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Aims To determine if urine C-peptide/creatinine ratio is a useful tool for monitoring β-cell function in new-onset Type 1 diabetes. Methods Data were obtained from a prospective immunomodulation study in people with Type 1 diabetes ≤ 3 months from diagnosis, with a standard mixed-meal tolerance test and measurement of urine C-peptide/creatinine ratio carried out at 0, 3, 6, 9 and 12 months. The change in the insulin-dose-adjusted HbA1c level was also correlated with the change in serum/urine C-peptide level during the 12-month follow-up period. Results A significant reduction in urine C-peptide/creatinine ratio, measured after a mixed-meal, was reached at 9 months (−45.4%), whilst the reduction in stimulated serum C-peptide level reached significance after 3 months (−54.7%) in placebo-treated participants. Neither change in stimulated serum C-peptide nor change in urine C-peptide level correlated with each other, and nor did change in insulin-dose-adjusted HbA1c level in the first 6 months, but all measures correlated significantly in the second half of the 12-month follow-up period. Conclusion Mixed-meal-stimulated urine C-peptide/creatinine ratio was similar to, although less sensitive than, stimulated serum C-peptide level in monitoring β-cell function during the first year after diagnosis. Because the former is significantly less invasive, it warrants inclusion in further studies in Type 1 diabetes and may represent an attractive alternative outcome measure in cohort studies and in children. [ABSTRACT FROM AUTHOR]

The chimeric transcription factor E2a-Pbx1 is expressed as a result of the 1;19 chromosomal translocation in some 5% of cases of pediatric acute lymphoblastic leukemia. We investigated the biological and transcriptional consequences of forced expression of E2a-Pbx1 in the interleukin-3 (IL-3) dependent, bone marrow-derived cell line Ba/F3. We show that forced expression of E2a-Pbx1 induces apoptosis in Ba/F3 cells without apparent effects on cell cycle progression. This pro-apoptotic effect is enhanced on cytokine deprivation. Furthermore, using cDNA representational difference analysis (RDA), we show that these cellular effects are associated with marked induction of the gene NDRG1, which was previously identified as a target of transcriptional repression by N-myc and induction by the tumor suppressor protein p53. We identify a portion of the NDRG1 promoter capable of mediating transcriptional induction by E2a-Pbx1 and show that NDRG1 is also induced on simple IL-3 deprivation of BaF3 cells. Although we show that E2a-Pbx1 induction of NDRG1 is not impaired as a result of targeting p53 using HPV E6, and therefore does not appear to be p53-dependent, our results overall are consistent with the notion that induction of NDRG1 by E2a-Pbx1 may represent part of an apoptotic or cytostatic cellular response to oncogene activation. [ABSTRACT FROM AUTHOR]

Objective: Familial hypercholesterolaemia (FH) elevates low-density lipoprotein cholesterol (LDL-C) and increases cardiovascular disease (CVD) risk. This study aimed to provide evidence for the feasibility of conducting a randomised controlled trial to evaluate the efficacy of an intervention designed to improve diet and physical activity in families with FH., Design: A parallel, randomised, waitlist-controlled, feasibility pilot trial., Setting: Three outpatient lipid clinics in the UK., Participants: Families that comprised children (aged 10-18 years) and their parent with genetically diagnosed FH., Intervention: Families were randomised to either 12-week usual care or intervention. The behavioural change intervention aimed to improve dietary, physical activity and sedentary behaviours. It was delivered to families by dietitians initially via a single face-to-face session and then by four telephone or email follow-up sessions., Outcome Measures: Feasibility was assessed via measures