Real-world treatment patterns in patients with systemic lupus erythematosus: associations with comorbidities and damage.

OBJECTIVE: To assess treatment patterns and the association between long-term glucocorticoid (GC) and hydroxychloroquine (HCQ) use and damage accrual in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective study including patients with SLE using the computerised database of a large health maintenance organisation. Patients were matched with subjects from the general population. Multivariable logistic regression models were used to assess the association between GC cumulative daily doses, HCQ and comorbidities: Osteoporosis, cardiovascular disease (CVD), hypertension and diabetes mellitus. Models were adjusted for age, sex, socioeconomic status, smoking, disease duration and HCQ use. RESULTS: A total of 1073 patients with SLE were included, 87.79% were women. The age at first diagnosis was 37.23±14.36 and the SLE disease duration was 12.89±6.23 years. Initiation of HCQ within 12 months of SLE diagnosis increased from 51.02% in 2000 to 83.67% in 2010 and 93.02% in 2018. The annual usage of GC gradually decreased from 45.34% in 2000 to 30.76% in 2020. CVD and osteoporosis were more prevalent in SLE than in the general population. Multivariable logistic regression models revealed increased odds for comorbidities in patients receiving a mean daily dose of prednisone of more than 5 mg/day compared with those receiving 5 mg/day or less. CONCLUSIONS: CVD and osteoporosis were more prevalent in SLE than in the general population. The dose and frequency of GC treatment in patients with SLE have decreased over the years. Prednisone usage in doses exceeding 5 mg/day is associated with significantly increased odds of osteoporosis and CVD.

Healthcare resource utilization and associated cost in patients with metastatic non-small cell lung cancer treated in the immunotherapy era.

BACKGROUND: Treatment approach for metastatic non-small cell lung cancer (mNSCLC) has revolutionized in the recent decade with the introduction of immunotherapy and targeted medications in first-line (1L) therapy. We present real-world data on clinical outcomes and direct healthcare resource utilization (HCRU) and cost in a 2.7-million-member Israeli health provider. PATIENTS AND METHODS: Newly diagnosed mNSCLC patients between January 2017 and December 2020 were categorized by 1L treatment: platinum-based chemotherapy, targeted therapy, or immunotherapy. HCRU and costs were calculated based on the Ministry of Health Prices and were assessed at a minimum of 6 months' follow-up (cutoff: 30 June 2021). RESULTS: A total of 886 patients were included in the study: 40.6% female, median age 68 years (IQR 61-74), 24.3% never smokers, 80.6% with adenocarcinoma, and 54% with a 0-1 performance status. The median follow-up was 27.12 months (95% CI, 24.7-29.6) and the median duration of first-line (1L) treatment was 2.3 months for platinum-based chemotherapy (n = 177), 12.3 months for targeted therapy (n = 255), and 4.8 months for immunotherapy (n = 463). The median overall survival was 9.09, 27.68, and 12.46 months, respectively. Total 1L costs were driven by radiotherapy for platinum-based chemotherapy and medication for targeted therapy or immunotherapy. Total costs for deceased patients over the entire follow-up were €121 155, €129 458, and €110 716, respectively. CONCLUSION: The treatment of mNSCLC carries a high economic burden, primarily driven by first-line therapy, especially with targeted and immune therapies. Further studies are needed to evaluate the impact of innovative treatments on the disease management costs of mNSCLC.

A machine learning model for early diagnosis of type 1 Gaucher disease using real-life data.

