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 INTERESTS:No funding was received for this study. All authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:N/A.

INTRODUCTION:Neonatal jaundice is a leading cause of early post-discharge referrals. Community follow-up commonly relies on visual assessment and clinic-based evaluation, generating avoidable visits. Scalable home pathways that maintain safety are needed. We evaluated a nurse-led home pathway that integrates transcutaneous bilirubin (TcB) screening with targeted pediatric teleconsultation. METHODS:A prospective before-after study was conducted within routine nurse-led home visits for eligible infants (firstborn or preterm) ≥35 weeks of gestation. A 3-month pre-intervention phase (usual visual assessment) was compared with a 9-month intervention using TcB-guided thresholds and teleconsultation via a secure digital platform. The primary analysis targeted infants who, under usual care, would be referred ("baseline-eligible"), estimating the absolute difference in referral at the home visit. Secondary outcomes were agreement between clinical cues and TcB, teleconsultation utilization, and phototherapy requirement. RESULTS:A total of 1,236 infants were enrolled (157 pre-intervention; 1,079 intervention). Among baseline-eligible infants (n = 840), 152 (18.1%) were referred; thus, 688/840 (81.9%) potential referrals were avoided (absolute reduction 81.9%; 95% CI 79.2-84.4; NNR 1.22, 95% CI 1.19-1.26). TcB identified all infants requiring phototherapy (4/1,079; 0.4%) within 14 days. Agreement between clinical cues and TcB-defined need for follow-up was slight (weighted κ = 0.075; 95% CI 0.059-0.091). The reduction in referrals corresponded to an absolute decrease of 0.67 visits per infant. CONCLUSIONS:A nurse-led, digitally supported home pathway that integrates TcB screening and targeted teleconsultation substantially reduces unnecessary neonatal referrals, with no missed cases requiring phototherapy. This pragmatic precision-triage model is implementable within existing community services and can relieve post-discharge system burden while preserving safety.

OBJECTIVE:Preterm birth presents a substantial health, psychological, and economic burden worldwide. Environmental factors, including temperature fluctuations, are known to influence the risk of preterm birth. This study aimed to investigate the association between high temperatures and heat load and preterm births. METHODS:Using a time-series analysis, we examined data from all births in five Israeli districts between 2010-2016. Meteorological indices were computed for each district. Distributed lag non-linear models (DLNM) incorporating Poisson regression were employed to investigate the associations between these meteorological indices and the daily number of preterm births across various time lags, assessing both short- and long-term associations, adjusting for seasonality, holidays and the general trend. RESULTS:During the study period, 1 216 040 newborns were delivered, of which 89 544 (7.36%) were preterm (<37 weeks) and 11 154 (0.91%) early preterm (<32 weeks). Significant non-linear associations were found between temperature, heat load, and daily preterm births. Acute exposure to a 1°C increase in mean daily temperature 14 days before delivery was associated with a higher risk of preterm birth (relative risk [RR] = 1.015; 95% confidence interval [CI]: 1.010-1.019). Similarly, acute exposure to a 1°C increase in maximal heat load 14 days before delivery was associated with elevated risk (RR = 1.018; 95% CI: 1.011-1.026). Cumulative effects over 14 days were substantial: a 1°C rise in mean daily temperature was linked to a 16% increase in risk (RR = 1.160; 95% CI: 1.145-1.176), while a 1°C increase in maximal heat load was associated with a 14% increase (RR = 1.139; 95% CI: 1.125-1.153). Similar associations were observed for heat load, and for early preterm and very low birth weight births; however, these subgroup analyses were based on fewer events and had wider CIs. CONCLUSION:High temperatures and heat load increase the risk of preterm birth over both short- and long-terms. In the context of global warming, these findings may warrant consideration of climate-related risks in maternal health planning and to develop preventive strategies against heat-related pregnancy complications.

BackgroundPain 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 findingsWe 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.ConclusionIn 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.

