Itamar Ben Shitrit

Pain and fever are common in pregnancy. Dipyrone is widely used in Europe, Latin America, and parts of Asia, but is banned in other countries due to concerns about agranulocytosis. Evidence on its safety in pregnancy remains limited and inconsistent. This study aimed to evaluate whether maternal dipyrone use during the first‐ and third‐trimesters is associated with major congenital malformations (MCMs) and adverse perinatal or early neonatal outcomes. A population‐based cohort of all pregnancies that delivered or underwent elective termination at Soroka University Medical Center from 1998 to 2018, linking maternal, neonatal, and termination records with pharmacy dispensations. Generalized full matching and Poisson regression were used to study the association of first‐and third‐trimester dipyrone exposure and risks of MCMs, perinatal outcomes, and early neonatal complications, including preterm ductal closure and renal injury. Among 264,858 singleton pregnancies analyzed for first‐trimester exposure, 8,987 (3.4%) were exposed to Dipyrone. MCMs occurred in 8.0% of exposed vs. 7.0% of unexposed; however, no association was found after matching (adjusted risk ratio (RR) 1.04, 95% CI: 0.88–1.22). No associations were observed with malformation in other organ systems. In third‐trimester analyses ( n = 257,285; 6,362 (2.5%) exposed), dipyrone was not associated with preterm birth, low birthweight, perinatal death, low Apgar scores, or evidence of renal toxicity or premature ductus arteriosus constriction. No dose–response was observed. Sensitivity Analysis for over‐the‐counter use indicated minimal possible misclassification bias. This study provides evidence supporting maternal dipyrone use in early or late pregnancy is not associated with MCMs, adverse perinatal outcomes, or early neonatal complications.

Background: Pain and fever are common in early pregnancy, yet their management poses a major clinical dilemma. Although not confirmed, recent studies have raised safety concerns regarding acetaminophen. Evidence on the use of nonsteroidal anti-inflammatory drugs (NSAID) in the first trimester remains inconclusive. This uncertainty has left clinicians with limited evidence to guide treatment decisions. This study evaluated the association between first-trimester NSAID exposure and the risk of major congenital malformations (MCMs) in a large, population-based cohort of pregnancies. Methods and findings: We conducted a population-based retrospective cohort study within the Southern Israeli Pregnancy Registry (siPREG) project, including all singleton pregnancies of women aged 15–45 years resulting in live births, stillbirths, or elective terminations for fetal malformations at a Soroka University Medical Center between 1998 and 2018. Pregnancies exposed to established teratogens, multiple gestations, and those with documented genetic or chromosomal anomalies were excluded. First-trimester NSAID exposure was defined by pharmacy dispensations (overall and by specific agents). MCMs were identified from linked clinical, hospitalization, and termination records through the first postnatal year. Propensity scores were estimated using covariates selected via a directed acyclic graph, including maternal age, ethnicity, diabetes, medical indication for NSAID use, exposure to other antipyretics, obesity, smoking, folic-acid use, gravidity, perinatal care, and year of pregnancy. Generalized full matching was used to balance covariates. Adjusted risk ratios were derived using weighted Poisson regression with G-computation, and two-way cluster-robust standard errors, jointly clustering by maternal identifier and matching subclass. Sensitivity analyses included a dose–response assessment across defined-daily-dose (DDD) categories and a tipping-point analysis evaluating the impact of potential misclassification from unrecorded over-the-counter NSAID use. A total of 264,858 singleton pregnancies were included in the final cohort; 20,202 (7.6%) were exposed to NSAID, most commonly ibuprofen (5.1%), diclofenac (1.6%), and naproxen (1.2%). NSAID exposure, in total and as individual agents, was not associated with MCMs overall (8.2% versus 7.0%; matched-adjusted-Relative Risk (aRR) = 0.99 (95% CI [0.90,1.10])) or with organ-system-specific MCMs, including cardiovascular (matched-aRR = 1.05 (95% CI [0.92,1.20]), musculoskeletal (matched-aRR = 1.03 (95% CI [0.77,1.39])), central nervous system (matched-aRR = 0.77 (95% CI [0.53,1.11])), cleft palate (matched-aRR = 0.95 (95% CI [0.47–1.91])), gastrointestinal (matched-aRR = 1.03 (95% CI [0.64–1.63])), and genitourinary (matched-aRR = 0.99 (95% CI [0.72,1.35])) malformations. Dose–response analyses showed no significant association with MCMs across cumulative NSAID exposure: short-term (1–7 DDD, matched-aRR = 1.06 (95% CI [0.97,1.15]), medium-term (8–21 DDD, matched-aRR = 1.10 (95% CI [0.99,1.22]), and long-term (>21 DDD, matched-aRR = 1.24 (95% CI [0.94,1.63])). The main limitation was the potential for minor exposure misclassification due to over-the-counter availability of ibuprofen, although sensitivity analyses simulating such misclassification suggested minimal impact on the risk estimates. Conclusion: In this large, population-based cohort, we found no evidence supporting an association between first-trimester exposure to NSAID and MCMs, providing reassuring evidence regarding their fetal safety in early pregnancy.

