Explainable multimodal machine learning model for classifying pregnancy drug safety.

MOTIVATION: Teratogenic drugs can cause severe fetal malformation and therefore have critical impact on the health of the fetus, yet the teratogenic risks are unknown for most approved drugs. This article proposes an explainable machine learning model for classifying pregnancy drug safety based on multimodal data and suggests an orthogonal ensemble for modeling multimodal data. To train the proposed model, we created a set of labeled drugs by processing over 100 000 textual responses collected by a large teratology information service. Structured textual information is incorporated into the model by applying clustering analysis to textual features. RESULTS: We report an area under the receiver operating characteristic curve (AUC) of 0.891 using cross-validation and an AUC of 0.904 for cross-expert validation. Our findings suggest the safety of two drugs during pregnancy, Varenicline and Mebeverine, and suggest that Meloxicam, an NSAID, is of higher risk; according to existing data, the safety of these three drugs during pregnancy is unknown. We also present a web-based application that enables physicians to examine a specific drug and its risk factors. AVAILABILITY AND IMPLEMENTATION: The code and data is available from https://github.com/goolig/drug_safety_pregnancy_prediction.git. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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.

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.

Levetiracetam in lactation: How much is excreted into human breast milk?

AIMS: In breastfeeding women, anti-epileptic therapy can lead to infant toxicities, even with newer anti-epileptic drugs such as levetiracetam. This study assessed levetiracetam breastmilk excretion and its correlation with the maternal oral dose and serum concentrations. METHODS: Women with epilepsy treated with levetiracetam were recruited to this study and completed a questionnaire. Levetiracetam concentrations were determined in serial breastmilk samples (pre-dose to 12 h post-dose period) and in a single pre-dose maternal serum sample. RESULTS: Twenty breastfeeding women and 21 infants (one woman with twins; 16 fully and five partially breastfed infants) participated in this study. The trough breastmilk/serum ratio of levetiracetam was 0.98 ± 0.20. The infant levetiracetam daily dose was 5.39 ± 1.96 and 2.70 ± 0.98 mg. kg-1. d-1 , and the relative infant dose (RID) was 13.8 ± 3.1% and 6.9 ± 1.6% in the fully and partially breastfed infants, respectively. Substantial correlations between the levetiracetam dose, maternal serum and breastmilk trough concentrations, and breastmilk AUC values were found. Three women reported somnolence in their fully breastfed infants, which resolved shortly after switching to partial breastfeeding. All the infants gained weight according to their age. CONCLUSIONS: Infant levetiracetam exposure via the breastmilk was close to the safety thresholds (trough breastmilk/serum ratio slightly below 1, RID > 10% in fully breastfed infants), and infant somnolescence reports could be related to exposure of the infants to levetiracetam via breastmilk. Further studies are warranted to reveal the short- and long-term safety of levetiracetam in breastfeeding.

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.

Analysis of 10 urinary BTEX metabolites using LC-MS/MS.

Benzene, toluene, ethylbenzene, and xylene (BTEX) are a group of volatile organic compounds that are ubiquitous in the environment due to numerous anthropogenic sources. Exposure to BTEX poses a health hazard by increasing the risk for damage to multiple organs, neurocognitive impairment and birth defects. Urinary BTEX metabolites are useful biomarkers for the evaluation of BTEX exposure, because of the ease of sampling and their longer physiological half-lives compared with parent compounds. A method that utilizes LC-MS/MS was developed and validated for simultaneously monitoring of 10 urinary BTEX metabolites. During the sample preparation an aliquot of urine was diluted with an equal volume of 1% formic acid; internal standard solution was added, and then the sample was centrifuged and analyzed. The analytes were separated on the Kinetex-F5 column by applying a linear gradient, consisting of 0.1% formic acid and methanol. The method was validated according to the FDA Bioanalytical Method Validation Guidance for Industry. The mean method's accuracies of the spiked matrix were 81-122%; the inter-day precision ranged from 4 to 20%; the limits of quantitation were 0.5-2 µg/L. The method was used for the evaluation of baseline levels of urinary BTEX metabolites in 87 firefighters.

Pregnancy outcomes following gestational exposure to papaverine: An observational comparative study.

