Specialized pericyte subtypes in the pulmonary capillaries.

Pericytes are essential for capillary stability and homeostasis, with impaired pericyte function linked to diseases like pulmonary arterial hypertension. Investigating pericyte biology has been challenging due to the lack of specific markers, making it difficult to distinguish pericytes from other stromal cells. Using bioinformatic analysis and RNAscope, we identified Higd1b as a unique gene marker for pericytes and subsequently generated a knock-in mouse line, Higd1b-CreERT2, that accurately labels pericytes in the lung and heart.

Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study.

Background And Objectives: Safety and efficacy of IV onasemnogene abeparvovec has been demonstrated for patients with spinal muscular atrophy (SMA) weighing <8.5 kg. SMART was the first clinical trial to evaluate onasemnogene abeparvovec for participants weighing 8.

Cross-modal contrastive learning for unified placenta analysis using photographs.

The placenta is vital to maternal and child health but often overlooked in pregnancy studies. Addressing the need for a more accessible and cost-effective method of placental assessment, our study introduces a computational tool designed for the analysis of placental photographs. Leveraging images and pathology reports collected from sites in the United States and Uganda over a 12-year period, we developed a cross-modal contrastive learning algorithm consisting of pre-alignment, distillation, and retrieval modules.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Enhance Phagocytosis Induced by CD47 Blockade in Sensitive and Resistant ALK-Driven Malignancies.

Background: Anaplastic lymphoma kinase (ALK) plays a role in the development of lymphoma, lung cancer and neuroblastoma. While tyrosine kinase inhibitors (TKIs) have improved treatment outcomes, relapse remains a challenge due to on-target mutations and off-target resistance mechanisms. ALK-positive (ALK+) tumors can evade the immune system, partly through tumor-associated macrophages (TAMs) that facilitate immune escape.

Mitochondrial DNA variant detection in over 6,500 rare disease families by the systematic analysis of exome and genome sequencing data resolves undiagnosed cases.

Background: Variants in the mitochondrial genome (mtDNA) cause a diverse collection of mitochondrial diseases and have extensive phenotypic overlap with Mendelian diseases encoded on the nuclear genome. The mtDNA is often not specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants.

Methods: Using dedicated pipelines to address the technical challenges posed by the mtDNA - circular genome, variant heteroplasmy, and nuclear misalignment - single nucleotide variants, small indels, and large mtDNA deletions were called from exome and genome sequencing data, in addition to RNA-sequencing when available.

CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans.

Four genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects.

Designing and implementing the IDEAL Study: A randomized clinical trial of genotype disclosure for late-onset Alzheimer's disease in an urban Latino population.

Introduction: The (IDEAL) Study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of apolipoprotein E () genotype disclosure for late-onset Alzheimer's disease (AD) among Latinos.

Methods: We used address-based sampling to recruit English- and Spanish-speaking Latinos aged 40-64 living in northern Manhattan for a community-based Baseline Survey about their knowledge and opinions about AD. Participants eligible for the clinical trial were invited to complete an Introductory Session, including AD and genetics education and informed consent, before undergoing genotyping for .

Evaluating the factor structure of the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV) in adults with congenital heart disease.

: While it is generally assumed that common neurobehavioral assessments, such as the Wechsler Adult Intelligence Scale, Fourth Edition (WAIS-IV), function similarly in clinical and non-clinical populations, this has not been validated in adults with congenital heart disease (CHD). In this study, we examined the latent factor structure of the WAIS-IV in adults with d-transposition of the great arteries (d-TGA) who participated in the Boston Circulatory Arrest Study. : The WAIS-IV was administered as part of a larger assessment battery.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Diagnostic Journey for Tuberous Sclerosis Complex-Interviews From a Clinical Trial.

Tuberous sclerosis complex (TSC) is a genetic condition characterized by both medical and neuropsychiatric diagnoses that emerge across the lifespan. As part of a clinical trial, caregivers of children with TSC were interviewed about their experiences navigating medical, school, and social services. Semistructured interviews (N = 20) with caregivers of children with TSC (27-60 months) were conducted upon exit from the study.

Constrained Multivariate Functional Principal Components Analysis for Novel Outcomes in Eye-Tracking Experiments.

Individuals with autism spectrum disorder (ASD) tend to experience greater difficulties with social communication and sensory information processing. Of particular interest in ASD biomarker research is the study of visual attention, effectively quantified in eye tracking (ET) experiments. Eye tracking offers a powerful, safe, and feasible platform for gaining insights into attentional processes by measuring moment-by-moment gaze patterns in response to stimuli.

Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder.

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants.

Implications of the choroid plexus in Niemann-Pick disease Type C neuropathogenesis.

