Medicine and Pharmacology

Abstract: Background: Adnexal torsion is an uncommon cause of abdominal pain, and its clinical presentation in children is nonspecific. In some studies, serum D-dimer showed promise as a biochemical marker. The aim of this multicenter prospective observational study was to evaluate the sensitivity and specificity of preoperative serum D-dimer levels for diagnosing adnexal torsion in children and adolescents. Methods: Female patients aged <18 years presenting to the emergency departments of participating centers with symptoms suggestive of adnexal torsion between January 2022 and December 2024 were invited to participate in the study. Preoperative serum D-dimer levels were measured in all patients undergoing surgical exploration. Patients’ characteristics were examined using descriptive and inferential statistics, and the accuracy of preoperative serum D-dimer levels for diagnosing adnexal torsion was assessed using univariate logistic regression and a receiver operating characteristic curve. Results: Twenty-eight patients aged 4–17 years were enrolled. Adnexal torsion was found in 17 patients, on the left side in 4 (23.53%) and on the right side in 13 (76.47%). Almost all patients were treated laparoscopically, and no postoperative complications occurred. Preoperative serum D-dimer levels were higher among patients with adnexal torsion than among those without. The univariate model of serum D-dimer levels had an odds ratio of 1, a sensitivity of 0.77, and a specificity of 0.82 (p = 0.27). Conclusions: No direct association was observed between preoperative serum D-dimer levels and adnexal torsion. Nonetheless, the sensitivity and specificity suggest the possible utility of including serum D-dimer levels in multi-marker diagnostic models to complement rather than replace existing tools.

Abstract: Background: Endotracheal intubation is a painful and stressful procedure for neonates, often triggering adverse physiological responses. In 2010, the American Academy of Pediatrics (AAP) recommended premedication for elective intubation in neonates to reduce pain and stress and to increase the chances of success. In recent years, several drugs have emerged as a treatment option to improve comfort and safety of neonates undergoing endotracheal intubation. Worldwide, a range of agents are used. As remifentanil is a short-acting analgesic with sedative effects, it may be a suitable option. Therefore, we evaluated the available evidence regarding benefits and side effects for this drug. Methods: In this narrative review, we describe the benefits and risks of remifentanil as drug of choice for neonatal intubation. Results: Literature search demonstrates a relatively limited number of randomized trials, indicating that current practice is informed by a combination of small clinical trials, observational studies, and pharmacological research. Owing to its unique pharmacokinetic profile, remifentanil is an effective agent in the neonatal population allowing the provision of intense analgesia with a rapid recovery profile and has a good clinical applicability in situations where early extubation of patients is desired following the end of the opioid infusion. Reported side effects include respiratory depression, apnea, bradycardia, and chest wall rigidity, similar to other opioids. Chest wall rigidity appears to be strongly influenced by dosing strategies and the speed of intravenous administration. Conclusions: Remifentanil's unique properties make it a promising option for neonatal intubation. However vigilance and close monitoring is required. Further research is warranted to compare remifentanil with other opioids that have a near similar pharmacological profile (e.g., fentanyl analogues).

Abstract:

