Assessing type 2 diabetes associated NeuroCognitive impairment using an e-screening tool in a South African population

Background: Type 2 diabetes has been found to be associated with cognitive impairments in planning, problem solving, organization, and working memory and also with an increased risk of dementia. Neurocognitive impairment may impact self-care and other health behaviours increasing the risk of poor health outcomes in this patient population. Detection of neurocognitive impairment in low and middle-income settings is challenging; there is a lack of validated screening tools suitable for local use in primary care and outpatient settings and access to formal neuropsychological testing services is limited. The inability to easily identify people with type 2 diabetes with neurocognitive impairments is constraining the development of context appropriate interventions to improve the care and outcomes in this sub-group of patients. Aim: The aim of the current analysis is to explore associations between neurocognitive function and measures of diabetes control (HbA1c, disease duration, type of blood glucose lowering treatment) at baseline in a population of people with type 2 diabetes participating in a clinical trial of treatment adherence support using SMS-text messages. Materials and Methods: Sms text Adherence suppoRt for type 2 Diabetes (StAR2D) is a randomised clinical trial testing if a system of SMS-text messages to support treatment adherence is more effective than usual care for controlling blood sugar among people with type 2 diabetes in sub-Sahara Africa (ISRCTN70768808). We have embedded neurocognitive assessment sub-studies into the Cape Town trial site. At baseline participants in the StAR2D trial complete a novel mobile-device based cognitive assessment, NeuroScreen, assisted by a field research assistant. The assessment contains 9 variants of tests found in the gold-standard neuropsychological test battery that have been adapted and normed for use in South Africa. It is available in English or isiXhosa. The assessment takes between 20 to 40 minutes depending on participant error rate. This cross-sectional analysis of baseline data uses linear and logistic regression models to explore associations between neurocognitive function and measures of diabetes control. Results: Six hundred participants eligible for enrolment in the StAR2D trial were recruited from the Cape Town trial site; 499 participants completed the baseline neurocognitive screening assessment (20 to 40 minutes to complete); 101 participants did not complete the assessment (commonly due to eyesight, hearing or motor difficulties e.g. hemiplegia due to previous stroke or technical difficulties.) We found differences in the scores in some but not all the neuropsychological tests. Using cut points suggested by an earlier validation study of NeuroScreen tool more than half of study participants would be scored as having at least mild neurocognitive impairment. HbA1c, duration of disease, type of blood glucose lowering treatment were not significantly associated with individual or overall neuropsychological test scores or odds of neurocognitive impairment. Conclusions: The prevalence of neurocognitive impairment may be substantial in this patient population. A novel tablet based neurocognitive screening tool was broadly feasible and acceptable to lay researchers and trial participants. There was no evidence that HbA1c, duration of disease, or type of blood glucose lowering treatment (oral agents alone or insulin containing regimens) was significantly associated with individual or overall neuropsychological test scores or odds of neurocognitive impairment. Validating this tool for this patient population and optimising its role in routine clinical care need further study

Using the Medical Research Council framework for development and evaluation of complex interventions in a low resource setting to develop a theory-based treatment support intervention delivered via SMS text message to improve blood pressure control

Several frameworks now exist to guide intervention development but there remains only limited evidence of their application to health interventions based around use of mobile phones or devices, particularly in a low-resource setting. We aimed to describe our experience of using the Medical Research Council (MRC) Framework on complex interventions to develop and evaluate an adherence support intervention for high blood pressure delivered by SMS text message. We further aimed to describe the developed intervention in line with reporting guidelines for a structured and systematic description

The effectiveness of peer and community health worker-led self-management support programs for improving diabetes health-related outcomes in adults in low- and-middle-income countries: a systematic review

Objective Community-based peer and community health worker-led diabetes self-management programs (COMP-DSMP) can benefit diabetes care, but the supporting evidence has been inadequately assessed. This systematic review explores the nature of COMP-DSMP in low- and middle-income countries’ (LMIC) primary care settings and evaluates implementation strategies and diabetes-related health outcomes. Methods We searched the Cochrane Library, PubMed-MEDLINE, SCOPUS, CINAHL PsycINFO Database, International Clinical Trials Registry Platform, Clinicaltrials.gov, Pan African Clinical Trials Registry (PACTR), and HINARI (Health InterNetwork Access to Research Initiative) for studies that evaluated a COMP-DSMP in adults with either type 1 or type 2 diabetes in World Bank-defined LMIC from January 2000 to December 2019. Randomised and non-randomised controlled trials with at least 3 months follow-up and reporting on a behavioural, a primary psychological, and/or a clinical outcome were included. Implementation strategies were analysed using the standardised implementation framework by Proctor et al. Heterogeneity in study designs, outcomes, the scale of measurements, and measurement times precluded meta-analysis; thus, a narrative description of studies is provided. Results Of the 702 records identified, eleven studies with 6090 participants were included. COMP-DSMPs were inconsistently associated with improvements in clinical, behavioural, and psychological outcomes. Many of the included studies were evaluated as being of low quality, most had a substantial risk of bias, and there was a significant heterogeneity of the intervention characteristics (for example, peer definition, selection, recruitment, training and type, dose, and duration of delivered intervention), such that generalisation was not possible. Conclusions The level of evidence of this systematic review was considered low according to the GRADE criteria. The existing evidence however does show some improvements in outcomes. We recommend ongoing, but well-designed studies using a framework such as the MRC framework for the development and evaluation of complex interventions to inform the evidence base on the contribution of COMP-DSMP in LMIC

