GAD65Abs Are Not Associated With Beta-Cell Dysfunction in Patients With T2D in the GRADE Study.

Context: Autoantibodies directed against the 65-kilodalton isoform of glutamic acid decarboxylase (GAD65Abs) are markers of autoimmune type 1 diabetes (T1D) but are also present in patients with Latent Autoimmune Diabetes of Adults and autoimmune neuromuscular diseases, and also in healthy individuals. Phenotypic differences between these conditions are reflected in epitope-specific GAD65Abs and anti-idiotypic antibodies (anti-Id) against GAD65Abs. We previously reported that 7.8% of T2D patients in the GRADE study have GAD65Abs but found that GAD65Ab positivity was not correlated with beta-cell function, glycated hemoglobin (HbA1c), or fasting glucose levels. Context: In this study, we aimed to better characterize islet autoantibodies in this T2D cohort. This is an ancillary study to NCT01794143. Methods: We stringently defined GAD65Ab positivity with a competition assay, analyzed GAD65Ab-specific epitopes, and measured GAD65Ab-specific anti-Id in serum. Results: Competition assays confirmed that 5.9% of the patients were GAD65Ab positive, but beta-cell function was not associated with GAD65Ab positivity, GAD65Ab epitope specificity or GAD65Ab-specific anti-Id. GAD65-related autoantibody responses in GRADE T2D patients resemble profiles in healthy individuals (low GAD65Ab titers, presence of a single autoantibody, lack of a distinct epitope pattern, and presence of anti-Id to diabetes-associated GAD65Ab). In this T2D cohort, GAD65Ab positivity is likely unrelated to the pathogenesis of beta-cell dysfunction. Conclusion: Evidence for islet autoimmunity in the pathophysiology of T2D beta-cell dysfunction is growing, but T1D-associated autoantibodies may not accurately reflect the nature of their autoimmune process.

Impact of Glucose-Lowering Medications on Health-Related Quality of Life in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: Diabetes is associated with reduced health-related quality of life (HRQoL). Information on the relationship between HRQoL and glucose-lowering medications in recently diagnosed type 2 diabetes (T2D) is limited. We assessed changes in HRQoL in participants with T2D receiving metformin plus one of four glucose-lowering medications in Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE). RESEARCH DESIGN AND METHODS: A total of 5,047 participants, baseline mean age 57 years, with <10 years T2D duration and glycated hemoglobin level 6.8-8.5% and taking metformin monotherapy, were randomly assigned to glargine, glimepiride, liraglutide, or sitagliptin. HRQoL was evaluated at baseline for 4,885 participants, and at years 1, 2, and 3, with use of the self-administered version of the Quality of Well-being Scale (QWB-SA) and SF-36 physical (PCS) and mental (MCS) component summary scales. Linear models were used to analyze changes in HRQoL over time in intention-to-treat analyses. RESULTS: None of the medications worsened HRQoL. There were no differences in QWB-SA or MCS by treatment group at any time point. PCS scores improved with liraglutide versus other groups at year 1 only. Greater weight loss during year 1 explained half the improvement in PCS scores with liraglutide versus glargine and glimepiride. Liraglutide participants in the upper tertile of baseline BMI showed the greatest improvement in PCS scores at year 1. CONCLUSIONS: Adding liraglutide to metformin in participants within 10 years of T2D diagnosis showed improvement in the SF-36 PCS in comparisons with the other medications at 1 year, which was no longer significant at years 2 and 3. Improvement was related to weight loss and baseline BMI.

A rotating white dwarf shows different compositions on its opposite faces.

White dwarfs, the extremely dense remnants left behind by most stars after their death, are characterized by a mass comparable to that of the Sun compressed into the size of an Earth-like planet. In the resulting strong gravity, heavy elements sink towards the centre and the upper layer of the atmosphere contains only the lightest element present, usually hydrogen or helium1,2. Several mechanisms compete with gravitational settling to change a white dwarf's surface composition as it cools3, and the fraction of white dwarfs with helium atmospheres is known to increase by a factor of about 2.5 below a temperature of about 30,000 kelvin4-8; therefore, some white dwarfs that appear to have hydrogen-dominated atmospheres above 30,000 kelvin are bound to transition to be helium-dominated as they cool below it. Here we report observations of ZTF J203349.8+322901.1, a transitioning white dwarf with two faces: one side of its atmosphere is dominated by hydrogen and the other one by helium. This peculiar nature is probably caused by the presence of a small magnetic field, which creates an inhomogeneity in temperature, pressure or mixing strength over the surface9-11. ZTF J203349.8+322901.1 might be the most extreme member of a class of magnetic, transitioning white dwarfs-together with GD 323 (ref. 12), a white dwarf that shows similar but much more subtle variations. This class of white dwarfs could help shed light on the physical mechanisms behind the spectral evolution of white dwarfs.