OBJECTIVE: The diagnosis of Gaucher disease (GD) presents a major challenge due to the high variability and low specificity of its clinical characteristics, along with limited physician awareness of the disease's early symptoms. Early and accurate diagnosis is important to enable effective treatment decisions, prevent unnecessary testing, and facilitate genetic counseling. This study aimed to develop a machine learning (ML) model for GD screening and GD early diagnosis based on real-world clinical data using the Maccabi Healthcare Services electronic database, which contains 20 years of longitudinal data on approximately 2.6 million patients. STUDY DESIGN AND SETTING: We screened the Maccabi Healthcare Services database for patients with GD between January 1998 and May 2022. Eligible controls were matched by year of birth, sex, and socioeconomic status in a 1:13 ratio. The data were partitioned into 75% training and 25% test sets and trained to predict GD using features obtained from medical and laboratory records. Model performances were evaluated using the area under the receiver operating characteristic curve and the area under the precision-recall curve. RESULTS: We detected 264 confirmed patients with GD to which we matched 3,429 controls. The best model performance (which included known GD signs and symptoms, previously unknown clinical features, and administrative codes) on the test set had an area under the receiver operating characteristic curve = 0.95 ± 0.03 and area under the precision-recall curve = 0.80 ± 0.08, which yielded a median GD identification of 2.78 years earlier than the clinical diagnosis (25th-75th percentile: 1.29-4.53). CONCLUSION: Using an ML approach on real-world data led to excellent discrimination between GD patients and controls, with the ability to detect GD significantly earlier than the time of actual diagnosis. Hence, this approach might be useful as a screening tool for GD and lead to earlier diagnosis and treatment. Furthermore, advanced ML analytics may highlight previously unrecognized features associated with GD, including clinical diagnoses and health-seeking behaviors. PLAIN LANGUAGE SUMMARY: Diagnosing Gaucher disease is difficult, which often leads to late or incorrect diagnoses. As a result, patients may undergo unnecessary tests and treatments and experience health deterioration despite medications availability for Gaucher disease. In this study, we used electronic health data to develop machine learning models for early diagnosis of Gaucher disease type 1. Our models, which included known Gaucher disease signs and symptoms, previously unknown clinical features, and administrative codes, were able to significantly outperform other models and expert opinions, detecting type 1 Gaucher disease 3 years on average before actual diagnosis. Our models also revealed new features linked to type 1 Gaucher disease, including specific diagnoses and patterns in patients' healthcare-seeking behaviors. We believe that the tool of machine learning can be valuable for patients with rare diseases.

The Use of National Cancer Registry Data for Breast Cancer Family History Assessment in Premenopausal Women.

Background: Population-based cancer registries are the best source of information to measure cancer burden. However, little is done to use this information for individual cancer risk assessment. In this study, we aimed at identifying women at high risk of breast and ovarian cancer using data on family history of cancer from the Israel national cancer registry. Methods: We used the family history assessment tool (FHAT) to score all females, 26 to 45 years of age, in a 2.6-million-member health provider in Israel (Maccabi Healthcare Services). Data on breast, ovarian, prostate, and pancreatic cancer history among the participants and their parents (identified using the national census) were retrieved from the national cancer registry. These data were used to calculate individual FHAT scores. Results: A total of 377,931 eligible women were included in the analysis. A relevant family history of cancer was detected in 20,386 (5.4%), with FHAT scores ranging from 1 to 16. FHAT score was higher in older women and among those with a history of breast cancer. Among women aged 35-39, an FHAT score of 10 or above was associated with an OR of 15.23 (95%CI: 7.41-28.19) for breast cancer compared to women with an FHAT of 0. Conclusions: Using individual-level data from national cancer registries may assist in detecting women with a relevant family history of cancer.

Real-World Adherence and Drug Survival of Biologics among Patients with Ankylosing Spondylitis.

Objectives: The objective of this study was to evaluate the real-world drug survival, adherence, and discontinuation risk of biologics disease-modifying anti-rheumatic drugs (bDMARDs) among patients with ankylosing spondylitis (AS). Methods: This was a retrospective study using a computerized database. Biologic-naïve and biologic-experienced AS patients who initiated treatment with bDMARDs (tumor necrosis factor alpha inhibitors {TNF-αis} or interleukin-17 inhibitor {IL-17i}) during 2015-2018 were included. Adherence was assessed using the proportion of days covered (PDC) method. Drug survival was analyzed using Kaplan-Meier estimates. Risk of discontinuation was estimated by the Cox proportional hazard model. Results: We identified 343 eligible patients utilizing 481 lines of therapy. The mean age was 44.6 years (SD ± 13.4), 57.7% were males, and 69.7% were biologic-naïve at baseline. The proportion of highly adherent patients (PDC ≥ 0.8) in the biologic-naïve group was 63.5% for golimumab, 69.2% for etanercept, and 71.6% for adalimumab (p > 0.9). Among the biologic-experienced group, secukinumab had the highest proportion of adherent patients (75.7%) and etanercept the lowest (50.0%) reaching statistical difference (p < 0.001). The Kaplan-Meier analysis did not show a significant difference in drug survival in either the biologic-naïve or the biologic-experienced groups (p = 0.85). Multivariable analysis demonstrated a similar risk for discontinuation for etanercept, golimumab, and secukinumab compared with adalimumab, regardless of biologic-experience status. Conclusions: Adherence, drug survival, and risk for discontinuation were similar for all TNF-αis and the IL-17i SEC, regardless of biologic-experience status. As drug survival is an indirect measure of drug efficacy, n, in real-world settings, we believe caregivers can integrate these results into treatment considerations.

