Possible associations between prenatal exposure to environmental pollutants and neurodevelopmental outcome in children.

This study aimed to evaluate associations between prenatal and childhood exposure to phthalates and prenatal exposure to polychlorinated biphenyls (PCBs) and the development of 4-year-old children. Urinary metabolites of five phthalates were measured in women upon delivery, as well as serum concentrations of four PCB congeners. Postnatal phthalate metabolites were measured from children's urine obtained at the time of developmental assessment. The primary outcome was cognitive function as evaluated by the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) administered at 4 years. Secondary outcomes were motor function and response to sensory stimuli as evaluated by the Developmental Coordination Disorder Questionnaire (DCDQ) and Short Sensory Profile (SSP) that the mothers filled out, respectively. The study included 57 mother-child pairs. Higher maternal phthalate metabolite concentrations were inversely associated with WPPSI-III scores among boys and not among girls. After using linear regression models and controlling for confounding variables, we found that higher levels of monobenzyl phthalate (MBzP) were the ones associated with lower WPPSI-III scores (p=0.004, 95 %CI [-14.18; -3.16]), lower DCDQ scores (p=0.007, 95 %CI [-6.08; -1.17] and lower SSP scores (p=0.004, 95 %CI [-7.47; -1.79]). No association was found between child urinary phthalate metabolite concentrations or maternal PCB blood concentrations and developmental function. These findings indicate that higher prenatal phthalate metabolite levels may be associated with deficits in neurologic development of young boys.

Association between prenatal phthalate exposure and ano-genital indices among offsprings in an Israeli cohort.

Background: In-utero phthalate exposure was shown to be associated with shortened anogenital distance (AGD) in male newborns, but findings among female are inconsistent. While phthalate exposure among pregnant women in Israel is widespread, no study has examined the association with offspring AGD. The objective of the current study was to investigate the association between maternal phthalates urinary concentration and offspring AGD at time of delivery among a birth cohort in Israel. Methods: We measured spot urinary concentration of monobutyl phthalate (MBP), monobenzyl phthalate (MBzP), mono-2-ethyl-5-carboxypentyl phthalate (MECPP), mono-2-ethyl-5-hydroxyhexylphthalate (MEHHP), mono-2-ethyl-5-oxohexyl phthalate (MEOHP) among women presenting to the delivery room at Shamir Medical Center in Israel. Birthweight, length and AGD were measured in all newborns using a standardized protocol. Each AGD measurement was adjusted to weight (ano-genital index). Confounders included socio-demographic characteristics, comorbidities and obstetrical history. Univariate and multivariate analyses assessed the associations between phthalates, confounders and AGD. Results: Overall, 193 mother and infant were analyzed. All newborns were born at term and had normal Apgar scores. Mean maternal age was 32 ± 4.7 years old. Mean birth weight and pregnancy week were 3183 ± 498 g and 39 ± 1.3, respectively. Median (IQR) urinary phthalate concentration adjusted to creatinine (ug/g) were 3.96 (2.2-6.6), 1.22 (0.7-2), 10.84 (7-20.4), 6.36 (3.3-11.2) and 0.64 (0.4-1.1) for MBP, MBzP, MECPP, MEHHP and MEOHP, respectively. Univariate comparison showed a significant association between higher than median MBzP concentration, higher Ano-Fourchetal index (AFI: 4.4 vs. 4.1, p = 0.037) and Ano-clitoral index (ACI: 11.5 vs. 10.4, p = 0.032) in infants. Total urinary phthalates concentration ≥26.25 µg/g was significantly associated with smaller penile width index (3.5 vs. 3.7, p = 0.022), higher ACI (11.6 vs. 10.3, p = 0.013) and a trend towards significance for higher AFI (4.3 vs. 4.1, p = 0.055). Following multivariate linear regression only PWI remained significantly associated with total phthalate urinary concentration. Conclusions: Maternal urinary phthalates concentration at delivery were not associated with female AGD, but total urinary phthalate concentration were inversely associated with penile width.