related to recruitment, retention and intervention fidelity. Postintervention qualitative interviews were conducted to explore intervention acceptability. Behavioural (dietary intake, physical activity and sedentary time) and clinical (blood pressure, body composition and blood lipids) outcomes were collected at baseline and endpoint assessments to evaluate the intervention's potential benefit., Results: Twenty-one families (38% of those approached) were recruited which comprised 22 children and 17 adults with FH, and 97% of families completed the study. The intervention was implemented with high fidelity and the qualitative data revealed it was well accepted. Between-group differences at the endpoint assessment were indicative of the intervention's potential for improving diet in children and adults. Evidence for potential benefits on physical activity and sedentary behaviours was less apparent. However, the intervention was associated with improvements in several CVD risk factors including LDL-C, with a within-group mean decrease of 8% (children) and 10% (adults)., Conclusions: The study's recruitment, retention, acceptability and potential efficacy support the development of a definitive trial, subject to identified refinements., Trial Registration Number: ISRCTN24880714., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Untreated heterozygous familial hypercholesterolaemia (FH) causes high low-density lipoprotein cholesterol (LDL-C) levels and increased cardiovascular disease (CVD) risk. Despite pharmacological treatment, many treated individuals remain at higher CVD risk than non-affected individuals. This may be due to LDL-C targets not being met and presence of other CVD risk factors. Adhering to dietary and physical activity (PA) recommendations developed for individuals with FH may further reduce CVD risk. However, there is insufficient research to support the efficacy of adhering to these guidelines on LDL-C and other CVD risk factors. The need for studies to investigate the effectiveness of nutrition and PA interventions in the FH population has been widely recognised and recommended. This paper describes the protocol of a pilot, randomised controlled trial designed to evaluate the feasibility and acceptability of a specifically developed nutrition and PA intervention aimed at improving the dietary intakes and PA levels of families with FH., Methods: A two-arm randomised waitlist-controlled pilot trial will be conducted across three National Health Service (NHS) sites in England, UK. Twenty-four young people with FH, aged 10-18 years, and their affected parent, will be recruited and randomly assigned to the intervention or waitlist and usual care control. The primary aim is to provide evidence for the feasibility and acceptability of delivering the intervention, explored quantitatively (rates of recruitment, retention and outcome measure completeness) and qualitatively (qualitative interviews). The secondary aim is to provide evidence for the potential efficacy of the intervention on dietary intake, PA, sedentary time, body composition, CVD risk factors and quality of life determined at baseline and endpoint assessments. The intervention will involve an hour-long consultation with a dietitian at baseline and four follow-up contacts across the 12-week intervention. It has been specifically developed for use with individuals with FH and incorporates behavioural change techniques to target identified enablers and barriers to adherence in this population., Discussion: This trial will estimate the feasibility and acceptability of the nutrition and PA intervention delivered to young people and parents with FH. If appropriate, this study can be used to inform the design of an adequately powered definitive trial., Trial Registration: ISRCTN, ISRCTN24880714. Registered 07/06/2018, http://www.isrctn.com/ISRCTN24880714., Competing Interests: Competing interestsNone declared., (© The Author(s) 2020.)

