medication use. The study followed the STROBE Statement. Results:The cohort comprised of 43,825 children with ADHD, of which 18,783 (43%) were Persistent users. Persistent users were more often of male sex (67.5% vs. 55.4%), lower socioeconomic status (44.7% vs. 42.4% with low or very low SES), and initiated treatment at a younger age (76.4% vs. 52.9% initiated treatment at 6-12 years). Lisdexamfetamine was associated with the highest odds of treatment persistence when used as the initial stimulant, compared with the reference group (OR = 2.2, CI = 1.86-2.59), although this finding was based on a relatively small sample (n = 654). Conclusion and Relevance:In this retrospective cohort study of pediatric patients with ADHD, male sex, low socioeconomic status, early treatment initiation, and first-line lisdexamfetamine were associated with higher persistence.

AIMS:Evaluating the association between polyendocrine metabolic ovarian syndrome (PMOS), traditionally termed polycystic ovary syndrome, and the broad spectrum of gestational dysglycemia in a large, universally screened population. MATERIALS AND METHODS:This retrospective cohort study used routinely collected data linked from Israeli military pre-recruitment medical evaluation (ages 16-19) and Maccabi Healthcare Services electronic health records, including two-step GDM screening during the first pregnancy, 2001-2019. Outcome was categorised into gestational normoglycemia, abnormal glucose challenge test (GCT) with a normal oral glucose tolerance test (OGTT), gestational impaired glucose tolerance (GIGT) and gestational diabetes mellitus (GDM). Multivariable logistic models were adjusted for birth year, adolescent BMI, socioeconomic position, country of birth, cognitive performance, education and age at GDM screening. RESULTS:Among 177 241 women, 13 648 (7.7%) had PMOS. Rates (95% CI) of abnormal GCT with normal OGTT, GIGT, GDM and any dysglycemia were 9.1% (8.6-9.6) versus 7.9% (7.8-8.0), 4.9% (4.5-5.3) versus 4.0% (3.9-4.1), 6.3% (5.9-6.7) versus 4.2% (4.1-4.3) and 20.3% (19.6-21.0) versus 16.1% (16.0-16.3) among women with versus without PMOS, respectively. Corresponding adjusted ORs (95% CI) were 1.18 (1.11-1.26), 1.26 (1.16-1.37), 1.61 (1.49-1.73) and 1.31 (1.25-1.37), respectively. An interaction was observed with the highest odds among women with both PMOS and high adolescent BMI (adjusted OR 1.77, 95% CI: 1.52-2.10). CONCLUSIONS:Women with PMOS, and particularly those with concomitantly high BMI, constitute a high-risk subgroup for subthreshold gestational dysglycemia and GDM, highlighting the importance of pre-pregnancy mitigation of modifiable risk factors.

BACKGROUND:Telemedicine is conventionally modeled as a dyadic clinician-patient encounter, yet a third party-caregiver, community health worker, nurse, or increasingly an artificial intelligence (AI) conversational agent-frequently participates. No principled basis exists for determining when such a third party is a genuine facilitator versus an instrument of one party, rendering cross-study comparison incommensurable and deployment decisions poorly grounded. METHODS:We conducted a narrative synthesis of literature spanning triadic clinical communication, shared decision-making, and AI-mediated interaction to derive a technology-neutral conceptual framework and classification model. RESULTS:We propose conversational capacity, operationalized through four functions (interpret, translate, advocate, adapt), as the minimum criterion for triadic facilitation. The framework defines a structural boundary separating genuine triadic architectures (Modes A and B) from augmented dyadic models (Mode C); a five-level Conversational Capacity Spectrum classifying human and AI facilitators; and a Clinical Situation Matrix mapping architecture to morbidity complexity, patient vulnerability, and decision complexity. Advocacy emerges as the discriminating function AI is least able to perform, making it the current limiting dimension of AI facilitation. The framework generates three testable hypotheses and identifies an equity paradox whereby high-vulnerability populations most in need of human facilitation are those most likely to be assigned AI on resource grounds. CONCLUSIONS:Triadic telemedicine should be defined by conversational capacity rather than mere third-party presence. Replacing the binary triadic-versus-dyadic distinction with two gradable, measurable constructs is a prerequisite for cumulative research and responsible AI deployment in clinical consultations.