LTK and ALK promote neuronal polarity and cortical migration by inhibiting IGF1R activity.

The establishment of axon-dendrite polarity is fundamental for radial migration of neurons, cortical patterning, and formation of neuronal circuits. Here, we show that the receptor tyrosine kinases, Ltk and Alk, are required for proper neuronal polarization. In isolated primary mouse embryonic neurons, the loss of Ltk and/or Alk causes a multiple axon phenotype. In mouse embryos and newborn pups, the absence of Ltk and Alk delays neuronal migration and subsequent cortical patterning. In adult cortices, neurons with aberrant neuronal projections are evident and axon tracts in the corpus callosum are disrupted. Mechanistically, we show that the loss of Alk and Ltk increases the cell-surface expression and activity of the insulin-like growth factor 1 receptor (Igf-1r), which activates downstream PI3 kinase signaling to drive the excess axon phenotype. Our data reveal Ltk and Alk as new regulators of neuronal polarity and migration whose disruption results in behavioral abnormalities.

Molecular autopsy in Chinese sudden cardiac death in the young.

Inherited cardiovascular conditions are significant causes of sudden cardiac death in the young (SCDY), making their investigation using molecular autopsy and prevention a public health priority. However, the molecular autopsy data in Chinese population is lacking. The 5-year result (2017-2021) of molecular autopsy services provided for victims of SCDY (age 1-40 years) was reviewed. The outcome of family cascade genetic screening and clinical evaluation was reviewed. A literature review of case series reporting results of molecular autopsy on SCDY in 2016-2023 was conducted. Among the 41 decedents, 11 were found to carry 13 sudden cardiac death (SCD)-causative genetic variants. Likely pathogenic (LP) variants were identified in the DSP, TPM1, TTN, and SCN5A genes. Cascade genetic testing identified four family members with LP variants. One family member with familial TPM1 variant was found to have hypertrophic cardiomyopathy upon clinical evaluation. This study provided insight into the genetic profile of molecular autopsy in a Chinese cohort of SCDY. The detection of important SCD-causative variants through molecular autopsy has facilitated family cascade screening by targeted genetic testing and clinical evaluation of at-risk family members. A literature review of the current landscape of molecular autopsy in the investigation of SCDY was conducted.

Clinical and molecular characteristics of hemophilia A affected individuals and carriers: A 24 years experience from three centers.

Hemophilia A is a rare bleeding disorder with variable expressivity and allelic heterogeneity. Despite the advancement of prenatal diagnostics and molecular studies, the number of studies reviewing the reproductive choices of hemophilia A carriers and affected individuals remains limited. Through this retrospective review, we hope to gain a deeper understanding of hemophilia A-affected individuals' clinical and molecular characteristics, as well as the reproductive choices of the at-risk couples. A total of 122 individuals harboring likely causative F8 gene alterations from 64 apparently unrelated families attending three centers between 3/2000 and 3/2023 were included in this study. Their clinical and molecular findings as well as reproductive choices were gathered in a clinical setting and verified through the electronic medical record database of the public health system. Forty-seven affected males and 75 female heterozygous carriers were included in the analysis. Among 64 apparently unrelated families, 36 distinct pathogenic/likely pathogenic variants were identified, of which 30.6% (11/36) of variants were novel. While the majority of clinical findings and genotype-phenotype correlations appear to be in accordance with existing literature, female carriers who had no fertility intention were significantly more likely to have affected sons than those who had fertility intention (5/19 vs. 4/5; p = 0.047). Through this retrospective review, we summarized the clinical and molecular characteristics of 122 individuals harboring pathogenic/likely pathogenic F8 variants, as well as their fertility intentions and reproductive outcomes. Further studies are required to look into the considerations involved in reproductive decision-making.

Implementation and outcomes of beta-lactam allergy management protocol at a comprehensive cancer center.