Real-World Drug Survival of Biologics and Targeted Synthetic Disease-Modifying Anti-rheumatic Drugs Among Patients with Psoriatic Arthritis.

BACKGROUND: While the variety of biologics (b) and targeted synthetic (ts) disease-modifying anti-rheumatic drugs (DMARDs) available for patients with psoriatic arthritis (PsA) has proved to be efficacious in randomized clinical trials, there is a growing importance to understand the benefits and potential drawbacks of these different therapies in real-world settings, which includes bio-experienced and older patients as well. OBJECTIVE: To evaluate the real-world adherence, drug survival, and discontinuation risk of bDMARDs and tsDMARDs among patients with PsA, comprising both younger and older patients. METHODS: A retrospective study using a computerized database. Treatment-naïve and treatment-experiencedpatients with PsA, younger and older than 60 years, who initiated treatment with bDMARDs [TNF-α inhibitors (TNF-αis), IL-17 inhibitors (IL-17is), IL-12/23 inhibitors (IL-12/23i)] or tsDMARDs (the PDE-4 inhibitor apremilast) during 2015-2018 were included. Adherence was assessed using the proportion of days covered (PDC) method. Time to discontinuation was analyzed using Kaplan-Meier estimates. Risk of discontinuation was estimated by Cox proportional hazard model. RESULTS: We identified 427 eligible patients (22.2 % were older than 60 years), utilizing 673 treatment lines. The proportion of adherent patients (PDC ≥ 0.8) was similar (62.1-66.5%) across all lines of therapy and across different biologics (70.0-72.0%), while apremilast showed the lowest, in both treatment-naïve and experienced settings (43.6% and 25.5%, respectively). The Kaplan-Meier analysis showed that in the treatment-naïve TNF-αis had higher drug survival compared with apremilast (P = 0.032). Apremilast also had the lowest drug survival in the treatment-experienced group (P < 0.0001). Kaplan-Meier analysis by age groups showed similar drug survival rates in older (≥ 60 years) and younger (age < 60 years) patients, regardless of treatment-experience status. The multivariable model showed that apremilast had increased risk for discontinuation compared with TNF-αis. CONCLUSION: Adherence, drug survival and risk for discontinuation were similar for all included bDMARDs, regardless of treatment experience status, while apremilast showed lower rates and increased risk. Adherence and discontinuation rate were similar in older and younger patients. With the variety of drug modes of action available for patients with PsA, these findings may assist caregivers in selecting the appropriate treatment.

Risk for Mortality in High versus Low Antiparkinsonian Therapy Dose During the First Year of Parkinson's Disease: A Real-World Study.

INTRODUCTION: Early, simple predictors for long-term survival in Parkinson's disease (PD) may help identify patients at elevated risk and are crucial for more personalized treatment. METHODS: This large, retrospective study examined whether higher levodopa equivalent daily dose (LEDD) a year after diagnosis predicts long-term survival. RESULTS: Mortality risk was increased among 292 patients receiving ≥ 600 mg LEDD versus 2233 patients receiving < 600 mg LEDD (hazard ratio 1.5; 95% confidence interval 1.3-1.7), particularly among patients aged < 75 years (1.8; 1.4-2.4). CONCLUSION: In PD, higher LEDD can be an early risk marker of increased mortality, probably because it reflects more severe disease.