Mobile phone text-messaging interventions aimed to prevent cardiovascular diseases (Text2PreventCVD): systematic review and individual patient data meta-analysis

Background A variety of small mobile phone text messaging interventions have indicated improvement in risk factors for cardiovascular disease (CVD). Yet the extent of this improvement and whether it impacts multiple risk factors together is uncertain. We aimed to conduct a systematic review and individual patient data (IPD) meta-analysis to investigate the effects of text-messaging interventions for CVD prevention. Methods Electronic databases were searched to identify trials investigating a text-messaging intervention focusing on CVD prevention with the potential to modify at least two CVD risk factors in adults. The main outcome was blood pressure (BP). We conducted standard and IPD meta-analysis on pooled data. We accounted for clustering of patients within studies and the primary analysis used random-effects models. Sensitivity and subgroup analyses were performed. Results Nine trials were included in the systematic review involving 3779 participants and 5 (n=2612) contributed data to the IPD meta-analysis. Standard metaanalysis showed that the weighted mean differences are as follows: systolic blood pressure (SBP), −4.13 mm Hg (95% CI −11.07 to 2.81, p<0.0001); diastolic blood pressure (DBP), −1.11 mm Hg (−1.91 to −0.31, p=0.002); and body mass index (BMI), −0.32 (−0.49 to −0.16, p=0.000). In the IPD meta-analysis, the mean difference are as follows: SBP, −1.3 mm Hg (−5.4 to 2.7, p=0.5236); DBP, −0.8 mm Hg (−2.5 to 1.0, p=0.3912); and BMI, −0.2 (−0.8 to 0.4, p=0.5200) in the random-effects model. The impact on other risk factors is described, but there were insufficient data to conduct meta-analyses. Conclusion Mobile phone text-messaging interventions have modest impacts on BP and BMI. Simultaneous but small impacts on multiple risk factors are likely to be clinically relevant and improve outcome, but there are currently insufficient data in pooled analyses to examine the extent to which simultaneous reduction in multiple risk factors occurs

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport

Tiina Paunio on työryhmän UK10K jäsen.The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions.Peer reviewe

Whole-genome sequence-based analysis of thyroid function

Tiina Paunio on työryhmän UK10K Consortium jäsen.Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N = 2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF >= 1%) associated with TSH and FT4 (N = 16,335). For TSH, we identify a novel variant in SYN2 (MAF = 23.5%, P = 6.15 x 10(-9)) and a new independent variant in PDE8B (MAF = 10.4%, P = 5.94 x 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/ SLC25A52 (MAF = 3.2%, P = 1.27 x 10(-9)) tagging a rare TTR variant (MAF = 0.4%, P = 2.14 x 10(-11)). All common variants explain >= 20% of the variance in TSH and FT4. Analysis of rare variants (MAFPeer reviewe

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

The effects of childbearing on women's body mass index, and on the risk of diabetes mellitus, or ischaemic heart disease after the menopause

Background: Excess adiposity, diabetes mellitus, and ischaemic heart disease are common important causes of morbidity and premature mortality in postmenopausal women in the UK. A large amount of data exists on known risk factors for these conditions, and for risk factors men and women share there is little evidence to suggest sex-based differences. It has been suggested that factors unique to women (such as parity and breastfeeding) may also influence risk. The nature of the relationship between childbearing and these conditions remains to be clarified. In this thesis I explore the association between women’s childbearing histories and their adiposity, and risk of diabetes or ischaemic heart disease after the menopause, to provide evidence on the character, repeatability and public health relevance of the associations.Aim: To explore the hypothesis that childbearing (specifically parity and breastfeeding) is associated with women’s body weight and risk of excess adiposity, and also with women’s risk of diabetes mellitus, and ischaemic heart disease after the menopause.Methods: Data are analysed from a large population-based cohort of middle-aged UK women recruited in 1996 to 2001 (the Million Women Study) with complete childbearing information, and who had baseline anthropometry, and were followed for incident diabetes or ischaemic heart disease through repeat survey questionnaires, hospital admission records, and central registry databases.Results: In a large ethnically homogeneous population of postmenopausal UK women increasing parity was associated with an increase in BMI, however this increase was offset in women who breastfed. The associations between parity, breastfeeding and BMI were of a similar order of magnitude to established risk factors known to be associated with BMI, for example smoking, and physical activity. The associations between childbearing and women’s risk of diabetes mellitus after the menopause appear to be largely due to the effects of childbearing on maternal BMI. There is only limited evidence to suggest a direct effect of childbearing on women’s risk of diabetes after the menopause. There is statistically significant evidence of an association between childbearing and women’s risk of ischaemic heart disease after the menopause. Parity was associated with a modest increase in risk whereas breastfeeding was associated with a small decrease in risk, however the effects were small in comparison to known important risk factors.Conclusions In a large population of UK women childbearing was found to have a persistent influence on women’s mean BMI after the menopause, and through this postmenopausal risk of diabetes mellitus. Childbearing was also found to be mod-estly associated with women’s risk of ischaemic heart disease after the menopause.</p