Hospital-wide access to genomic data advanced pediatric rare disease research and clinical outcomes.

Boston Children's Hospital has established a genomic sequencing and analysis research initiative to improve clinical care for pediatric rare disease patients. Through the Children's Rare Disease Collaborative (CRDC), the hospital offers CLIA-grade exome and genome sequencing, along with other sequencing types, to patients enrolled in specialized rare disease research studies. The data, consented for broad research use, are harmonized and analyzed with CRDC-supported variant interpretation tools.

Adverse Drug Events in Ambulatory Care: A Cross-Sectional Study.

Background: Adverse drug events (ADEs) are understudied in the ambulatory care setting. We aim to estimate the prevalence and characteristics of ADEs in outpatient care using electronic health records (EHRs).

Methods: This cross-sectional study included EHR data for patients who had an outpatient encounter at an academic medical center from 1 October 2018 through 31 December 2019.

Tracking the gene expression programs and clonal relationships that underlie mast, myeloid, and T lineage specification from stem cells.

T cells develop from hematopoietic progenitors in the thymus and protect against pathogens and cancer. However, the emergence of human T cell-competent blood progenitors and their subsequent specification to the T lineage have been challenging to capture in real time. Here, we leveraged a pluripotent stem cell differentiation system to understand the transcriptional dynamics and cell fate restriction events that underlie this critical developmental process.

Nucleotide Transformer: building and evaluating robust foundation models for human genomics.

The prediction of molecular phenotypes from DNA sequences remains a longstanding challenge in genomics, often driven by limited annotated data and the inability to transfer learnings between tasks. Here, we present an extensive study of foundation models pre-trained on DNA sequences, named Nucleotide Transformer, ranging from 50 million up to 2.5 billion parameters and integrating information from 3,202 human genomes and 850 genomes from diverse species.

Does enhanced meaning after meaning-centered group psychotherapy mediate a reduction in depressive symptoms in cancer survivors? A mediation analysis in the context of a randomized controlled trial.

Purpose: After meaning-centered group psychotherapy for cancer survivors (MCGP-CS), depressive symptoms tend to decrease. An enhanced sense of meaning may play a mediating role in this decrease. The aim of this study was to assess whether personal meaning mediates the relationship between MCGP-CS and depressive symptoms.

The ClinGen Syndromic Disorders Gene Curation Expert Panel: Assessing the Clinical Validity of 111 Gene-Disease Relationships.

Purpose: The Clinical Genome Resource (ClinGen) Gene Curation Expert Panels (GCEPs) have historically focused on specific organ systems or phenotypes; thus, the ClinGen Syndromic Disorders GCEP (SD-GCEP) was formed to address an unmet need.

Methods: The SD-GCEP applied ClinGen's framework to evaluate the clinical validity of genes associated with rare syndromic disorders. 111 Gene-Disease Relationships (GDRs) associated with 100 genes spanning the clinical spectrum of syndromic disorders were curated.

Molecular convergence of risk variants for congenital heart defects leveraging a regulatory map of the human fetal heart.

Congenital heart defects (CHD) arise in part due to inherited genetic variants that alter genes and noncoding regulatory elements in the human genome. These variants are thought to act during fetal development to influence the formation of different heart structures. However, identifying the genes, pathways, and cell types that mediate these effects has been challenging due to the immense diversity of cell types involved in heart development as well as the superimposed complexities of interpreting noncoding sequences.

Neutrophil CRACR2A Promotes Neutrophil Recruitment in Sterile Inflammation and Ischemic Stroke.

Background: Ca release-activated Ca channel regulator 2A (CRACR2A) has been linked to immunodeficiency attributable to T-cell dysfunction in humans. We discovered that neutrophil CRACR2A promotes neutrophil adhesive and migratory functions by facilitating Ca mobilization and β2 integrin activation.

Methods: Myeloid-specific cracr2a conditional knockout mice and intravital microscopy were used to investigate the physiologic role of neutrophil cracr2a in neutrophil recruitment in vascular inflammation.

Intranasal M2SR and BM2SR Vaccine Viruses Do Not Shed or Transmit in Ferrets.

Background/objectives: Live influenza vaccines are considered to stimulate better overall immune responses but are associated with safety concerns regarding shedding and the potential for transmission or reassortment with wild-type influenza viruses. Intranasal M2SR and BM2SR (M2- and BM2-deficient single replication), intranasal influenza viruses, have shown promise as broadly cross-reactive next-generation influenza vaccines. The replication deficiency, shedding, and transmissibility of M2SR/BM2SR viruses were evaluated in a ferret model.

Development and in vitro testing of an orthodontic miniscrew for use in the mandible.

Objective: Temporary anchorage devices (TADs) have been successfully used in the maxilla. However, in the mandible, lower success rates present a challenge in everyday clinical practice. A new TAD design will be presented that is intended to demonstrate optimization of the coupling structure as well as in the thread area for use in the mandible.

Selective metabolic regulations by p53 mutant variants in pancreatic cancer.

Background: Approximately half of all human cancers harbour mutations in the p53 gene, leading to the generation of neomorphic p53 mutant proteins. These mutants can exert gain-of-function (GOF) effects, potentially promoting tumour progression. However, the clinical significance of p53 GOF mutations, as well as the selectivity of individual variants, remains controversial and unclear.

Comparative studies of seafood and reptile α- and β-parvalbumins.

Small calcium-binding proteins such as parvalbumins (PVs) are major seafood and fish allergens. However, the impact of structural changes on their capacity to bind IgE has not been studied in detail. Therefore, fish and reptilian PVs, as well as human α-PV, were selected for biochemical, structural, and IgE binding studies.

Cerebral amyloid angiopathy impacts neurofibrillary tangle burden and cognition.

Cerebral amyloid angiopathy commonly co-occurs with amyloid β plaques and neurofibrillary degeneration and is proposed to contribute to cognitive impairment. However, the interplay among these pathologic changes of Alzheimer disease is not well understood. Here we replicate and extend findings of a recent study that suggested the association of cerebral amyloid angiopathy and cognitive impairment is mediated by neurofibrillary degeneration.

ACSS1-dependent acetate utilization rewires mitochondrial metabolism to support AML and melanoma tumor growth and metastasis.

Cancer cells often use alternative nutrient sources to support their metabolism and proliferation. One important alternative nutrient source for many cancers is acetate. Acetate is metabolized into acetyl-coenzyme A (CoA) by acetyl-CoA synthetases 1 and 2 (ACSS1 and ACSS2), which are found in the mitochondria and cytosol, respectively.

The cortical vein opacification score (COVES) is independently associated with DSA ASITN collateral score.

: Pretreatment CTA-based Cortical Vein Opacification Score (COVES) has been shown to predict good functional outcomes at 90 days in patients with acute ischemic stroke secondary to large vessel occlusion (AIS-LVO). This is thought to be related to its ability to measure collateral status (CS). However, its association with the reference standard test, the DSA-based American Society of Interventional and Therapeutic Neuroradiology (ASITN) collateral score, has yet to be established.