Background: Vitamin D–binding protein (DBP) is the principal carrier of circulating 25-hydroxyvitamin D3 [25(OH)D₃] and is independently synthesized by the neonate. Whether neonatal DBP at birth adds predictive value beyond baseline 25(OH)D₃ for supplementation response remains unclear. Methods: This single-center prospective cohort study enrolled 101 neonates. Neonates with 25(OH)D₃ <20 ng/mL (supplementation-response cohort; n = 59: 29 preterm, 30 term) received 800 IU/day oral cholecalciferol for 8 weeks; neonates with 25(OH)D₃ ≥20 ng/mL served as baseline reference controls (n = 42). Serum 25(OH)D₃ and DBP were measured at baseline and week 8 in the supplementation-response cohort. Results: Median baseline 25(OH)D₃ was 8.60 [6.70–12.05] ng/mL and median baseline DBP was 4.97 [3.70–8.19] µg/mL. After supplementation, 25(OH)D₃ increased significantly (median Δ = 17.70 ng/mL; p <0.001), with 55/59 (93.2%) achieving sufficiency. In multivariable regression, gestational age was the strongest independent predictor of Δ25(OH)D3 (β = −0.440, p = 0.001), followed by baseline 25(OH)D3 (β = −0.314, p = 0.015); baseline DBP was not significant (β = 0.072, p = 0.551). Conclusions: Baseline DBP did not independently predict supplementation response. Lower gestational age and lower baseline 25(OH)D₃ were associated with greater increases in 25(OH)D₃ after supplementation, whereas baseline DBP provided no additional predictive value. Supplementation with 800 IU/day for 8 weeks was effective across gestational-age categories. Routine DBP measurement does not appear to provide additional clinical value for guiding neonatal vitamin D supplementation.

Abstract: Background: Common Variable Immunodeficiency (CVID), a heterogeneous syndrome characterized by hypogammaglobulinemia and defective humoral immunity, is the most prevalent symptomatic primary immunodeficiency. CVID-8 is a monogenic variant due to bi-allelic mutation in the LRBA gene. Individuals carrying a single mutated LRBA allele are considered phenotypically healthy. However, immune dysregulation may arise in certain heterozygous carriers likely via haploinsufficiency or dominant-negative activity. LRBA critically regulates CTLA-4 recycling, directly linking this deficiency to immune checkpoint biology. Case Presentation: We report a 7-year-old female, born to consanguineous Lebanese parents, with a family history of thrombocytopenia, presented with chronic refractory ITP first diagnosed at age 2. The patient was resistant to multiple sequential therapeutic interventions including immunosuppressive agents and splenectomy. Whole exome sequencing (WES) detected compound heterozygous LRBA variants c.7937T>G (p.Ile2646Ser) and c.7046T>A p.Leu2349*, the former is pathogenic associated with CVID-8. Immunological assessment revealed hypogammaglobulinemia with suppressed IgG1, IgG3, IgA and IgM levels. Her latest hospitalization was marked by abdominal pain, impaired consciousness, acute liver injury, coagulopathy, peripheral leukocytosis, and lung infiltrates on imaging, suggesting autoimmune enteropathy complicated by infection. Conclusion: This report raises important questions regarding the clinical impact of heterozygous LRBA variant. It highlights the diagnostic value of WES in refractory cytopenias and inherited immune deficiencies. Abatacept, a CTLA-4-Ig fusion protein, is a promising targeted therapy for LRBA deficiency cases; yet its unavailability in Lebanon impeded its use, emphasizing the critical gap in access to targeted biologics in the MENA region.

Abstract: Numerous adverse effects caused by oxidative stress are commonly observed in preterm infants. This stress is caused by the oxidative burden resulting mainly from supplemental oxygen and parenteral nutrition (PN), and by their precarious antioxidant defense system. The natural antioxidant defense against these oxidant molecules relies on glutathione, levels of which are low in preterm infants. Given that several short- and long-term biological complications, including lung damage, are associated with this oxidative stress, the aim of this review was to discuss possible methods for reducing it. Consequently, after briefly discussing the effectiveness of reducing oxidative stress-related effects achieved through adequate photoprotection of PN, it is proposed to correct glutathione deficiency by adding glutathione to PN intended for premature infants. This article addresses the 1) importance and efficacy of parenteral glutathione in preventing oxidative stress, 2) causes of glutathione deficiency and ways to prevent it, 3) reasons why the disulfide form (GSSG) is recommended over the reduced form (GSH) for enriching PN, and 4) safety profile of glutathione infusion. In conclusion, we believe that the time has come to improve the health of premature infants by providing them with GSSG supplemented PN that is adequately photoprotected.

