Purpose:Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to analyze the genotype distribution of FCS-causing genes in the United Kingdom. Methods:Data were anonymously collated from 2 genetic testing laboratories providing national genetic diagnosis services for severe hypertriglyceridemia in the United Kingdom. Results:As of December 2023, 880 individuals underwent genetic testing for FCS. The mean (SD) age at the time of genetic testing was 42.5 (15.3) years. After genotyping, 12.9% of the individuals (n = 114) received a genetic diagnosis of FCS. The detection rate of variant-positive multifactorial chylomicronemia syndrome, ie, heterozygous for pathogenic/likely pathogenic (P/LP) variants in 1 of the 5 canonical genes was 11.4% (n = 100).Among 114 genetically proven FCS individuals, 52.6% (n = 60) had biallelic P/LP LPL variants (ie, LPL-FCS), 45.6% (n = 52) had biallelic non-LPL P/LP variants (ie, non-LPL-FCS) and 1.7% (n = 2) individuals were digenic. Among non-LPL-FCS (n = 52), the most common gene implicated was GPIHBP1 (42.3%, n = 22), followed by APOA5 (32.7%, n = 17), LMF1 (13.5%, n = 7) and APOC2 (11.5%, n = 6). Most variant-positive multifactorial chylomicronemia syndrome harbored P/LP variants in LPL (61%) or APOA5 (37%).The geographical distribution of FCS demonstrated regional variability, where the Northwest of England had the highest number of FCS cases per million population. Individuals of European geographic ancestry predominantly had LPL-FCS (60.9%); however, genotype was more diverse in individuals of non-European origin (LPL 47.1%, GPIHBP1 30.9%, APOA5 8.8%, LMF1 7.4%, and APOC2 4.4%). Variants in specific causal genes, GPIHBP1 and LMF1, were predominantly observed in non-European FCS individuals. Conclusion:The genetic architecture of FCS in the United Kingdom is complex, with a substantial proportion affected by non-LPL FCS-causing genes. It also displays a significant regional and ethnic variations.

People with type 2 diabetes (T2D) are more likely to experience binge eating than the general population, which may interfere with their diabetes management. Guided self-help (GSH) is one of the recommended treatment options for binge eating disorder, but there is currently a lack of evidenced treatment for binge eating in individuals living with T2D. The aims of this pilot study were to test the feasibility and acceptability of recruiting and delivering the adapted, online Working to Overcome Eating Difficulties GSH intervention to adults with T2D and binge eating. The intervention comprises GSH materials presented online in seven sections delivered over 12 weeks, supported by a trained Guide. Twenty-two participants were recruited in a case series design to receive the intervention and we interviewed four Guides and five participants afterwards. We measured binge eating, mental wellbeing, quality of life and weight at pre-post and 12-week follow-up. Results showed a significant reduction in binge eating at the end of the intervention, which continued to improve at follow-up. Before the programme, 92 % of participants scored above cut-off for binge eating. This reduced to 41 % post-intervention and no-one at follow-up. These changes were accompanied by significant improvements in depression, anxiety and small changes in eating disorder symptoms. Participants reported making better lifestyle choices, eating more mindfully and having increased self-confidence. The study shows preliminary evidence for online GSH tailored to the needs of individuals with T2D as a feasible and acceptable approach to improving binge eating, diabetes management and mental wellbeing.

Background and aims Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it. Methods A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis. Results At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83–0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m2, and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score. Conclusions Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance.

BACKGROUND:Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS). METHODS:The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project. RESULTS:FCS was relatively common in non-Europeans and those with parental consanguinity (P<0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P=0.001), recurrent pancreatitis (92% versus 63%; P<0.001), unexplained abdominal pain (84% versus 52%; P<0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P<0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P<0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS (P<0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS (P=0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS. CONCLUSIONS:The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS.

Background and aims: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies.Methods: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks.Results: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 x 109/L.Conclusions: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure.

We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase (LPL) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.

Background: Being able to function cognitively is imperative for successful achievement in school, working life, and disease self-management. Diabetes is known to cause changes in brain structure and long-term cognitive dysfunction. This work investigated cystic fibrosis-related diabetes (CFRD) as a mechanism for cognitive impairment in people with CF. It was hypothesised that cognition would be poorer in adults with CFRD than in those with CF without diabetes (CFND) or in healthy controls. Methods: Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery which provides a comprehensive cognitive assessment with tests mapping onto specific brain regions. Demographic, clinical and self-reported health data were documented for all participants. CF specific clinical variables were recorded for the two CF groups. Results: Ninety-eight people with CF (49CFRD,49CFND) and 49 healthy controls were recruited. People with CF demonstrated deficits in aspects of verbal and spatial memory, processing speed and cognitive flexibility compared with healthy controls, with all areas of the brain implicated. Those with CFRD had additional difficulties with higher-level processes known collectively as 'executive function', which demand greater cognitive load and recruit the prefrontal cortex. Compared with healthy controls, those with CFND and CFRD had an estimated 20% and up to 40% reduction in processing speed respectively. Conclusion: Managing CF requires higher order executive function. Impairments may be sufficient to interfere with self-care and the ability to perform everyday tasks efficiently. At which point in the CF disease trajectory these difficulties begin, and what may attenuate them, has yet to be determined. (c) 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

BackgroundProprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) are an important but underutilised option to help optimise lipid management. We developed a new service to improve patient access to these medicines in line with National Institute for Health and Care Excellence recommendations. This paper describes the model and provides lipid-lowering results and feedback from the first 100 referred patients.MethodsThe service is based on a centralised multidisciplinary clinic that is the sole prescriber of PCSK9i therapy in the area. Referred patients are assessed for eligibility and given tailored, person-centred support, education and monitoring to promote treatment adherence and lipids optimisation. The clinic also supports referred patients that do not meet PCSK9i eligibility criteria.ResultsAmong the first 100 patients referred (n=62 male; mean age: 62.9±10.5 years), 48 were initiated on PCSK9i therapy. Mean total cholesterol decreased from 7.7±1.6 mmol/L at baseline to 4.5±1.4 mmol/L at 3 months (41% reduction), while mean low-density lipoprotein-cholesterol (LDL-C) fell from 5.0±1.6 mmol/L to 2.1±1.3 mmol/L (58% reduction; p<0.0001) and median LDL-C decreased from 4.8 mmol/L to 1.6 mmol/L (67% reduction) over the same period. These decreases were maintained at 12 months (45%, 65% and 67% reductions, respectively; p<0.0001 for the decrease in mean LDL-C from baseline). Patient feedback on the clinic was positive and overall satisfaction was high.ConclusionsThis innovative, person-centred, multidisciplinary service successfully initiated PCSK9i therapy for eligible patients and drove long-term monitoring, adherence and cholesterol lowering. It also provided medicines optimisation and adherence assistance to PCSK9i-ineligible patients. The model could be used in other areas to support better uptake and optimisation of PCSK9i therapy.

BackgroundRenal blood flow (RBF) can be measured with dynamic contrast enhanced‐MRI (DCE‐MRI) and arterial spin labeling (ASL). Unfortunately, individual estimates from both methods vary and reference‐standard methods are not available. A potential solution is to include a third, arbitrating MRI method in the comparison.PurposeTo compare RBF estimates between ASL, DCE, and phase contrast (PC)‐MRI.Study TypeProspective.PopulationTwenty‐five patients with type‐2 diabetes (36% female) and five healthy volunteers (HV, 80% female).Field Strength/SequencesA 3 T; gradient‐echo 2D‐DCE, pseudo‐continuous ASL (pCASL) and cine 2D‐PC.AssessmentASL, DCE, and PC were acquired once in all patients. ASL and PC were acquired four times in each HV. RBF was estimated and split‐RBF was derived as (right kidney RBF)/total RBF. Repeatability error (RE) was calculated for each HV, RE = 1.96 × SD, where SD is the standard deviation of repeat scans.Statistical TestsPaired t‐tests and one‐way analysis of variance (ANOVA) were used for statistical analysis. The 95% confidence interval (CI) for difference between ASL/PC and DCE/PC was assessed using two‐sample F‐test for variances. Statistical significance level was P < 0.05. Influential outliers were assessed with Cook's distance (Di > 1) and results with outliers removed were presented.ResultsIn patients, the mean RBF (mL/min/1.73m2) was 618 ± 62 (PC), 526 ± 91 (ASL), and 569 ± 110 (DCE). Differences between measurements were not significant (P = 0.28). Intrasubject agreement was poor for RBF with limits‐of‐agreement (mL/min/1.73m2) [−687, 772] DCE‐ASL, [−482, 580] PC‐DCE, and [−277, 460] PC‐ASL. The difference PC‐ASL was significantly smaller than PC‐DCE, but this was driven by a single‐DCE outlier (P = 0.31, after removing outlier). The difference in split‐RBF was comparatively small. In HVs, mean RE (±95% CI; mL/min/1.73 m2) was significantly smaller for PC (79 ± 41) than for ASL (241 ± 85).ConclusionsASL, DCE, and PC RBF show poor agreement in individual subjects but agree well on average. Triangulation with PC suggests that the accuracy of ASL and DCE is comparable.Evidence Level2Technical EfficacyStage 2

Pyomyositis is a rare and serious acute purulent bacterial infection of the skeletal muscle. Diabetes is the most important predisposing factor and, if left untreated, the infection has significant complications. We report the case of an adult male who presented acutely with a history of abdominal pain, nausea and vomiting and bilateral thigh pain. His abdominal examination was unremarkable, but a fluctuant swelling was identified in both thighs. Biochemical investigations revealed raised inflammatory markers and diagnostic chemistry of diabetic ketoacidosis. Pyomyositis was treated with intravenous antibiotics and surgical abscess drainage. MRI is the definitive investigation of choice to diagnose pyomyositis. Differential diagnoses include cellulitis, septic arthritis and deep vein thrombosis.