BMI, insulin sensitivity, and cognition in early type 2 diabetes: The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study.

OBJECTIVE: This study explored the association of BMI and insulin sensitivity with cognitive performance in type 2 diabetes. METHODS: A cross-sectional analysis of data from the baseline assessment of the Glycemia Reduction Approaches in Diabetes: a Comparative Effectiveness Study (GRADE) was conducted. BMI was used as a surrogate of adiposity and the Matsuda index as the measure of insulin sensitivity. Cognitive tests included the Spanish English Verbal Learning Test, the Digit Symbol Substitution Test, and the letter and animal fluency tests. RESULTS: Cognitive assessments were completed by 5018 (99.4%) of 5047 participants aged 56.7 ± 10.0 years, of whom 36.4% were female. Higher BMI and lower insulin sensitivity were related to better performance on memory and verbal fluency tests. In models including BMI and insulin sensitivity simultaneously, only higher BMI was related to better cognitive performance. CONCLUSIONS: In this study, higher BMI and lower insulin sensitivity in type 2 diabetes were cross-sectionally associated with better cognitive performance. However, only higher BMI was related to cognitive performance when both BMI and insulin sensitivity were considered simultaneously. The causality and mechanisms for this association need to be determined in future studies.

Defining Minimum Necessary Communication During Care Transitions for Patients on Antihyperglycemic Medication: Consensus of the Care Transitions Task Force of the IPRO Hypoglycemia Coalition.

INTRODUCTION: Antihyperglycemic agents are significant contributors to adverse drug events, responsible for emergency department visits, hospitalizations, and death. Nationally, the rate of serious hypoglycemic events associated with these agents remains high despite widespread efforts to improve drug safety. Transitions of care between healthcare settings can lead to communication challenges between care professionals and increase the risk of adverse drug events. System-based improvements are needed to assure the safe transitions for patients with diabetes who are on antihyperglycemic agents. The objective of this study was to develop a consensus list of requisite elements that should be communicated between care settings during transitions of patients who are prescribed antihyperglycemic agents. METHODS: The Island Peer Review Organization (IPRO) Hypoglycemia Coalition identified suboptimal transitions of care as a barrier to improving patient safety and quality of diabetes care. The Coalition formed a multidisciplinary Task Force with experts in the field of diabetes care. The Task Force created a draft list of requisite communication elements through literature review and deliberation on monthly conference calls. A blinded iterative Delphi process was subsequently performed to generate a consensus list of requisite communication elements that participating experts agreed were necessary to safely and effectively assume the management of patients with diabetes upon care transitions. RESULTS: The Task Force completed a series of four iterative polls from September 2015 to August 2016, resulting in a final list of 22 requisite communication elements (the Diabetes Management Discharge Communication List), with the elements conceptually categorized into three domains: diagnosis and treatment, factors affecting glycemic control or patient risk, and patient self-management. CONCLUSIONS: The Diabetes Management Discharge Communication List provides an initial framework for the development of diabetes-specific resources to improve clinical communication between care settings.

Islet Autoimmunity is Highly Prevalent and Associated With Diminished ß-Cell Function in Patients With Type 2 Diabetes in the Grade Study.

Islet autoimmunity may contribute to ß-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and ß-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. ß-cell function calculated as iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ΔC-peptide(0-30)/Δglucose(0-30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T+ patients had 17% higher HbA1c (95% CI 0·07, 0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T- patients. We conclude that islet autoimmunity is much more prevalent in T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished ß-cell function and worse glycemic control.

Differences in complications, cardiovascular risk factor, and diabetes management among participants enrolled at veterans affairs (VA) and non-VA medical centers in the glycemia reduction approaches in diabetes: A comparative effectiveness study (GRADE).