PURPOSE: Beta-lactam allergy (BLA) is associated with increased broad-spectrum antibiotic (Br-ABX) use and worse clinical outcomes. We evaluated our hospital-wide BLA protocol (BLA-P) that used following categories: intolerance, low-risk, and high-risk. METHODS: Hospitalized adult patients with listed BLA during 10/2021-12/2022 were eligible. Exclusions were critically ill, surgical, hospice or comfort care, or non-verbal patients. Assessment was counted each time a pharmacist evaluated BLA. Interventions were no further action (high-risk allergy, patient refusal, unstable clinical status), updated allergy label, or delabeled. Delabeling was done either based on antibiotic history (direct-delabeling), or via test-dose challenge for low-risk patients. Br-ABX usage was compared in the unique delabeled patients: the empiric antibiotic use 90 days post-delabeling versus pre-delabeling using McNemar test (SPSS). RESULTS: A total of 700 assessments in 631 patients were identified. 441 assessments in 377 patients (median 63 years-old, 41% male, 50% hematological cancer) met inclusion criteria. The assessments revealed 9% intolerance, 55% low-risk, 23% high-risk and 13% unknown reaction. Interventions resulted in no further action 7%, updated label 72%, and delabeling 21%. 65% of the delabeling was via direct-delabeling and 35% test-dose challenge. Among patients who received a test-dose challenge, 36/36(97%) had no documented allergic reactions, and 1/26(3%) developed a mild rash. The use of aztreonam (pre-delabeling 28% vs. post-delabeling 1.2%, p < 0.001) and meropenem (13% vs. 2.4%, p = 0.022) significantly decreased while cefepime (24% vs. 50%, p = 0.001) and piperacillin-tazobactam (3.7% vs. 22%, p < 0.001) increased after delabeling. CONCLUSION: BLA-P led to 21% delabeling, which resulted in increased preferred Br-ABX and decrease in aztreonam/meropenem use among delabeled patients.

KBG syndrome in a Chinese population: A case series.

KBG syndrome (OMIM #148050) is an autosomal dominant neurodevelopmental disorder characterized by the presence of macrodontia of the permanent central upper incisors, characteristic facial features, delay in development, intellectual disability, short stature, and various skeletal abnormalities. Over 200 affected individuals have been described worldwide, though underdiagnosis is suspected because the characteristic features are variably present and affected individuals can have a mild phenotype. This case series provides a summary of the clinical and molecular characteristics of 10 Chinese KBG syndrome patients recruited from a single center. To our knowledge, this is the first case series for Chinese KBG patients. This case series aimed at exploring potential ethnicity-related variability in KBG syndrome.

The first case report of Strømme syndrome in a Chinese patient: Expanding the phenotype and literature review.

Strømme syndrome (MIM #243605) is a rare autosomal recessive ciliopathy resulting from compound heterozygous or homozygous pathogenic alterations in the CENPF gene (# 600236). Although there are a number of case reports featuring individuals with clinically compatible Strømme syndrome, only 13 affected individuals had molecular confirmation worldwide. Herein, we report a 24 years old Chinese gentleman with molecularly confirmed Strømme syndrome with compound heterozygous pathogenic nonsense variants in NM_016343.3(CENPF):c.436C > T, p.(Gln146*) and c.9280C > T, p.(Arg3094*). He presented with microcephaly, unilateral microphthalmia, single central upper incisor and bilateral preaxial polydactyly. To our knowledge, this is the first reported Chinese individual with molecularly confirmed Strømme syndrome.

Extending the phenotype of DeSanto-Shinawi syndrome: A case report and literature review.

DeSanto-Shinawi syndrome (DESSH, OMIM #616708) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function variants in the WAC gene. Affected individuals are characterized by neonatal hypotonia, developmental delay, intellectual disability, behavioral problems, and dysmorphism. Epilepsy is present in some of the patients with DESSH. By far, less than 30 affected individuals have been reported worldwide. Herein, we report a 9-year-old Chinese girl with molecularly substantiated DESSH with a de novo nonsense c. 1648C>T p.(Arg550*) variant identified in the WAC gene. Aside from developmental delay and the characteristic facial gestalt, our proband also exhibited tethered cord syndrome due to filar lipoma and left duplex kidney complicated with hydronephrosis, features not observed in any of the previously reported individuals with DESSH.

CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series.

CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.

Food Insecurity Negatively Impacts Gluten Avoidance and Nutritional Intake in Patients With Celiac Disease.

BACKGROUND: Food insecurity is a major public health challenge. For patients with celiac disease (CeD), food insecurity may be particularly detrimental as it threatens the cornerstone of their treatment: adoption of a gluten-free diet (GFD). We aimed to characterize the prevalence of food insecurity in patients with CeD and evaluate its impact on GFD adoption and nutritional intake. METHODS: We analyzed data from patients with CeD participating in the US National Health and Nutrition Examination Survey (NHANES) from 2009 to 2014. Food insecurity was defined using the US Department of Agriculture 18-Item Standard Food Security Survey Module. Survey-weighted logistic regression was used to assess differences in demographic characteristics of CeD patients living with food insecurity and the impact of food security on GFD adoption. Multivariable survey-weighted linear regression was used to evaluate the effect of food insecurity on nutritional intake of macronutrients and micronutrients. RESULTS: Overall, 15.9% (95% confidence interval: 10.6%, 23.1%) of patients with CeD in the United States [weighted N=2.9 million (95% confidence interval: 2.2, 3.5 million)] are food insecure. Food insecure patients with CeD were disproportionately younger, poorly educated, nonwhite, living in poverty, and were significantly less likely to adopt a GFD (24.1% vs. 67.9%, P =0.02). Food insecurity was associated with significantly lower consumption of protein, carbohydrates, fat, and most vitamins and minerals. CONCLUSIONS: One in 6 patients with CeD are food insecure, negatively impacting GFD adoption and the ability to meet recommended daily intake of most micronutrients. Less than one quarter of food insecure CeD patients adhere to a GFD.

Gender Disparities in Food Security, Dietary Intake, and Nutritional Health in the United States.

INTRODUCTION: Food insecurity is associated with negative nutritional outcomes and is experienced differently by women vs men. We evaluated the effects of gender on food insecurity and dietary intake in the United States. METHODS: Data from the National Health and Nutrition Examination Survey (2007-2016) were analyzed. Survey-weighted linear and logistic regression models were used to evaluate predictors of food security and the effect of food security on dietary consumption and body anthropometrics. Gender was modeled as a covariable and as an effect modifier. RESULTS: A total of 30,251 respondents were included. Approximately 15.1% (95% confidence interval [CI]: 14.1%-16.1%) of participants were food insecure. This increased over time from 11.7% in 2007-2008 to 18.2% in 2015-2016. A higher proportion of women experienced food insecurity compared with men (53.3% vs 46.7%, P = 0.02), although this was not significant after adjusting for poverty and other confounders (adjusted odds ratio 1.01; 95% CI: 0.93-1.09; P = 0.81). Among food insecure women, 32.4% (95% CI: 30.0%-34.9%) received emergency food assistance and 75.0% (95% CI: 71.5%-78.2%) received supplemental nutrition assistance benefits. Relative to men, food insecure women were less likely to meet the recommended dietary allowance of most macronutrients and micronutrients. They were also significantly more likely to be obese, have a wider waist circumference, and have higher total body fat percentage (P interaction all <0.001). DISCUSSION: Food insecurity represents a substantial public health challenge in the United States that differentially affects women compared with men. Alternative strategies may be required to meet the nutritional requirements for food insecure women.

Clinical and molecular characterization study of Chinese Kabuki syndrome in Hong Kong.

Kabuki syndrome (OMIM #147920 and 300867) is a rare genetic disorder characterized by a distinctive facial gestalt, intellectual disability and multiple congenital anomalies. We summarized the clinical features and molecular findings of the Kabuki syndrome (KS) patients diagnosed in Hong Kong between January 1991 and December 2019. There were 21 molecularly confirmed KS. Twenty of them were due to pathogenic KMT2D variants and one patient had KDM6A deletion. Nine KMT2D variants were novel. The clinical phenotype of our Chinese KS patients was largely comparable with that reported in patients of other ethnicities. This study expands the mutation spectrum but also provide important natural history information of Chinese KS in literature.