Background: Niemann-Pick Disease Type C (NPC) is an ultra-rare disorder characterized by progressive psychiatric and neurologic manifestations, with late infantile, juvenile, and adolescent/adult presentations. We examined morphological properties of the choroid plexus, a protective blood-cerebrospinal fluid barrier, in NPC, and their relationship with neurodegeneration, clinical status, and circulatory markers. This study also determined whether choroid plexus morphology differentiates between NPC and more prevalent illnesses, schizophrenia (SZ) and bipolar disorder (BD), which have overlapping psychiatric symptoms with adolescent and adult-onset NPC and are associated with misdiagnosis.

Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips.

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms.

Statistical Fragility of Findings From Randomized Phase 3 Trials in Pediatric Oncology.

Purpose: The fragility index (FI) is an adjunctive metric to facilitate the interpretation of p-values in clinical trials. The FI has not been studied in phase 3 trials in pediatric oncology.

Methods: PubMed was used to identify phase 3 pediatric oncology trials published between 1980 and 2020.

Anatomic characteristics of the right aortic arch with aberrant left subclavian artery in patients who do and do not undergo vascular ring repair.

Introduction: It is unclear if certain anatomic characteristics in patients with a right aortic arch with aberrant left subclavian artery (RAA ALSCA) are associated with undergoing surgical repair.

Methods: This was a single-center retrospective study of patients with RAA ALSCA and computed tomography or cardiovascular magnetic resonance from July 2013-September 2023. The size of the proximal ALSCA or diverticulum of Kommerell (DoK), thoracic inlet index, angle of the proximal ALSCA/DoK from the aortic arch, the position of descending aorta, location of the DoK, and tracheal size were compared between patients who did or did not undergo surgery.

Further delineation of the SCAF4-associated neurodevelopmental disorder.

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder.

Why physicians use sodium bicarbonate during cardiac arrest: A cross-sectional survey study of adult and pediatric clinicians.

Background: Despite recommendations against routine use, sodium bicarbonate (SB) is administered in approximately 50% of adult and pediatric in-hospital cardiac arrest (IHCA).

Methods: Cross-sectional electronic survey of adult and pediatric attending physicians at two academic hospitals in Boston, Massachusetts. The survey included two IHCA vignettes.

Remote monitoring of social attention in neurogenetic syndromes and idiopathic neurodevelopmental disability.

Social attention is a key aspect of neurodevelopment and is significantly altered in neurodevelopmental genetic syndromes and many individuals with idiopathic autism spectrum disorder (ASD). The primary aim of the present study was to examine the psychometric properties of webcam-collected social attention measurements, including four new specific aspects of social attention, in three genetic syndromes (PTEN Hamartoma Tumor Syndrome-PHTS; Malan Syndrome-NFIX; and SYNGAP1-related disorder-SYNGAP1), a mixed group of other neurodevelopmental genetic syndromes (Other NDGS), and individuals with a range of idiopathic neurodevelopmental disorder (NDD). The secondary aim was to evaluate the construct validity of these social attention measurements, including evaluating known-groups validity across study groups and concurrent validity for separating ASD and non-ASD cases.

Going Back in Time: Prenatal Presentations of Postnatal Genetic Diagnoses Made in a Neonatal Intensive Care Unit.

Objectives: Prenatal genetic diagnosis can impact care across the perinatal continuum; however, prenatal suspicion for genetic disorders may be complicated by incomplete knowledge of fetal rare-disease phenotypes. Here, we describe the prenatal presentations of a cohort of infants with rare genetic conditions who were diagnosed postnatally in a neonatal intensive care unit (NICU), to characterize prenatal presenting features and evaluate why the diagnosis was not identified prenatally.

Methods: Retrospective cohort study of infants born over a 7 year period (2017-2023) who were admitted to a Level IV NICU and received a postnatal genetic diagnosis prior to 1 year of age.

Pyroptotic cell corpses are crowned with F-actin-rich filopodia that engage CLEC9A signaling in incoming dendritic cells.

While apoptosis dismantles the cell to enforce immunological silence, pyroptotic cell death provokes inflammation. Little is known of the structural architecture of cells undergoing pyroptosis, and whether pyroptotic corpses are immunogenic. Here we report that inflammasomes trigger the Gasdermin-D- and calcium-dependent eruption of filopodia from the plasma membrane minutes before pyroptotic cell rupture, to crown the resultant corpse with filopodia.

Comparison of 3D facial photographs and clinical documentation in patients with craniofacial morphea.

Diagnosis of craniofacial morphea (CM) relies upon clinical examination of progressive craniofacial changes. We assess the utility of 3D stereophotogrammetry in documenting asymmetry of the face compared to clinical notetaking. This retrospective study of 3D images and clinical documentation included 32 patients (mean age 15.