Improving diagnosis of adult-onset diabetes using islet autoantibodies

The diagnosis of diabetes type in adulthood can be difficult due to overlapping phenotypes and lack of clear classification guidelines. Type 1 and type 2 diabetes have very different treatment and care requirements, and incorrect classification can lead to life-threatening consequences. Islet autoantibodies are biomarkers of the autoimmune pathology of type 1 diabetes and can be used in prediction of risk and classification of diabetes type, however current tests have imperfect specificity and sensitivity, and there are a number of remaining questions for optimal use. The overall aim of this thesis was to refine the use of islet autoantibody testing in the diagnosis of adult-onset diabetes by: 1. Exploring optimal test thresholds, and whether these are influenced by age. 2. Determining whether islet antibody level has potential utility in patients with clinically diagnosed type 1 diabetes. 3. Examining whether recently developed assays to specific GAD epitopes, isotype and affinity can improve test utility. In Chapter 1 we provide an introduction to diabetes and the different types, and present some of the difficulties surrounding diabetes classification. Next, we provide a detailed background into islet autoantibodies and review the current evidence for their use in clinical practice and challenges in interpreting their results. In Chapter 2, we looked at whether the use of age-related positivity thresholds are necessary to improve zinc transporter 8 autoantibody (ZnT8A) assay performance using the commercially available RSR ELISA assay. Our first key finding was that the prevalence of detectable ZnT8A differed between those tested under and over 30 years of age in the general population. ZnT8A age-related positivity thresholds improved the specificity of the assay whilst maintaining sensitivity, and that using one positivity threshold can result in misclassification of diabetes type. In Chapter 3, we looked at the utility of islet autoantibody level at diagnosis of type 1 diabetes. Our main finding was a bimodal distribution of levels of glutamate decarboxylase (GADA) and islet antigen-2 autoantibodies (IA-2A) at diagnosis of type 1 diabetes, but not for ZnT8A. Those with high level GADA were older at diagnosis, more likely to be female and to be diagnosed with another autoimmune disease. In contrast, those with high level IA-2A were more likely to be younger at diagnosis and have ZnT8A as additional islet autoimmunity. This was replicated in a second cohort using an alternative method of islet autoantibody assessment. These findings increased our understanding of how islet autoantibody levels at diagnosis are associated with differences in the underlying pathology between age groups at diabetes diagnosis. In Chapter 4 we looked at GADA epitope specificity, affinity and IgG subclass response in those positive for GADA, clinically diagnosed with type 2 diabetes in adult-hood. In full-length (f-)GADA positive adult-onset diabetes, our novel finding was that testing for truncated (t-)GAD(96-585) autoantibodies stratified risk of progression to early insulin therapy (within 5 years) and identified those with a more type 1 diabetes-like phenotype; lower C-peptide, higher type 1 diabetes genetic susceptibility and positivity for IA-2A. In contrast, testing for f-GADA affinity and IgG subclass response did not stratify risk of progression to early insulin requirement. These findings provide evidence to support the testing for t-GADA in adult-onset patients. In Chapter 5, we summarize the key findings, the limitations of this work and its implications. Then we present ideas for future research and how to take these findings further. In summary, here we have provided evidence for the improvement of islet autoantibody testing by taking three different approaches. Firstly, we have shown how using age-related cut-offs improves specificity of a commercially available assay and how these thresholds reduce the risk of misclassification. Secondly, that some differences between child- and adult-onset diabetes are associated with islet autoantibody level and thirdly, that testing for GADA epitope specificity in adult-onset diabetes, can help predict who will require early insulin therapy. Implementation of these findings in clinical testing will improve outcomes for individuals with diabetes.Novo Nordisk (UK Research Foundation)Research Englan

Cardiac Rehabilitation in India: Results from the International Council of Cardiovascular Prevention and Rehabilitation’s Global Audit of Cardiac Rehabilitation

Background: Cardiac rehabilitation (CR) is recommended in clinical practice guidelines for comprehensive secondary prevention. While India has a high burden of cardiovascular diseases (CVD), availability and nature of services delivered there is unknown. In this study, we undertook secondary analysis of the Indian data from the global CR audit and survey, conducted by the International Council of Cardiovascular Prevention and Rehabilitation (ICCPR). Methods: In this cross-sectional study, an online survey was administered to CR programs, identified in India by CR champions and through snowball sampling. CR density was computed using Global Burden of Disease study ischemic heart disease (IHD) incidence estimates. Results: Twenty-three centres were identified, of which 18 (78.3%) responded, from 3 southern states. There was only one spot for every 360 IHD patients/year, with 3,304,474 more CR spaces needed each year. Most programs accepted guideline-indicated patients, and most of these patients paid out-of-pocket for services. Programs were delivered by a multidisciplinary team, including physicians, physiotherapists, among others. Programs were very comprehensive. Apart from exercise training, which was offered across all centers, some centers also offered yoga therapy. Top barriers to delivery were lack of patient referral and financial resources. Conclusions: Of all countries in ICCPR’s global audit, the greatest need for CR exists in India, particularly in the North. Programs must be financially supported by government, and healthcare providers trained to deliver it to increase capacity. Where CR did exist, it was generally delivered in accordance with guideline recommendations. Tobacco cessation interventions should be universally offered