Prenatal phenotype of Kabuki syndrome: A case series and literature review.

OBJECTIVES: Kabuki syndrome (KS) is a genetic disorder characterized by intellectual disability, facial dysmorphism and congenital anomalies. We aim to investigate the prenatal features of fetuses with KS and to provide a comprehensive review of the literature on prenatal sonographic abnormalities associated with KS. METHODS: We retrospectively reviewed the prenatal ultrasound findings of all mothers of children with molecularly confirmed KS in Hong Kong, between 1991 and 2019. We also performed systematic review of the literature to identify studies on the prenatal findings in KS. RESULTS: We identified 11 cases with KS with detectable fetal ultrasound findings ranging from no detectable abnormalities to a variety of non-specific findings including increased nuchal translucency, pleural effusion, cardiac anomalies, renal anomalies, intrauterine growth restriction, polyhydramnios, oligohydramnios and single umbilical artery. In combining our cases with the 77 cases published, 42 (50.6%) of them had more than one abnormal antenatal ultrasound finding. The most frequent ultrasound features observed were cardiac anomalies (49.4%), followed by polyhydramnios (28.9%), genitourinary anomalies (26.5%), single umbilical artery (15.7%), intrauterine growth restriction (14.5%) and hydrops fetalis/pleural effusion/ascites (12.0%). CONCLUSIONS: These cases demonstrate the prenatal phenotypic heterogeneity associated with KS. Although the ultrasound abnormalities are non-specific, KS should be considered in the differential diagnosis when these fetal findings following normal microarray analysis/karyotyping.

Ibalizumab-uiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: A case report.

WHAT IS KNOWN AND OBJECTIVE: Treatment for diffuse large B-cell lymphoma (DLBCL) in persons with AIDS consists of chemotherapy alongside antiretroviral therapy (ART). To determine optimal HIV treatment, drug-drug interactions, toxic effects and ART resistance must be considered. CASE DESCRIPTION: A 40-year-old man with drug-resistant HIV and DLBCL initiating chemotherapy which had drug interactions with his ART. During chemotherapy, darunavir/cobicistat was held and ibalizumab-uiyk was started to ensure he was on three active HIV medications. WHAT IS NEW AND CONCLUSION: Ibalizumab-uiyk has no known drug-drug interactions and may be used as bridge therapy for patients with drug-resistant HIV undergoing chemotherapy.

Mowat-Wilson syndrome in a Chinese population: A case series.

Mowat-Wilson syndrome (MWS) is characterized clinically by a distinctive facial gestalt, intellectual disability, microcephaly, epilepsy, and nonobligatory congenital malformations such as Hirschsprung disease, urogenital anomalies, congenital heart disease, eye malformations. This article summarized the clinical features and molecular findings of 15 Chinese MWS patients. The results revealed a higher incidence of congenital heart disease in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and genitourinary malformation appeared to be lower. This suggests possible ethnicity-related modifying effects in the MWS phenotype.

Eruptive disseminated Spitz naevus (EDSN) in a young girl of Indian origin.

Eruptive disseminated Spitz naevus (EDSN) is a rare entity and has never been documented in a South-east Asian individual (of Indian origin) previously. We report an adolescent with this condition which, to our knowledge, has only been previously reported a few times.

Mail-Order Pharmacy Dispensing of Mifepristone for Medication Abortion After In-Person Screening.