Abstract: Background: Highly effective CFTR modulation with Elexacaftor/Tezacaftor/Ivacaftor (ETI) markedly improves clinical outcomes in people with cystic fibrosis (CF). Data on its effects on physical activity, sleep, sinonasal symptoms and parent-perceived outcomes in preschool-aged children are limited. Methods: In this prospective, observational, single-center cohort study, ten children with cystic fibrosis (aged 2–6 years) and at least one CFTR variant eligible for ETI were included. Data were collected using wrist-worn Garmin vívofit Junior 2 activity trackers and standardized questionnaires one month before ETI initiation and at 1, 3, 6, and 12 months after start of ETI. Outcomes included step count, minutes of moderate-to-vigorous physical activity, sleep parameters, sinonasal symptoms and parental perceptions. Results: ETI was well tolerated. Sweat chloride levels decreased significantly. Physical activity improved at 3 and 6 months (step count and active minutes/day; p < 0.05) but declined to near-baseline levels at 12 months. Parental assessments of physical and sporting performance showed sustained improvement. Sleep duration remained stable, with no changes in deep or light sleep phases or nighttime awakenings. Sinonasal symptoms remained low. Discussion & Conclusions: Preliminary findings of this pilot study show that improvement in physical activity after three and six months of ETI therapy might be attributable to seasonality as therapy was started in winter months. No changes in sleep duration or sleep patterns are reassuring in young children with CF. ETI therapy was safe and well tolerated. Parental appraisal of their childrens’ physical performance improved after start of ETI. Longitudinal, controlled studies involving larger cohorts are required to validate these findings and to account for potential confounding factors, such as seasonal variation.

Abstract: Adolescents with congenital heart disease (CHD) increasingly survive into reproductive age, making contraceptive counseling a routine component of pediatric cardiology, adolescent medicine, and transition care. For this population, contraceptive choice is not determined by efficacy alone. It is shaped by lesion-specific pregnancy risk, cyanosis, ventricular function, pulmonary vascular disease, thrombosis history, mechanical valves, anticoagulation, menstrual bleeding burden, adherence, confidentiality, and the risk of interruption during transfer to adult congenital heart disease care. This practical clinical review translates current contraceptive guidance and congenital heart disease literature into a same-day workflow for initiation and follow-up. The proposed sequence is to obtain a confidential reproductive and cardiac history; identify whether pregnancy and estrogen exposure would be poorly tolerated; determine whether pregnancy can be reasonably excluded; initiate the safest effective method without unnecessary delay; address emergency contraception when indicated; and structure follow-up around bleeding, adherence, medication changes, and evolving cardiovascular status. Long-acting reversible contraception, particularly levonorgestrel intrauterine devices and etonogestrel implants, should be prioritized when pregnancy would carry substantial maternal risk. Estrogen-containing methods require caution or avoidance in high-risk cardiovascular states, including Fontan circulation, cyanosis or right-to-left shunting, pulmonary arterial hypertension, Eisenmenger physiology, prior thrombosis, mechanical valves, major ventricular dysfunction, and selected aortopathies. The goal is not to replace cardiology or gynecology judgment, but to provide a lesion-aware, same-day clinical pathway that reduces avoidable delays, supports adolescent autonomy, and preserves contraceptive safety during transition to adult care.

Abstract: Background/Objectives: Chorioamnionitis, an inflammation, with or without infection, involving the amniotic fluid, placenta, fetal membranes or decidua, can significantly impact fetal and neonatal development. This study aimed to determine the incidence of chorioamnionitis and confirm its correlation with neonatal morbidity and mortality, in a single tertiary center. Materials and Methods: This observational, retrospective study was conducted over three years (2019-2021) in a tertiary neonatal intensive care unit, examining 80 preterm infants born at 23-28 weeks of gestation. Pearson correlation and χ² tests were used to assess associations between chorioamnionitis exposure and neonatal outcomes. Results: Among the 80 newborns analysed, clinical chorioamnionitis was identified in 12 preterm infants, while 46 presented histological chorioamnionitis. A weak but significant negative correlation (r = –0.27, p = 0.0152) between gestational age and chorioamnionitis stage indicated that preterm infants born at lower gestational ages are more frequently exposed to this intrauterine infection. Histological chorioamnionitis stage was significantly associated with early onset sepsis (r=0.31, p=0.0048), severity of respiratory distress syndrome (r=0.25, p=0.0242), bronchopulmonary dysplasia (r=0.26, p=0.0212), and retinopathy of prematurity (r=0.26, p=0.0249). Conclusion: Histological chorioamnionitis was significantly associated with early onset sepsis, respiratory distress syndrome, bronchopulmonary dysplasia, and retinopathy of prematurity. No significant association was found between chorioamnionitis and neonatal mortality. While clinical diagnostic criteria for chorioamnionitis demonstrated good specificity, their poor sensitivity underscores the urgent need for improved diagnostic tools.

