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BACKGROUND AND OBJECTIVE: Autosomal recessive genetic disorders pose significant health challenges in regions where consanguineous marriages are prevalent. The utilization of exome sequencing as a frequently employed methodology has enabled a clear delineation of diagnostic efficacy and mode of inheritance within multiplex consanguineous families. However, these aspects remain less elucidated within simplex families. METHODS: In this study involving 12 unrelated simplex Iranian families presenting syndromic autism, we conducted singleton exome sequencing. The identified genetic variants were validated using Sanger sequencing, and for the missense variants in FOXG1 and DMD, 3D protein structure modeling was carried out to substantiate their pathogenicity. To examine the expression patterns of the candidate genes in the fetal brain, adult brain, and muscle, RT-qPCR was employed. RESULTS: In four families, we detected an autosomal dominant gene (FOXG1), an autosomal recessive gene (CHKB), and two X-linked autism genes (IQSEC2 and DMD), indicating diverse inheritance patterns. In the remaining eight families, we were unable to identify any disease-associated genes. As a result, our variant detection rate stood at 33.3% (4/12), surpassing rates reported in similar studies of smaller cohorts. Among the four newly identified coding variants, three are de novo (heterozygous variant p.Trp546Ter in IQSEC2, heterozygous variant p.Ala188Glu in FOXG1, and hemizygous variant p.Leu211Met in DMD), while the homozygous variant p.Glu128Ter in CHKB was inherited from both healthy heterozygous parents. 3D protein structure modeling was carried out for the missense variants in FOXG1 and DMD, which predicted steric hindrance and spatial inhibition, respectively, supporting the pathogenicity of these human mutants. Additionally, the nonsense variant in CHKB is anticipated to influence its dimerization - crucial for choline kinase function - and the nonsense variant in IQSEC2 is predicted to eliminate three functional domains. Consequently, these distinct variants found in four unrelated individuals with autism are likely indicative of loss-of-function mutations. CONCLUSIONS: In our two syndromic autism families, we discovered variants in two muscular dystrophy genes, DMD and CHKB. Given that DMD and CHKB are recognized for their participation in the non-cognitive manifestations of muscular dystrophy, it indicates that some genes transcend the boundary of apparently unrelated clinical categories, thereby establishing a novel connection between ASD and muscular dystrophy. Our findings also shed light on the complex inheritance patterns observed in Iranian consanguineous simplex families and emphasize the connection between autism spectrum disorder and muscular dystrophy. This underscores a likely genetic convergence between neurodevelopmental and neuromuscular disorders.

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OBJECTIVE: To quantify the risk of long-term post-radical prostatectomy (RP) erectile dysfunction (ED) in men with diabetes mellitus (DM). METHODS: We included men who underwent RP and were followed for ≥24 months at our institution; men were excluded if they received androgen deprivation therapy or radiation therapy. Erectile function recovery (EFR) was assessed using the International Index of Erectile Function (IIEF) Erectile Function Domain (EFD) score pre-RP and serially during follow-up. We performed logistic regression analysis to investigate a potential association between erectile function 24 months post-RP. RESULTS: Of 2261 men included, 8% were diabetic. Men in the diabetic group tended to present with more vascular comorbidities. For men with DM, the median time from diagnosis was 4 years pre-RP, and the median hemoglobin A1c pre-RP was 6.7%. After 24 months post-RP, EFR was significantly lower among the diabetic group. The median EFD was 7. Men with DM had a lower proportion of functional EFR (17%) and a greater proportion of severe ED (57%). In the univariable logistic regression model to analyze DM diagnosis was a significant predictor of functional EFR (OR 0.43, P <.001) and severe ED (OR 1.85, P <.001) 24 months post-RP. Furthermore, this was not observed for a multivariable analysis. CONCLUSION: Twenty-four months after RP, EFR is compromised in individuals with DM.