AIMS: We evaluated differences in participants with type 2 diabetes (T2DM) enrolled in the GRADE study at VA vs non-VA sites, focusing on cardiovascular risk factors and rates of diabetes care target achievements. METHODS: We compared baseline characteristics between participants at VA (n = 1216) and non-VA (n = 3831) sites, stratifying analyses by cardiovascular disease (CVD) history. RESULTS: VA and non-VA participants had similar diabetes duration (4.0 years), HbA1c (7.5%), and BMI (34 kg/m2); however, VA participants had more individuals ≥ 65 years (37.3% vs 19.8%, p < 0.001), men (90.0% vs 55.2%, p < 0.001), hypertension (75.8% vs 63.6%, p < 0.001), hyperlipidemia (76.6% vs 64.6%, p < 0.001), current smokers (19.0% vs 12.1%, p < 0.001), nephropathy (20.4% vs 17.0%, p < 0.05), albuminuria (18.4% vs 15.1%, p < 0.05), and CVD (10.4% vs 5.2%, p < 0.001). In those without CVD, more VA participants were treated with lipid (70.8% vs 59.5%, p < 0.001) and blood pressure (74.9% vs 65.4%, p < 0.001) lowering medications, and had LDL-C < 70 mg/dl (32.9% vs 24.2%, p < 0.05). Among those with CVD, more VA participants had BP < 140/90 (80.2% vs 70.1%, p < 0.05) after adjusting for demographics. CONCLUSION: GRADE participants at VA sites had more T2DM complications, greater CVD risk and were more likely to be treated with medications to reduce it, leading to more LDL-C at goal than non-VA participants, highlighting differences in diabetes populations and care.

Collisions in a gas-rich white dwarf planetary debris disc.

WD 0145+234 is a white dwarf that is accreting metals from a circumstellar disc of planetary material. It has exhibited a substantial and sustained increase in 3-5 [Formula: see text]m flux since 2018. Follow-up Spitzer photometry reveals that emission from the disc had begun to decrease by late 2019. Stochastic brightening events superimposed on the decline in brightness suggest the liberation of dust during collisional evolution of the circumstellar solids. A simple model is used to show that the observations are indeed consistent with ongoing collisions. Rare emission lines from circumstellar gas have been detected at this system, supporting the emerging picture of white dwarf debris discs as sites of collisional gas and dust production.

Correction to: Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus.

The article Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus, written by Willy M. Valencia, Hermes J. Florez and Ana M. Palacio was originally published Online First without open access.

Very regular high-frequency pulsation modes in young intermediate-mass stars.

Asteroseismology probes the internal structures of stars by using their natural pulsation frequencies1. It relies on identifying sequences of pulsation modes that can be compared with theoretical models, which has been done successfully for many classes of pulsators, including low-mass solar-type stars2, red giants3, high-mass stars4 and white dwarfs5. However, a large group of pulsating stars of intermediate mass-the so-called δ Scuti stars-have rich pulsation spectra for which systematic mode identification has not hitherto been possible6,7. This arises because only a seemingly random subset of possible modes are excited and because rapid rotation tends to spoil regular patterns8-10. Here we report the detection of remarkably regular sequences of high-frequency pulsation modes in 60 intermediate-mass main-sequence stars, which enables definitive mode identification. The space motions of some of these stars indicate that they are members of known associations of young stars, as confirmed by modelling of their pulsation spectra.

Computer-aided Diagnosis of Skin Cancer: A Review.

Cancer is currently one of the main health issues in the world. Among different varieties of cancers, skin cancer is the most common cancer in the world and accounts for 75% of the world's cancer. Indeed, skin cancer involves abnormal changes in the outer layer of the skin. Although most people with skin cancer recover, it is one of the major concerns of people due to its high prevalence. Most types of skin cancers grow only locally and invade adjacent tissues, but some of them, especially melanoma (cancer of the pigment cells), which is the rarest type of skin cancer, may spread through the circulatory system or lymphatic system and reach the farthest points of the body. Many papers have been reviewed about the application of image processing in cancer detection. In this paper, the automatic skin cancer detection and also different steps of such a process have been discussed based on the implantation capabilities.

Suitable Use of Injectable Agents to Overcome Hypoglycemia Risk, Barriers, and Clinical Inertia in Community-Dwelling Older Adults with Type 2 Diabetes Mellitus.