Firefighters are subject to significant risks to their health, including an increased risk for significant morbidities due to exposure to pollutants. The aim of this study was to examine the magnitude of firefighters' exposure to various hazardous substances in a large cross-sectional study. Detailed activity records of 108 firefighters, questionnaires blood and urine samples were collected and compared with 104 men with other occupations. Heavy metals, carboxyhemoglobin and PBDE levels were compared between firefighters and controls. Correlations were explored between pollutant levels and individual exposure frequencies to the total number of fire events, and by subtypes. Significant differences between firefighters and controls were observed in levels of Cr (0.41 ± 0.52 vs. 0.2 ± 0.14 µg/g creatinine, p-value = 0.006), Ni (0.55 ± 0.63 vs. 1.13 ± 0.59, p-value < 0.001) and Pb (0.26 ± 0.23 vs. 0.36 ± 0.21, p-value < 0.001). No significant difference was found in other metals, As (12.7 ± 10.7 vs. 11.8 ± 10.8), Cd (0.26 ± 0.14 vs. 0.23 ± 0.10), Hg (0.42 ± 0.43 vs. 0.59 ± 0.81), as well in COHb levels (2.80%±1.66 vs. 3.01%±1.58). Smokers exhibited significantly higher COHb levels. When adjusted for age and education, firefighters had significantly higher levels of As (p < 0.001) and lower levels of Ni (p < 0.001) vs. controls. We found low PBDEs levels, suggesting low exposure compared to firefighters from other countries. Exposure to fire events was not correlated with pollutant levels among firefighters. Israeli firefighters show low exposure to carbon monoxide, heavy metals, and PBDEs compared to international cohorts, though PBDEs levels exceed controls. No correlation exists between firefighting activities and pollutant levels, suggesting effective protective equipment use.

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.

AimsThe aim of this study was to assess the risk of major congenital malformations following first-trimester pseudoephedrine (PSE) exposure.MethodsA population-based observational cohort study was conducted on pregnancies of women aged 15-49 years, insured by Clalit Health Services in southern Israel, who gave birth or had elective pregnancy terminations due to suspected fetal malformation at Soroka Medical Center (1999-2017). The study focused on Clarinase, a drug that contains a high dose of PSE (120 mg) and 5 mg of loratadine. Multivariable negative binomial regression models were used to evaluate the risk for major congenital malformations, adjusting for potential confounders.ResultsOf 251 543 pregnancies, 313 (0.12%) were exposed to high-dose PSE in the first trimester. PSE exposure was not associated with major congenital malformations overall (adjusted relative risk [aRR] = 0.90, 95% confidence interval [CI] 0.558-1.45; P = 0.66) or by organ system (cardiovascular: aRR = 0.938, 95% CI 0.499-1.762; central nervous system: aRR = 0.618, 95% CI 0.086-4.451; musculoskeletal: aRR = 1.800, 95% CI 0.801-4.042; gastrointestinal: aRR = 1.013, 95% CI 0.142-7.241; genitourinary: aRR = 0.704, 95% CI 0.225-2.204).ConclusionsFirst-trimester PSE exposure was not an independent risk factor for major congenital malformations, either overall or by organ system.