AIMS: Papaverine is indicated for abdominal pain of various aetiologies. However, data on maternal and foetal safety following gestational exposure are lacking. The aim was to examine whether first trimester exposure to papaverine is associated with increased risk for major malformation and whether gestational exposure at any stage is associated with increased risk for preterm delivery, lower birthweight, small for gestational age, caesarean section (CS), lower Apgar score and perinatal death. METHODS: A retrospective comparative study consisted of pregnant women treated with papaverine between February 2010 and October 2019 at a large tertiary center. The control group comprised of livebirth deliveries randomly selected from the institutional obstetric database. RESULTS: The study group consisted of 498 pregnancies, which resulted in 537/544 (98.7%) live births, of whom 46/537 (8.6%) were exposed during the first trimester. The control group consisted of 498 pregnancies and 514 live births. Rate of major malformations did not differ between study group (2/46, 4.3%) and control (25/315, 4.9%, P = .67). Papaverine exposure was associated with higher rate of preterm delivery (22.3 vs. 10.3%, P < .001), CS (35.9 vs. 24.1%, P < .001) and lower birth weight (3207 vs. 3246 g, P = .02). Adjustment for treatment indication demonstrated that these remained significant only when given for obstetrical/surgical aetiologies. Comparable rates were observed for the remaining outcomes. CONCLUSIONS: Short-term gestational exposure to papaverine adjusted for indication was not associated with preterm deliveries, CS, lower birthweight, small for gestational age or perinatal death. Rate of major malformations among 46 first trimester exposures was comparable to controls.

Ectopic Expression of Mouse Melanopsin in Drosophila Photoreceptors Reveals Fast Response Kinetics and Persistent Dark Excitation.

The intrinsically photosensitive M1 retinal ganglion cells (ipRGC) initiate non-image-forming light-dependent activities and express the melanopsin (OPN4) photopigment. Several features of ipRGC photosensitivity are characteristic of fly photoreceptors. However, the light response kinetics of ipRGC is much slower due to unknown reasons. Here we used transgenic Drosophila, in which the mouse OPN4 replaced the native Rh1 photopigment of Drosophila R1-6 photoreceptors, resulting in deformed rhabdomeric structure. Immunocytochemistry revealed OPN4 expression at the base of the rhabdomeres, mainly at the rhabdomeral stalk. Measurements of the early receptor current, a linear manifestation of photopigment activation, indicated large expression of OPN4 in the plasma membrane. Comparing the early receptor current amplitude and action spectra between WT and the Opn4-expressing Drosophila further indicated that large quantities of a blue absorbing photopigment were expressed, having a dark stable blue intermediate state. Strikingly, the light-induced current of the Opn4-expressing fly photoreceptors was ∼40-fold faster than that of ipRGC. Furthermore, an intense white flash induced a small amplitude prolonged dark current composed of discrete unitary currents similar to the Drosophila single photon responses. The induction of prolonged dark currents by intense blue light could be suppressed by a following intense green light, suggesting induction and suppression of prolonged depolarizing afterpotential. This is the first demonstration of heterologous functional expression of mammalian OPN4 in the genetically emendable Drosophila photoreceptors. Moreover, the fast OPN4-activated ionic current of Drosophila photoreceptors relative to that of mouse ipRGC, indicates that the slow light response of ipRGC does not arise from an intrinsic property of melanopsin.

Functional cooperation between the IP3 receptor and phospholipase C secures the high sensitivity to light of Drosophila photoreceptors in vivo.