Background and Aims: In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011., Methods: Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients., Results: Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA., Conclusions: The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Individuals with heterozygous familial hypercholesterolaemia (FH) are at high risk of developing cardiovascular disease (CVD). This risk can be substantially reduced with lifelong pharmacological and lifestyle treatment; however, research suggests adherence is poor. We synthesised the qualitative research to identify enablers and barriers to treatment adherence., Design: This study conducted a thematic synthesis of qualitative studies., Data Sources: MEDLINE, Embase, PsycINFO via OVID, Cochrane library and CINAHL databases and grey literature sources were searched through September 2018., Eligibility Criteria: We included studies conducted in individuals with FH, and their family members, which reported primary qualitative data regarding their experiences of and beliefs about their condition and its treatment., Data Extraction and Synthesis: Quality assessment was undertaken using the Critical Appraisal Skills Programme for qualitative studies. A thematic synthesis was conducted to uncover descriptive and generate analytical themes. These findings were then used to identify enablers and barriers to treatment adherence for application in clinical practice., Results: 24 papers reporting the findings of 15 population samples (264 individuals with FH and 13 of their family members) across 8 countries were included. Data captured within 20 descriptive themes were considered in relation to treatment adherence and 6 analytical themes were generated: risk assessment; perceived personal control of health; disease identity; family influence; informed decision-making; and incorporating treatment into daily life. These findings were used to identify seven enablers (eg, 'commencement of treatment from a young age') and six barriers (eg, 'incorrect and/or inadequate knowledge of treatment advice') to treatment adherence. There were insufficient data to explore if the findings differed between adults and children., Conclusions: The findings reveal several enablers and barriers to treatment adherence in individuals with FH. These could be used in clinical practice to facilitate optimal adherence to lifelong treatment thereby minimising the risk of CVD in this vulnerable population., Prospero Registration Number: CRD42018085946., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4( DRB1*0401 )-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation., (Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This consensus statement addresses the current three main modalities of treatment of homozygous familial hypercholesterolaemia (HoFH): pharmacotherapy, lipoprotein (Lp) apheresis and liver transplantation. HoFH may cause very premature atheromatous arterial disease and death, despite treatment with Lp apheresis combined with statin, ezetimibe and bile acid sequestrants. Two new classes of drug, effective in lowering cholesterol in HoFH, are now licensed in the United Kingdom. Lomitapide is restricted to use in HoFH but, may cause fatty liver and is very expensive. PCSK9 inhibitors are quite effective in receptor defective HoFH, are safe and are less expensive. Lower treatment targets for lipid lowering in HoFH, in line with those for the general FH population, have been proposed to improve cardiovascular outcomes. HEART UK presents a strategy combining Lp apheresis with pharmacological treatment to achieve these targets in the United Kingdom (UK). Improved provision of Lp apheresis by use of existing infrastructure for extracorporeal treatments such as renal dialysis is promoted. The clinical management of adults and children with HoFH including advice on pregnancy and contraception are addressed. A premise of the HEART UK strategy is that the risk of early use of drug treatments beyond their licensed age restriction may be balanced against risks of liver transplantation or ineffective treatment in severely affected patients. This may be of interest beyond the UK., (Crown Copyright © 2016. Published by Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: High-sensitivity troponin assays facilitate the rapid exclusion of acute myocardial infarction (AMI). However, elevated results are also seen in other conditions causing myocardial injury. Serial measurements increase the specificity for AMI, helping to rapidly identify patients for whom revascularisation may be appropriate. In this study, we explore a strategy for rapidly excluding AMI in symptomatic patients using serial high-sensitivity troponin measurements., Main Findings: (1) all patients presenting more than 3 h after symptom onset with a negative result had a second negative result; (2) AMI was excluded in all patients with two results falling below the lower limit of detection of a standard troponin assay by 8 h post-symptom onset.

Autosomal dominant hypercholesterolaemia is genetically heterogeneous, but most commonly (approximately 93%) caused by mutations in low-density lipoprotein receptor (LDLR), where the disease is known as familial hypercholesterolaemia (FH), or apolipoprotein B-100 (APOB) (approximately 5.5%), where the disease is known as familial defective APOB (FDB), while in approximately 2% of patients the mutation is in the proprotein convertase subtilisin/kexin type 9 gene. Homozygous FH having inheritance of two LDLR mutations is a rare but recognized syndrome associated with an extreme hypercholesterolaemia and early-onset coronary artery disease. We present a 15-year-old girl with untreated total cholesterol levels of 8.8 mmol/L who was heterozygous for both the LDLR p.Leu479Pro and APOB p.Arg3527Gln mutation. Cascade testing confirmed the paternal origin of the LDLR mutation and revealed a maternal diagnosis of FDB. This case provides further evidence that the combined effect of an LDLR and an APOB mutation give rise to a phenotype more severe than either mutation alone and is more severe than homozygous FDB, but less severe than homozygous FH. It also highlights the need to consider the presence of additional mutations in families where relatives have varying phenotypes.