Stuttering in adolescence and the risk for dysglycemia in early adulthood.

AIMS: To investigate the association between stuttering during adolescence and the onset of dysglycemia (prediabetes or type 2 diabetes) in early adulthood among men and women. MATERIALS AND METHODS: This cohort study included Maccabi Health Services members assessed for mandatory military service at ages 16-19 during 1990-2019 and followed until 31 December 2020. Stuttering status was recorded in the baseline medical evaluation. Incident cases of dysglycemia were identified systematically using prediabetes and diabetes registries. Cox proportional hazard models were applied for men and women separately, adjusting for sociodemographics and medical status. RESULTS: The study cohort comprised 866,304 individuals (55% men; 0.21% with stuttering) followed for a total of 12,696,250 person-years. During the study period, 7.6% (n = 36,603) of men and 9.0% (n = 34,723) of women were diagnosed with dysglycemia. The mean ages at diagnosis were 34 and 32 years for men and women, respectively. Women with stuttering exhibited the highest dysglycemia incidence rate (102.3 per 10,000 person-years) compared with the other groups (61.4, 69.0, and 51.9 per 10,000 person-years for women without stuttering, men with stuttering, and men without stuttering, respectively). For both men and women, those with stuttering showed an increased risk of being diagnosed with dysglycemia compared with those without (adjusted hazard ratios 1.18 [1.01-1.38] and 1.61 [1.15-2.26], respectively). The associations persisted in extensive sub-analyses. CONCLUSIONS: Stuttering in adolescence is associated with a higher risk of dysglycemia in early adulthood for men and women. Screening and targeted prevention in this population, especially women, may be beneficial.

Epidemiology and Healthcare Service Utilization among Adults with Chronic Cough.

Background and objective: Chronic cough (CC) is a prevalent yet underexplored medical condition, with limited real-world data regarding its healthcare burden. This study investigates the epidemiology, associated comorbidities, and healthcare service utilization among patients with CC. Methods: In this retrospective cohort study, adult patients with at least 3 physician diagnoses of cough over a period spanning a minimum of 8 weeks and a maximum of 12 months anytime between 2009 and 2018, were defined as patients with CC (PwCC). The reference group were adults without cough matched in a 1:1 ratio for age, sex, and place of residence. Results: The study included 91,757 PwCC, reflecting a prevalence of 5.5%. Of those, 59,296 patients (mean [SD] age, 53.9 [16.8] years; 59.6% females) were first diagnosed with CC during the study period, representing a 10-year incidence rate of 3.26% (95%CI: 3.24-3.29%). Diseases associated with the highest OR for CC included lung cancer (OR = 3.32; 95%CI: 2.90-4.25), whooping cough (OR = 3.04; 95%CI: 2.70-3.60), and respiratory infections (OR = 2.81; 95%CI: 2.74-2.88). Furthermore, PwCC demonstrated increased healthcare service utilization, leading to a higher adjusted annual estimated mean cost (USD 4038 vs. USD 1833, p < 0.001). Conclusions: Chronic cough emerges as a relatively prevalent complaint within community care, exerting a considerable economic burden. This study underscores the need for heightened awareness, comprehensive management strategies, and resource allocation to address the multifaceted challenges associated with chronic cough.

Clinical and Economic Implications of Hydroxyurea Intolerance in Polycythemia Vera in Routine Clinical Practice.

