Data-driven Cluster Analysis Reveals Increased Risk for Severe Insulin-Deficient Diabetes in Black/African Americans.

Context: Diabetes is a heterogenic disease and distinct clusters have emerged, but the implications for diverse populations have remained understudied.

Objective: Apply cluster analysis to a diverse diabetes cohort in the U.S.

Exercise mitigates reductive stress-induced cardiac remodeling in mice.

The endoplasmic reticulum (ER) regulates protein folding and maintains proteostasis in cells. We observed that the ER transcriptome is impaired during chronic reductive stress (RS) in cardiomyocytes. Here, we hypothesized that a prolonged moderate treadmill exercise mitigates the RS-induced ER dysfunction and cardiac remodeling in cardiac-specific constitutively active Nrf2 mice (CaNrf2-TG).

Characteristics and determinants of pulmonary long COVID.

BACKGROUNDPersistent cough and dyspnea are prominent features of postacute sequelae of SARS-CoV-2 (also termed "long COVID"); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFT) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary long COVID.METHODSThis single-center retrospective study included 1,097 patients with clinically defined long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for 1 or more months after resolution of primary COVID infection.

Characteristics and Determinants of Pulmonary Long COVID.

Rationale: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined.

Objectives: Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID.

Methods: The University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection.

Medical and psychosocial outcomes of state-funded population genomic screening.

As the uptake of population screening expands, assessment of medical and psychosocial outcomes is needed. Through the Alabama Genomic Health Initiative (AGHI), a state-funded genomic research program, individuals received screening for pathogenic or likely pathogenic variants in 59 actionable genes via genotyping. Of the 3874 eligible participants that received screening results, 858 (22%) responded to an outcomes survey.

A Primer in Precision Nephrology: Optimizing Outcomes in Kidney Health and Disease through Data-Driven Medicine.

This year marks the 63rd anniversary of the International Society of Nephrology, which signaled nephrology's emergence as a modern medical discipline. In this article, we briefly trace the course of nephrology's history to show a clear arc in its evolution-of increasing resolution in nephrological data-an arc that is converging with computational capabilities to enable precision nephrology. In general, precision medicine refers to tailoring treatment to the individual characteristics of patients.

Circulating SARS-CoV-2+ megakaryocytes are associated with severe viral infection in COVID-19.

Several independent lines of evidence suggest that megakaryocytes are dysfunctional in severe COVID-19. Herein, we characterized peripheral circulating megakaryocytes in a large cohort of inpatients with COVID-19 and correlated the subpopulation frequencies with clinical outcomes. Using peripheral blood, we show that megakaryocytes are increased in the systemic circulation in COVID-19, and we identify and validate S100A8/A9 as a defining marker of megakaryocyte dysfunction.

Generation and characterization of NGLY1 patient-derived midbrain organoids.

NGLY1 deficiency is an ultra-rare, autosomal recessive genetic disease caused by mutations in the gene encoding N-glycanase one that removes N-linked glycan. Patients with pathogenic mutations in NGLY1 have complex clinical symptoms including global developmental delay, motor disorder and liver dysfunction. To better understand the disease pathogenesis and the neurological symptoms of the NGLY1 deficiency we generated and characterized midbrain organoids using patient-derived iPSCs from two patients with distinct disease-causing mutations-one homozygous for p.

Are we prepared to deliver gene-targeted therapies for rare diseases?

The cost and time needed to conduct whole-genome sequencing (WGS) have decreased significantly in the last 20 years. At the same time, the number of conditions with a known molecular basis has steadily increased, as has the number of investigational new drug applications for novel gene-based therapeutics. The prospect of precision gene-targeted therapy for all seems in reach… or is it? Here we consider practical and strategic considerations that need to be addressed to establish a foundation for the early, effective, and equitable delivery of these treatments.

COVID-19 bacteremic co-infection is a major risk factor for mortality, ICU admission, and mechanical ventilation.

Background: Recent single-center reports have suggested that community-acquired bacteremic co-infection in the context of Coronavirus disease 2019 (COVID-19) may be an important driver of mortality; however, these reports have not been validated with a multicenter, demographically diverse, cohort study with data spanning the pandemic.

Methods: In this multicenter, retrospective cohort study, inpatient encounters were assessed for COVID-19 with community-acquired bacteremic co-infection using 48-h post-admission blood cultures and grouped by: (1) confirmed co-infection [recovery of bacterial pathogen], (2) suspected co-infection [negative culture with ≥ 2 antimicrobials administered], and (3) no evidence of co-infection [no culture]. The primary outcomes were in-hospital mortality, ICU admission, and mechanical ventilation.

An induced pluripotent stem cell-derived NMJ platform for study of the NGLY1-Congenital Disorder of Deglycosylation.

There are many neurological rare diseases where animal models have proven inadequate or do not currently exist. NGLY1 Deficiency, a congenital disorder of deglycosylation, is a rare disease that predominantly affects motor control, especially control of neuromuscular action. In this study, NGLY1-deficient, patient-derived induced pluripotent stem cells (iPSCs) were differentiated into motoneurons (MNs) to identify disease phenotypes analogous to clinical disease pathology with significant deficits apparent in the NGLY1-deficient lines compared to the control.