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BACKGROUND: Most manual wheelchair users with pediatric-onset spinal cord injury (SCI) will experience shoulder pain or pathology at some point in their life. However, guidelines for preservation of the upper limb in children with SCI are limited. RESEARCH QUESTION: What are the relationships between manual wheelchair handrim kinetics and quantitative ultrasound parameters related to subacromial impingement in individuals with pediatric-onset SCI? METHODS: Subacromial impingement risk factors including supraspinatus tendon thickness (SST), acromiohumeral distance (AHD), and occupation ratio (OR; SST/AHD) were measured with ultrasound in 11 manual wheelchair users with pediatric-onset SCI. Handrim kinetics were acquired during the stroke cycle, including peak resultant force (FR), peak rate of rise of resultant force (ROR) and fractional effective force (FEF). Variability of handrim kinetics was computed using the coefficient of variation and linear regression was performed to assess correlations between handrim metrics and quantitative ultrasound parameters. RESULTS: Peak resultant force significantly increased 1.4 % and variability of FEF significantly decreased 8.0 % for every 0.1 cm increase in AHD. FEF decreased 3.5 % for every 0.1 cm increase in SST. Variability of peak resultant force significantly increased 3.6 % and variability of peak ROR of resultant force significantly increased 7.3 % for every 0.1 cm increase in SST. FEF variability significantly decreased 11.6 % for every 0.1 cm increase in SST. Peak ROR significantly decreased 1.54 % with every 10 % increase in OR. FEF variability significantly decreased 1.5 % with every 10 % increase in OR. SIGNIFICANCE: This is the first study to investigate relationships among handrim kinetics and shoulder structure in manual wheelchair users with pediatric-onset SCI. Associations were identified between subacromial impingement risk factors and magnitude and variability of wheelchair handrim kinetics. These results indicate the critical need to further explore the relationships among wheelchair handrim kinetics, shoulder joint dynamics, and shoulder pathology in manual wheelchair users with pediatric-onset SCI.

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Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment. Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC. Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains. Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents. Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

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BACKGROUND: Behavioral or mental health disorders are common in children, adolescents, and young adults. Medication use is increasingly common, with few data describing drug-drug combinations in ambulatory settings. The objectives of this study were to describe the pharmaco-epidemiology of behavioral and mental health (BMH) medications among children, adolescents, and young adults in New York Medicaid and assess the prevalence of contraindicated drug pairs within this population. METHODS: This observational cross-sectional study evaluated New York State Medicaid managed care and fee-for-service enrollees under 21 years of age dispensed BMH medications in 2014. Main outcomes included number of members with prescriptions filled; number filling > 1 medication prescription concurrently for ≥ 30 days (polypharmacy), and number and nature of potentially contraindicated drug pairs. RESULTS: Of 2,430,434 children, adolescents, and young adults, 422,486 (17.4%) had a visit associated with a BMH diagnosis and 141,363 (5.8%) received one or more BMH medications. With 84 distinct medications evaluated, polypharmacy was common, experienced by 53,388 individuals (37.8% of those with a prescription filled), generating 11,115 distinct drug combinations. 392 individuals filled prescriptions for a contraindicated pair of ≥ 2 BMH medications for 30 days or longer. With ≥ 1 day overlap, 651 were exposed to contraindicated medications. The most common contraindicated pairs increased potential risk for prolonged QT interval and serotonin syndrome (n = 378 and n = 250 patients, respectively). Most combinations involved ziprasidone (3247.1 per 10,000 ziprasidone prescriptions filled). CONCLUSIONS: With nearly 6% of members dispensed a BMH medication, contraindicated drug pairs were uncommon. However, any of those combinations represent a potential risk. Clinicians should attend to the balance of potential risks and benefits before contraindicated pairs are dispensed. The methodology described could serve as a basis for monitoring such rare instances and might reduce harm.

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BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

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Anesthesia clinicians often navigate a delicate balance between maternal and fetal safety. Interventions for at fetal well-being may introduce risks of harm to the mother and raise ethical dilemmas. Emergency procedures often focus on direct fetal safety, sidelining maternal physical and mental well-being. The clash between ethical principles, particularly nonmaleficence and beneficence, often arises, with maternal autonomy guiding decisions. Fetal surgery exemplifies risking maternal health for fetal benefit, whereas emergent cesarean deliveries pose physical and psychological challenges for both the mother and child.

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Choline contributes to the biogenesis of methyl groups, neurotransmitters, and cell membranes. Our genome-wide association study (GWAS) of circulating choline in 2228 college students found that alleles in SLC25A48 (rs6596270) influence choline concentrations in men (p = 9.6 × 10-8), but not women. Previously, the subcellular location and function of SLC25A48 were unknown. Using super-resolution immunofluorescence microscopy, we localized SLC25A48 to the inner mitochondrial membrane. Our results suggest that SLC25A48 transports choline across the inner mitochondrial membrane.