Characteristics for Medical Cannabis Treatment Adherence among Autistic Children and Their Families: A Mixed-Methods Analysis.

Introduction: Medical cannabis treatment for autistic children has recently become popular, and studies have focused on examining the treatment's effects on children's symptom presentation, reported side effects, and dropout rates. However, no previous study has investigated the factors influencing adherence and dropout rates in cannabis treatment. Method: This explanatory sequential mixed-methods study explored these factors by examining the characteristics of 87 autistic children and their families and deepening parents' perspectives and experiences of the 6-month CBD-rich cannabis treatment's benefits and barriers. Results: We found this treatment to have a high (75%) adherence rate, relatively mild side effects, and substantial reported benefits for the children and families. However, this treatment was not free of barriers; the intake regime, some side effects, and in some cases, unrealistic parental expectations made adherence difficult for some families. Conclusion: Our results highlight the importance of providing professional guidance and knowledge to parents of autistic children, enhancing their understanding of the impact of CBD-rich cannabis treatment on their children and expected related challenges, and coordinating realistic treatment expectations. We hope that addressing these important aspects will influence parents' ability to adhere to and enjoy the benefits of cannabis treatment for their autistic children.

Effects of Medical Cannabis Treatment for Autistic Children on Anxiety and Restricted and Repetitive Behaviors and Interests: An Open-Label Study.

Background: The literature supports the benefits of medical cannabis for core and comorbid symptoms in autistic individuals and anxiety-related symptoms in individuals without autism. However, no study has specifically investigated how cannabidiol (CBD)-rich cannabis affects anxiety subtypes in autistic children or its relationship with restricted and repetitive behaviors and interests (RRBI). Understanding the effects of CBD-rich cannabis treatment on anxiety subtypes and RRBI could offer more precise treatment approaches to managing anxiety symptoms and reducing RRBI frequency in autistic children. Objectives: To examine (1) the impact of CBD-rich cannabis treatment on autistic children's (1a) anxiety levels and subtypes and (1 b) RRBI and subtypes and (2) whether changes in anxiety explain changes in RRBI following cannabis treatment. Method: In this open-label study, we analyzed data from 65 autistic children (5-12 years) who had participated in research on the effects of CBD-rich cannabis on children with autism. Their parents completed the Repetitive Behavior Scale-revised to assess the frequency and severity of six subgroups of their children's recurrent behaviors and the Screen for Child Anxiety-Related Emotional Disorders for symptoms related to five types of anxiety disorders. They completed these assessments at three time points: (T1) before treatment, (T2) after 3 months, and (T3) after 6 months of treatment. Results: The results indicated reduced RRBI and symptoms related to various anxiety subtypes in autistic children following 6 months of CBD-rich cannabis treatment. Specifically, we observed significant differences in the autistic children's overall anxiety and in some anxiety subtypes (i.e., general, social, panic, and separation anxieties). Significant improvements were observed in RRBI, including the total score, and specifically in compulsive, ritualistic, and sameness behaviors. Our findings revealed that reduced anxiety, particularly within the panic- and separation-related subtypes, predicted a subsequent decrease in RRBI, specifically sameness behaviors, following cannabis treatment. Conclusions: The findings of the cannabis treatment's potential benefits for alleviating anxiety symptoms, leading to reduced RRBI, may provide evidence for the meaningful relationship between these variables and for the potential benefits of cannabis treatment for autistic children. We strongly recommend further double-blind, placebo-controlled studies using standardized assessments to validate these findings.

Amphetamine use for attention deficit hyperactive disorder during breastfeeding and children's neurodevelopmental outcomes: A pilot study.