The precision medicine process for treating rare disease using the artificial intelligence tool mediKanren.

There are over 6,000 different rare diseases estimated to impact 300 million people worldwide. As genetic testing becomes more common practice in the clinical setting, the number of rare disease diagnoses will continue to increase, resulting in the need for novel treatment options. Identifying treatments for these disorders is challenging due to a limited understanding of disease mechanisms, small cohort sizes, interindividual symptom variability, and little commercial incentive to develop new treatments.

An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome.

Activity-dependent neuroprotective protein (ADNP) syndrome is a rare genetic condition associated with intellectual disability and autism spectrum disorder. Preclinical evidence suggests that low-dose ketamine may induce expression of ADNP and that neuroprotective effects of ketamine may be mediated by ADNP. The goal of the proposed research was to evaluate the safety, tolerability, and behavioral outcomes of low-dose ketamine in children with ADNP syndrome.

Why rare disease needs precision medicine-and precision medicine needs rare disease.

With one in ten suffering from one of 10,000 rare diseases, precision medicine opens a path toward identifying therapies for rare patients. Conversely, it is rare patients-through their collective experience and the knowledge captured in their genetics-who open the path toward identifying therapies for common patients.

Loss of IRF2BPL impairs neuronal maintenance through excess Wnt signaling.

De novo truncations in () lead to severe childhood-onset neurodegenerative disorders. To determine how loss of causes neural dysfunction, we examined its function in and zebrafish. Overexpression of either or , the ortholog, represses Wnt transcription in flies.

Functional characterization and potential therapeutic avenues for variants in the NTRK2 gene causing developmental and epileptic encephalopathies.

Variants within the Neurotrophic Tyrosine Kinase Receptor Type 2 (NTRK2) gene have been discovered to play a role in developmental and epileptic encephalopathies, a group of debilitating conditions for which little is known about cause or treatment. Here, we determine the functional consequences of two variants: p.Tyr434Cys (Y434C) (located in the transmembrane domain) and p.

cdev: a ground-truth based measure to evaluate RNA-seq normalization performance.

Normalization of RNA-seq data has been an active area of research since the problem was first recognized a decade ago. Despite the active development of new normalizers, their performance measures have been given little attention. To evaluate normalizers, researchers have been relying on measures, most of which are either qualitative, potentially biased, or easily confounded by parametric choices of downstream analysis.

Generation of two gene corrected human isogenic iPSC lines (NCATS-CL6104 and NCATS-CL6105) from a patient line (NCATS-CL6103) carrying a homozygous p.R401X mutation in the NGLY1 gene using CRISPR/Cas9.

NGLY1 deficiency is a rare recessive genetic disease caused by mutations in the NGLY1 gene which codes for N-glycanase 1 (NGLY1). Here, we report the generation of two gene corrected iPSC lines using a patient-derived iPSC line (NCATS-CL6103) that carried a homozygous p.R401X mutation in the NGLY1 gene.

Water-soluble tocopherol derivatives inhibit SARS-CoV-2 RNA-dependent RNA polymerase.

The recent emergence of a novel coronavirus, SARS-CoV-2, has led to the global pandemic of the severe disease COVID-19 in humans. While efforts to quickly identify effective antiviral therapies have focused largely on repurposing existing drugs , the current standard of care, remdesivir, remains the only authorized antiviral intervention of COVID-19 and provides only modest clinical benefits . Here we show that water-soluble derivatives of α-tocopherol have potent antiviral activity and synergize with remdesivir as inhibitors of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp).

Hormonal intervention for the treatment of veterans with COVID-19 requiring hospitalization (HITCH): a multicenter, phase 2 randomized controlled trial of best supportive care vs best supportive care plus degarelix: study protocol for a randomized controlled trial.

Background: Therapeutic targeting of host-cell factors required for SARS-CoV-2 entry is an alternative strategy to ameliorate COVID-19 severity. SARS-CoV-2 entry into lung epithelium requires the TMPRSS2 cell surface protease. Pre-clinical and correlative data in humans suggest that anti-androgenic therapies can reduce the expression of TMPRSS2 on lung epithelium.

An induced pluripotent stem cell line (NCATS-CL9075) from a patient carrying compound heterozygote mutations, p.R390P and p.L318P, in the NGLY1 gene.

NGLY1 deficiency is a rare disorder caused by mutations in the NGLY1 gene which codes for the highly conserved N-glycanase1 (NGLY1). This enzyme functions in cytosolic deglycosylation of N- linked glycoproteins. An induced pluripotent stem cell (iPSC) line was generated from the dermal fibroblasts of a 2-year-old patient carrying compound heterozygous mutations, p.

Rare disease patient matchmaking: development and outcomes of an internet case-finding strategy in the Undiagnosed Diseases Network.

Background: Although clinician, researcher, and patient resources for matchmaking exist, finding similar patients remains an obstacle for rare disease diagnosis. The goals of this study were to develop and test the effectiveness of an Internet case-finding strategy and identify factors associated with increased matching within a rare disease population.

Methods: Public web pages were created for consented participants.