AIMS:Papaverine hydrochloride functions as an antispasmodic and vasodilator medication. Data concerning the teratogenic risk of papaverine is currently lacking. The aims of this paper are to examine the association between first-trimester exposure to papaverine and major congenital malformations and the association between third trimester exposure to papaverine and late adverse pregnancy outcomes. METHODS:We conducted a population-based retrospective cohort study that included pregnant women 15-49 years old insured by 'Clalit Health Services' in southern Israel, who gave birth or had an elective pregnancy termination due to suspected fetal malformation at Soroka Medical Center between 1999 and 2017. Multivariate negative binomial regression models were used to examine the associations between papaverine during the first trimester and major congenital malformations, and between papaverine during the third trimester and late adverse pregnancy outcomes, adjusting for potential confounders. RESULTS:The study included a total of 254 333 pregnancies, of which 3604 (1.41%) were exposed to papaverine during the first trimester, and 1253 (0.49%) during the third trimester. No significant associations were found between first-trimester exposure to papaverine and total congenital major malformations or specific malformations according to organ systems in the multivariate analysis (adjusted RR for: total major malformations = 1.021; 95% confidence interval (CI) [0.895-1.165], cardiovascular = 1.073; 95% CI [0.905-1.273], central nervous system = 0.784; 95% CI [0.484-1.271], musculoskeletal = 0.823; 95% CI [0.588-1.153], gastrointestinal = 0.887; 95% CI [0.457-1.718], genitourinary = 1.076; 95% CI [0.805-1.438]). Additionally, we did not detect significant associations between third-trimester exposure to papaverine and late adverse pregnancy outcomes. CONCLUSIONS:Exposure to papaverine during pregnancy was not associated with adverse pregnancy outcomes in the population studied, compared with non-exposed pregnancies.

BackgroundWhile individual socioeconomic attributes have been widely studied in relation to child growth, the associations with broader, area-level socio-demographic characteristics of residential areas have not been thoroughly assessed.ObjectivesTo examine the associations between area-level socio-demographic features of small residential areas and child growth trajectories.MethodsWe conducted a population-based retrospective cohort study, including all children born in Israel from 2004 to 2018, who underwent postnatal follow-up in the Mother and Child Health Clinics (MCHC) of the Ministry of Health. The MCHC network covers a significant proportion of the Israeli paediatric population, providing vaccination and developmental assessments to children up to 6 years old. Socio-demographic scoring was retrieved from the Israel Bureau of Statistics' geographical unit grading system, established for 990 rural areas and 1629 micro-geographical areas in 81 cities, using various population measurements. Height-for-age (HAZ) and weight-for-age (WAZ) z-scores were calculated using data from MCHC visits at birth and specific intervals.ResultsA total of 1,485,198 children were included (51.3% male). The mean birthweight and length were 3210 +/- 52.2 g (z = -0.22) and 49.4 +/- 3.33 cm (z = -0.06), respectively. Children resided in low (47%), intermediate (24.4%) and high (28.5%) socioeconomic areas. Throughout follow-up, children from low SES areas had consistently lower HAZ and WAZ scores across all birthweight groups, particularly among those with normal and high birthweight. In linear mixed-effects models, birth HAZ and WAZ scores were higher in high vs. low SES areas (beta = 0.3 and beta = 0.1, respectively), with non-linear growth trajectories characterised by early advantages in higher SES groups, a plateau in mid-childhood and renewed growth acceleration later in childhood.ConclusionsThe study provides evidence of impaired child growth in lower socio-demographic areas. This underscores the importance of identifying areas based on global attributes to identify regions predisposed to child growth impairment, particularly in developed nations.

Doxycycline is frequently prescribed during pregnancy, yet evidence on fetal safety is inconsistent and often excludes non-live births. We assessed whether exposure during the first or third trimester is associated with major congenital malformations or late-pregnancy adverse outcomes in a population-based cohort that also included stillbirths and terminations. Using data from Clalit Health Services Southern district, we identified 265,686 pregnancies in women aged 15–45 years (from 1998 to 2017). Pharmacy records classified doxycycline dispensation in the first trimester (≤ 13 weeks) or third trimester (≥ 27 weeks). Crude and adjusted negative-binomial models estimated relative risks (RRs) for total and organ-specific major congenital malformations diagnosed up to age 1 year and for perinatal mortality, preterm birth, low/very-low birthweight, and low Apgar scores. Sensitivity analyses explored dose-response relations and propensity-score-matched cohorts. Among 2,696 first-trimester exposures, major malformations occurred in 7.7