Abstract: Purpose. Whole-exome (WES) and whole-genome sequencing (WGS) have transformed paediatric diagnostics, with reported yields ranging from 25% in unselected cohorts to over 50% in highly consanguineous populations. The Saudi paediatric population—with consanguinity rates of 56–60%—offers a unique window into the diagnostic ceiling achievable when autosomal recessive Mendelian conditions dominate the case mix. We synthesised the published Saudi exome and genome sequencing literature to estimate the pooled diagnostic yield, examine subgroup heterogeneity, and identify factors influencing diagnostic success.Methods. We searched PubMed, Embase, Scopus, Web of Science, the Cochrane Library, and the Saudi Digital Library from inception to December 2024. Studies reporting WES or WGS results in Saudi paediatric cohorts (≥10 patients, age <18 years) were eligible. Two reviewers screened, extracted, and appraised studies independently using the JBI Prevalence and QUADAS-2 tools. We pooled diagnostic yield using a logit-transformed random-effects model with REML estimation of τ² and Hartung–Knapp–Sidik–Jonkman adjustment. Pre-specified subgroup analyses examined sequencing modality, phenotype group, and family design, with meta-regression on calendar year.Results. Twelve studies reporting on 3,252 paediatric patients were included. The pooled diagnostic yield was 51.8% (95% CI 47.8–55.9; 95% prediction interval 39.1–64.3; I² = 78%; τ² = 0.059). Yield was highest in metabolic phenotypes (58.9%) and lowest in renal disease (46.2%). WES trio (53.3%) and singleton (52.3%) showed comparable yields; WGS yield (48.4%) did not differ materially. Egger's test showed no asymmetry (p = 0.19); meta-regression revealed no temporal trend (slope p = 0.78).Conclusion. Saudi paediatric WES/WGS achieves a pooled diagnostic yield of ~52%, substantially higher than published international averages and consistent with consanguinity-driven enrichment for autosomal recessive disease. The plateau across modalities suggests that incremental gains will require improved phenotyping, reanalysis pipelines, and integration of multi-omic data rather than simple migration from WES to WGS.

