Antisense Oligonucleotide Therapy for Calmodulinopathy.

Background: Calmodulinopathies are rare inherited arrhythmia syndromes caused by dominant heterozygous variants in , , or , which each encode the identical CaM (calmodulin) protein. We hypothesized that antisense oligonucleotide (ASO)-mediated depletion of an affected calmodulin gene would ameliorate disease manifestations, whereas the other 2 calmodulin genes would preserve CaM level and function.

Methods: We tested this hypothesis using human induced pluripotent stem cell-derived cardiomyocyte and mouse models of pathogenic variants.

Selective haematological cancer eradication with preserved haematopoiesis.

Haematopoietic stem cell (HSC) transplantation (HSCT) is the only curative treatment for a broad range of haematological malignancies, but the standard of care relies on untargeted chemotherapies and limited possibilities to treat malignant cells after HSCT without affecting the transplanted healthy cells. Antigen-specific cell-depleting therapies hold the promise of much more targeted elimination of diseased cells, as witnessed in the past decade by the revolution of clinical practice for B cell malignancies. However, target selection is complex and limited to antigens expressed on subsets of haematopoietic cells, resulting in a fragmented therapy landscape with high development costs.

Suture Contamination During Arthroscopic Rotator Cuff Repair Is Associated With Significantly Higher Retear Rates in Magnetic Resonance Imaging: A Matched-Pair Analysis.

Purpose: To evaluate the correlation between suture contamination and rotator cuff tendon retear after arthroscopic rotator cuff repair.

Methods: Patients undergoing primary arthroscopic rotator cuff repair from April 1, 2020, to September 30, 2022, were enrolled. Those younger than 18 years, with a history of shoulder surgeries or shoulder infection episodes, or who declined participation were excluded.

Safety Assessment and Probiotic Potential Comparison of subsp. BLI-02, LPL28, TYCA06, and ET-66.

subsp. BLI-02, ET-66, LPL28, and TYCA06, isolated from healthy breast milk, miso, and the healthy human gut, were assessed for safety in this study. BLI-02, LPL28, TYCA06, and ET-66 exhibited no antibiotic resistance and mutagenic activity in the Ames test at the highest dosage (5000 μg/plate).

Optimization of base editors for the functional correction of SMN2 as a treatment for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is caused by mutations in SMN1. SMN2 is a paralogous gene with a C•G-to-T•A transition in exon 7, which causes this exon to be skipped in most SMN2 transcripts, and results in low levels of the protein survival motor neuron (SMN). Here we show, in fibroblasts derived from patients with SMA and in a mouse model of SMA that, irrespective of the mutations in SMN1, adenosine base editors can be optimized to target the SMN2 exon-7 mutation or nearby regulatory elements to restore the normal expression of SMN.

Measuring the 3-30-300 rule to help cities meet nature access thresholds.

The 3-30-300 rule offers benchmarks for cities to promote equitable nature access. It dictates that individuals should see three trees from their dwelling, have 30 % tree canopy in their neighborhood, and live within 300 m of a high-quality green space. Implementing this demands thorough measurement, monitoring, and evaluation methods, yet little guidance is currently available to pursue these actions.

Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study.

Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018.

Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer.

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state.

Base editing as a genetic treatment for spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease caused by mutations in the gene. Despite the development of various therapies, outcomes can remain suboptimal in SMA infants and the duration of such therapies are uncertain. is a paralogous gene that mainly differs from by a C•G-to-T•A transition in exon 7, resulting in the skipping of exon 7 in most transcripts and production of only low levels of survival motor neuron (SMN) protein.

Rejuvenation: Turning Back Time by Enhancing CISD2.

The aging human population with age-associated diseases has become a problem worldwide. By 2050, the global population of those who are aged 65 years and older will have tripled. In this context, delaying age-associated diseases and increasing the healthy lifespan of the aged population has become an important issue for geriatric medicine.

DNA methyltransferase 3 alpha and TET methylcytosine dioxygenase 2 restrain mitochondrial DNA-mediated interferon signaling in macrophages.

Deleterious somatic mutations in DNA methyltransferase 3 alpha (DNMT3A) and TET mehtylcytosine dioxygenase 2 (TET2) are associated with clonal expansion of hematopoietic cells and higher risk of cardiovascular disease (CVD). Here, we investigated roles of DNMT3A and TET2 in normal human monocyte-derived macrophages (MDM), in MDM isolated from individuals with DNMT3A or TET2 mutations, and in macrophages isolated from human atherosclerotic plaques. We found that loss of function of DNMT3A or TET2 resulted in a type I interferon response due to impaired mitochondrial DNA integrity and activation of cGAS signaling.

