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.

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.

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.

Use of monoclonal antibody therapy in hematologic patients with mild-to-moderate COVID-19: A retrospective single-center experience.

INTRODUCTION: In November 2020, the FDA issued an emergency use authorization (EUA) for monoclonal antibody (mAb) therapy in patients with mild-to-moderate COVID-19 at high risk for disease progression. METHODS: We retrospectively reviewed 38 adult hematology patients who received mAbs from 11/2020 to 2/2021. RESULTS: Thirty (79%) patients received bamlanivimab and 8 (21%) casirivimab-imdevimab. Four (11%) patients were hospitalized due to COVID-19, two (5%) progressed to severe disease and one patient (3%) died within 30 days from COVID-19 disease. Most patients (n = 34, 89%) ultimately tested negative for SARS-CoV-2, with 34% (n = 13) clearing the virus within 14 days after mAb infusion. The median time to clearance of viral shedding was 25.5 days (range: 7-138). After mAb infusion, most patients with hematological malignancies (HM) (n = 10/15; 67%) resumed therapy for underlying disease with a median delay of 21.5 days (range: 12-42). We observed a significant difference in hospitalization among patients who received a HCT versus non-HCT (0% n = 0/26 and 36% n = 4/11, respectively; p < 0.01). CONCLUSIONS: This study demonstrates that SARS-CoV-2 specific mAb was safe and may reduce hospitalization compared to what is reported in malignant hematology patients at high risk for disease progression. Our HCT cohort patients had less hospitalization rate compared with HM cohort patients.

Patient-centered perinatal palliative care: family birth plans, outcomes, and resource utilization in a diverse cohort.

BACKGROUND: Perinatal palliative care is an emerging concept in fetal medicine that offers quality-of-life options and anticipatory grief management for families of fetuses with complex conditions. Few perinatal palliative care outcomes are detailed in peer-reviewed literature. OBJECTIVE: This study aimed to describe outcomes of perinatal palliative care at the Fetal Center of the University of Texas Health Science Center at Houston and Women's Center at Children's Memorial Hermann Hospital. STUDY DESIGN: This was a retrospective cohort of families receiving perinatal palliative care for life-limiting fetal diagnosis, such as trisomy 13 or 18 and some major structural anomalies between 2016 and 2020. The primary outcome was whether delivery events matched families' birth plans, including fetal/neonatal clinical course matching expectations described by consultant notes. Secondary outcomes included maternal safety outcomes, use of perinatal interventions, delivery outcomes, and resource utilization outcomes. RESULTS: Of 187 perinatal palliative care consults, delivery events matched families' plans and clinicians' expectations in 89% of cases (165/185); 39% (73/187) of families requested some perinatal interventions, 64% of whom planned postnatal comfort care even while choosing antenatal interventions. Demographics and median income were similar between families who chose some interventions and those who chose comfort care. Patients choosing any interventions had more mismatches between their plans and delivery events (19% vs 2%; P<.001), were more likely to change their plans (24% vs 6%; P=.001), and unsurprisingly used more healthcare resources. They were also more likely to have intraamniotic infection or postpartum hemorrhage (9% vs 22%; P=.02), but this was associated with mode of delivery and not choice of interventions. CONCLUSION: Most families' perinatal experiences matched birth plans and expectations in this perinatal palliative care program. Families who desired interventions used more healthcare resources, but often did so with plans for postnatal comfort care, demonstrating insight into neonatal prognosis but achieving value-consistent goals, such as meeting a live neonate. Perinatal palliative care was safe for maternal patients and equitable across racial, ethnic, and income groups. Perinatal palliative care and some perinatal interventions are options for care of the whole family in complex fetal medicine cases.

Genotype/phenotype correlation in 123 Chinese patients with Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a multisystemic neurocutaneous disorder with autosomal dominant inheritance. We performed mutation analyses on 123 Chinese patients with "definite TSC" according to the latest diagnostic criteria. Pathogenic / likely-pathogenic variants were identified in 72.2% of all index patients (70/97), in which 35.7% (25/70) had TSC1 variants and 64.3% (45/70) had TSC2 variants. 84.5% (82/97) cases were sporadic and 15.5% (15/97) cases were familial. 62 unique variants were reported, in which 41.9% (26/62) were novel. Male patients had significantly more subependymal nodules (p=0.029) than females, whereas renal angiomyolipoma (p=0.032) occurred predominantly in females. Sporadic cases also had more renal angiomyolipoma (p=0.004), cortical tubers (p=0.008), hypopigmented macules (p=0.018) and fibrous cephalic plaques (p=0.028) than cases with known inheritance. Patients with TSC2 pathogenic variants were more likely to have mental retardation (p<0.001), cardiac rhabdomyoma (p=0.004), renal angiomyolipoma (p=0.006) and facial angiofibromas (p=0.026) than those with TSC1 pathogenic variants, while mutation-negative cases showed a mixed phenotype between those with TSC1 and TSC2 variants. There were no significant phenotypic differences between patients with and without TSC1/TSC2 variants, but TSC2 missense and in-frame variants were associated with higher frequencies of mental retardation (P<0.001), renal angiomyolipoma (p=0.001), cardiac rhabdomyoma (p=0.012) and facial angiofibroma (p=0.021) than those with TSC1 frameshift and splice site variants. Furthermore, a higher frequency of mental retardation (p=0.013) was observed in patients with TSC2 missense and in-frame variants than those with frameshift and splice site variants. All 14 antenatal-onset patients had cardiac rhabdomyoma. They had fewer seizures (p=0.028) than patients with paediatric-onset, but were more likely to have mental retardation (p=0.035) than individuals with adult-onset disease. Generally, paediatric-onset patients had more neurological manifestations, while initial presentations of adult-onset TSC were more diverse.