Attention deficit hyperactive disorder (ADHD) medication use rises among women of childbearing age and during pregnancy. Little is known on the safety of amphetamine stimulants for ADHD treatment during breastfeeding. Most data on the safety of these medications are from recreational abuse of methamphetamine. This study followed children (N = 13) exposed to amphetamine stimulants during breastfeeding. Assessments by Pediatric Quality of Life and Denver Developmental Scale evaluated neurodevelopment and outcomes. Study results showed normal neurodevelopment with no significant adverse effects. Findings suggest amphetamines are likely compatible with breastfeeding; however larger studies are needed.

Influence of cytochrome P450 2D6*10/*10 genotype on the risk for tramadol associated adverse effects: a retrospective cohort study.

Background: Tramadol is primarily metabolized by the highly polymorphic CYP2D6 enzyme, leading to a large spectrum of adverse events and clinical response. Ample evidence pointed a reduced CYPD26 activity score in individuals harboring the CYP2D6*10/*10 genotype, nevertheless, there is scarce studies on the impact of CYP2D6*10/*10 genetic polymorphism on long-term tramadol's adverse effects. Aim: To test the correlation between CYP2D6*10/*10 expression and the risk for tramadol-associated adverse effects. Method: Using a database of Leumit Healthcare Services in Israel, we retrospectively assessed the occurrence of adverse events in patients who were prescribed tramadol. A binary logistic regression model was applied to model the relationship between CYP2D6*10/*10 genotype and the occurrence of adverse effects. Results: Data from four hundred ninety-three patients were included in this study. Only 25 (5.1%) patients were heterozygous for the CYP2D6*10 variant, while 56 patients (11%) were tested positive to the CYP2D6*10/*10 genotype. Compared to carriers of other variants, patients with the CYP2D6*10/*10 variant exhibited a higher occurrence of adverse events (odds ratio [OR] = 6.14, 95% confidence interval 3.18-11.83); the odds ratio for central nervous system adverse events and gastrointestinal adverse events were 5.13 (95% CI 2.84-9.28), and 3.25 (95% CI 1.78-5.93), respectively. Conclusion: Among the different CYP2D6 genotypes, CYP2D6*10/*10 genotype carries the higher risk of tramadol related adverse events. Appreciating the frequency of this specific allele it seems prudent to pharmacogenetically screen patients considered for long term tramadol treatment for better tolerability and efficacy outcomes.

The Safety, Tolerability, and Efficacy of DL-Lactic Acid Syrup (Tonsitin) in Children With Recurrent Tonsillitis: A Pilot Study.

To evaluate Tonsitin (10% DL-lactic acid) safety, tolerability, and efficacy, as a treatment for recurrent tonsillitis (RT) in children. This is a clinical prospective, randomized, double blind pilot study, to evaluate the safety, tolerability and efficacy of Tonsitin in healthy children with RT. Safety evaluated in terms of adverse events (AEs), tolerability in terms of compliance, and efficacy in terms of tonsils' size and frequency of tonsillitis, and quality of life. The study included 51 children. The treatment regimen was tolerable among the participants. Six children experienced AEs, but mostly mild. Tonsil size declined in both groups, but these results did not reach statistical significance. Tonsillitis episodes' frequencies were random and not significant. Tonsitin treatment was found to be feasible in the clinical setup and was well tolerated, and appears to be safe. Study efficacy results did not reach statistical significance.

Effect of CYP2C19 Pharmacogenetic Testing on Predicting Citalopram and Escitalopram Tolerability and Efficacy: A Retrospective, Longitudinal Cohort Study.

