The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.

Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues.

Community Health Centers' Response to COVID-19 and Serving the Community: This Feeling of Never Being Enough and Never Doing Enough.

Objective: Community health centers (CHCs) are a vital safety net for under-resourced and medically underserved patients. As few studies have explored how they implemented broad-based organizational changes throughout the COVID-19 pandemic, we aimed to qualitatively examine CHCs' longitudinal, comprehensive pandemic response through the perspectives of staff, administrators, and researchers working in CHCs.

Methods: 25 clinic leaders, staff, and researchers from three CHC networks and two academic medical centers in Northern California and the Central Valley of California participated in 18 focus groups and interviews between April and October 2022.

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

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 not always specifically evaluated in patients with suspected Mendelian disease, resulting in overlooked diagnostic variants. Here, we analyzed a cohort of 6,660 rare disease families (5,625 genetically undiagnosed [84%]) from the Genomics Research to Elucidate the Genetics of Rare diseases (GREGoR) Consortium, as well as other rare disease cohorts.

Alternative start codon selection shapes mitochondrial function during evolution, homeostasis, and disease.

Mitochondrial endosymbiosis was a pivotal event in eukaryotic evolution, requiring core proteins to adapt to function both within the mitochondria and in the host cell. Here, we systematically profile the localization of protein isoforms generated by alternate start codon selection during translation. We identify hundreds of pairs of differentially-localized protein isoforms, many of which affect mitochondrial targeting and are essential for mitochondrial function.

X-linked sideroblastic anemia in females.

X-linked sideroblastic anemia (XLSA) in female carriers of 5-aminolevulinic acid synthase 2 mutations is not uncommon. We describe unique features and genotype/phenotype correlations in females with XLSA and evaluate the contributions of X-chromosome skewing and clonal hematopoiesis, emphasizing the importance of distinguishing it from myelodysplastic syndromes with ring sideroblasts.

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.

Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency.

Protein lipoylation, a vital lysine post-translational modification, plays a crucial role in the function of key mitochondrial tricarboxylic acid cycle enzymatic complexes. In eukaryotes, lipoyl post-translational modification synthesis occurs exclusively through de novo pathways, relying on lipoyl synthesis/transfer enzymes, dependent upon mitochondrial fatty acid and Fe-S cluster biosynthesis. Dysregulation in any of these pathways leads to diminished cellular lipoylation.

Intensity of Social Needs Case Management Services and Changes in Hospital and Emergency Department Use Among Adult Medicaid Beneficiaries.

Objectives: We identify the association between high- and low-intensity case management services on hospital and emergency department (ED) use among CommunityConnect patients.

Background: Social needs case management services vary in intensity, including the modality, workforce specialization, and maximum caseload. CommunityConnect is a social needs case management program implemented by Contra Costa Health, a county safety-net health system in California's San Francisco Bay Area.

Rental Housing Deposits and Health Care Use.

Importance: Housing deposits and tenancy supports have become new Medicaid benefits in multiple states; however, evidence on impacts from these specific housing interventions is limited.

Objective: To evaluate the association of rental housing deposits and health care use among Medicaid beneficiaries receiving social needs case management as part of a Whole-Person Care (Medicaid 1115 waiver) pilot program in California.

Design, Setting, And Participants: This cohort study compared changes in health care use among a group of adults who received a housing deposit between October 2018 and December 2021 along with case management vs a matched comparison group who received case management only in Contra Costa County, California, a large county in the San Francisco Bay Area.

Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform.

Comprehensive Genomic Analysis Identifies a Diverse Landscape of Sideroblastic and Nonsideroblastic Iron-Related Anemias with Novel and Pathogenic Variants in an Iron-Deficient Endemic Setting.

Inherited iron metabolism defects are possibly missed or underdiagnosed in iron-deficient endemic settings because of a lack of awareness or a methodical screening approach. Hence, we systematically evaluated anemia cases (2019 to 2021) based on clinical phenotype, normal screening tests (high-performance liquid chromatography, α gene sequencing, erythrocyte sedimentation rate, C-reactive protein, and tissue transglutaminase), and abnormal iron profile by targeted next-generation sequencing (26-gene panel) supplemented with whole-exome sequencing, multiplex ligation probe amplification/mitochondrial DNA sequencing, and chromosomal microarray. Novel variants in ALAS2, STEAP3, and HSPA9 genes were functionally validated.

Folate depletion induces erythroid differentiation through perturbation of de novo purine synthesis.

Folate, an essential vitamin, is a one-carbon acceptor and donor in key metabolic reactions. Erythroid cells harbor a unique sensitivity to folate deprivation, as revealed by the primary pathological manifestation of nutritional folate deprivation: megaloblastic anemia. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines and primary murine erythroid progenitors.

Globalizing transit worker stress.

Health scientists have claimed that urban transit workers suffer from higher rates of stress-related disease than workers in most other occupations. This paper examines how a network of scientists and labor organizers constructed the problem of transit worker stress as a global phenomenon. According to study participants, transit workers worldwide are subject to a similar set of stress-related risks, which can serve as a basis for worker solidarity.

Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease.

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium.

Organizational and community resilience for COVID-19 and beyond: Leveraging a system for health and social services integration.

Objective: To examine how a preexisting initiative to align health care, public health, and social services influenced COVID-19 pandemic response.

Data Sources And Study Setting: In-depth interviews with administrators and frontline staff in health care, public health, and social services in Contra Costa County, California from October, 2020, to May, 2021.

Study Design: Qualitative, semi-structured interviews examined how COVID-19 response used resources developed for system alignment prior to the pandemic.

Greater Covid-19 vaccine uptake among enrollees offered health and social needs case management: Results from a randomized trial.

Objective: To investigate Covid-19 vaccination as a potential secondary public health benefit of case management for Medicaid beneficiaries with health and social needs.

Data Sources And Study Setting: The CommunityConnect case management program for Medicaid beneficiaries is run by Contra Costa Health, a county safety net health system in California. Program enrollment data were merged with comprehensive county vaccination records.

Medical neutrality and structural competency in conflict zones: Israeli healthcare professionals' reaction to political violence.

This article explores the meaning, manifestations, and ramifications of medical neutrality in conflict zones. We analyse how Israeli healthcare institutions and leaders responded to the escalation of the Israeli-Palestinian conflict in May 2021 and how they represented the role of the healthcare system in society and during conflict. Based on content analysis of documents, we found that healthcare institutions and leaders called for cessation of violence between Jewish and Palestinian citizens of Israel, describing the Israeli healthcare system as a neutral space of coexistence.

Single-cell multi-omics of mitochondrial DNA disorders reveals dynamics of purifying selection across human immune cells.

Pathogenic mutations in mitochondrial DNA (mtDNA) compromise cellular metabolism, contributing to cellular heterogeneity and disease. Diverse mutations are associated with diverse clinical phenotypes, suggesting distinct organ- and cell-type-specific metabolic vulnerabilities. Here we establish a multi-omics approach to quantify deletions in mtDNA alongside cell state features in single cells derived from six patients across the phenotypic spectrum of single large-scale mtDNA deletions (SLSMDs).

Between health care and social services: Boundary objects and cross-sector collaboration.

Health care systems throughout the United States are initiating collaborations with social services agencies. These cross-sector collaborations aim to address patients' social needs-such as housing, food, income, and transportation-in health care settings. However, such collaborations can be challenging as health care and social service sectors are composed of distinct missions, institutions, professional roles, and modes of distributing resources.