Old and new perspectives on Neurofibromatosis type 1: Clinical and molecular characterization of 832 patients from a single centre over 16 years.

Neurofibromatosis type 1 (NF1; OMIM #162200) is the commonest multi-systemic neurocutaneous tumour-predisposition disorder. It has an age-related complete penetrance but a highly variable inter- and intra-familial expressivity. This article summarizes the clinical features and molecular characteristics of 832 clinically or molecularly confirmed NF1 patients from 697 unrelated families recruited from a single centre in Hong Kong diagnosed during the 16 years period from Jan 2005 to Jan 2021. In this study, we have estimated the incidences of clinical features, reported on the molecular findings and explored new genotype-phenotype correlations.

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.

Mail-order pharmacy dispensing of mifepristone for medication abortion after in-person clinical assessment.

OBJECTIVE(S): To estimate the effectiveness, acceptability, and feasibility of medication abortion with mifepristone dispensed by a mail-order pharmacy after in-person clinical assessment. STUDY DESIGN: This is an interim analysis of an ongoing prospective cohort study conducted at five sites. Clinicians assessed patients in clinic and, if they were eligible for medication abortion and ≤ 63 days' gestation, electronically sent prescriptions for mifepristone 200 mg orally and misoprostol 800 mcg buccally to a mail-order pharmacy, which shipped medications for next-day delivery. Participants completed surveys three and 14 days after enrollment, and we abstracted medical chart data. RESULTS: Between January 2020 and April 2021 we enrolled 240 participants and obtained clinical outcome information for 227 (94.6%); 3 reported not taking either medication. Of those with abortion outcome information (N = 224), 216 (96.4%) completed day-3 and 212 (94.6%) day-14 surveys. Of the 224 that took medications, none reported taking past 70 days' gestation, and complete medication abortion occurred for 217 participants (96.9%, 95% CI 93.7%-98.7%). Most received medications within three days (82.1%, 95% CI 76.5%-86.9%). In the day-3 survey, 95.4% (95% CI 91.7%-97.8%) reported being very (88.4%) or somewhat (6.9%) satisfied with receiving medications by mail. In the day-14 survey, 89.6% (95% CI 84.7%-93.4%) said they would use the mail-order service again if needed. Eleven (4.9%, 95% CI 2.5%-8.6%) experienced adverse events; two were serious (one blood transfusion, one hospitalization), and none were related to mail-order pharmacy dispensing. CONCLUSIONS: Medication abortion with mail-order pharmacy dispensing of mifepristone appears effective, feasible, and acceptable to patients. IMPLICATIONS: The in-person dispensing requirement for mifepristone, codified in the drug's Risk Evaluation and Mitigation Strategy, should be removed.

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.

Trends in U.S. Health Care Spending on Inflammatory Bowel Diseases, 1996-2016.

BACKGROUND: Inflammatory bowel diseases (IBD) are rising in prevalence and are associated with high health care costs. We estimated trends in U.S. health care spending in patients with IBD between 1996 and 2016. METHODS: We used data on national health care spending developed by the Institute for Health Metrics and Evaluations for the Disease Expenditure Project. We estimated corresponding U.S. age-specific prevalence of IBD from the Global Burden of Diseases Study. From these 2 sources, we estimated prevalence-adjusted, temporal trends in U.S. health care spending in patients with IBD, stratified by age groups (<20 years, 20-44 years, 45-64 years, ≥65 years) and by type of care (ambulatory, inpatient, emergency department [ED], pharmaceutical prescriptions, and nursing care), using joinpoint regression, expressed as an annual percentage change (APC) with 95% confidence intervals. RESULTS: Overall, annual U.S. health care spending on IBD increased from $6.4 billion (95% confidence interval, 5.7-7.4) in 1996 to $25.4 billion (95% confidence interval, 22.4-28.7) in 2016, corresponding to a per patient increase in annual spending from $5714 to $14,033. Substantial increases in per patient spending on IBD were observed in patients aged ≥45 years. Between 2011 and 2016, inpatient and ED care accounted for 55.8% of total spending and pharmaceuticals accounted for 19.9%, with variation across age groups (inpatient/ED vs pharmaceuticals: ages ≥65 years, 57.6% vs 11.2%; ages 45-64 years, 49.5% vs 26.9%; ages 20-44 years, 59.2% vs 23.6%). CONCLUSIONS: Even after adjusting for rising prevalence, U.S. health care spending on IBD continues to progressively increase, primarily in middle-aged and older adults, with unplanned health care utilization accounting for the majority of costs.

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.

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.

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.

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.