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OBJECTIVE: To evaluate predictors of implant length for men undergoing primary IPP placement. METHODS: A multicenter, retrospective cohort study was performed for men undergoing primary IPP placement at 16 high-volume surgical centers. Patient demographics, comorbidities, operative approach, and implanted cylinder and rear-tip extender length were recorded. Associations between potential preoperative and intraoperative predictors of total device length were tested using non-parametric correlation and Kruskal-Wallis tests, followed by multiple regression. RESULTS: Of 3951 men undergoing primary IPP placement from July 2016 to July 2021, the median implant length was 20 cm (IQR: 19-22). Shorter implant length was associated with increasing age in years (ß = -0.01, P = .009), Asian ethnicity (ß = -2.34, P = .008), history of radical prostatectomy (ß = -0.35, P = .001), and use of an infrapubic surgical approach (ß = -1.02, P <.001). Black or African American ethnicity was associated with the implantation of longer devices (ß = 0.35, P <.001). No significant associations were recorded with BMI, history of intracavernosal injections, diabetes mellitus, tobacco use, radiation therapy, Peyronie's disease, priapism, or cavernosal dilation technique. CONCLUSION: The length of an implanted penile prosthesis was found to be associated with preoperative and intraoperative factors including history of radical prostatectomy and operative approach. The knowledge of these associations may assist in the preoperative counseling of patients receiving IPP and help create accurate postoperative expectations.

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BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

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The COVID-19 pandemic has highlighted the need to upgrade systems for infectious disease surveillance and forecasting and modeling of the spread of infection, both of which inform evidence-based public health guidance and policies. Here, we discuss requirements for an effective surveillance system to support decision making during a pandemic, drawing on the lessons of COVID-19 in the U.S., while looking to jurisdictions in the U.S. and beyond to learn lessons about the value of specific data types. In this report, we define the range of decisions for which surveillance data are required, the data elements needed to inform these decisions and to calibrate inputs and outputs of transmission-dynamic models, and the types of data needed to inform decisions by state, territorial, local, and tribal health authorities. We define actions needed to ensure that such data will be available and consider the contribution of such efforts to improving health equity.

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A substantial proportion of Hong Kong's aging population suffers from osteoarthritis in both knees. Bilateral total knee arthroplasty (BTKA) is a surgical option for addressing this condition and can be performed via two approaches: simultaneous BTKA (SimBTKA) and staged BTKA (StaBTKA). We compared the cost-effectiveness and safety of these two methods in our institution. We retrospectively reviewed 2,372 patients (SimBTKA, 772; StaBTKA, 1,600; females, 1,780; males, 592; mean age at SimBTKA, 70.4 ± 7.99 years; mean age at StaBTKA, 66.4 ± 7.50 years; p < 0.001) who underwent BTKA in our institution from 2001 to 2022. Patients were categorized according to the surgical approach. Patients undergoing BTKA in our institution were included. Particularly for SimBTKA, patients were assessed by anesthetists to be medically fit before undergoing the procedure according to their age, American Society of Anesthesiologists status, and osteoarthritis severity. The primary outcome was the length of stay (LOS) after surgery. The secondary outcomes were the 30-day unintended readmission, intensive care unit (ICU) admission, and death. SimBTKA had a shorter mean total LOS (acute hospital + rehabilitation center; SimBTKA, 13.09 days; StaBTKA, 18.12 days; p < 0.001) and mean LOS in acute hospital (SimBTKA, 7.70 days; StaBTKA, 10.42 days; p < 0.001). However, no significant difference was found in the mean LOS in rehabilitation centers (SimBTKA, 5.47 days; StaBTKA, 6.32 days; p > 0.05) between the two approaches. The 30-day unintended readmission rate was lower in SimBTKA (SimBTKA, 2.07%; StaBTKA, 3.30%; odds ratio [OR] = 1.60; p > 0.05) but statistically insignificant. SimBTKA was less costly than StaBTKA by US$ 8,422.22 per patient. No significant differences in ICU admission and death rates were found (p > 0.05) between the two groups. SimBTKA had a shorter LOS and lower cost than StaBTKA and comparable complication rates. Therefore, SimBTKA should be indicated in medically stable patients.

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Pediatric intracerebral hemorrhage is a rare condition among children. We discuss the case of a 7-year-old Filipino male with generalized tonic seizures and diagnosed to have both SARS-CoV-2 infection and hypertension secondary to renal arterial stenosis. The occurrence of intracerebral hemorrhage in children, though commonly caused by arteriovenous malformations, may be secondary to an acute hypertensive episode. In this case, the presence of COVID-19 in the patient may have been contributory to the development of spontaneous intracerebral hemorrhage due to its direct endothelial effects, as well as its dysregulatory action on the renin-angiotensin-aldosterone system.