Drosophila phototransduction is a model system for the ubiquitous phosphoinositide signaling. In complete darkness, spontaneous unitary current events (dark bumps) are produced by spontaneous single Gqα activation, while single-photon responses (quantum bumps) arise from synchronous activation of several Gqα molecules. We have recently shown that most of the spontaneous single Gqα activations do not produce dark bumps, because of a critical phospholipase Cß (PLCß) activity level required for bump generation. Surpassing the threshold of channel activation depends on both PLCß activity and cellular [Ca(2+)], which participates in light excitation via a still unclear mechanism. We show here that in IP3 receptor (IP3R)-deficient photoreceptors, both light-activated Ca(2+) release from internal stores and light sensitivity were strongly attenuated. This was further verified by Ca(2+) store depletion, linking Ca(2+) release to light excitation. In IP3R-deficient photoreceptors, dark bumps were virtually absent and the quantum-bump rate was reduced, indicating that Ca(2+) release from internal stores is necessary to reach the critical level of PLCß catalytic activity and the cellular [Ca(2+)] required for excitation. Combination of IP3R knockdown with reduced PLCß catalytic activity resulted in highly suppressed light responses that were partially rescued by cellular Ca(2+) elevation, showing a functional cooperation between IP3R and PLCß via released Ca(2+). These findings suggest that in contrast to the current dogma that Ca(2+) release via IP3R does not participate in light excitation, we show that released Ca(2+) plays a critical role in light excitation. The positive feedback between PLCß and IP3R found here may represent a common feature of the inositol-lipid signaling.

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.

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.

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.

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.

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.

The impact of pregnancy on the pharmacokinetics of antiseizure medications: A systematic review and meta-analysis of data from 674 pregnancies.

OBJECTIVE: Increasing evidence suggests that the physiological changes of pregnancy may impact pharmacokinetics of antiseizure medications (ASM), and this may affect treatment outcomes. The aim of this study was to quantify the pregnancy impact on the ASM pharmacokinetics. METHODS: A systematic literature search was conducted in PubMed/EMBASE in November 2022 and updated in August 2023 for studies comparing levels of ASM in the same individuals during pregnancy and in the preconception/postpartum period. Alteration ratios between the 3rd trimester and baseline were estimated. We also performed a random-effects meta-analysis calculating between-timepoint differences in mean differences (MDs) and 95% confidence intervals (95%CIs) for dose-adjusted plasma concentrations (C/D ratios). Study quality was assessed using the ClinPK guidelines. RESULTS: A total of 65 studies investigating 15 ASMs in 674 pregnancies were included. The largest differences were reported for lamotrigine, oxcarbazepine and levetiracetam (alteration ratio 0.42, range 0.07-2.45, 0.42, range 0.08-0.82 and 0.52, range 0.04-2.77 respectively): accordingly, C/D levels were lower in the 3rd trimester for lamotrigine, levetiracetam and the main oxcarbazepine metabolite monohydroxycarbazepine (MD = -12.33 × 10-3, 95%CI = -16.08 to -8.58 × 10-3 (µg/mL)/(mg/day), p < 0.001, MD = -7.16 (µg/mL)/(mg/day), 95%CI = -9.96 to -4.36, p < 0.001, and MD = -4.87 (µg/mL)/(mg/day), 95%CI = -9.39 to -0.35, p = 0.035, respectively), but not for oxcarbazepine (MD = 1.16 × 10-3 (µg/mL)/(mg/day), 95%CI = -2.55 to 0.24 × 10-3, p = 0.10). The quality of studies was acceptable with an average rating score of 11.5. CONCLUSIONS: Data for lamotrigine, oxcarbazepine (and monohydroxycarbazepine) and levetiracetam demonstrate major changes in pharmacokinetics during pregnancy, suggesting the importance of therapeutic drug monitoring to assist clinicians in optimizing treatment outcomes.

Compartmentalization and Ca2+ buffering are essential for prevention of light-induced retinal degeneration.

Fly photoreceptors are polarized cells, each of which has an extended interface between its cell body and the light-signaling compartment, the rhabdomere. Upon intense illumination, rhabdomeric calcium concentration reaches millimolar levels that would be toxic if Ca(2+) diffusion between the rhabdomere and cell body was not robustly attenuated. Yet, it is not clear how such effective attenuation is obtained. Here we show that Ca(2+) homeostasis in the photoreceptor cell relies on the protein calphotin. This unique protein functions as an immobile Ca(2+) buffer localized along the base of the rhabdomere, separating the signaling compartment from the cell body. Generation and analyses of transgenic Drosophila strains, in which calphotin-expression levels were reduced in a graded manner, showed that moderately reduced calphotin expression impaired Ca(2+) homeostasis while calphotin elimination resulted in severe light-dependent photoreceptor degeneration. Electron microscopy, electrophysiology, and optical methods revealed that the degeneration was rescued by prevention of Ca(2+) overload via overexpression of CalX, the Na(+)-Ca(2+) exchanger. In addition, Ca(2+)-imaging experiments showed that reduced calphotin levels resulted in abnormally fast kinetics of Ca(2+) elevation in photoreceptor cells. Together, the data suggest that calphotin functions as a Ca(2+) buffer; a possibility that we directly demonstrate by expressing calphotin in a heterologous expression system. We propose that calphotin-mediated compartmentalization and Ca(2+) buffering constitute an effective strategy to protect cells from Ca(2+) overload and light-induced degeneration.