Background Diabetic kidney disease (DKD) remains one of the leading causes of premature death in diabetes. DKD is classified on albuminuria and reduced kidney function (estimated glomerular filtration rate (eGFR)) but these have modest value for predicting future renal status. There is an unmet need for biomarkers that can be used in clinical settings which also improve prediction of renal decline on top of routinely available data, particularly in the early stages. The iBEAt study of the BEAt-DKD project aims to determine whether renal imaging biomarkers (magnetic resonance imaging (MRI) and ultrasound (US)) provide insight into the pathogenesis and heterogeneity of DKD (primary aim) and whether they have potential as prognostic biomarkers in DKD (secondary aim). Methods iBEAt is a prospective multi-centre observational cohort study recruiting 500 patients with type 2 diabetes (T2D) and eGFR ≥30 ml/min/1.73m 2 . At baseline, blood and urine will be collected, clinical examinations will be performed, and medical history will be obtained. These assessments will be repeated annually for 3 years. At baseline each participant will also undergo quantitative renal MRI and US with central processing of MRI images. Biological samples will be stored in a central laboratory for biomarker and validation studies, and data in a central data depository. Data analysis will explore the potential associations between imaging biomarkers and renal function, and whether the imaging biomarkers improve the prediction of DKD progression. Ancillary substudies will: (1) validate imaging biomarkers against renal histopathology; (2) validate MRI based renal blood flow measurements against H 2 O 15 positron-emission tomography (PET); (3) validate methods for (semi-)automated processing of renal MRI; (4) examine longitudinal changes in imaging biomarkers; (5) examine whether glycocalyx and microvascular measures are associated with imaging biomarkers and eGFR decline; (6) explore whether the findings in T2D can be extrapolated to type 1 diabetes. Discussion iBEAt is the largest DKD imaging study to date and will provide valuable insights into the progression and heterogeneity of DKD. The results may contribute to a more personalised approach to DKD management in patients with T2D. Trial registration Clinicaltrials.gov ( NCT03716401 ).

Diabetes mellitus is a chrome condition characterized by the presence of fasting hyperglycemia and the development of vascular complications. The pathogenesis of the vascular complications of diabetes is not entirely clear, although evidence from the recently presented Diabetes, Control and Complications Trial indicates quite unequivocally that improved metabolic control in diabetic patients leads to a reduction in the incidence of microvascular complications. The principal role of the fibrinolytic system is the breakdown and removal of intravascular fibrin and thrombus, permitting unimpeded vascular blood flow, and of extravascular fibrin in wounds and inflammatory exudates. The numerous metabolic and biochemical consequences of diabetes mellitus offer a number of candidate factors that may influence the development of suppression of fibrinolysis. The hydrolysis of deposited fibrin by plasmin occurs specifically at peptide bonds containing lysine or arginine residues. Glycosylation reduces the susceptibility of fibrin to lysis by plasmin, probably by competing for the active site of hydrolysis.

Cellular and molecular mechanisms of thoracic aortic aneurysm are still not clear and therapeutic approaches are mostly absent. The role of endothelial cells in aortic wall integrity is emerging from recent studies. Although Notch pathway ensures endothelial development and integrity, and NOTCH1 mutations have been associated with thoracic aortic aneurysms, the role of this pathway in aneurysm remains elusive. The purpose of the present work was to study functions of Notch genes in endothelial cells of patients with sporadic thoracic aortic aneurysm.Aortic endothelial cells were isolated from aortic tissue of patients with thoracic aortic aneurysm and healthy donors. Gene expression of Notch and related BMP and WNT/β-catenin pathways was estimated by qPCR; WNT/β-catenin signaling was studied by TCF-luciferase reporter. To study the stress-response the cells were subjected to laminar shear stress and the expression of corresponding genes was estimated by qPCR.Analyses of mRNA expression of Notch genes, Notch target genes and Notch related pathways showed that endothelial cells of aneurysm patients have dysregulated Notch/BMP/WNT pathways compared to donor cells. Activity of Wnt pathway was significantly elevated in endothelial cells of the patients. Cells from patients had attenuated activation of DLL4, SNAIL1, DKK1 and BMP2 in response to shear stress.In conclusion endothelial cells of the patients with thoracic aortic aneurysm have dysregulated Notch, BMP and WNT/β-catenin related signaling. Shear stress-response and cross-talk between Notch and Wnt pathways that normally ensures aortic integrity and resistance of endothelial cells to stress is impaired in aneurysmal patients.