Background/Objectives: Polycythemia vera (PV) is a chronic hematologic neoplasm commonly treated with hydroxyurea (HU). We utilized the advanced digitalized database of Maccabi Healthcare Services to retrospectively investigate the clinical and economic implications of HU intolerance in the routine clinical care of PV patients in Israel. Methods: We collected data on demographics, physician visits, hospitalizations, laboratory results, medication purchases, cardiovascular and thrombotic events, mental health, economic outcomes, and mortality. Outcomes included cardiovascular and other thrombotic events, disease progression, mental health events, economic outcomes, and overall mortality. Results: Of the 830 patients studied, 3 (0.4%) were resistant to HU treatment, 318 (38.3%) were intolerant to HU treatment, and 509 (61.3%) were stable on HU treatment. The venous thrombosis rate was significantly higher among HU-intolerant compared to HU-stable patients (1.58 vs. 0.47 per 100 person-years [PY], respectively; p < 0.001). The rate of progression to myelofibrosis was 6 vs. 0.9 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001), and the rate of progression to acute myeloid leukemia (AML) was 1.16 vs. 0.2 per 100 PY in HU-intolerant patients vs. HU-stable patients, respectively (p < 0.001). The phlebotomy requirement, mortality rate, and total hospitalization days among HU-intolerant patients were significantly higher than in HU-stable patients (p = 0.049, p < 0.001, p < 0.001, respectively). More mental health-related events were noted in HU-intolerant patients vs. HU-stable patients (p = 0.007), and the total healthcare cost ratio was 2.65 for the HU-intolerant patients compared with HU-stable patients. Conclusions: This study suggests that HU-intolerant patients are more likely to have worse outcomes than HU-stable patients, highlighting the need for the close monitoring of these patients for disease-related complications or progression.

Heritability of Body Mass Index Among Familial Generations.

Importance: Studies on the familial effects of body mass index (BMI) status have yielded a wide range of data on its heritability. Objective: To assess the heritability of obesity by measuring the association between the BMIs of fathers, mothers, and their offspring at the same age. Design, Setting, and Participants: This cohort study used data from population-wide mandatory medical screening before compulsory military service in Israel. The study included participants examined between January 1, 1986, and December 31, 2018, whose both parents had their BMI measurement taken at their own prerecruitment evaluation in the past. Data analysis was performed from May to December 2023. Main Outcomes and Measures: Spearman correlation coefficients were calculated for offsprings' BMI and their mothers', fathers', and midparental BMI percentile (the mean of the mothers' and fathers' BMI cohort- and sex-specific BMI percentile) to estimate heritability. Logistic regression models were applied to estimate the odds ratios (ORs) and 95% CIs of obesity compared with healthy BMI, according to parental BMI status. Results: A total of 447 883 offspring (235 105 male [52.5%]; mean [SD] age, 17.09 [0.34] years) with both parents enrolled and measured for BMI at 17 years of age were enrolled in the study, yielding a total study population of 1 343 649 individuals. Overall, the correlation between midparental BMI percentile at 17 years of age and the offspring's BMI at 17 years of age was moderate (ρ = 0.386). Among female offspring, maternal-offspring BMI correlation (ρ = 0.329) was somewhat higher than the paternal-offspring BMI correlation (ρ = 0.266). Among trios in which both parents had a healthy BMI, the prevalence of overweight or obesity in offspring was 15.4%; this proportion increased to 76.6% when both parents had obesity and decreased to 3.3% when both parents had severe underweight. Compared with healthy weight, maternal (OR, 4.96; 95% CI, 4.63-5.32), paternal (OR, 4.48; 95% CI, 4.26-4.72), and parental (OR, 6.44; 95% CI, 6.22-6.67) obesity (midparent BMI in the ≥95th percentile) at 17 years of age were associated with increased odds of obesity among offspring. Conclusions and Relevance: In this cohort study of military enrollees whose parents also underwent prerecruitment evaluations, the observed correlation between midparental and offspring BMI, coupled with a calculated narrow-sense heritability of 39%, suggested a substantive contribution of genetic factors to BMI variation at 17 years of age.

Adherence with statins and all-cause mortality in days with high temperature.

PURPOSE: It has been suggested that statins may exert thermo-protective effects that can reduce mortality on hot days. We aimed to examine the relationship between statin adherence and mortality in days with high temperature. METHODS: Utilizing data from a prior historical new-user cohort study, we analyzed a cohort of 229 918 individuals within a state-mandated health provider in Israel who initiated statin therapy between 1998 and 2006. Adherence to statins was assessed through the mean proportion of days covered (PDC) with statins during the follow-up period. The study's primary outcome was all-cause mortality during hot days. RESULTS: During the study follow-up period, a total of 13 165 individuals (5.7%) died. In a multivariable model, a 10% increase in PDC with statins was associated with an HR of (0.85; 95% CI: 0.72-1.00) for deaths (n = 16) in extremely hot days (≥39°C). This association was numerically stronger compared to HR = 0.94 (0.93-0.94) in cooler days and displayed a significant difference between sexes. In males, the fully-adjusted HR for a 10% increase in PDC with statins was 0.66 (0.45-0.95), while in women, it was 0.98 (0.78-1.23). In contrast, no such effect modification was observed for death in cooler days. CONCLUSIONS: These findings align with earlier research, supporting the notion that adherence with statin treatment may be associated with a reduced risk of death during extremely hot days, particularly among men.

