Search

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p

Abstract SLC1A4 is a trimeric neutral amino acid transporter essential for shuttling L‐serine from astrocytes into neurons. Individuals with biallelic variants in SLC1A4 are known to have spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM) syndrome, but individuals with heterozygous variants are not thought to have disease. We identify an 8‐year‐old patient with global developmental delay, spasticity, epilepsy, and microcephaly who has a de novo heterozygous three amino acid duplication in SLC1A4 (L86_M88dup). We demonstrate that L86_M88dup causes a dominant‐negative N‐glycosylation defect of SLC1A4, which in turn reduces the plasma membrane localization of SLC1A4 and the transport rate of SLC1A4 for L‐serine.

Biallelic pathogenic variants in UQCRFS1 underlie a rare form of isolated mitochondrial complex III deficiency associated with lactic acidosis and a distinctive scalp alopecia previously described in two unrelated probands. Here, we describe a participant in the Undiagnosed Diseases Network (UDN) with a dual diagnosis of two autosomal recessive disorders revealed by genome sequencing: UQCRFS1-related mitochondrial complex III deficiency and GJA8-related cataracts. Both pathogenic variants have been reported before: UQCRFS1 (NM_006003.3:c.215–1 G>C, p.Val72_Thr81del10) in a case with mitochondrial complex III deficiency and GJA8 (NM_005267.5:c.736 G>T, p.Glu246*) as a somatic change in aged cornea leading to decreased junctional coupling. A multi-modal approach combining enzyme assays and cellular proteomics analysis provided clear evidence of complex III respiratory chain dysfunction and low abundance of the Rieske iron-sulfur protein, validating the pathogenic effect of the UQCRFS1 variant. This report extends the genotypic and phenotypic spectrum for these two rare disorders and highlights the utility of deep phenotyping and genomics data to achieve diagnosis and insights into rare disease.

Introduction: Remote consultations help reduce contact between people and prevent cross-contamination. Little is known about the changes in consultation in European rural primary care during the SARS-CoV-2 (COVID-19) pandemic. The purpose of this mixed-methods cross-sectional study was to find out more about the effects of the pandemic on changes in patient consultations in European rural primary care. Methods: A key informant survey from 16 member countries of the European Rural and Isolated Practitioners Association (EURIPA) was undertaken using a self-developed questionnaire. The steering committee of this project, called EURIPA Covid-19 study, developed a semi-structured questionnaire with 68 questions, 21 of which included free-text comments. Proportions were calculated for dichotomized or categorized data, and means were calculated for continuous data. Multivariate analysis by logistic regression model was used to assess the association of multiple variables. Results: A total of 406 questionnaires from primary care providers (PCPs) in 16 European countries were collected; 245 respondents (60.5%) were females, 152 PCPs were rural (37.5%), 124 semi-rural (30.5%). Mean age of the respondents was 45.9 years (standard deviation (SD) 11.30) while mean seniority (length of experience) was 18.2 years (SD 11.6). A total of 381 (93.8%) respondents were medical doctors. Significant differences were found between countries in adopting alternative arrangements to face-to-face consultation: remote teleconsultation is well appreciated by both healthcare professionals and patients, but the most common way of remote consultation remains telephone consultation. A factor significantly inversely associated with the adoption of video consultation was the seniority of the PCP (odds ratio 1.19, 95% confidence interval 1.02-1.40, p=0.03). Conclusion: Telephone consultation is the most common form of remote consultation. The adoption of video-consultation is inversely related to the seniority of the informants.

Introduction: This article describes the views of European rural general practitioners regarding the strengths, weaknesses, opportunities and threats (SWOT) of the implementation of a chronic care model (CCM) in European rural primary care. Methods: This was a mixed-methods online survey. Data were collected from 227 general practitioners between May and December 2017. Categorical data were analysed using descriptive methods while free-text responses were analysed using qualitative methods. The setting was rural primary care in nine European countries (including Central and Eastern Europe). Main outcomes measures were respondents' evaluations of a chronic care model in their rural healthcare settings in terms of SWOT. Results: The SWOT analysis showed that the expertise of healthcare professionals and the strength of relationships and communications between professionals, caregivers and patients are positive components of the CCM system. However, ensuring adequate staffing levels and staff competency are issues that would need to be addressed. Opportunities included the need to enable patients to participate in decision making by ensuring adequate health literacy. Conclusion: The CCM could certainly have benefits for health care in rural settings but staffing levels and staff competency would need to be addressed before implementation of CCM in such settings. Improving health literacy among patients and their carers will be essential to ensure their full participation in the implementation of a successful CCM.