Abstract: Background. Saudi Arabia implemented mandatory premarital screening and genetic counseling (PMSGC) for sickle cell disease and β-thalassaemia in February 2004. Over two decades the programme has screened more than eight million individuals, yet its cumulative outcomes have never been synthesized. We assessed the long-term impact of the PMSGC programme on at-risk marriage detection, marriage cancellation, regional heterogeneity, and hemoglobinopathy burden from 2004 to 2024. Methods.We conducted a systematic review and meta-analysis following PRISMA 2020. Six databases (PubMed/MEDLINE, Embase, Scopus, Web of Science, Cochrane CENTRAL, Saudi Digital Library) were searched from January 2004 to December 2024 without language restrictions. Studies reporting outcomes of the Saudi PMSGC programme — prevalence, at-risk couples, marriage cancellation rates, knowledge/attitudes/practices, or cost — were eligible. Two reviewers screened and extracted data independently in Rayyan. Risk of bias was assessed with Joanna Briggs Institute checklists. Random-effects meta-analysis pooled proportions using the Freeman–Tukey double arcsine transformation. Meta-regression tested temporal trends and regional moderators. The review was registered with PROSPERO (CRD420261378326). Findings. Of 3,008 records identified from databases and 145 from other sources, 62 studies met inclusion criteria, with 47 contributing to the meta-analysis. The pooled prevalence of sickle cell trait was 45.4 per 1,000 (95% CI 42.5–48.4; I² = 99.7%; 10 studies, >9.6 million individuals), with marked regional gradient (Eastern Province 134 per 1,000 vs Northern regions 13–14 per 1,000; ~10-fold). Pooled β-thalassaemia trait prevalence was 21.0 per 1,000 (95% CI 17.4–24.8; I² = 99.9%). Marriage cancellation rate among at-risk couples rose from 9.2% in 2004 to 51.9% in 2009 (Era 1 pooled 24.9%, 95% CI 13.0–39.2), to 60.5% in 2010–2019 (95% CI 49.6–70.9), to 76.7% in 2020–2024 (95% CI 63.1–87.9). Meta-regression on year midpoint showed a significant positive trend (β = +3.28 percentage points per year, P < 0.001). Decision-tree cost analysis indicated approximately 73% healthcare cost reduction attributable to the programme for sickle cell disease (~US$29.7 million annual saving). Interpretation. The Saudi PMSGC programme has achieved substantial population-level impact on hemoglobinopathy prevention over two decades, with marriage cancellation rates rising eight-fold and persistent — though narrowing — regional heterogeneity. Gaps remain in expanding the screening panel (spinal muscular atrophy, cystic fibrosis, phenylketonuria), in cost-effectiveness evidence, and in standardized outcome reporting. These findings support Saudi Vision 2030 health transformation goals and inform regional neighbours considering similar programmes.

Abstract: Allergic diseases are increasing globally, particularly among children, who are highly vulnerable due to critical windows of immune development. This review examines climate change as a key environmental determinant driving the rising burden of pediatric allergic diseases, including asthma, allergic rhinitis (AR), atopic dermatitis (AD), and food allergy (FA). Climate change influences disease risk through interconnected pathways, such as increased air pollution, altered aeroallergen patterns, and more frequent extreme weather events. Elevated carbon dioxide (CO₂) levels and rising temperatures prolong pollen seasons and enhance allergenicity, while pollutants such as ozone (O₃) and particulate matter (PM) exacerbate airway inflammation and immune dysregulation. Emerging evidence emphasizes the role of early-life exposure, particularly during prenatal and early postnatal periods, when environmental insults can induce long-term effects via epigenetic modifications and immune reprogramming. These mechanisms may increase susceptibility to allergic sensitization and subsequent disease development. Epidemiological studies consistently link exposure to air pollution, including PM₂.₅ (PM with aerodynamic diameter < 2.5 μm) and nitrogen dioxide (NO₂), with increased risk of allergic diseases in children. Additionally, climate change-related events such as wildfires, sand and dust storms, and thunderstorms further elevate exposure to allergens and pollutants, contributing to acute exacerbations and disease progression. Addressing this growing public health challenge requires integrated mitigation strategies to reduce greenhouse gas (GHG) emissions and improve air quality, alongside adaptive interventions to enhance resilience and reduce exposure. Understanding these mechanisms is essential for developing targeted prevention strategies and protecting child health in a changing climate.