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OBJECTIVE: To study the identification of rare genetic variants in the PCDH genetic family in a cohort of transgender women (TGW) and their potential role in gender identity. DESIGN: Exome sequencing and functional ontology analysis. SETTING: Outpatient gender health and reproductive endocrinology clinics. PATIENT(S): A total of 24 TGW and 22 cisgender men (CM). INTERVENTION(S): Exome sequencing followed by variant confirmation through Sanger sequencing and functional classification analysis using the Database for Annotation, Visualization, and Integrated Discovery tool. MAIN OUTCOME MEASURE(S): Identification of rare, functionally significant genetic variants in the PCDH gene family and their prevalence in TGW compared with CM. RESULT(S): Exome sequencing revealed 38,524 genetic variants, of which 2,441 were rare and predicted to be functionally significant. The Database for Annotation, Visualization, and Integrated Discovery analysis demonstrated a statistically enriched functional group, "homophilic cell adhesion via plasma membrane adhesion molecules," containing 55 genes, including 18 PCDH gene family members. A total of 37 rare variants in 21 PCDH genes were identified, with 36 confirmed using Sanger sequencing. A statistically significant increase in these variants was observed in TGW compared with CM (Z = 2.08905). CONCLUSION(S): Transgender women exhibited a greater than threefold increase in functionally significant PCDH gene variants compared with CM. These findings suggest that the PCDH family may play a role in the genetic pathways associated with gender identity in TGW.

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IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

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Viral respiratory illness surveillance has traditionally focused on single pathogens (e.g., influenza) and required fever to identify influenza-like illness (ILI). We developed an automated system applying both laboratory test and syndrome criteria to electronic health records from 3 practice groups in Massachusetts, USA, to monitor trends in respiratory viral-like illness (RAVIOLI) across multiple pathogens. We identified RAVIOLI syndrome using diagnosis codes associated with respiratory viral testing or positive respiratory viral assays or fever. After retrospectively applying RAVIOLI criteria to electronic health records, we observed annual winter peaks during 2015-2019, predominantly caused by influenza, followed by cyclic peaks corresponding to SARS-CoV-2 surges during 2020-2024, spikes in RSV in mid-2021 and late 2022, and recrudescent influenza in late 2022 and 2023. RAVIOLI rates were higher and fluctuations more pronounced compared with traditional ILI surveillance. RAVIOLI broadens the scope, granularity, sensitivity, and specificity of respiratory viral illness surveillance compared with traditional ILI surveillance.

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Galectins are a large and diverse protein family defined by the presence of a carbohydrate recognition domain (CRD) that binds ß-galactosides. They play important roles in early development, tissue regeneration, immune homeostasis, pathogen recognition, and cancer. In many cases, studies that examine galectin biology and the effect of manipulating galectins are aided by, or require the ability to express and purify, specific members of the galectin family. In many cases, E. coli is employed as a heterologous expression system, and galectin expression is induced with isopropyl ß-galactoside (IPTG). Here, we show that galectin-3 recognizes IPTG with micromolar affinity and that as IPTG induces expression, newly synthesized galectin can bind and sequester cytosolic IPTG, potentially repressing further expression. To circumvent this putative inhibitory feedback loop, we utilized an autoinduction protocol that lacks IPTG, leading to significantly increased yields of galectin-3. Much of this work was done within the context of a course-based undergraduate research experience, indicating the ease and reproducibility of the resulting expression and purification protocols.

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The molecular basis of mullerian aplasia, also known as Mayer-Rokitansky-Kuster Hauser (MRKH) or congenital absence of the uterus and vagina, is largely unknown. We applied a multifaceted genetic approach to studying the pathogenesis of MRKH including exome sequencing of trios and duos, genome sequencing of families, qPCR, RT-PCR, and Sanger sequencing to detect intragenic deletions, insertions, splice variants, single nucleotide variants, and rearrangements in 132 persons with MRKH. We identified two heterozygous variants in ZNHIT3 localized to a commonly involved CNV region at chromosome 17q12 in two different families with MRKH. One is a frameshift, truncating variant that is predicted to interfere with steroid hormone binding of the LxxLL sequence of the C-terminal region. The second variant is a double missense/stopgain variant. Both variants impair protein expression in vitro. In addition, four more probands with MRKH harbored the stopgain variant without the nearby missense variant. In total, 6/132 (4.5%) of patients studied, including five with associated anomalies (type 2 MRKH), had ZNHIT3 variants that impair function in vitro. Our findings implicate ZNHIT3 as an important gene associated with MRKH within the 17q12 CNV region.

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