STUDY QUESTION: Is maternal paracetamol exposure during the first and third trimesters of pregnancy associated with major congenital malformations and adverse perinatal and postnatal outcomes? SUMMARY ANSWER: Maternal paracetamol use during the first or third trimester was not associated with major congenital malformations or adverse perinatal and postnatal outcomes. WHAT IS KNOWN ALREADY: Paracetamol is the most commonly used analgesic and antipyretic during pregnancy and has long been considered safe. However, recent concerns have been raised regarding potential fetal and perinatal risks, with inconsistent findings across studies. STUDY DESIGN, SIZE, DURATION: In this population-based retrospective study, the cohort included 265 143 singleton pregnancies resulting in delivery or elective termination at a single tertiary medical center between 1998 and 2018. Separate analytic cohorts comprised 264 858 pregnancies for first-trimester analyses and 257 285 pregnancies for third-trimester analyses. Follow-up extended through delivery and the first year of life for congenital malformation ascertainment. There was no loss to follow-up for primary outcomes due to complete registry linkage. PARTICIPANTS/MATERIALS, SETTING, METHODS: All singleton pregnancies among women aged 15–45 years, insured by a regional health maintenance organization and managed at a tertiary university medical center, were included. Pregnancies with chromosomal or genetic abnormalities, teratogenic drug exposure, or multiple gestations were excluded. Paracetamol exposure (prescription and over-the-counter dispensations) was assessed separately for the first trimester (≤13 weeks) and third trimester (≥27 weeks) and categorized by total defined daily doses. Exposed and unexposed pregnancies were compared using multivariable Poisson regression and propensity score-based generalized full matching. Matching incorporated maternal demographics, comorbidities, pregnancy characteristics, and indications for paracetamol use. After matching, covariate balance was achieved (standardized mean differences <0.1 for all variables). MAIN RESULTS AND THE ROLE OF CHANCE: During the first trimester, paracetamol exposure was recorded in 41 011 pregnancies (15.5%); major congenital malformations occurred in 7.9% of exposed versus 6.9% of unexposed pregnancies (crude RR 1.14; 95% CI, 1.1–1.18), with no association after matching (adjusted RR 1.04; 95% CI, 0.98–1.10) and no associations with organ-specific malformations. Third-trimester exposure was recorded in 36 375 pregnancies (14.1%) and was not associated, in the matched analyses, with preterm birth, low or very low birth weight, perinatal death, low Apgar scores, or markers of premature ductus arteriosus closure or neonatal renal impairment. Dose–response and sensitivity analyses showed no evidence of increased risk, and the results were robust to plausible levels of exposure misclassification. LIMITATIONS, REASONS FOR CAUTION: Paracetamol exposure was based on dispensation rather than confirmed intake, and miscarriages were not captured. Exposure misclassification due to unrecorded over-the-counter use is possible; however, sensitivity analyses suggest it is unlikely to materially affect the findings. WIDER IMPLICATIONS OF THE FINDINGS: These findings are consistent with large cohort studies and contribute to the evidence supporting the relative safety of paracetamol use during early and late pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Current evaluations of large language models (LLMs) in healthcare have largely emphasized theoretical benchmarks and clinician oversight, with limited exploration of real-world physician-AI interaction. In this two-stage prospective study, we assessed physician satisfaction with LLM-generated responses to real clinical queries. This study did not evaluate clinical accuracy, patient outcomes, or patient safety. In the first unblinded stage, physicians used three models - a general-purpose model (GPT-4o), a reasoning-focused model (GPT-o1), and a healthcare-specific model (OpenEvidence) - to address 25 clinical dilemmas - and rated the quality of the responses. In the second blinded stage, the same physicians evaluated responses generated either by an LLM or by a human alone, without knowledge of the source. Across 100 real-world medical responses, median physician scores on a 5-point Likert scale were comparable between unblinded and blinded evaluations (p = 0.90). Satisfaction was not associated with physicians’ resistance to change, nor did it correlate with the accuracy or relevance of cited literature. These findings suggest that physicians did not favor information generated by LLMs over externally provided responses, and that clinician satisfaction alone may not serve as a reliable proxy for validating decision support tools.

