Deep metabolic phenotyping of humans with protein-altering variants in using a genome-first approach.

Background & Aim: An unbiased genome-first approach can expand the molecular understanding of specific genes in disease-agnostic biobanks for deeper phenotyping. represents a good candidate for this approach due to its known association with steatotic liver disease (SLD).

Methods: We screened participants with whole-exome sequences in the Penn Medicine Biobank (PMBB, n >40,000) and the UK Biobank (UKB, n >200,000) for protein-altering variants in and evaluated their association with liver phenotypes and clinical outcomes.

Long-term outcome of autologous haematopoietic stem cell transplantation in patients with systemic sclerosis: a comparison with patients treated with rituximab and with traditional immunosuppressive agents.

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is more effective than conventional immunosuppressive therapies (CIT) in improving the outcome of patients with rapidly progressive diffuse cutaneous systemic sclerosis (dcSSc). So far, there is still a paucity of data comparing AHSCT with rituximab (RTX). Aim of the study is to retrospectively compare, in patients with dcSSc, the effectiveness of AHSCT with that of RTX and CIT.

Overexpression of BAG3 (Bcl2-associated athanogene 3) in serum and skin of patients with systemic sclerosis.

Objectives: BAG3 (Bcl2-associated athanogene3) is able to induce the transformation of cancer-associated fibroblasts to alpha smooth muscle actin (a-SMA) positive (+) myofibroblasts. In systemic sclerosis (SSc), a-SMA+ myofibroblasts also play an important role in the progression of fibrosis in the skin and involved internal organs. The aim of the study was to investigate whether BAG3 is overexpressed in SSc and may be a biomarker of fibrogenesis.

Longitudinal analysis of clinical and laboratory biomarkers in a patient with familial lecithin: cholesterol acyltransferase deficiency (FLD) and accelerated eGFR decline: A case study.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is an ultra-rare autosomal recessive disease characterized by very low high-density lipoprotein cholesterol (HDL-C) levels, corneal opacity, anemia, and progressive renal disease. The rate and severity of renal disease are variable across FLD patients and the biomarkers and risk factors for disease progression are poorly understood. Here we report a 30 year-long comparative analysis of the clinical and laboratory biomarkers in an FLD patient with accelerated renal decline, who underwent two kidney and one liver transplantations.

Investigating gunshot wounds in charred bone with XRF spectroscopy: a technical note.

The analysis of traces of injuries can be difficult in cases of charred human remains since the alteration and fragmentation are high. The aim of this study is to explore the use of X-Ray Fluorescence (XRF) technique as a screening tool for detecting and analyzing gunshot residues (GSR) on cremated and highly fragmented materials, as it is a technique that allows for fast qualitative investigations without altering the sample or requiring sample preparation. The study was carried out on two steps: firstly, on completed skeletonized bones to verify if GSR survive to burning; secondly, we considered a more realistic situation, in which soft tissues were present before the shooting.

Safety and Immunogenicity of a 4-Component Generalized Modules for Membrane Antigens Shigella Vaccine in Healthy European Adults: Randomized, Phase 1/2 Study.

Background: We report data from stage 1 of an ongoing 2-staged, phase 1/2 randomized clinical trial with a 4-component generalized modules for membrane antigens-based vaccine against Shigella sonnei and Shigella flexneri 1b, 2a, and 3a (altSonflex1-2-3; GSK).

Methods: Europeans aged 18-50 years (N = 102) were randomized (2:1) to receive 2 injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at prespecified time points.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

Background: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain.

Methods: Metabolic phenotypes and outcomes associated with ERLIN1 p.

Testing GMMA with and without Aluminium Salt-Based Adjuvants in Animal Models.

Shigellosis is one of the leading causes of diarrheal disease in low- and middle-income countries, particularly in young children, and is more often associated with antimicrobial resistance. Therefore, a preventive vaccine against shigellosis is an urgent medical need. We have proposed Generalised Modules for Membrane Antigens (GMMA) as an innovative delivery system for O-antigen, and an Alhydrogel formulation (1790GAHB) has been extensively tested in preclinical and clinical studies.

Telerehabilitation for Lee Silverman Voice Treatment (Tele-LSVT)-Loud on voice intensity and voice use in daily living in people with multiple sclerosis: A protocol for a feasibility and pilot randomized controlled study.

Objective: Alterations in voice intensity and quality may constitute a social life limitation in people with multiple sclerosis (MS), but only 2% of cases receive speech therapy. Especially the Lee Silverman Voice Treatment (LSVT)-Loud is a highly effective intensive method for voice intensity, requiring subjects' repeated attendance at the clinic. Telerehabilitation may represent a feasible solution to bypass potential barriers related to speech therapy attendance, scaling up the beneficial effects of the treatment to a broader population.