Importance: Before 2021, the US Food and Drug Administration required mifepristone to be dispensed in person, limiting access to medication abortion. Objective: To estimate the effectiveness, acceptability, and feasibility of dispensing mifepristone for medication abortion using a mail-order pharmacy. Design, Setting, and Participants: This prospective cohort study was conducted from January 2020 to May 2022 and included 11 clinics in 7 states (5 abortion clinics and 6 primary care sites, 4 of which were new to abortion provision). Eligible participants were seeking medication abortion at 63 or fewer days' gestation, spoke English or Spanish, were age 15 years or older, and were willing to take misoprostol buccally. After assessing eligibility for medication abortion through an in-person screening, mifepristone and misoprostol were prescribed using a mail-order pharmacy. Patients had standard follow-up care with the clinic. Clinical information was collected from medical records. Consenting participants completed online surveys about their experiences 3 and 14 days after enrolling. A total of 540 participants were enrolled; 10 withdrew or did not take medication. Data were analyzed from August 2022 to December 2023. Intervention: Mifepristone, 200 mg, and misoprostol, 800 µg, prescribed to a mail-order pharmacy and mailed to participants instead of dispensed in person. Main Outcomes and Measures: Proportion of patients with a complete abortion with medications only, reporting satisfaction with the medication abortion, and reporting timely delivery of medications. Results: Clinical outcome information was obtained and analyzed for 510 abortions (96.2%) among 506 participants (median [IQR] age, 27 [23-31] years; 506 [100%] female; 194 [38.3%] Black, 88 [17.4%] Hispanic, 141 [27.9%] White, and 45 [8.9%] multiracial/other individuals). Of these, 436 participants (85.5%; 95% CI, 82.2%-88.4%) received medications within 3 days. Complete abortion occurred after medication use in 499 cases (97.8%; 95% CI, 96.2%-98.9%). There were 24 adverse events (4.7%) for which care was sought for medication abortion symptoms; 3 patients (0.6%; 95% CI, 0.1%-1.7%) experienced serious adverse events requiring hospitalization (1 with blood transfusion); however, no adverse events were associated with mail-order dispensing. Of 477 participants, 431 (90.4%; 95% CI, 87.3%-92.9%) indicated that they would use mail-order dispensing again for abortion care, and 435 participants (91.2%; 95% CI, 88.3%-93.6%) reported satisfaction with the medication abortion. Findings were similar to those of other published studies of medication abortion with in-person dispensing. Conclusions and Relevance: The findings of this cohort study indicate that mail-order pharmacy dispensing of mifepristone for medication abortion was effective, acceptable to patients, and feasible, with a low prevalence of serious adverse events. This care model should be expanded to improve access to medication abortion services.

Outcomes of Rituximab-abbs versus Rituximab in Patients with Diffuse Large B-Cell Lymphoma in a Noninferiority Study.

BACKGROUND: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the first line treatments for diffuse large B-cell lymphoma (DLBCL). Rituximab comprises most of the treatment cost for this regimen; therefore, biosimilars, such as rituximab-abbs are crucial to provide affordable care. Although rituximab-abbs was studied primarily in follicular lymphoma, the Food and Drug Administration (FDA) approved this drug for all indications of the reference product on the basis of extrapolation. Effectiveness and safety data surrounding the use of rituximab-abbs in DLBCL is lacking. OBJECTIVE: To evaluate the effectiveness and safety of rituximab-abbs and reference product rituximab as R-CHOP treatment for patients with DLBCL. PATIENTS AND METHODS: This noninferiority (NI) study compared the 2-year overall survival (OS), overall response rate (ORR), and incidence of adverse events (AEs) between rituximab-abbs and its reference product (RP) in R-CHOP among adult patients with newly diagnosed DLBCL. The study inclusion period was from 1 January 2019 to 31 December 2020. Analyses were performed on the basis of a noninferiority lower limit of 10% for OS and ORR, and an upper limit of 10% for serious AEs. RESULTS: There were 240 patients who received RP rituximab, while 295 patients received rituximab-abbs. The cohort had a mean age of 63.7±12.2 years and 43% were female. The 2-year OS was 81.0% and 79.6% (NI p < 0.01) while the ORR was 80.0% and 69.6% (NI p < 0.01), among the rituximab-abbs and rituximab groups, respectively. The incidence of infusion reaction AEs (NI p < 0.01) and noninfusion reaction AEs (NI p < 0.01) also met noninferiority. CONCLUSIONS: We demonstrated that rituximab-abbs was noninferior to rituximab in both effectiveness and safety among patients receiving R-CHOP for DLBCL in this study. Long-term follow-up would be needed to confirm these results.