Unusual free oligosaccharides in human bovine and caprine milk.

Free oligosaccharides are abundant macronutrients in milk and involved in prebiotic functions and antiadhesive binding of viruses and pathogenic bacteria to colonocytes. Despite the importance of these oligosaccharides, structural determination of oligosaccharides is challenging, and milk oligosaccharide biosynthetic pathways remain unclear. Oligosaccharide structures are conventionally determined using a combination of chemical reactions, exoglycosidase digestion, nuclear magnetic resonance spectroscopy, and mass spectrometry.

GRPEL2 Knockdown Exerts Redox Regulation in Glioblastoma.

Malignant brain tumors are responsible for catastrophic morbidity and mortality globally. Among them, glioblastoma multiforme (GBM) bears the worst prognosis. The GrpE-like 2 homolog () plays a crucial role in regulating mitochondrial protein import and redox homeostasis.

Federated learning for predicting clinical outcomes in patients with COVID-19.

Federated learning (FL) is a method used for training artificial intelligence models with data from multiple sources while maintaining data anonymity, thus removing many barriers to data sharing. Here we used data from 20 institutes across the globe to train a FL model, called EXAM (electronic medical record (EMR) chest X-ray AI model), that predicts the future oxygen requirements of symptomatic patients with COVID-19 using inputs of vital signs, laboratory data and chest X-rays. EXAM achieved an average area under the curve (AUC) >0.

The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release.

Inositol-1,4,5-triphosphate (IP) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson's disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models.

Federated Learning used for predicting outcomes in SARS-COV-2 patients.

'Federated Learning' (FL) is a method to train Artificial Intelligence (AI) models with data from multiple sources while maintaining anonymity of the data thus removing many barriers to data sharing. During the SARS-COV-2 pandemic, 20 institutes collaborated on a healthcare FL study to predict future oxygen requirements of infected patients using inputs of vital signs, laboratory data, and chest x-rays, constituting the "EXAM" (EMR CXR AI Model) model. EXAM achieved an average Area Under the Curve (AUC) of over 0.

The RSNA International COVID-19 Open Radiology Database (RICORD).

The coronavirus disease 2019 (COVID-19) pandemic is a global health care emergency. Although reverse-transcription polymerase chain reaction testing is the reference standard method to identify patients with COVID-19 infection, chest radiography and CT play a vital role in the detection and management of these patients. Prediction models for COVID-19 imaging are rapidly being developed to support medical decision making.

Gene Expression Profiling in Uveal Melanoma: Five-Year Prospective Outcomes and Meta-Analysis.

Introduction: The prognostic 15-gene expression profile (15-GEP) test for uveal melanoma (UM) predicts metastatic risk based on primary tumor biology. Here we report outcomes from a prospective registry of 15-GEP-tested patients, and a meta-analysis with published cohorts.

Objectives: Management and 5-year clinical outcomes following 15-GEP testing were evaluated.

Presence of Subclinical Hypercortisolism in Clinical Aldosterone-Producing Adenomas Predicts Lower Clinical Success.

The clinical characteristics and outcomes in patients with clinical aldosterone-producing adenomas harboring mutations with or without subclinical hypercortisolism remain unclear. This prospective study is aimed at determining factors associated with subclinical hypercortisolism in patients with clinical aldosterone-producing adenomas. Totally, 82 patients were recruited from November 2016 to March 2018 and underwent unilateral laparoscopic adrenalectomy with at least a 12-month follow-up postoperatively.

Renin-Angiotensin-Aldosterone System Inhibitors and Risks of Severe Acute Respiratory Syndrome Coronavirus 2 Infection: A Systematic Review and Meta-Analysis.

The viral spike coat protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) engages the human ACE (angiotensin-converting enzyme) 2 cell surface receptor to infect the host cells. Thus, concerns arose regarding theoretically higher risk for coronavirus disease-19 (COVID-19) in patients taking ACE inhibitors/angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]). We systematically assessed case-population and cohort studies from MEDLINE (Ovid), Cochrane Database of Systematic Reviews PubMed, Embase, medRXIV, the World Health Organization database of COVID-19 publications, and ClinicalTrials.

Tepotinib in Non-Small-Cell Lung Cancer with Exon 14 Skipping Mutations.

Background: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.

Methods: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed exon 14 skipping mutation.

Blood neurofilament light levels segregate treatment effects in multiple sclerosis.

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs.