Shlomo Vinker

Fibromyalgia (FM) has been linked to autonomic dysregulation, but population-level evidence on blood pressure (BP) in FM is sparse, and whether BP differences are present before diagnosis is unknown. We conducted a population-based case–control study within Leumit Health Services, Israel, comparing 15,869 adults with FM with 79,345 controls matched 5:1 on sex, birth year, and membership start. BP, heart rate (HR), and body temperature were summarized as each individual’s minimum, mean, and maximum values over the full observation period and within a pre-diagnosis window extending up to 20 years before the index date with a 30-day blackout. Over the full period, FM patients had lower minimum systolic BP (99.1 ± 11.1 vs. 102.6 ± 12.3 mmHg; standardized mean difference [SMD] −0.29, 95% CI −0.31 to −0.27), lower minimum diastolic BP and pulse pressure, and higher maximum HR (SMD +0.22), whereas mean systolic BP differed little (SMD −0.08). The lower-tail BP difference was already present before diagnosis (minimum systolic BP −3.27 mmHg, 95% CI −3.51 to −3.04; SMD −0.24), in every interval from 20 years before the index date, and with 90-, 180-, and 365-day blackouts and across diagnostic-criteria eras. FM patients had more BP readings (22.1 vs. 15.3 per patient), and greater measurement intensity amplified the observed difference; nevertheless, the association persisted, attenuated, when measurement opportunity was standardized (first 3, 5, or 10 readings; measurement count strata; patient-level 10th percentile) and after multivariable adjustment for measurement intensity and cardiometabolic and cardiovascular covariates (−1.18 mmHg, 95% CI −1.37 to −0.99). The HR difference was small after adjustment (+0.25 bpm, 95% CI 0.03 to 0.48). Coded hypotensive, orthostatic, and autonomic diagnoses and dispensing of midodrine and fludrocortisone were more frequent in FM before diagnosis. A modest but reproducible lower-tail BP difference therefore precedes the recorded diagnosis of FM by many years. Because symptoms also antedate diagnosis, these data establish precedence over diagnosis rather than over disease onset, and they are compatible with, but do not prove, altered cardiovascular-autonomic regulation.

Background/Objectives: To evaluate the association between fibromyalgia and dementia, with emphasis on temporal directionality and Alzheimer’s disease-related dementia. Methods: We conducted a nationwide, population-based matched case–control study including 9232 patients with fibromyalgia and 46,160 age- and sex-matched controls. Diagnoses in the Leumit Health Services database are recorded using a hybrid coding scheme that combines ICD-9-CM and WHO ICD-10 codes; the specific codes used to ascertain fibromyalgia and each dementia subtype are listed in the Methods. Outcomes were assessed within two predefined windows: up to 20 years before and up to 10 years after fibromyalgia diagnosis. Alzheimer disease-related dementia was defined as the primary outcome. Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results: During the 20 years preceding fibromyalgia diagnosis, no increased dementia prevalence was observed; Alzheimer disease-related dementia was less frequent among fibromyalgia patients (0.16% vs. 0.31%; absolute difference −0.15 percentage points; OR 0.52, 95% CI 0.31–0.89). In contrast, during the 10 years following diagnosis, fibromyalgia was associated with a higher prevalence of Alzheimer’s disease-related dementia (1.43% vs. 0.99%; absolute difference +0.44 percentage points; OR 1.45, 95% CI 1.18–1.78). No consistent associations were found for other dementia subtypes, which should be interpreted as exploratory given low event counts. Conclusions: Fibromyalgia is associated with a higher prevalence of Alzheimer’s disease-related dementia in the years following diagnosis, with no evidence of pre-diagnostic elevation. Although this temporal pattern argues against reverse causation, the prevalence-based design and residual confounding preclude causal inference. Fibromyalgia should be regarded as a potential risk marker for subsequent Alzheimer-related neurodegeneration rather than a demonstrated causal factor.