This review aimed to explore the psychometric properties of quality of life (QOL) scales to identify appropriate tools for research and clinical practice in Arabic-speaking adults. A systematic search of the Cumulative Index to Nursing and Allied Health Literature® (EBSCO Information Services, Ipswich, Massachusetts, USA), MEDLINE® (National Library of Medicine, Bethesda, Maryland, USA), EMBASE (Elsevier, Amsterdam, Netherlands) and PsycINFO (American Psychological Association, Washington, District of Columbia, USA) databases was conducted according to Preferred Reporting Items Systematic Reviews and Meta- Analysis guidelines. Quality assessment criteria were then utilised to evaluate the psychometric properties of identified QOL scales. A total of 27 studies relating to seven QOL scales were found. While these studies provided sufficient information regarding the scales’ validity and reliability, not all reported translation and cross-cultural adaptation processes. Researchers and clinicians should consider whether the psychometric properties, subscales and characteristics of their chosen QOL scale are suitable for use in their population of interest. Keywords: Quality of Life; Cross-Cultural Comparison; Translations; Psychometrics; Validity and Reliability; Surveys and Questionnaires; Systematic Review.

Phospholipid transfer protein activity (PLTPa) is associated with insulin levels and has been implicated in atherosclerotic disease in both mice and humans. Variation at the PLTP structural locus on chromosome 20 explains some, but not all, heritable variation in PLTPa. In order to detect quantitative trait loci (QTLs) elsewhere in the genome that affect PLTPa, we performed both oligogenic and single QTL linkage analysis on four large families (n = 227 with phenotype, n = 330 with genotype, n = 462 total), ascertained for familial combined hyperlipidemia. We detected evidence of linkage between PLTPa and chromosome 19p (lod = 3.2) for a single family and chromosome 2q (lod = 2.8) for all families. Inclusion of additional marker and exome sequence data in the analysis refined the linkage signal on chromosome 19 and implicated coding variation in LASS4, a gene regulated by leptin that is involved in ceramide synthesis. Association between PLTPa and LASS4 variation was replicated in the other three families (P= 0.02), adjusting for pedigree structure. To our knowledge, this is the first example for which exome data was used in families to identify a complex QTL that is not the structural locus.

The genetic factors associated with carotid artery disease (CAAD) are not fully known. Because of its role in lipid metabolism, we hypothesized that common genetic variation in the very low density lipoprotein receptor (VLDLR) gene is associated with severe CAAD (>80% stenosis), body mass index (BMI), and lipid traits in humans. VLDLR was resequenced for variation discovery in 92 subjects, and single nucleotide polymorphisms (tagSNPs) were chosen for genotyping in a larger cohort (n = 1,027). Of the 17 tagSNPs genotyped, one tagSNP (SNP 1226; rs1454626) located in the 5′ flanking region of VLDLR was associated with CAAD, BMI, and LDL-associated apolipoprotein B (apoB). We also identified receptor-ligand genetic interactions between VLDLR 1226 and APOE genotype for predicting CAAD case status. These findings may further our understanding of VLDLR function, its ligand APOE, and ultimately the pathogenesis of CAAD in the general population.

Paraoxonase 1 (PON1) activity is consistently predictive of vascular disease, although the genotype at four functional PON1 polymorphisms is not. To address this inconsistency, we investigated the role of all common PON1 genetic variability, as measured by tagging single-nucleotide polymorphisms (tagSNPs), in predicting PON1 activity for phenylacetate hydrolysis, LDL susceptibility to oxidation ex vivo, plasma homocysteine (Hcy) levels, and carotid artery disease (CAAD) status. The biological goal was to establish whether additional common genetic variation beyond consideration of the four known functional SNPs improves prediction of these phenotypes. PON2 and PON3 tagSNPs were secondarily evaluated. Expanded analysis of an additional 26 tagSNPs found evidence of previously undescribed common PON1 polymorphisms that affect PON1 activity independently of the four known functional SNPs. PON1 activity was not significantly correlated with LDL oxidative susceptibility, but genotypes at the PON1-108 promoter polymorphism and several other PON1 SNPs were. Neither PON1 activity nor PON1 genotype was significantly correlated with plasma Hcy levels. This study revealed previously undetected common functional PON1 polymorphisms that explain 4% of PON1 activity and a high rate of recombination in PON1, but the sum of the common PON1 locus variation does not explain the relationship between PON1 activity and CAAD.

Paraoxonase (PON1) is an HDL-associated enzyme. Low PON1 activity predicts vascular disease status and is a more reliable predictor of vascular disease than are functional PON1 genotypes. There is evidence that the relationship of PON1 to vascular disease is, in part, due to its antioxidant activity. However, the physical relationship of PON1 with HDL and the existence of cholesterol pathway regulatory elements at the PON1 locus suggest a further relationship of PON1 with lipoproteins, which may contribute to its role in vascular disease. We investigated the relationship of PON1 activity and genotype to lipid-related traits in 91 Caucasian men with severe carotid artery disease and 184 without vascular disease who were not on lipid-lowering medications. Prior studies of PON1 relationship to lipids have not stratified by disease status..We found that PON1 activity was correlated with HDL traits in controls and with LDL- and VLDL-related traits in cases. We hypothesize differences in the joint regulation of PON1 and lipoproteins in cases and controls.