Apolipoprotein E isoforms differentially affect LCAT-dependent cholesterol esterification.

Background And Aims: LCAT esterifies cholesterol in both HDL (α-activity) and apoB-containing lipoproteins (β-activity). The main activator of LCAT β-activity is apoE, which in humans exists in 3 main different isoforms (E2, E3 and E4). Here, to gather insights into the potential role of LCAT in apoB-containing lipoprotein metabolism, we investigated the ability of apoE isoforms to promote LCAT-mediated cholesterol esterification.

A next-generation GMMA-based vaccine candidate to fight shigellosis.

Shigellosis is a leading cause of diarrheal disease in low-middle-income countries (LMICs). Effective vaccines will help to reduce the disease burden, exacerbated by increasing antibiotic resistance, in the most susceptible population represented by young children. A challenge for a broadly protective vaccine against shigellosis is to cover the most epidemiologically relevant serotypes among >50 Shigella serotypes circulating worldwide.

Quantitative image analysis of microplastics in bottled water using artificial intelligence.

The ubiquitous occurrence of microplastics (MPs) in the environment and the use of plastics in packaging materials result in the presence of MPs in the food chain and exposure of consumers. Yet, no fully validated analytical method is available for microplastic (MP) quantification, thereby preventing the reliable estimation of the level of exposure and, ultimately, the assessment of the food safety risks associated with MP contamination. In this study, a novel approach is presented that exploits interactive artificial intelligence tools to enable automation of MP analysis.

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids.

Background: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis.

Aim: To examine the effects of missense variants in MTTP on hepatic and circulating lipids.

Methods: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444).

Comparison of the structure-function properties of wild-type human apoA-V and a C-terminal truncation associated with elevated plasma triglycerides.

Background: Plasma triglycerides (TGs) are causally associated with coronary artery disease and acute pancreatitis. Apolipoprotein A-V (apoA-V, gene ) is a liver-secreted protein that is carried on triglyceride-rich lipoproteins and promotes the enzymatic activity of lipoprotein lipase (LPL), thereby reducing TG levels. Little is known about apoA-V structure-function; naturally occurring human variants can provide novel insights.

Factors Associated With Treatment-Related Changes in Voice Volume in People With Multiple Sclerosis.

Background: Vocal disorders are frequent in people with multiple sclerosis (MS). Cognitive impairment, fatigue, depression, and other clinical characteristics can be associated with treatment effectiveness in rehabilitation. Finding baseline characteristics that identify those who are responding to treatment can help the clinical decision-making process, which can then help improve the effectiveness of voice treatment.

Rapid Single Particle Atmospheric Solids Analysis Probe-Mass Spectrometry for Multimodal Analysis of Microplastics.

Despite mass spectrometry (MS) being proven powerful for the characterization of synthetic polymers, its potential for the analysis of single particle microplastics (MPs) is yet to be fully disclosed. To date, MPs are regarded as ubiquitous contaminants, but the limited availability of techniques that enable full characterizations of MPs results in a lack of systematic data regarding their occurrence. In this study, an atmospheric solid analysis probe (ASAP) coupled to a compact quadrupole MS is proposed for the chemical analysis of single particle microplastics, while maintaining full compatibility with complementary staining and image analysis approaches.

Profibrotic Effects of Endothelin-1 on Fibroblasts Are Mediated by Aldosterone in Vitro: Relevance to the Pathogenesis and Therapy of Systemic Sclerosis and Pulmonary Arterial Hypertension.

Endothelin-1 (ET-1) is a vasoactive and profibrotic peptide that plays a pivotal role in diseases such as systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH), by inducing fibrosis and vascular remodeling. Such effects may be sustained by the induction of aldosterone production and reactive oxygen species (ROS). We have used fibroblasts obtained from skin of healthy donors and SSc patients and commercial fibroblasts from lung to evaluate whether ET-1 is able to stimulate ROS production directly or indirectly through aldosterone induction.

TRIB1 regulates LDL metabolism through CEBPα-mediated effects on the LDL receptor in hepatocytes.

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice.

Long term results of Dorsal Root Entry Zone (DREZ) lesions for the treatment of intractable pain: A systematic review of the literature on 1242 cases.

Background: Different Dorsal root entry zone (DREZ) lesion techniques have been reported as effective treatment for intractable painful conditions, though with contradictory results. Overall, good results were reported especially in specific conditions, such as pain due to brachial plexus avulsion, spinal cord injuries and oncological pain management. However, data on long term results in different clinical conditions are still missing.