The Relations between Repetitive Behaviors and Family Accommodation among Children with Autism: A Mixed-Methods Study.

Restricted and repetitive behaviors and interests (RRBI) are a significant component in diagnosing autism spectrum disorder (ASD). They often pose the main challenge in day-to-day functions for children with ASD and their families. Research addressing family accommodation behaviors (FAB) in the ASD population is scarce, and associations with the characteristics of the children's behaviors are unclear. This sequential mixed-methods study assessed the correlation between RRBI and FAB within the ASD group to deepen the understanding of parents' subjective experiences regarding their children's RRBI. It included a quantitative phase with a follow-up qualitative study. A total of 29 parents of children with autism (5-13 yr) completed the study questionnaires; a total of 15 also were interviewed regarding their children's RRBI and related FAB. We used the Repetitive Behavior Scale-Revised (RBS-R) to assess RRBI, and the Family Accommodation Scale (FAS-RRB) to assess FAS. In-depth interviews from phenomenological methodology were used in the qualitative phase. We found significant positive correlations between the RRBI and FAB overall and their subscores. Qualitative research supports these findings, adding descriptive examples of the accommodations families make to address the RRBI-related challenges. The results indicate relations between RRBI and FAB and the importance of practically addressing children with autism's RRBI and their parents' experiences. Both affect and are affected by the children's behaviors.

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.

Magnitude of Lamotrigine Exposure Through Breastfeeding.

Importance: Lamotrigine use during breastfeeding has significantly increased in the recent years, whereas breast milk lamotrigine pharmacokinetics data are still sparse. Objectives: To assess lamotrigine exposure in breastfed infants by monitoring maternal serum and breast milk concentrations. Methods: Breastfeeding women treated with lamotrigine were recruited to this study. Maternal trough breast milk and serum samples were collected, and additional breast milk samples were collected 1, 3, 6, 9, 12 hours after lamotrigine consumption. Trough breast milk/serum ratios (M/S ratio) and breast milk area under the curve (AUC) values were calculated. Results: Twenty-one breastfeeding women were recruited to this study, and the final dataset was based on the samples collected from 17 women. Lamotrigine trough serum and mother's milk concentrations were 5.1 ± 3.3 mg/L and 3.1 ± 1.9 mg/L, respectively (mean ± standard deviation). The trough M/S ratio of lamotrigine was 0.66 ± 0.22. The lamotrigine breast milk average AUC was 41.7 ± 24.6 mg·h/L. The estimated infant dose of lamotrigine was 0.52 ± 0.31 mg/kg/day and 0.26 ± 0.15 mg/kg/day for fully and partially breastfed infants, respectively. Significant correlation was found between the maternal lamotrigine serum trough concentrations and the breast milk parameters: trough breast milk concentrations (Spearman's rho = 0.986, p < 0.0001) and breast milk AUC values (Spearman's rho = 0.941, p < 0.0001). No significant correlation was found between the maternal lamotrigine daily dose and serum trough concentrations, breast milk trough concentrations, and breast milk AUC values (Spearman's rho = 0.294, 0.285, and 0.438, p = 0.252, 0.396, and 0.078, respectively). Conclusion and Relevance: High correlation between the maternal lamotrigine trough serum concentrations and the breast milk AUC values was found, implying that monitoring the maternal lamotrigine serum concentrations can be useful for prediction of exposure of infants to lamotrigine through the breast milk. The trial was registered in the Israeli trials registry MOH_2021-09-05_010243 at September 5, 2021 Retrospectively registered https://my.health.gov.il/CliniTrials.