One hundred thirty-four germ line PU.1 variants and the agammaglobulinemic patients carrying them.

Leukopoiesis is lethally arrested in mice lacking the master transcriptional regulator PU.1. Depending on the animal model, subtotal PU.

Effect of siponimod on retinal thickness, a marker of neurodegeneration, in participants with SPMS: Findings from the EXPAND OCT substudy.

Background: People with MS show abnormal thinning of the retinal layers, which is associated with clinical disability and brain atrophy, and is a potential surrogate marker of neurodegeneration and treatment effects.

Objective: To evaluate the utility of retinal thickness as a surrogate marker of neurodegeneration and treatment effect in participants with secondary progressive MS (SPMS) from the optical coherence tomography (OCT) substudy of the EXPAND Phase 3 clinical trial (siponimod versus placebo).

Methods: In the OCT substudy population (n = 159), treatment effects on change in the average thickness of the retinal layer, peripapillary retinal nerve fiber layer (pRNFL), and combined macular ganglion cell and inner plexiform layers (GCIPL) were analyzed by high-definition spectral domain OCT at months 3, 12, and 24.

Etiology and Phenotypes of Cardiomyopathy in Southern Africa: The IMHOTEP Multicenter Pilot Study.

Background: Cardiomyopathies are an important cause of heart failure in Africa yet there are limited data on etiology and clinical phenotypes.

Objectives: The IMHOTEP (African Cardiomyopathy and Myocarditis Registry Program) was designed to systematically collect data on individuals diagnosed with cardiomyopathy living in Africa.

Methods: In this multicenter pilot study, patients (age ≥13 years) were eligible for inclusion if they had a diagnosis of cardiomyopathy or myocarditis.

Predictive equation derived from 6,497 doubly labelled water measurements enables the detection of erroneous self-reported energy intake.

Nutritional epidemiology aims to link dietary exposures to chronic disease, but the instruments for evaluating dietary intake are inaccurate. One way to identify unreliable data and the sources of errors is to compare estimated intakes with the total energy expenditure (TEE). In this study, we used the International Atomic Energy Agency Doubly Labeled Water Database to derive a predictive equation for TEE using 6,497 measures of TEE in individuals aged 4 to 96 years.

Interpretation and classification of FBN1 variants associated with Marfan syndrome: consensus recommendations from the Clinical Genome Resource's FBN1 variant curation expert panel.

Background: In 2015, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) developed standardized variant curation guidelines for Mendelian disorders. Although these guidelines have been widely adopted, they are not gene- or disease-specific. To mitigate classification discrepancies, the Clinical Genome Resource FBN1 variant curation expert panel (VCEP) was established in 2018 to develop adaptations to the ACMG/AMP criteria for FBN1 in association with Marfan syndrome.

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.

Clinical importance of patient-reported outcome measures in severe asthma: results from U-BIOPRED.

Rationale: Knowledge about the clinical importance of patient-reported outcome measures (PROMs) in severe asthma is limited.

Objectives: To assess whether and to what extent asthma exacerbations affect changes in PROMS over time and asthma-specific PROMs can predict exacerbations in adult patients with severe asthma in usual care.

Methods: Data of 421 patients with severe asthma (62% female; mean age 51.

Switching from natalizumab to antiCD20 monoclonal antibodies: Short transition interval is associated with improved outcome.

Objective: To investigate the impact of transition interval length when switching from natalizumab (NTZ) to anti-CD20 monoclonal antibodies (antiCD20) on recurrent disease activity and safety in relapsing multiple sclerosis (RMS).

Methods: Aggregating data from 8 MS centres in Austria, Switzerland, and Germany, we included RMS patients who (i) continuously received NTZ for ≥3 months, (ii) were switched to antiCD20, and (iii) had ≥12 months follow-up after switch. The primary endpoint was occurrence of relapse after switch, secondary endpoints included severe infections (CTCAE grade ≥3).

Disability progression is a question of definition-A methodological reappraisal by example of primary progressive multiple sclerosis.

Background: Different definitions of disability progression by Expanded Disability Status Scale (EDSS) may influence frequency and/or time to event.

Methods: In this multicenter cohort study, we included PPMS patients with follow-up ≥24 months and ≥3 available EDSS scores overall (≥1 per year). We applied 672 definitions of disability progression including different minimal EDSS increase, required confirmation and fixed/roving-baseline score.

Ultra-high-resolution 40 keV virtual monoenergetic imaging using spectral photon-counting CT in high-risk patients for coronary stenoses.

Objectives: To assess the image quality of ultra-high-resolution (UHR) virtual monoenergetic images (VMIs) at 40 keV compared to 70 keV, using spectral photon-counting CT (SPCCT) and dual-layer dual-energy CT (DECT) for coronary computed tomography angiography (CCTA).

Methods And Materials: In this prospective IRB-approved study, 26 high-risk patients were included. CCTA was performed both with an SPCCT in UHR mode and with one of two DECT scanners (iQOn or CT7500) within 3 days.

Leptomeningeal metastatic disease: new frontiers and future directions.

Leptomeningeal metastatic disease (LMD), encompassing entities of 'meningeal carcinomatosis', neoplastic meningitis' and 'leukaemic/lymphomatous meningitis', arises secondary to the metastatic dissemination of cancer cells from extracranial and certain intracranial malignancies into the leptomeninges and cerebrospinal fluid. The clinical burden of LMD has been increasing secondary to more sensitive diagnostics, aggressive local therapies for discrete brain metastases, and improved management of extracranial disease with targeted and immunotherapeutic agents, resulting in improved survival. However, owing to drug delivery challenges and the unique microenvironment of LMD, novel therapies against systemic disease have not yet translated into improved outcomes for these patients.

Baseline Nodal Status on Ga-PSMA-11 Positron Emission Tomography/Computed Tomography in Men with Intermediate- to High-risk Prostate Cancer Is Prognostic for Treatment Failure: Follow-up of the proPSMA Trial.

Background And Objective: There is uncertainty regarding the clinical significance of Ga-PSMA-11 positron emission tomography (PET) computed tomography (CT) findings in men with prostate cancer. In this prespecified objective of the proPSMA study, we report the prognostic value of PET-defined nodal involvement.

Methods: Men with intermediate- to high-risk prostate cancer (grade group 3-5, prostate-specific antigen [PSA] ≥20 ng/ml, or clinical stage ≥T3) underwent Ga-PSMA-11 PET-CT or CT and bone scanning as first- or second-line imaging.

Accurate non-invasive detection of MASH with fibrosis F2-F3 using a lightweight machine learning model with minimal clinical and metabolomic variables.

Background: There are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis-the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3.

Methods: Clinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASH, including cirrhosis and healthy controls.

International expert guidance for defining and monitoring small bowel strictures in Crohn's disease on intestinal ultrasound: a consensus statement.

Background: Diagnostic imaging using CT enterography, magnetic resonance enterography, and intestinal ultrasound are important tools in evaluating stricturing Crohn's disease. Definitions of strictures have been developed for CT enterography and magnetic resonance enterography. However, expert recommendations for definitions and treatment response of strictures on intestinal ultrasound are not available.