Background-Various antidepressant agents are metabolized by the CYP2C19 enzyme, including Citalopram and Escitalopram. Variation in CYP2C19 expression might give rise to different plasma concentrations of the active metabolites, potentially affecting both drugs' efficacy and tolerability. Aim-The aim of this study was to evaluate differences in the Escitalopram and Citalopram efficacy and tolerability between different CYP2C19 genotype-based metabolizing categories in outpatients suffering from major depressive disorder (MDD). Methods-In a retrospective, longitudinal cohort study of electronic medical-record data, 283 patients with MDD who were prescribed Escitalopram or Citalopram with the available CYP2C19-genotyping test were enrolled. The primary efficacy end point was adverse drug reactions recorded in the medical files. A proportional-odds, multilevel-regression model for longitudinal ordinal data was used to estimate the relation between the CYP2C19 genotype and adverse drug reactions, adjusting for potential confounding variables and other explanatory variables. Latent-class analysis (LCA) was utilized to detect the presence of clinically significant subgroups and their relation to an individual's metabolizing status for CYP2D6/CYP2C19. Results-With poor CYP2C19 metabolizers as a reference, for each unit difference in the activity score of the CYP2C19 phenotype, the odds ratio for drug intolerability was lowered by 0.73 (95% credible intervals: 0.56-0.89), adjusting for significant covariates. In addition, applying LCA, we identified two qualitatively different subgroups: the first group (61.85%) exhibited multiple side effects, low compliance, and frequent treatment changes, whereas the second group (38.15%) demonstrated fewer side effects, good adherence, and fewer treatment changes. The CYP2C19 phenotype was substantially associated with the group membership. Conclusions-We found a positive association between the CYP2C19 activity scores, as inferred from the genotype, and both the efficacy of and tolerability to both Es/Citalopram. LCA enabled valuable insights into the underlying structure of the population; the CYP2C19 phenotype has a predictive value that discriminates between low-adherence, low-drug-tolerance, and low-response patients and high-adherence, high-drug-tolerance, and high-response patients. Personalized medicine based on CYP2C19 genotyping could evolve as a promising new avenue towards mitigating Escitalopram and Citalopram therapy and the associated side effects and enhancing treatment success.

Acceptance rate of clinical pharmacists' recommendations-an ongoing journey for integration.

Introduction: Multidisciplinary expert team collaboration in the clinical setting, which includes clinical pharmacist involvement can facilitate significant improvements in outcomes and optimize patient management by preventing drug-related problems (DRP). This type of collaboration is particularly valuable in patients with multi-morbidity and polypharmacy such as diabetic foot patients. Evidence regarding the successful integration of a new clinical pharmacist, without previous experience into a unit is still scarce. Therefore, this study aimed to describe and evaluate the actual successful integration process of the clinical pharmacist into a diabetic foot unit by measuring the change in recommendation acceptance rate over time. Methods: A prospective, exploratory treatment effectiveness study based on the recommendation acceptance rate of a new clinical pharmacist introduced into the diabetic foot unit was conducted over a 9- month period. The clinical pharmacist identified medical and drug-related problems (DRP) or any discrepancies in the prescribing and administration of medications. Each identified DRP was documented and formulated as a recommendation by the clinical pharmacist. The main outcome measure was the acceptance rate of recommendations over time. Results: A total of 86 patients, of which 67% were men, averagely aged 66.5 (SD 11.8) years were evaluated. Calculated BMI was 30.2 (SD 6.2). The average number of medical diagnoses was 8.9 (SD3.2), and 11.1 (SD 3.7) prescribed drugs for each patient. Cardiovascular disease was presented by 95% (n = 82) of the patients and 33% of them (n = 28) had uncontrolled hyperglycemia. Averagely, 3.3 (SD 1.9) DRPs were identified pre patient. The efficacy-related DRP recommendation acceptance rate increased over the study period from 37.8% in the first 4 months to 79.4% after a period of 4.75 months. Safety-related DRP recommendation acceptance rate increased from 56% to 67.6%. Conclusion: Improved clinical outcomes and optimized pharmacologic patient management may be achieved by the successful integration of a clinical pharmacist into the team. This study provides evidence of the increasing recommendation acceptance rate of integrated, pharmacist-driven comprehensive medication management in an unexperienced unit. To overcome challenges, team members should collaborate to fully integrate the clinical pharmacist into the team-based structure and utilize proper strategies to minimize and transcend barriers.

Glucose-6-phosphate dehydrogenase deficiency and long-term risk of immune-related disorders.

Introduction: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic disorder that is particularly prevalent in Africa, Asia, and the Middle East. This study aimed to assess the long-term health risks associated with G6PD deficiency. Methods: A retrospective cohort study was conducted using data from a national healthcare provider in Israel (Leumit Health Services). A total of 7,473 G6PD-deficient individuals were matched with 29,892 control subjects in a 1:4 ratio, based on age, gender, socioeconomic status, and ethnic groups. The exposure of interest was recorded G6PD diagnosis or positive G6PD diagnostic test. The main outcomes and measures included rates of infectious diseases, allergic conditions, and autoimmune disorders between 2002 and 2022. Results: Significantly increased rates were observed for autoimmune disorders, infectious diseases, and allergic conditions in G6PD-deficient individuals compared to the control group. Specifically, notable increases were observed for rheumatoid arthritis (odds ratio [OR] 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR 18.70, p<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, p=0.001), and Hashimoto's thyroiditis (OR 1.26, p=0.001). These findings were supported by elevated rates of positive autoimmune serology and higher utilization of medications commonly used to treat autoimmune conditions in the G6PD-deficient group. Discussion: In conclusion, individuals with G6PD deficiency are at a higher risk of developing autoimmune disorders, infectious diseases, and allergic conditions. This large-scale observational study provides valuable insights into the comprehensive association between G6PD deficiency and infectious and immune-related diseases. The findings emphasize the importance of considering G6PD deficiency as a potential risk factor in clinical practice and further research is warranted to better understand the underlying mechanisms of these associations.

Therapeutic drug monitoring of lacosamide among children: is it helpful?

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.

Glucose-6-Phosphate Dehydrogenase Deficiency and Coronavirus Disease 2019.

In this cohort study conducted in a national healthcare organization in Israel, we found that individuals with glucose-6-phosphate dehydrogenase deficiency had an increased risk of coronavirus disease 2019 (COVID-19) infection and severity, with higher rates of hospitalization and diagnosed long COVID.

Process of drug registration in Israel: the correlation between the number of discussions within the Ministry of Health and postapproval variations by EMA and/or FDA.

OBJECTIVES: US FDA and EMA allow facilitated regulatory pathways to expedite access to new treatments. Limited supportive data may result in major postapproval variations. In Israel, partly relying on Food and Drug Administration (FDA) and European Medicines Agency (EMA), clinical data are reviewed independently by the Advisory Committee of Drug Registration (ACDR). In this study, the correlation between the number of discussions at the ACDR and major postapproval variations is examined. DESIGN: This is an observational retrospective comparative cohort study. SETTING: Applications with FDA and/or EMA approval at time of assessment in Israel were included. The timeframe was chosen to allow a minimum of 3 years of postmarketing approval experience for potential major label variations. Data regarding the number of discussions at ACDR were extracted from protocols. Data on postapproval major variations were extracted from the FDA and EMA websites. RESULTS: Between 2014 and 2016, 226 (176 drugs) applications, met the study criteria. 198 (87.6%) and 28 (12.4%) were approved following single and multiple discussions, respectively. A major postapproval variation was recorded in 129 (65.2%) compared with 23 (82.1%) applications approved following single and multiple discussions, respectively (p=0.002). Increased risk for major variation was found for medicines approved following multiple discussions (HR=1.98, 95% CI: 1.26 to 3.09) with a median time of 1.2 years, applications approved based on phase II trials (HR=2.58, 95% CI: 1.72 to 3.87), surrogate endpoints (HR=1.99, 95% CI: 1.44 to 2.74) and oncologic indications (HR=2.48, 95% CI: 1.78 to 3.45). CONCLUSIONS: Multiple ACDR discussions associated with limited supportive data are predictive for major postapproval variations. Moreover, our findings demonstrate that approval by the FDA and/or EMA does not pave the way to automatic approval in Israel. In a substantial per cent of the cases, submission of the same clinical data resulted in different safety and efficacy considerations, requiring additional supporting data in some cases or even rejection of the application in others.