Purpose: While migraine is linked to increased cerebrovascular risk, its association with non-arteritic anterior ischemic optic neuropathy (NAION) remains underexplored. Methods: We conducted a retrospective case–control study using population-based electronic medical records. NAION patients were compared to propensity score-matched controls regarding migraine prevalence and clinical characteristics. Results: From 2001 to 2022, among 6,566,619 patients, 1629 NAION cases (mean age 67 ± 13 years; 45% female) and 6433 propensity matched controls were identified. The prevalence of migraine was similar in both groups (3.8% vs. 3.3%, p = 0.3). Among migraine patients, those with NAION (n = 62, age 62 ± 11) and controls (n = 212, age 60 ± 11) had comparable baseline characteristics, except for congestive heart failure (9.7% vs. 2.4%, p = 0.027). Within the NAION cohort, migraineurs (n = 64) were younger (62 ± 12 vs. 67 ± 13 years, p < 0.001), and had lower rates of diabetes mellitus (35% vs. 57%, p < 0.001) and peripheral vascular disease (1.6% vs. 9.6%, p = 0.03). Female migraineurs developed NAION at a younger age than females without migraine (60 ± 12 vs. 69 ± 12 years, p < 0.001); no such difference was seen in males. Multinomial logistic regression revealed that migraine was independently associated with younger age at NAION onset, particularly in patients aged 70. An independent 1:4 migraine to non-migraine matched cohort (n = 310) showed similar age-dependent trends. Conclusions: While migraine was not more prevalent among NAION patients, females with migraine developed NAION at a younger age and had fewer vascular comorbidities. Congestive heart failure was more prevalent among migraine patients who developed NAION, suggesting a potential contributory role of systemic hypoperfusion.

Medical students often begin their studies with preconceived notions about specialties, which may evolve as they gain clinical experience. This study aimed to assess changes in specialty preferences over six years of medical training and to compare two cohorts of first-year students. A repeat cross-sectional design was used, analyzing survey data from the 2019 class during preclinical (first–second year) and clinical (sixth year) stages, and from the 2024 first-year cohort. A total of 367 students participated. Comparing preclinical and clinical students revealed a significant increase in interest in ophthalmology (2.9% vs. 11%, p = 0.012), along with non-significant upward trends in obstetrics and gynecology and family medicine. Declines were observed in psychiatry, oncology, neurosurgery, and surgery. The 2024 cohort included a higher proportion of students with a prior medical background compared with the 2019 cohort (43% vs. 23%, p = 0.002), but no other demographic or specialty preference differences were identified. These findings suggest that specialty preferences among medical students may shift during clinical training, while initial preferences appear relatively consistent across cohorts. Understanding how medical education influences career development may guide curricular strategies to balance specialty distribution and address workforce needs.

Objective: To investigate whether maternal diabetes during pregnancy is associated with increased risk of strabismus and refractive errors (RE) in their offspring. Methods: This retrospective cohort study utilized electronic medical records from Clalit Health Services (CHS) in Israel, 2001–2023. Births were categorized by maternal diabetes type (type 1, type 2, or gestational) or no diabetes. Mixed models compared demographics and ocular conditions, including RE and strabismus, while generalized estimating equations calculated odds ratios adjusting for confounders. Results: A total of 505 928 maternal and offspring records were analyzed. Strabismus prevalence was 496 (2.0%) in children of diabetic mothers versus 7346 (1.5%) in those of non‐diabetic mothers (odds ratio [OR] 1.29, 95% confidence interval [CI]: 1.18–1.42), and remained significant after adjustment (OR 1.40, 95% CI: 1.27–1.55). In children of mothers with HbA1c >6.5%, strabismus prevalence was 49 (2.9%) compared to 7793 (1.5%) with HbA1c ≤6.5% (adjusted OR 1.78, 95% CI: 1.30–2.43). RE prevalence was 753 (3%) among offspring of diabetic mothers versus 10 785 (2.2%) among non‐diabetic mothers (OR 1.34, 95% CI: 1.24–1.44), with maternal diabetes remaining significantly associated with RE after adjustment (OR 1.61, 95% CI: 1.48–1.74). In the HbA1c >6.5% group, RE prevalence was 71 (4.2%) versus 11 467 (2.3%) with normal HbA1c (adjusted OR 1.97, 95% CI: 1.54–2.53). Conclusion: Maternal diabetes during pregnancy is associated with strabismus and RE in the offspring, with higher risk with high HbA1c levels.