Toxoplasma gondii establishes latent infection in a substantial proportion of the global population, yet the long-term health consequences of this infection remain incompletely characterized. We conducted a retrospective observational matched cohort study using longitudinal electronic health record data from a nationwide integrated healthcare provider, including members aged 18–45 years who underwent routine Toxoplasma serologic screening, typically performed in obstetric evaluation, excluding patients with clinical toxoplasmosis, immunosuppression, or HIV. Seropositive individuals were matched 1:1 without replacement to seronegative controls to align demographic, temporal, and socioeconomic variables. Time-to-event associations with predefined medical conditions were evaluated using Cox proportional hazards models with false discovery rate correction. The final cohort included 19,443 seropositive individuals and 19,443 matched controls (96.7% female), with a tight baseline balance of demographic and temporal characteristics. During follow-up, seropositivity was associated with increased risks of tobacco dependence (aHR 1.65), alcohol dependence (2.32), suicide attempt (1.82), motor vehicle accidents (1.22), and work accidents (1.27), as well as multiple infectious conditions, including hepatitis B (1.55), hepatitis C (2.15), and syphilis (2.43), with an overall trend toward increased all-cause mortality (1.32, 95% CI [1.00–1.74]). These findings suggest that asymptomatic Toxoplasma infection in young adults is associated with increased long-term behavioral and medical comorbidity.

Objective: Current data on the association between attention-deficit/hyperactivity disorder (ADHD) and essential hypertension (EH) in pediatric populations are very limited, as most research has focused on adults. This study investigated the long-term prevalence of EH in Israeli youth aged 5–18 years with ADHD, examining also trends in antihypertensive medication use. Methods: A retrospective cohort study was conducted using data from Leumit Health Services. The ADHD cohort (N = 18,558) was compared in a 1:2 ratio to controls (N = 37,116), who were strictly matched for age, gender, birth year and quarter, socioeconomic status (SES), sectors, region, and cumulative years of LHS membership up to the index date. Diagnoses of ADHD and EH were identified using ICD-9/10 codes, depending on the year of diagnosis. Logistic regression analyses were used to assess the associations between ADHD, EH and the use of antihypertensive medications over a 20-year follow-up. Results: ADHD-diagnosed children had a higher prevalence of EH, with odds ratios (ORs) of 3.17 (95% CI: 1.46–7.16, p = 0.0017) at 5 years, 2.94 (95% CI: 1.45–6.09, p = 0.0013) at 10 years, and 1.92 (95% CI: 1.26–2.93, p = 0.0015) at 20 years. ADHD patients showed a greater use of antihypertensive medications, including calcium channel blockers (OR 1.85, 95% CI: 1.02–3.35, p = 0.035), renin angiotensin system blockers (OR 2.20, 95% CI: 1.15–4.25, p = 0.013), and diuretics (OR 1.77, 95% CI: 1.21–2.60, p = 0.0028). Conclusions: These findings highlight an association between ADHD diagnosis and EH, suggesting regular cardiovascular monitoring of children with ADHD. Further studies are needed to uncover the role of stimulant medications and shared biological and behavioral factors involved in the pathogenesis.

Background/Objectives: The increasing rate of complex patients with multiple chronic somatic and/or mental disorders in modern medicine is challenging, necessitating special management programs. The aim of the present study was to identify clinical variables and the use of health services associated with the primary-physician-driven inclusion of complex patients in the “Team Management for Complex Patients” (TMCP) special program. Methods: Using validated electronic medical records of a nationwide health maintenance organization, a case–control study was performed. The study compared parameters before enrollment of complex patients included in the TMCP program with those of complex patients during the same time period who were not included, and were matched using a propensity score for age, sex, socioeconomic status, place of residence, ethnicity, smoking status, physical activity, and the balance before the day of enrollment for the major body measurements and laboratory results. Results: The control group was well-balanced, except for the South region and no physical activity. Several respiratory, cardiac, gastrointestinal, neurological, inflammatory and autoimmune diseases were significantly more common among patients included in the TMCP program than among those not included. Complex patients included in the program presented significantly higher previous rates of attending outpatient urgent care centers, visiting hospital emergency departments, hospitalization, and medication use. Conclusions: Although limited by subjective inclusion criteria and potential confounding, the present comparative study identified clinical variables associated with the identification of complex patients for enrollment into a special managed program. These associations may inform future work to develop and validate criteria to support physician decision-making in selecting complex patients for managed programs and designing healthcare resources for patients who need them most. We currently meticulously follow the outcomes of the patients included in the special managed program.