An "On Demand" canakinumab regimen for treating children with Colchicine-Resistant familial Mediterranean fever - A multicentre study.

OBJECTIVES: Canakinumab, a human monoclonal antibody targeted at interleukin-1 beta, has demonstrated safety and efficacy in preventing familial Mediterranean fever (FMF) attacks among individuals with colchicine-resistant (crFMF). The manufacturer orders prescribe monthly subcutaneous injections. However, a subset of our patients is treated with an "canakinumab on demand " (COD) strategy, with wider intervals between drug administrations. Therefore, we aimed to compare disease activity and drug safety between COD and "canakinumab fixed frequency" (CFF) policies. METHODS: This retrospective study collected data from three Israeli paediatric rheumatology centres, of children with crFMF who were treated with canakinumab. Epidemiological and clinical parameters, cumulative drug dosages, and adverse events were compared between children treated by both policies. RESULTS: Twenty-five (49 %) children were treated according to COD policy and 26 according to CFF policy. Demographic parameters and most of the disease features did not differ significantly between the groups. Both groups showed significant reduction in attacks after canakinumab introduction. The median number (interquartile range) of attacks per month did not differ significantly between the COD and CFF groups (0.33 (0.08, 0.58) and 0.13 (0, 0.5), respectively, p = 0.485 (even though, per definition, COD patients presumably had an attack before receiving the second canakinumab dose). The mean monthly dose was lower for the COD than the CFF group (1.13 ± 1.13 vs. 3.16 ± 1.46 mg/kg, p < 0.001). Adverse events were similar between the groups. CONCLUSION: For individuals with crFMF, COD compared to CFF policy can achieve similar efficacy and safety, with a lower accumulated canakinumab dose, rendering it less immunosuppressive and less expensive.

Clinical Outcomes of Patients with HER2 Positive Metastatic Breast Cancer to the Brain, with First-Line Trastuzumab, Pertuzumab and Chemotherapy, in a Real-World Setting.

Background: In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel. Methods: Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021). Results: We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44-63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0-1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9-27.7) and 7.9 months (95% CI = 5.6-10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4-71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0-NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5-NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4-NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0-34.6). Conclusion: Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.

Assessing the diagnostic utility of the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system using real-world data.

BACKGROUND: Gaucher disease (GD) is a rare autosomal recessive condition associated with clinical features such as splenomegaly, hepatomegaly, anemia, thrombocytopenia, and bone abnormalities. Three clinical forms of GD have been defined based on the absence (type 1, GD1) or presence (types 2 and 3) of neurological signs. Early diagnosis can reduce the likelihood of severe, often irreversible complications. The aim of this study was to validate the ability of factors from the Gaucher Earlier Diagnosis Consensus (GED-C) scoring system to discriminate between patients with GD1 and controls using real-world data from electronic patient medical records from Maccabi Healthcare Services, Israel's second-largest state-mandated healthcare provider. METHODS: We applied the GED-C scoring system to 265 confirmed cases of GD and 3445 non-GD controls matched for year of birth, sex, and socioeconomic status identified from 1998 to 2022. The analyses were based on two databases: (1) all available data and (2) all data except free-text notes. Features from the GED-C scoring system applicable to GD1 were extracted for each individual. Patients and controls were compared for the proportion of the specific features and overall GED-C scores. Decision tree and random forest models were trained to identify the main features distinguishing GD from non-GD controls. RESULTS: The GED-C scoring distinguished individuals with GD from controls using both databases. Decision tree models for the databases showed good accuracy (0.96 [95% CI 0.95-0.97] for Database 1; 0.95 [95% CI 0.94-0.96] for Database 2), high specificity (0.99 [95% CI 0.99-1]) for Database 1; 1.0 [95% CI 0.99-1] for Database 2), but relatively low sensitivity (0.53 [95% CI 0.46-0.59] for Database 1; 0.32 [95% CI 0.25-0.38]) for Database 2). The clinical features of splenomegaly, thrombocytopenia (< 50 × 109/L), and hyperferritinemia (300-1000 ng/mL) were found to be the three most accurate classifiers of GD in both databases. CONCLUSION: In this analysis of real-world patient data, certain individual features of the GED-C score discriminate more successfully between patients with GD and controls than the overall score. An enhanced diagnostic model may lead to earlier, reliable diagnoses of Gaucher disease, aiming to minimize the severe complications associated with this disease.

