The impact of hypoglycaemia on quality of life among adults with type 1 diabetes:Results from “YourSAY: Hypoglycaemia”

Aims Research on hypoglycaemia and quality of life (QoL) has focused mostly on severe hypoglycaemia and psychological outcomes, with less known about other aspects of hypoglycaemia (e.g., self-treated episodes) and impacts on other QoL domains (e.g., relationships). Therefore, we examined the impact of all aspects of hypoglycaemia on QoL in adults with type 1 diabetes (T1DM). Methods Participants completed an online survey, including assessment of hypoglycaemia-specific QoL (using the 12-item Hypoglycaemia Impact Profile). Mann-Whitney U tests examined differences in hypoglycaemia-specific QoL by hypoglycaemia frequency, severity, and awareness. Hierarchical linear regression examined associations with QoL. Results Participants were 1028 adults with T1DM (M ± SD age: 47 ± 15 years; diabetes duration: 27 ± 16 years). Severe and self-treated hypoglycaemia and impaired awareness negatively impacted on overall QoL and several QoL domains, including leisure activities, physical health, ability to keep fit/be active, sleep, emotional well-being, spontaneity, independence, work/studies, and dietary freedom. Diabetes distress was most strongly associated with hypoglycaemia-specific QoL, followed by generic emotional well-being, fear of hypoglycaemia, and confidence in managing hypoglycaemia. Hypoglycaemia frequency and awareness were no longer significantly associated with QoL once psychological factors were considered. Conclusions Hypoglycaemia negatively impacts on several QoL domains. Psychological factors supersede the effect of hypoglycaemia frequency and awareness in accounting for this negative impact

Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia:the Hypo-RESOLVE QoL

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL.Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement.Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46–0.59), internal consistency (α=0.91) and test–retest reliability (intraclass correlation coefficient =0.87).Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint

Development of a new health-related quality of life measure for people with diabetes who experience hypoglycaemia:the Hypo-RESOLVE QoL

Aims/hypothesis: Valid and reliable patient-reported outcome measures are vital for assessing disease impact, responsiveness to healthcare and the cost-effectiveness of interventions. A recent review has questioned the ability of existing measures to assess hypoglycaemia-related impacts on health-related quality of life for people with diabetes. This mixed-methods project was designed to produce a novel health-related quality of life patient-reported outcome measure in hypoglycaemia: the Hypo-RESOLVE QoL.Methods: Three studies were conducted with people with diabetes who experience hypoglycaemia. In Stage 1, a comprehensive health-related quality of life framework for hypoglycaemia was elicited from semi-structured interviews (N=31). In Stage 2, the content validity and acceptability of draft measure content were tested via three waves of cognitive debriefing interviews (N=70 people with diabetes; N=14 clinicians). In Stage 3, revised measure content was administered alongside existing generic and diabetes-related measures in a large cross-sectional observational survey to assess psychometric performance (N=1246). The final measure was developed using multiple evidence sources, incorporating stakeholder engagement.Results: A novel conceptual model of hypoglycaemia-related health-related quality of life was generated, featuring 19 themes, organised by physical, social and psychological aspects. From a draft version of 76 items, a final 14-item measure was produced with satisfactory structural (χ2=472.27, df=74, p<0.001; comparative fit index =0.943; root mean square error of approximation =0.069) and convergent validity with related constructs (r=0.46–0.59), internal consistency (α=0.91) and test–retest reliability (intraclass correlation coefficient =0.87).Conclusions/interpretation: The Hypo-RESOLVE QoL is a rigorously developed patient-reported outcome measure assessing the health-related quality of life impacts of hypoglycaemia. The Hypo-RESOLVE QoL has demonstrable validity and reliability and has value for use in clinical decision-making and as a clinical trial endpoint