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency and Long-Term Risk of Immune-Related diseases.

BACKGROUND: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive enzymatic disorder, particularly prevalent in Africa, Asia and the Middle East. In the US, about 14% of black men are affected. Individuals with G6PD deficiency are often asymptomatic but may develop hemolysis following an infection or upon consumption of specific medications. Despite some evidence that G6PD deficiency affects the immune system, the long- term health risks associated with G6PD deficiency had not been studied in a large population. METHODS: In this retrospective cohort study, health records from G6PD deficient individuals were compared to matched controls in a national healthcare provider in Israel (Leumit Health Services). Rates of infectious diseases, allergic conditions and autoimmune disorders were compared between groups. RESULTS: The cohort included 7,473 G6PD deficient subjects (68.7% men) matched with 29,892 control subjects (4:1 ratio) of the same age, gender, socioeconomic status and ethnic group, followed during 14.3±6.2 years.Significantly increased rates for autoimmune disorders, infectious diseases and allergic conditions were observed throughout this period. Notable increases were observed for rheumatoid arthritis (OR 2.41, p<0.001), systemic lupus erythematosus (OR 4.56, p<0.001), scleroderma (OR 6.87, p<0.001), pernicious anemia (OR=18.70, P<0.001), fibromyalgia (OR 1.98, p<0.001), Graves' disease (OR 1.46, P=0.001), and Hashimoto's thyroiditis (OR 1.26, P=0.001). These findings were corroborated with elevated rates of positive autoimmune serology and higher rates of treatment with medications commonly used to treat autoimmune conditions in the G6PD deficient group. CONCLUSION: G6PD deficient individuals suffer from higher rates of autoimmune disorders, infectious diseases, and allergic conditions.

Ultra-processed food (UPF) intake in pregnancy and maternal and neonatal outcomes.

PURPOSE: Ultra-processed food (UPF), as defined by the NOVA classification, is related to lower diet quality, which may adversely affect maternal health and neonatal outcomes. This study aims to describe nutrient intake of pregnant women by the share of UPF in the diet and to identify associations between UPF intake and maternal and neonatal outcomes. METHODS: In this cross-sectional study, pregnant women (n = 206) were recruited upon arrival to the obstetrics ward for delivery, and asked to complete a Food Frequency Questionnaire (FFQ), and questionnaires regarding environmental exposures, and socio-demographic characteristics. Neonatal measurements and clinical data were obtained following delivery. UPF energy intake was expressed as absolute and in terms of percent from total energy. Women with high intake of energy from UPF were compared to those with low intake. RESULTS: Among 206 pregnant women, dietary intake of UPF ranged from 15.6% to 43.4% of total energy in the first and fourth quartiles of UPF consumption, respectively. Women in the fourth quartile of energy from UPF had lower intakes of vitamin C, beta-carotene, vitamin B6, and potassium, which is indicative of inferior diet quality. Percent energy from UPF was associated with maternal obesity (BMI ≥ 30) (OR = 1.06, 95% CI: 1.06, 1.10, p = 0.008) and shorter male infant ano-genital distance (AGD) (B = -1.9, 95% CI: -3.5, -0.24, p = 0.02). CONCLUSIONS: UPF intake during pregnancy is associated with undesirable maternal and neonatal outcomes and more research is needed to confirm these findings.

Prenatal exposure to heavy metal mixtures and anthropometric birth outcomes: a cross-sectional study.

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.

Use of Medical Cannabis in Patients with Gilles de la Tourette's Syndrome in a Real-World Setting.