Previous studies evaluating the risk of spontaneous abortions following exposure to macrolides reported controversial results. The goal of the current study was to examine the risk for spontaneous abortions following exposure to macrolides during pregnancy.We conducted a population-based retrospective cohort study by linking three computerized databases: Clalit Health Services drug dispensation database, Soroka Medical Center (SMC) birth database, and SMC hospitalizations database. Multivariate time-varying Cox regressions were performed and adjusted for suspected confounders and known risk factors for spontaneous abortions. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated. A secondary analysis was performed to assess the association between exposure to macrolides in terms of the defined daily dose dispensed and spontaneous abortions.The study cohort included 65,457 pregnancies that ended at Soroka Medical Center between 2004 and 2009, of which 6508 (9.9%) resulted in a spontaneous abortion. A total of 825 (1.26%) pregnancies were exposed to macrolides during the exposure period. Exposure to macrolides was not associated with spontaneous abortions as a group (adjusted HR 1.00 95% CI 0.77-1.31) or as specific medications. There was no evidence of a dose-response relationship between exposure to macrolides and spontaneous abortions.In conclusion, this population-based retrospective cohort study did not detect an increased risk for spontaneous abortion following exposure to macrolides during the first trimester of pregnancy.

Prenatal exposure to aromatic hydrocarbons has been associated with adverse health outcomes in animal studies; However, there have been limited studies of the associations between prenatal exposure to these compounds and measurable outcomes in human newborns. We recruited pregnant women who lived in urban areas in Israel and were admitted to the delivery rooms of two major hospitals between 2016 and 2020. The primary outcomes were newborn birthweight, length, and head circumference, measured by neonatologists in delivery rooms. Urine samples were collected from all mothers within 24 hours of admission for further BTEX analysis. A total of 883 women and their term-born infants (n(%) 462 (52%) male; mean±SD infant gestational age, 39.5±1.3 weeks) were recruited; Traces of toluene, xylene, and ethylbenzene metabolites were detected in all samples and were lower than those previously reported among worldwide population, with mean (±SD) concentrations of benzylmercapturic-acid (23.8±51.5 μg/g creatinine); methylhippuric-acid (292.5±527.2 μg/g creatinine); and phenylglyoxylic-acid (555.2±737.7 μg/g creatinine), respectively. An increase in phenylglyoxylic-acid levels was found to be associated with a decrease in males birthweight (b= -40.856 g; 95% confidence interval (CI) -73.073 to -8.639). Further exclusion of newborns considered small and large for gestational age resulted in an association between an increase in phenylglyoxylic-acid levels and head circumference of males (b= -.07 cm; 95%CI:-.146 to -.005). Prenatal exposure to Styrene and Ethylbenzene in relatively low levels is associated with decreased birth weight and head circumference among males by a mechanism that is yet to be fully understood and requires further analysis.

Objective This study aimed to investigate the efficacy and tolerability of Lacosamide (LCM) in a pediatric population with refractory epilepsy in relation to serum concentration, age, and dosage. Methods Demographic and clinical data were collected from the medical records of children with refractory epilepsy treated with LCM at Shamir Medical Center between February 2019 to September 2021, in whom medication blood levels were measured. Trough serum LCM concentration was measured in the biochemical laboratory using High-Performance Liquid Chromatography (HPLC) and correlated with the administered dose and clinical report. Results Forty-two children aged 10.43 ± 5.13 (range: 1–18) years old were included in the study. The average daily dose of LCM was 306.62 ± 133.20 mg (range: 100–600). The average number of seizures per day was 3.53±7.25 compared to 0.87±1.40 before and after LCM treatment, respectively. The mean LCM serum concentration was 6.74±3.27 mg/l. No statistically significant association was found between LCM serum levels and the clinical response (p=0.58), as well as the correlation between LCM dosage and the change in seizure rate (p=0.30). Our study did not find a correlation between LCM serum concentration and LCM dosage and the gender of the participants: males (n=17,) females (n=23) (p=0.31 and p=0.94, respectively). A positive trend was found between age and LCM serum concentrations (r=0.26, p=0.09). Conclusion Determination of serum concentrations is not needed in all children treated with LCM. Serum concentrations may be valuable in patients with refractory epilepsy for compliance evaluation or in patients with satisfactory control of seizures to determine their therapeutic baseline.