Abstract: Background: The integration of Artificial Intelligence (AI) into the management of pediatric metabolic diseases offers unprecedented opportunities for precision medicine. However, the explosive growth of research literature production has led to a fragmented research landscape, often skewed by the indexing biases of major academic databases. Objective: This study aims to conduct a comparative thematic analysis of the Web of Science and Scopus databases to uncover the distinct research paradigms governing AI in pediatric metabolic diseases. Methods: We employed the Synthetic Knowledge Synthesis methodology, integrating automated bibliometric mapping (co-word analysis via VOSviewer) with qualitative content analysis. Metadata was extracted from both databases and author keywords were clustered to evaluate underlying thematic structures. Results: The comparative analysis revealed a significant thematic divergence. Literature indexed in WoS predominantly emphasizes algorithmic novelty and methodological advancement, highlighting the use of Deep Learning, Large Language Models (LLMs), and complex metabolomic integrations. Conversely, Scopus encapsulates a distinctly clinical and translational paradigm, prioritizing Explainable AI (XAI), the integration of Natural Language Processing (NLP) with Electronic Health Records (EHR), and the application of clinical decision support systems like Continuous Glucose Monitoring (CGM). Conclusion: Relying on a singular bibliographic database provides an incomplete view of the field, creating a disconnect between algorithmic development and clinical implementation. To successfully bridge the "algorithm-to-clinic" gap in pediatric endocrinology, researchers must adopt a holistic approach that synthesizes the predictive power emphasized in WoS with the clinical transparency and applicability highlighted in Scopus.

Abstract: Background/Objective: To evaluate the long-term effects of eosinophilic esophagitis (EoE) on children’s nutritional status and growth. Methods: We performed a retrospective cohort study assessing longitudinal growth patterns (height and BMI z-scores) in pediatric patients (<18 years) newly diagnosed with EoE and followed for at least one year. Nutritional status was classified using BMI-based criteria from the American Dietetic Association and the World Health Organization. Results: Among 50 patients, 20% presented with impaired nutritional status at diagnosis, including 12% with moderate malnutrition (BMI z-score < –2) and 8% with obesity (BMI z-score > 2). After a mean follow-up of 24.5 months, the prevalence of moderate malnutrition decreased to 6%, whereas obesity increased to 12%. Height z-scores remained largely stable over time. Conclusion: EoE affects children across the full BMI spectrum. Long-term follow-up highlights the importance of monitoring nutritional status in all pediatric patients with EoE, given the risks of both malnutrition and obesity.

Abstract: Background: In Japan, the total number of births is decreasing, while the proportions of late preterm and early term infants are increasing. Infants born at 36 weeks of gestation (hereinafter “36-week infants”) are not considered an indication for hospitalization, resulting in limited clinical data and insufficient understanding of their actual conditions. In this study, we aimed to examine the characteristics of 36-week infants. Methods: We reviewed the medical records of mothers and their 36-week infants born at the Kyorin University Hospital from April 2014 to March 2015. We evaluated birth weight using “standard values for physical measurements at birth according to gestational age.” F-test and Student’s t-test were used to examine the difference in mean gestational age between the 36-week infants who were hospitalized and those who were not hospitalized. Results: We included 84 infants, with multiple births accounting for 63%. Overall, 20% of the infants were born through assisted reproductive technology, 54% required hospitalization, 87% were fed orally rather than through a gastric tube, and 82% received a simple glucose solution for intravenous nutrition. Among the full-term infants, 3.6% weighed below the 10th percentile of the standard weight. Of the 11 children who underwent developmental and intelligence tests, 3 had below-average scores. Conclusions: Infants born at 36 weeks of gestation is an absolute indication for hospitalization. ​Proactive tube feeding may be considered for 36-week infants. Extending follow-up throughout infancy and early childhood is beneficial for 36-week infants.