Objective: Tourette's syndrome (TS) is a neurodevelopmental disorder characterized by vocal and motor tics and other comorbidities. Clinical recommendations for the use of medical cannabis are established, yet further guidance is needed. The aim of this study was to describe the experience of patients with TS with medical cannabis. Materials and Methods: TS patients were recruited from a registry of patients ("Tikun Olam" company). Questionnaires were answered before and after 6 months of treatment. Patients were divided into two groups: (A) patients who responded and (B) patients who did not respond to the follow-up questionnaire. In group A, an analysis was made to evaluate the presence and frequency of motor and vocal tics. The patients' general mood, employment status, quality of life, and comorbidities were also included in the analysis. Results: Seventy patients were identified. The tetrahydrocannabinol and cannabidiol mean daily dose was 123 and 50.5 mg, respectively. In group A, a statistically significant improvement was identified in quality of life (p<0.005), employment status (p=0.027), and in the reduction of the number of medications (p<0.005). Sixty-seven percent and 89% of patients with obsessive-compulsive disorder and anxiety comorbidities, respectively, reported an improvement. No statistically significant improvement was identified in motor tics (p=0.375), vocal tics (p>0.999), tics frequency (p=0.062), or general mood (p=0.129). The most frequent adverse effects were dizziness (n=4) and increased appetite (n=3). Conclusion: Subjective reports from TS patients suggest that medical cannabis may improve their quality of life and comorbidities. More studies are needed to evaluate the efficacy and safety of medical cannabis. Registry in the MOH: https://www.moh.gov.sg/ (Trial number: 0185-19-ASF).

Medical cannabis for the treatment of comorbid symptoms in children with autism spectrum disorder: An interim analysis of biochemical safety.

Background: Autistic Spectrum Disorder (ASD) is a common neurodevelopmental disorder and no effective treatment for the core symptoms is currently available. The present study is part of a larger clinical trial assessing the effects of cannabis oil on autism co-morbidities. Objectives: The aim of the present study was to assess the safety of a CBD-rich oil treatment in children and adolescents with ASD. Methods: Data from 59 children and young adults (ages 5-25 years) from a single-arm, ongoing, prospective, open-label, one center, phase III study was analyzed. Participants received the Nitzan Spectrum® Oil, with cannabis extracts infused in medium chain triglyceride (MCT) oil with a cannabidiol:THC ratio of 20:1, for 6 months. Blood analysis was performed before treatment initiation, and after 3 months. Complete blood count, glucose, urea, creatinine, electrolytes, liver enzymes (AST, ALT, gamma glutamyl transferase), bilirubin, lipid profile, TSH, FT4, thyroid antibodies, prolactin, and testosterone measurements were performed at baseline, prior to starting treatment and at study midpoint, after 3 months of treatment. Results: 59 children (85% male and 15% female) were followed for 18 ± 8 weeks (mean ±SD). The mean total daily dose was 7.88 ± 4.24 mg/kg body weight. No clinically significant differences were found in any of the analytes between baseline and 3 months follow up. Lactate dehydrogenase was significantly higher before treatment (505.36 ± 95.1 IU/l) as compared to its level after 3 months of treatment (470.55 ± 84.22 IU/L) (p = 0.003). FT4 was significantly higher after 3 months of treatment (15.54 ± 1.9) as compared to its level before treatment (15.07 ± 1.88) (p = 0.03), as was TSH [(2.34 ± 1.17) and (2.05 ± 1.02)] before and after 3 months of treatment, respectively (p = 0.01). However, all these values were within normal range. A comparison of the group with additional medications (n = 14) to those who received solely medical cannabis (n = 45) showed no difference in biochemical analysis, including liver enzymes, which remained stable, except for change in potassium level which was significantly higher in the group that did not receive additional medications (0.04 ± 0.37) compared to the group receiving concomitant drug therapy (-0.2 ± 0.33) (p = 0.04). A comparison of patients who received a high dose of the cannabis oil (upper quartile-16 patients), with those receiving a low dose (lower quartile-14 patients) showed no significant difference between the two groups, except for the mean change of total protein, which was significantly higher among patients receiving high dose of CBD (0.19 ± 2.74) compared to those receiving a low dose of CBD (1.71 ± 2.46 (p = 0.01), and mean change in number of platelets, that was significantly lower among patients who received high dose of CBD (13.46 ± 31.38) as compared to those who received low dose of CBD (29.64 ± 26.2) (p = 0.0007). However, both of these changes lack clinical significance. Conclusion: CBD-rich cannabis oil (CBD: THC 20:1), appears to have a good safety profile. Long-term monitoring with a larger number of participants is warranted.