Background: Cardiopulmonary exercise testing (CPET) is a valuable diagnostic and prognostic tool for assessing the integrated function of the cardiopulmonary and muscular systems during exercise. The initiation of a CPET program is complex, and data on early implementation in academic centers remain relatively limited. Objective: to evaluate the initial integration of CPET within a pulmonary department, focusing on patient demographics, referral indications, test performance, and factors associated with anaerobic threshold achievement. Methods: A retrospective cohort study was conducted at a single tertiary care center, including all patients who underwent their first CPET between February 2016 and December 2022. Demographic, clinical, and functional parameters were extracted. Multivariable logistic regression was used to identify variables associated with anaerobic threshold achievement, defined as a respiratory exchange ratio (RER) ≥ 1.1. Results: The cohort included 434 patients (mean age 60.3 ± 14.1 years; 54% male; mean BMI 29.2 ± 5.6 kg/m²). The most common indication for testing was dyspnea (50%). Tests were most frequently terminated due to leg discomfort (39%) and dyspnea (38.8%). Achievement of RER ≥ 1.1 was independently associated with lower BMI (aOR = 0.91; 95% CI: 0.88–0.95; p < 0.001), higher FVC % predicted (aOR = 1.02; 95% CI: 1.00–1.03; p = 0.028), and greater minute ventilation volume (aOR = 1.02; 95% CI: 1.01–1.03; p < 0.001), and it was less likely in patients referred for cardiovascular disease (aOR = 0.37; 95% CI: 0.21–0.64; p < 0.001). No consistent temporal trend in RER achievement was observed across the study period. Conclusions: CPET was most commonly utilized in response to patient-reported dyspnea, with test termination frequently driven by subjective symptoms rather than objective clinical criteria. Anaerobic threshold achievement was more strongly associated with individual physiological characteristics than with institutional experience. These findings underscore the importance of patient preparation and pulmonary functional capacity in optimizing CPET performance.

Abdominal pain is a leading cause of primary care visits and emergency department admissions. The recent surge in the implementation of point-of-care ultrasound into primary care underscores the necessity for specialized training to enhance the expertise of primary care physicians and foster a positive attitude toward its routine use in clinical activities. This prospective cohort study, conducted between March and August 2023 at Ben Gurion University, introduced an integrative abdominal ultrasound program for 48 participating primary care physicians with no prior formal experience in abdominal ultrasound. Physicians' knowledge, practical skills, and attitudes towards abdominal ultrasound integration were evaluated using a pre/post-course clips-based pathology test, a hands-on exam immediately following the course, and a survey conducted ten weeks later. Post-course evaluations showed an improvement in primary care physicians' proficiency with hands-on skills, increasing from 26 to 69% (p < 0.001), with increased comfort using abdominal ultrasound (from 0 to 42%, p < 0.001) and enhanced understanding of its capabilities and limitations (from 0 to 58%, p < 0.001). Pattern recognition skills, assessed through clips, presented a notable rise from an average of 26% to 69% (p < 0.001). Ten weeks following the training, an increase in its utilization was observed; weekly usage rose from zero to 44%, and the proportion not using it declined from 94 to 19% (p < 0.001, p < 0.001, respectively). An integrative two-day training program increases the application of abdominal bedside ultrasound in clinical settings, demonstrating the effectiveness of combining practical training with flexible, theoretical learning.

Purpose: Point-of-care ultrasonography (PoCUS) has improved the diagnostic capacity of medical conditions; however, integrating it into medical curricula is constrained by cost, time, accessibility, and teaching style variability. This study examines whether simulator-based self-learning for cardiac PoCUS is noninferior to instructor-guided teaching. Method: This randomized controlled trial, conducted at Ben-Gurion University of the Negev, enrolled 116 medical students as part of the medical school’s PoCUS curriculum. Participants were randomly assigned to a simulator-based self-learning or conventional instructor-guided teaching group. After training, which took place January 29 to February 22, 2023, participants completed exams on February 23, 2023, assessing their abilities to obtain specific cardiac views, capture images of quality, and correctly identify common cardiac pathologies. Results: Of 116 participants, 57 (49.1%) were categorized into the instructor-guided group and 59 (50.9%) the self-learning group. Participants in the self-learning group had higher total test scores compared with the instructor-guided group (81.6% vs 77.2%, P = .30), with only the apical 2-chamber view reaching statistical significance in favor of the self-learning group (81.3% vs 68.3%, P = .04). The self-learning group also scored higher on image quality, but the difference was not statistically significant (59.5% vs 55.6%, P = .26). There was no significant difference in total scores for cardiac pathology identification (93.5% in the self-learning group vs 94.7% in the instructor-guided group, P = .81). A multivariable logistic regression presented no significant difference in achieving an above median score when adjusted for gender, chest anatomy academic grade, and prior PoCUS training (adjusted odds ratio, 1.55; 95% CI, 0.69–3.53; P = .30). Conclusions: This study suggests that the self-learning approach is noninferior to instructor-guided teaching for cardiac ultrasonography training. Incorporating these programs into medical curricula may enhance the quantity and proficiency of PoCUS operators, improving diagnostic capabilities and treatment outcomes across medical specialties.