Abstract: Background: The clinical relevance of food-specific IgG antibodies in pediatric gastrointestinal disorders remains controversial. While current guidelines discourage their use as standalone diagnostic tools, their association with objective markers of intestinal inflammation has not been sufficiently investigated. Methods: This prospective observational study included 126 children aged 2–18 years with chronic gastrointestinal symptoms and 90 asymptomatic controls. All participants underwent food-specific IgG testing using a 216-antigen ELISA panel and standardized abdominal ultrasound. Bowel wall thickening (>3 mm) and mesenteric lymphadenopathy (>8 mm) were assessed. A robust multilevel statistical framework was applied, integrating inferential comparisons, correlation analyses, multivariable logistic regression modeling, and receiver operating characteristic (ROC) curve analysis to evaluate independent associations and predictive accuracy. Results: IgG positivity (≥5 foods ≥12 arbitrary units/mL (AU/mL) was significantly higher in symptomatic children compared to controls (76.2% vs. 12.0%, p < 0.001). Bowel wall thickening was detected in 30.9% of symptomatic patients and was associated with abdominal pain (84.6% vs. 52.1%; OR = 4.9, 95% CI: 1.7–13.6, p = 0.003) and altered bowel habits (p = 0.02). IgG positivity correlated with ultrasound abnormalities (r = 0.41, p < 0.01), with a threefold higher prevalence of thickening in IgG-positive children (34% vs. 11%, p < 0.001). In multivariate analysis, IgG polysensitization independently predicted bowel wall thickening (adjusted OR = 3.8, 95% CI: 1.5–9.6, p = 0.004). ROC analysis demonstrated moderate diagnostic performance (AUC = 0.78). Conclusions: Food-specific IgG reactivity is associated with gastrointestinal symptoms and ultrasound-detected intestinal changes in children. While these findings do not support a diagnostic role for IgG testing, they suggest that IgG may serve as a marker of immune exposure within a multimodal assessment framework. Integration of serological and imaging data may help identify subgroups of patients with potential low-grade intestinal involvement, warranting further investigation in longitudinal and interventional studies.

Abstract: Acute chest syndrome (ACS) is a frequent and potentially life-threatening complication of sickle cell disease (SCD), often developing during hospitalization for vaso-occlusive crisis (VOC). Early identification of pediatric patients at risk remains challenging, particularly in high-prevalence settings. We conducted a retrospective cohort study of children and adolescents (≤18 years) with confirmed SCD admitted for VOC to Cayenne Hospital Center, French Guiana, between January 2014 and September 2024. ACS occurring during hospitalization or within 7 days of admission was recorded. Multivariable logistic regression was used to identify independent predictors, and model performance was assessed using receiver operating characteristic (ROC) analysis. Among 824 VOC episodes in 190 patients, 239 (29%) were complicated by ACS. Independent predictors of ACS were thoracic or abdominal pain at presentation (adjusted odds ratio [aOR] 2.88, 95% CI 1.45–5.72), prior history of ACS (aOR 2.20, 95% CI 1.28–2.90), and HbSS or Sβ⁰ genotype (aOR 1.91, 95% CI 1.30–2.60). Hydroxyurea use at admission was less frequent among patients who developed ACS. The predictive model showed good discrimination (AUC ~0.90), high specificity (96%), and positive predictive value (85%). These findings support targeted monitoring and early preventive strategies during pediatric VOC admissions.

Abstract: More than 30 lines of discrete, independent evidence implicate the exposure of susceptible babies and children to acetaminophen with the etiology of autism spectrum disorder (ASD). The most abundant source of evidence is from the fields of pharmacology and toxicology, with clinical and epidemiological observations, numerous miscellaneous observations, and studies in laboratory animal models providing conclusive support. This narrative review summarizes that evidence, and discusses recent work with sibling control analysis that has been unfortunately misinterpreted as a result of incorrect assignment of interacting variables as confounding factors. Susceptibility to acetaminophen-induced injury is imposed by a range of genetic, epigenetic, and environmental factors associated with oxidative stress, and is apparently the greatest immediately after birth. Susceptibility then decreases until about six years of age, which is outside of the developmental window in which regression into ASD typically occurs. Although associations between heavy use of acetaminophen during pregnancy and ASD suggest some risk may be present during pregnancy, insufficient evidence is available to know if sporadic use of acetaminophen during pregnancy poses any risks. Given continued use of acetaminophen during labor and delivery, and routine use during early childhood including for indications including circumcision, vaccination, and some chronic medical conditions, a course correction in clinical practice is much needed.