The management of type 2 diabetes mellitus in older adults requires a comprehensive understanding of the relationship between the disease (medical) and the functional, psychological/cognitive, and social geriatric domains, to individualize both glycemic targets and therapeutic approaches. Prevention of hypoglycemia is a major priority that should be addressed as soon as its presence or risk is detected, adjusting the target and therapeutics accordingly. Nonetheless, treatment intensification should not be neglected when applicable, consistent with recommendations from organizations such as the American Geriatrics Society and the American Diabetes Association, to reduce not only long-term macrovascular and microvascular complications (individualization), but also short-term complications from hyperglycemia (polyuria, volume depletion, urinary incontinence). Such complications can negatively impact the physical and cognitive function of older adults, worsen their quality of life, and additionally affect their families and society. We emphasize individualization, utilizing the multiple classes of antihyperglycemic agents available. Metformin remains as first-line therapy, and additional agents offer advantages and disadvantages that ought to be considered when developing a patient-centric plan of care. For selected cases, injectable therapies such as long-acting basal insulin analogs and glucagon-like peptide-1 receptor agonists can offer advantages to counter hypoglycemia risk, patient-related barriers, and clinical inertia. Furthermore, some injectable agents could potentially simplify regimens while providing safe and effective glycemic control. In this review, we discuss the use of injectable therapies for selected community-dwelling older adults, barriers to transition to injectable therapy, and measures aimed at removing these barriers and assisting physicians and their teams to transition older patients to injectable therapies when appropriate.

Baseline Characteristics of Randomized Participants in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).

OBJECTIVE: GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) is a 36-center unmasked, parallel treatment group, randomized controlled trial evaluating four diabetes medications added to metformin in people with type 2 diabetes (T2DM). We report baseline characteristics and compare GRADE participants to a National Health and Nutrition Examination Survey (NHANES) cohort. RESEARCH DESIGN AND METHODS: Participants were age ≥30 years at the time of diagnosis, with duration of T2DM <10 years, HbA1c 6.8-8.5% (51-69 mmol/mol), prescribed metformin monotherapy, and randomized to glimepiride, sitagliptin, liraglutide, or insulin glargine. RESULTS: At baseline, GRADE's 5,047 randomized participants were 57.2 ± 10.0 years of age, 63.6% male, with racial/ethnic breakdown of 65.7% white, 19.8% African American, 3.6% Asian, 2.7% Native American, 7.6% other or unknown, and 18.4% Hispanic/Latino. Duration of diabetes was 4.2 ± 2.8 years, with mean HbA1c of 7.5 ± 0.5% (58 ± 5.3 mmol/mol), BMI of 34.3 ± 6.8 kg/m2, and metformin dose of 1,944 ± 204 mg/day. Among the cohort, 67% reported a history of hypertension, 72% a history of hyperlipidemia, and 6.5% a history of heart attack or stroke. Applying GRADE inclusion criteria to NHANES indicates enrollment of a representative cohort with T2DM on metformin monotherapy (NHANES cohort average age, 57.9 years; mean HbA1c, 7.4% [57 mmol/mol]; BMI, 33.2 kg/m2; duration, 4.2 ± 2.5 years; and 7.2% with a history of cardiovascular disease). CONCLUSIONS: The GRADE cohort represents patients with T2DM treated with metformin requiring a second diabetes medication. GRADE will inform decisions about the clinical effectiveness of the addition of four classes of diabetes medications to metformin.

Modelling the accumulation and transport of floating marine micro-plastics around South Africa.

Plastic pollution of South Africa's marine environment is widespread, yet limited research exists on the distribution, accumulation and transport of plastic debris around South Africa. In this paper, numerical modelling is used to provide a first approximation of the pathways and accumulation of marine micro-plastics around South Africa. To account for a range of plastic classes, particles with two different densities are considered. Low-density (LD) particles represent low- and high-density polyethylene while high-density (HD) particles are representative of Polyethylene terephthalate and Polyvinyl chloride. While the majority of micro-plastic particles that enter the ocean from the five major coastal urban-industrialised centers beach along the coastline of South Africa, a third is exported to the open ocean. LD and HD particles are primarily exported to the South Atlantic and South Indian Ocean, respectively. Particles that beach along South Africa's coastline tend to accumulate in close proximity to the coastal urban-industrialised centers.

Core crystallization and pile-up in the cooling sequence of evolving white dwarfs.

White dwarfs are stellar embers depleted of nuclear energy sources that cool over billions of years1. These stars, which are supported by electron degeneracy pressure, reach densities of 107 grams per cubic centimetre in their cores2. It has been predicted that a first-order phase transition occurs during white-dwarf cooling, leading to the crystallization of the non-degenerate carbon and oxygen ions in the core, which releases a considerable amount of latent heat and delays the cooling process by about one billion years3. However, no direct observational evidence of this effect has been reported so far. Here we report the presence of a pile-up in the cooling sequence of evolving white dwarfs within 100 parsecs of the Sun, determined using photometry and parallax data from the Gaia satellite4. Using modelling, we infer that this pile-up arises from the release of latent heat as the cores of the white dwarfs crystallize. In addition to the release of latent heat, we find strong evidence that cooling is further slowed by the liberation of gravitational energy from element sedimentation in the crystallizing cores5-7. Our results describe the energy released by crystallization in strongly coupled Coulomb plasmas8,9, and the measured cooling delays could help to improve the accuracy of methods used to determine the age of stellar populations from white dwarfs10.