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

Background: Several lines of evidence suggest that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but complete mapping of the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors that may be involved in one subtype may not be in others. We investigate the possibility that this network could be mapped using microarray technologies and contemporary bioinformatics methods on a dataset derived from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls. Methodology/Principal Findings: We have used two different analytical methodologies: a non-standard differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that are statistically overrepresented in genes that are either differentially expressed (or differentially co-expressed) in cases and controls (e.g., V$KROX_Q6, p-value ,3.31E-6; V$CREBP1_Q2, p-value ,9.93E-6, V$YY1_02, p-value ,1.65E-5). Conclusions/Significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. The most significant transcription factor motifs were for the Early Growth Response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families. These transcription factors are involved in early T-lymphocyte specification and commitment as well as in oligodendrocyte dedifferentiation and development, both pathways that have significant biological plausibility in MS causation

Comparing genotyping algorithms for Illumina's Infinium whole-genome SNP BeadChips

The Brassica napus 60K Illumina Infinium™ SNP array has had huge international uptake in the rapeseed community due to the revolutionary speed of acquisition and ease of analysis of this high-throughput genotyping data, particularly when coupled with the newly available reference genome sequence. However, further utilization of this valuable resource can be optimized by better understanding the promises and pitfalls of SNP arrays. We outline how best to analyze Brassica SNP marker array data for diverse applications, including linkage and association mapping, genetic diversity and genomic introgression studies. We present data on which SNPs are locus-specific in winter, semi-winter and spring B. napus germplasm pools, rather than amplifying both an A-genome and a C-genome locus or multiple loci. Common issues that arise when analyzing array data will be discussed, particularly those unique to SNP markers and how to deal with these for practical applications in Brassica breeding applications

Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations

Background: The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial. Methods: We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice. Results: We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133- cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133- tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133- cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133- cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment. Conclusion: We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133- cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Type 1 diabetes and disordered eating behaviour: Exploring the role of executive function

Disordered eating behaviour is prevalent in young adults with type 1 diabetes, and is associated with significant morbidity and mortality. This thesis explored the involvement of higher-order cognitive function (executive function) in influencing this relationship. Findings collectively indicated that executive function difficulties were over-represented in young adults with type 1 diabetes, and that executive function may be uniquely and more strongly related to disordered eating behaviours in this clinical group relative to those without diabetes

A systematic review and meta-analysis of executive function in type 1 diabetes mellitus

<b>Objective</b>\ud \ud To examine the current evidence for <i>executive function</i> (EF) performance differences between groups with <i>Type 1 diabetes mellitus</i> (T1DM) and non-diabetic control groups during adolescence and early adulthood, and to explore the relationships between EF and diabetes-related risk factors. \ud \ud <b>Methods</b>\ud \ud A systematic review of the literature examining EF performance in groups with T1DM was conducted according to the PRISMA guidelines. Electronic database searches for published and unpublished literature yielded a final set of 26 articles after application of inclusion and exclusion criteria. A meta-analysis was conducted on a subset of these articles (n = 17) comparing EF performance in T1DM and control groups, across a total sample size of 1619. \ud \ud <b>Results</b>\ud \ud Sixteen of 26 studies found significantly lower EF on at least one task in groups with T1DM. Meta-analyses of the performance difference between T1DM groups and control groups without diabetes showed that inhibition (g = -0.28, p < .001), working memory (g = -0.34, p < .001), set-shifting (g = -0.31, p = .012), and overall EF performance across these domains (g = -0.42, p < .001) were all significantly lower in groups with T1DM. Performance on specific EF domains also appeared to be differentially associated with early age of diabetes onset, chronic hyperglycemia and its complications, and severe hypoglycemia. \ud \ud <b>Conclusions</b>\ud \ud T1DM and its associated risk factors are related to subtle impairments across the inhibition, working memory, and set-shifting domains of EF. Lower EF may be a key factor contributing to behavioral and clinical problems experienced by individuals with T1DM

Correction to:The suitability of patient-reported outcome measures used to assess the impact of hypoglycaemia on quality of life in people with diabetes: a systematic review using COSMIN methods (Diabetologia, (2021), 64, 6, (1213-1225), 10.1007/s00125-021-05382-x)

The authors omitted one hypoglycaemia-specific patientreported outcome measure (TRIM-HYPO) from their systematic review. The original article has now been corrected to include TRIM-HYPO. An incorrect entry in Table 5 for the HFS instrument has also been corrected. The overall conclusion has not changed