Utilization of Luminescent Carbon Nanodots from Soybean Husk Wastes for Fingerprint Identification using Tracker Software Spectrum Analysis

Visible fingerprints (FPs) play a crucial role in forensic identification, and luminescent carbon nanodots (C-Dots) have shown promise in enhancing their visibility. However, the optimal concentration of C-Dots for effective coating remains largely unexplored. This research aimed to determine the ideal C-Dots concentration for FPs identification. The fingerprint (FP) patterns of two subjects, L and P, were analyzed, revealing intensity peaks in 200 mm - 250 mm and 100 mm - 150 mm, respectively. The FP patterns were observed using a light microscope and Tracker software spectral analysis. The C-Dots samples were produced with variation in concentrations of (%W/V) 40%, 43.4%, and 47.6%. The spectrophotometer ultraviolet-visible (UV-Vis) test of the C-Dots showed absorption peaks at 270 nm and 330 nm wavelengths. The photoluminescence test indicated that the C-Dots have cyan luminescence. The X-ray diffraction (XRD) test showed that the C-Dots were amorphous. The spectrometer Fourier transform infrared (FTIR) test showed the presence of C = C functional groups. The scanning electron microscope (SEM) images with 5000x magnification showed the surface morphology of the C-Dots mimicking crumpled papers. Using Tracker software, FPs were successfully differentiated, with the clearest visual FPs observed when using a C-Dots concentration of 43.4%. Thus, the optimal concentration of C-Dots for FP identification was 43.4%.

Corrected score methods for estimating Bayesian networks with error-prone nodes

Motivated by inferring cellular signaling networks using noisy flow cytometry data, we develop procedures to draw inference for Bayesian networks based on error-prone data. Two methods for inferring causal relationships between nodes in a network are proposed based on penalized estimation methods that account for measurement error and encourage sparsity. We discuss consistency of the proposed network estimators and develop an approach for selecting the tuning parameter in the penalized estimation methods. Empirical studies are carried out to compare the proposed methods and a naive method that ignores measurement error with applications to synthetic data and to single cell flow cytometry data

Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis

<b>Background</b><p></p> It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use.<p></p> <b>Methods</b><p></p> Quantitative and systematic review of the literature on the consequences of chronic maternal opioid use during pregnancy on neurobehavioral function of children was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched Cinahl, EMBASE, PsychINFO and MEDLINE between the periods of January 1995 to January 2012.<p></p> <b>Results</b><p></p> There were only 5 studies out of the 200 identified that quantitatively reported on neurobehavioral function of children after maternal opioid use during pregnancy. All 5 were case control studies with the number of exposed subjects within the studies ranging from 33–143 and 45–85 for the controls. This meta-analysis showed no significant impairments, at a non-conservative significance level of p < 0.05, for cognitive, psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children. However, all domains suggested a trend to poor outcomes in infants/children of opioid using mothers. The magnitude of all possible effects was small according to Cohen’s benchmark criteria.<p></p> <b>Conclusions</b><p></p> Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers, although in all domains there was a trend to poorer outcomes. The findings of this review are limited by the small number of studies analysed, the heterogenous populations and small numbers within the individual studies. Longitudinal studies are needed to determine if any neuropsychological impairments appear after the age of 5 years and to help investigate further the role of environmental risk factors on the effect of ‘core’ phenotypes

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Experience and Challenges from Clinical Trials with Malaria Vaccines in Africa.

Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained

Global perspectives on heart disease rehabilitation and secondary prevention: a scientific statement from the Association of Cardiovascular Nursing and Allied Professions, European Association of Preventive Cardiology, and International Council of Cardiovascular Prevention and Rehabilitation

Cardiovascular disease is a leading cause of death, morbidity, disability, and reduced health-related quality of life, as well as economic burden worldwide, with some 80% of disease burden occurring in the low- and middle-income country (LMIC) settings. With increasing numbers of people living longer with symptomatic disease, the effectiveness and accessibility of secondary preventative and rehabilitative health services have never been more important. Whilst LMICs experience the highest prevalence and mortality rates, the global approach to secondary prevention and cardiac rehabilitation, which mitigates this burden, has traditionally been driven from clinical guidelines emanating from high-income settings. This state-of-the art review provides a contemporary global perspective on cardiac rehabilitation and secondary prevention, contrasting the challenges of and opportunities for high vs. lower income settings. Actionable solutions to overcome system, clinician, programme, and patient level barriers to cardiac rehabilitation access in LMICs are provided