Background: Chronic mast cell–mediated angioedema (MC-AE) and chronic spontaneous urticaria (CSU) both involve mast cell activation but may differ in long-term systemic outcomes. Limited data exist comparing their comorbidity profiles over extended follow-up. Objective: To compare systemic comorbidities in patients with chronic MC-AE versus CSU using a large, population-based dataset. Methods: We conducted a retrospective matched case–control study using electronic health records from Leumit Health Services, a nationwide Israeli health maintenance organization. Patients diagnosed with chronic MC-AE between 2005 and 2023 (n = 2133) were matched 1:1 by age, sex, and year of diagnosis to patients with CSU (n = 2133). Comorbidities were assessed at diagnosis and after a mean follow-up of 10.2 ± 2.9 years. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression was used to assess the association between medications and MC-AE diagnosis. Results: MC-AE patients exhibited significantly higher baseline rates of hypertension (23.8% vs. 18.5%), ischemic heart disease (5.67% vs. 3.84%), and type 2 diabetes (10.45% vs. 6.42%) compared to CSU. These differences persisted or increased at follow-up, including myocardial infarction (4.13% vs. 2.25%) and chronic kidney disease (4.13% vs. 2.91%). CSU patients had consistently higher rates of atopic dermatitis, viral infections, and herpes zoster. Statin use was inversely associated with MC-AE (adjusted OR = 0.63; 95% CI: 0.44–0.90). Conclusions: Chronic MC-AE is associated with a distinct and sustained cardiometabolic and renal comorbidity burden compared to CSU, supporting its classification as a systemic disease phenotype requiring differentiated long-term care.

Background: Folic acid is essential for DNA synthesis and fetal development, with deficiency linked to anemia, cardiovascular disease and pregnancy complications. The clinical guidelines for women of reproductive age mandate supplementation as a universal preventive treatment regardless of blood folic acid levels; therefore, routine folic acid level testing is not recommended for this population. However, the vast majority of pregnant women do not implement the recommended preventive actions, indicating that new strategies are needed to improve that situation. Objectives: This study examined the impact of modifying the laboratory test-ordering interface in the medical record system, designed to simplify the ordering of folic acid level tests, on testing rates, deficiency detection and supplement consumption among women of reproductive age. Methods: This retrospective cohort analysis compared outcomes reflecting the impact of the modification on 43,952 women aged 18–42 years, assessed over one year pre- and post-integration. Statistical analyses included Chi-squared tests and logistic regression, with adjustments for age and socio-geographic status. Results: Post-intervention, testing rates increased from 14.74% to 17.35% (p < 0.0001), and deficiency detection rose from 6.30% to 7.38% (p < 0.0001). Supplement consumption tripled from 5.45% to 15.98% (p < 0.0001), with 91.37% of post-intervention consumers being new users. Conclusions: Modifying the presentation of tests in the laboratory test-ordering interface within electronic medical records significantly improved testing rates, enhanced deficiency detection and had a meaningful impact on treatment outcomes. These findings underscore the potential of system-level digital interventions to advance preventive care and overall health. Future research should focus on examining scalability, implementation and long-term outcomes across diverse healthcare settings.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder that progressively damages the autonomic and central nervous systems, leading to hallmark symptoms such as resting tremor, bradykinesia, and rigidity. Despite extensive research, the underlying cause of PD remains unclear, and current treatments are unable to halt the progression of the disease. In this retrospective study, based on historical electronic health records (EHR) from a national health provider covering the period from 2003 to 2023, we investigated the impact of vaccination and medication purchases on PD occurrence and severity. Methods: Using a case–control design, we compared the vaccination histories of 1446 PD patients with 7230 matched controls to assess the association between vaccination and PD onset. Additionally, we explored statistical associations between vaccination, medication purchases, and PD severity over an average of 9 years of follow-up, utilizing a machine learning algorithm to quantify disease severity based on annual antiparkinsonian medication purchases. Results: Our analysis revealed a significant reduction in PD occurrence following tetanus–diphtheria (Td) vaccination, with an adjusted odds ratio of 0.17 (95% CI [0.04, 0.70]) for PD onset within 5 years post-vaccination. Furthermore, a time-dependent relationship was identified between the duration since vaccination and both the rate of PD onset and disease progression. Notably, we observed that antimicrobial treatments significantly influenced disease severity, consistent with the antibiotic sensitivity profile of Clostridium tetani. Conclusions: These findings support the hypothesis that tetanus vaccination and/or C. tetani eradication may reduce PD occurrence and slow its progression, suggesting promising directions for future research in PD prevention and treatment.