BACKGROUND:Several studies have associated prenatal exposure to volatile organic compounds (VOCs) with adverse health outcomes among newborns. However, little is known about the associations of VOCs at relatively low concentrations with newborn outcomes. Hence, this study aimed to investigate the potential associations between prenatal exposure to VOCs and VOC mixtures with newborn anthropometric measures. METHODS:In this cross-sectional study, 883 mother-term infant pairs who lived in urban areas in Israel and were admitted to the delivery rooms of two major hospitals between 2016 and 2020 were recruited. Associations between VOC metabolites detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using single-exposure linear models and weighted quantile sum (WQS) approach. RESULTS:Toluene, ethylbenzene/styrene, and xylene metabolites were detected in most samples at levels comparable to OECD populations. In male newborns, higher levels of phenylglyoxylic acid (PGA), a metabolite of ethylbenzene/styrene, were associated with lower birth weight (β = -0.08, 95% CI: 0.14, -0.01; P = 0.03). WQS models suggested PGA as the most prominent contributor to this association. CONCLUSION:This study suggests that moderate exposure to ethylbenzene/styrene may be associated with reduced birth weight in male newborns. The sex-specific finding requires further research for the potential endocrine-disrupting mechanisms of these compounds. While the effect size was small, these results highlight the need to better understand the associations of frequent VOC exposures in levels similar to those common in OECD countries with fetal and child development.

Objective: This study aimed to investigate the efficacy and tolerability of Lacosamide (LCM) in a pediatric population with epilepsy using LCM serum concentration and its correlation to the age of the participants and the dosage of the drug. Methods: Demographic and clinical data were collected from the medical records of children with epilepsy treated with LCM at Shamir Medical Center between February 2019 to September 2021, in whom medication blood levels were measured. Trough serum LCM concentration was measured in the biochemical laboratory using High-Performance Liquid Chromatography (HPLC) and correlated with the administered weight-based medication dosing and clinical report. Results: Forty-two children aged 10.43 ± 5.13 years (range: 1–18) were included in the study. The average daily dose of LCM was 306.62 ± 133.20 mg (range: 100–600). The average number of seizures per day was 3.53 ± 7.25 compared to 0.87 ± 1.40 before and after LCM treatment, respectively. The mean LCM serum concentration was 6.74 ± 3.27 mg/L. No statistically significant association was found between LCM serum levels and the clinical response ( p = 0.58), as well as the correlation between LCM dosage and the change in seizure rate ( p = 0.30). Our study did not find a correlation between LCM serum concentration and LCM dosage and the gender of the participants: males (n = 17) females (n = 23) ( p = 0.31 and p = 0.94, respectively). A positive trend was found between age and LCM serum concentrations (r = 0.26, p = 0.09). Conclusion: Based on the data that has been obtained from our study, it appears that therapeutic drug monitoring for LCM may not be necessary. Nonetheless, further research in this area is needed in the light of the relatively small sample size of the study.