Children and adolescents with ASD treated with CBD-rich cannabis exhibit significant improvements particularly in social symptoms: an open label study.

In recent years there has been growing interest in the potential benefits of CBD-rich cannabis treatment for children with ASD. Several open label studies and one double-blind placebo-controlled study have reported that CBD-rich cannabis is safe and potentially effective in reducing disruptive behaviors and improving social communication. However, previous studies have mostly based their conclusions on parental reports without the use of standardized clinical assessments. Here, we conducted an open label study to examine the efficacy of 6 months of CBD-rich cannabis treatment in children and adolescents with ASD. Longitudinal changes in social communication abilities and restricted and repetitive behaviors (RRB) were quantified using parent report with the Social Responsiveness Scale and clinical assessment with the Autism Diagnostic Observation Schedule (ADOS). We also quantified changes in adaptive behaviors using the Vineland, and cognitive abilities using an age-appropriate Wechsler test. Eighty-two of the 110 recruited participants completed the 6-month treatment protocol. While some participants did not exhibit any improvement in symptoms, there were overall significant improvements in social communication abilities as quantified by the ADOS, SRS, and Vineland with larger improvements in participants who had more severe initial symptoms. Significant improvements in RRB were noted only with parent-reported SRS scores and there were no significant changes in cognitive scores. These findings suggest that treatment with CBD-rich cannabis can yield improvements, particularly in social communication abilities, which were visible even when using standardized clinical assessments. Additional double-blind placebo-controlled studies utilizing standardized assessments are highly warranted for substantiating these findings.

Lacosamide effects on placental carriers of essential compounds in comparison with valproate: Studies in perfused human placentas.

OBJECTIVE: Lacosamide is increasingly being prescribed to pregnant women, although its effects on the developing fetus have not been fully clarified yet. Previously, we have shown that several antiseizure medications, particularly valproate, can affect the expression of carriers of essential compounds in placental cells. Here, our aim was to assess the effect of short ex vivo exposure of human placentas to lacosamide on the expression of carriers of essential nutrients required by the human fetus. METHODS: Placentas were obtained from cesarean deliveries of women with no known epilepsy. Cotyledons were cannulated and perfused over 180 min in the presence of lacosamide at 2.5 µg/ml (10 µmol·L-1 , n = 7) or 10 µg/ml (40 µmol·L-1 , n = 6), representing low and high therapeutic concentrations, respectively, in the maternal perfusate. Valproate (83 µg/ml, 500 µmol·L-1 , n = 6) and the perfusion solution (n = 6) were used as the respective positive and negative controls. A customized gene panel array was used to analyze the expression of carrier genes in the perfused cotyledons. RESULTS: Following a 3-h perfusion, the mRNA expression of SLC19A1 (encoding the reduced folate carrier 1) was downregulated in placentas treated with 10 µg/ml lacosamide (50%) as compared with the vehicle (p < .05). Across all groups, a significant difference was observed in the expression of SLC19A3 (thiamine transporter 2; 52%, 20%, and 9% decrease by 10 µg/ml lacosamide, 83 µg/ml valproate, and 2.5 µg/ml lacosamide, respectively; p < .05). SIGNIFICANCE: Lacosamide at high therapeutic concentrations exerted pharmacological effects on the human placenta. Our findings, if manifested in vivo, suggest that lacosamide could potentially affect folate supply to the fetus and support therapeutic monitoring and careful adjustment of lacosamide plasma concentrations during pregnancy.