Abstract: A recent report on the prevalence of autism spectrum disorder (ASD) from California describes unprecedented levels of ASD in that population. The data indicate a transition or changepoint in 2015-2016 in which the prevalence of ASD began to accelerate more rapidly after almost a decade of consistent yearly increases. The changepoint is associated strongly with socioeconomic status, being most readily observable in black children and in low-income counties. Herein we propose the hypothesis that legalization of recreational cannabis in late 2016 led to several cultural changes that in turn caused socioeconomic-dependent increases in very frequent cannabis use and/or cannabis use disorder (CUD). CUD is strongly associated with ASD, and we hypothesize that an adverse drug-drug interaction between acetaminophen and a component or components of cannabis may be at play. It remains unknown whether prenatal or postnatal exposures may be more critical, and further work aimed at evaluating very frequent cannabis use and/or CUD and ASD rates in subsets of the population is strongly encouraged. Paradoxically, caution is urged so that work to decrease CUD does not impede ongoing and promising work using cannabis and cannabis-derived products for the treatment of patients with ASD.

Abstract: Background: An estimated 2–5% of infants are born with significant congenital defects and/or go on to develop severe neurodevelopmental disorders in early childhood, with a substantial proportion attributed to underlying genetic causes. Variants in the MED13L gene have been linked to a syndromic neurodevelopmental disorder characterized by developmental delay, intellectual disability, and, in some cases, congenital heart defects. However, the pathogenicity of many MED13L variants—particularly missense changes—remains poorly understood. Methods: This study analyzed clinically and genomically annotated data from the 100,000 Genomes Project (Genomics England), focusing on individuals with rare MED13L variants. A structured pipeline was developed to extract, filter, and interpret missense and truncating variants using the Interactive Variant Analysis (IVA) tool and associated resources. Detailed clinical phenotypes were manually cross-referenced through the Participant Explorer, and variants were classified following ACMG guidelines. Results: After filtering, eight probands were identified with clinically relevant, previously unreported, MED13L variants: five variants of uncertain significance (VUS) and three likely pathogenic. Despite differences in classification, both VUS and likely pathogenic variants were associated with a consistent neurodevelopmental phenotype. One additional patient carried an intronic MED13L variant with predicted spliceogenic potential and presented with a congenital heart defect, raising the possibility of a regulatory effect on cardiac gene expression. Notably, four of the eight individuals also harbored additional pathogenic or likely pathogenic variants in other genes known to contribute to neurodevelopmental phenotypes, illustrating potential genetic heterogeneity. The study also identified a disproportionately high rate of VUS among individuals of non-European ancestry, highlighting challenges in variant interpretation due to underrepresentation in population databases. Conclusions: This work emphasizes the value of large-scale genomic datasets in refining variant classification and improving diagnostic accuracy. It highlights the complexity of interpreting MED13L variants, the importance of considering genetic heterogeneity, and the need for increased diversity in genomic reference databases. Findings underscore the necessity of trio sequencing and functional studies to reclassify VUS and advance understanding of MED13L-associated syndromes.

Abstract: Congenital heart defects (CHDs) are the most common congenital anomalies, with identifiable genetic etiologies in approximately 5–30% of affected infants, depending on the clinical presentation and comorbidities. This study included 216 children with CHD, predominantly syndromic, to explore the role of genetic variants in their morphological phenotypes. Chromosomal microarray (CMA) and whole-exome sequencing (WES) were performed, revealing clinically significant copy number variations (csCNVs) in 27.3% of patients, with the most common deletions at 22q11.21 (11.9%) and 7q11.23 (8.5%). WES was conducted in 28.0% of cases, achieving a detection rate of 29.5%, primarily identifying variants related to Noonan syndrome. Genetic diagnoses were confirmed in 33.3% of patients, with clinically significant CNVs and SNV/INDELs found exclusively in those with syndromic CHD, leading to a 36.5% diagnosis rate in those patients. The identified variants most frequently affected genes encoding transcription factors (40.4%), followed by genes involved in the RAS signaling pathway and structural proteins (17.0%), and chromatin remodeling proteins (12.8%).