Trends of Diagnosis, Disease Course, and Treatment of Atopic Dermatitis 2012-2021: Real-World Data from a Large Healthcare Provider.

In the last decade, new treatments for atopic dermatitis (AD) have emerged. We aimed to describe trends of the diagnosis, disease course, and treatment of AD over a decade (2012-2021) using data from Maccabi Healthcare Services (a 2.7-million-member healthcare provider in Israel). The AD prevalence was stable (4.0% on 31 December 2021 vs. 4.3% on 31 December 2012). The annual AD incidence was also stable (5.8/1000 in 2012 and 5.7/1000 in 2021). AD-related treatment use was highest in the first year post-diagnosis, and it included, among children (n = 87,414) vs. adults (n = 36,865), low-potency topical corticosteroids (TCS) (41.8% vs. 27.1%), mid-potency TCS (30.1% vs. 28.1%), high-potency TCS (34.9% vs. 60.3%), topical calcineurin inhibitor (10.8% vs. 10.1%), phosphodiesterase-4-inhibitor (0.3% vs. 0.7% overall; approved in 2019), phototherapy (0.1% vs. 2.3%), and systemic/biologic treatments (13.0% vs. 13.3%). Among children diagnosed in 2012 and followed through to 2021 (n = 5248), 21.5% had ≥1 AD diagnosis/treatment 10 years later (among 3223 adults: 38.3%). We conclude that the incidence and prevalence rates of AD were comparable to those in similar database studies and remained relatively stable over the past decade. The results underscore the burden of medication use among children and adults, particularly in the first year after AD diagnosis, and the low rate of AD diagnosis among patients originally diagnosed as children 10 years earlier.

Calcium score of the entire thoracic aorta is an independent predictor of all-cause mortality in patients referred to chest computed tomography.

BACKGROUND: Thoracic arterial calcifications (TAC) are not routinely reported or quantified in chest CT scans. We aimed to evaluate the association between TAC of the entire thoracic aorta and all-cause mortality (ACM) in patients referred to standard chest CT. METHODS: A retrospective analysis of consecutive standard chest CT scans (non-gated, non-contrast) for the quantification of TAC, CAC and aortic valve calcification. TAC was divided into 4 sample-derived categories (TAC 1 = 0, TAC 2 = 1-65, TAC 3 = 66-439 and TAC 4 ≥ 440). Data regarding ACM was retrieved from the health care provider database. Multivariate Cox proportional regression models were used to assess associations between the TAC categories and ACM. RESULTS: The study cohort included 415 patients (mean age 67 years, 52% male); 107 ACM events were recorded during a median follow-up of 9 years (inter-quartile range: 7.4-10.4). The rate of ACM was 13%, 25%, 32%, 41% according to TAC category (p < 0.001). The highest TAC category (≥ 440) was a strong and independent predictor of ACM [HR = 1.69 (1.13-2.52; 0.01)] in multivariate analysis. Other independent predictors of ACM included age [HR = 1.07 (1.04-1.10; p < 0.001)], male sex [HR = 2.27 (1.49-3.46; 0.001)] and malignancy [HR = 2.21 (1.49-3.23; < 0.001)]. CONCLUSIONS: Severe TAC (≥ 440) was found to be an independent predictor of ACM. Thus, we suggest that documenting and quantifying TAC should be routinely incorporated into standard chest CT reports.

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.