Child malnutrition is a major issue in conflict zones. Evidence-based interventions and their thorough evaluation could help to eliminate malnutrition. We aimed to assess the causal effect of a community-based multidisciplinary nutrition program for children in a chronic conflict zone near the northeastern border of Armenia on two main outcomes: stunting and anemia. We further compared the interpretations and public health relevance of the obtained effect estimates. In 2016, the study measured hemoglobin and anthropometric measures and collected data from the children’s caregivers. We used propensity score matching analyses, inverse probability weighting, and overlap weighting methods to examine the average treatment effects among treated population (ATT), and among population with overlapping weights (ATO). The ATT for stunting among children who participated in the intervention program estimated by propensity score matching analyses (PSM-ATT) was (1.95; 95%CI 1.15–3.28). Nevertheless, children who took part in the program had a lower risk of anemia (0.28; 95%CI 0.19–0.42). The ATT, estimated by inverse probability weighting (IPTW-ATT), was slightly lower for stunting (1.82; 95%CI 1.16–2.86) while similar for anemia (0.33; 95%CI 0.23–0.46) compared to PSM-ATT. Compared to the IPTW-ATT and PSM-ATT the ATO was lower for stunting (1.75; 95%CI 1.14–2.68) and similar for anemia (0.31; 95%CI 0.22–0.43). Marginal models could be used in similar quasi-experimental settings to identify the causal effect of interventions in specific populations of interest. Nonetheless, these methods do not eliminate threats to internal validity. Thorough study design and accurate data collection are necessary to improve the efficiency of marginal models.

AbstractBackgroundThe standard chemotherapy treatment protocol for patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) requires as long as 56 days of hospitalization over six months. Where the 5‐Fluorouracil (5‐FU) pump is available, most treatment will be on outpatient bases, however patients will still be under chemotherapy treatment for a comparable period of time (around 50 days).AimA modified protocol was assessed to decrease hospitalization and/or chemotherapy treatment time without sacrificing outcomes, to potentially increase patient quality of life.Methods and resultsA retrospective analysis (2005–2018) of recurrent/metastatic HNSCC patients with a modified treatment protocol was performed. Treatment consisted of cisplatin, cetuximab, 5‐fluorouracil bolus and leucovorin administered on day 1 of a 2‐week cycle, and a continuous infusion of 5‐fluorouracil on days 1–2 of the cycle. Outcomes were measured by progression‐free survival, overall survival, and patient hospitalization time. Analysis was done using the Kaplan–Meier survival function curve.The study cohort consisted of 27 patients. The modified treatment protocol resulted in a median progression‐free survival of nine months and median overall survival of 14 months, while hospitalization time was reduced by almost 80% in the first six months of treatment.ConclusionsModification of the cisplatin, cetuximab, 5‐FU and leucovorin protocol to a bi‐weekly regimen utilizing alternative drug delivery methods, significantly reduced patient hospitalization from 56 days to 12 days in the first 6 months of treatment. This was achieved without compromising treatment outcome, while significantly reducing the days patients were exposed to chemotherapy, and thus potentially improving quality of life.

Background Numerous studies have suggested significant associations between prenatal exposure to heavy metals and newborn anthropometric measures. However, little is known about the effect of various heavy metal mixtures at relatively low concentrations. Hence, this study aimed to investigate associations between prenatal exposures to a wide range of individual heavy metals and heavy metal mixtures with anthropometric measures of newborns. Methods We recruited 975 mother–term infant pairs from two major hospitals in Israel. Associations between eight heavy metals (arsenic, cadmium, chromium, mercury, nickel, lead, selenium, and thallium) detected in maternal urine samples on the day of delivery with weight, length, and head circumference at birth were estimated using linear and Bayesian kernel machine regression (BKMR) models. Results Most heavy metals examined in our study were observed in lower concentrations than in other studies, except for selenium. In the linear as well as the BKMR models, birth weight and length were negatively associated with levels of chromium. Birth weight was found to be negatively associated with thallium and positively associated with nickel. Conclusion By using a large sample size and advanced statistical models, we could examine the association between prenatal exposure to metals in relatively low concentrations and anthropometric measures of newborns. Chromium was suggested to be the most influential metal in the mixture, and its associations with birth weight and length were found negative. Head circumference was neither associated with any of the metals, yet the levels of metals detected in our sample were relatively low. The suggested associations should be further investigated and could shed light on complex biochemical processes involved in intrauterine fetal development.