Relation of Diabetes to Cognitive Function in Hispanics/Latinos of Diverse Backgrounds in the United States.

Objectives:To examine the association between diabetes and cognitive function within U.S. Hispanics/Latinos of Central American, Cuban, Dominican, Mexican, Puerto Rican, and South American background. Method: This cross-sectional study included 9,609 men and women (mean age = 56.5 years), who are members of the Hispanic Community Health Study/Study of Latinos. We classified participants as having diabetes, prediabetes, or normal glucose regulation. Participants underwent a neurocognitive battery consisting of tests of verbal fluency, delayed recall, and processing speed. Analyses were stratified by Hispanic/Latino subgroup. Results: From fully adjusted linear regression models, compared with having normal glucose regulation, having diabetes was associated with worse processing speed among Cubans (ß = -1.99; 95% CI [confidence interval] = [-3.80, -0.19]) and Mexicans (ß = -2.26; 95% CI = [-4.02, -0.51]). Compared with having normal glucose regulation, having prediabetes or diabetes was associated with worse delayed recall only among Mexicans (prediabetes: ß = -0.34; 95% CI = [-0.63, -0.05] and diabetes: ß = -0.41; 95% CI = [-0.79, -0.04]). No associations with verbal fluency. Discussion: The relationship between diabetes and cognitive function varied across Hispanic/Latino subgroup.

G2A Attenuates Propionibacterium acnes Induction of Inflammatory Cytokines in Human Monocytes.

BACKGROUND: Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to Propionibacterium acnes (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium. OBJECTIVE: To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation. Furthermore, our study sought to investigate pathways by which lipids modulate immune responses in response to PA. METHODS: Our studies focused on monocytes collected from human peripheral blood mononuclear cells, the monocytic cell line THP-1, and a lab strain of PA. Our studies involved the use of enzyme-linked immunosorbent, Western blot, reverse transcription polymerase chain reaction, small interfering RNA (siRNA), and microarray analysis of human acne lesions in the measurements of inflammatory markers. RESULTS: G2A gene expression is higher in acne lesions compared to normal skin and is inducible by the acne therapeutic, 13-cis-retinoic acid. In vitro, PA induces both the Toll-like receptor 2-dependent expression of G2A as well as the production of the G2A ligand, 9-hydroxyoctadecadienoic acid, from human monocytes. G2A gene knockdown through siRNA enhances PA stimulation of interleukin (IL)-6, IL-8, and IL-1ß possibly through increased activation of the ERK1/2 MAP kinase and nuclear factor kappa B p65 pathways. CONCLUSION: G2A may play a role in quelling inflammatory cytokine response to PA, revealing G2A as a potential attenuator of inflammatory response in a disease associated with a commensal bacterium.

G2A Attenuates Propionibacterium acnes Induction of Inflammatory Cytokines in Human Monocytes

BACKGROUND: Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to Propionibacterium acnes (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium. OBJECTIVE: To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation. Furthermore, our study sought to investigate pathways by which lipids modulate immune responses in response to PA. METHODS: Our studies focused on monocytes collected from human peripheral blood mononuclear cells, the monocytic cell line THP-1, and a lab strain of PA. Our studies involved the use of enzyme-linked immunosorbent, Western blot, reverse transcription polymerase chain reaction, small interfering RNA (siRNA), and microarray analysis of human acne lesions in the measurements of inflammatory markers. RESULTS: G2A gene expression is higher in acne lesions compared to normal skin and is inducible by the acne therapeutic, 13-cis-retinoic acid. In vitro, PA induces both the Toll-like receptor 2-dependent expression of G2A as well as the production of the G2A ligand, 9-hydroxyoctadecadienoic acid, from human monocytes. G2A gene knockdown through siRNA enhances PA stimulation of interleukin (IL)-6, IL-8, and IL-1β possibly through increased activation of the ERK1/2 MAP kinase and nuclear factor kappa B p65 pathways. CONCLUSION: G2A may play a role in quelling inflammatory cytokine response to PA, revealing G2A as a potential attenuator of inflammatory response in a disease associated with a commensal bacterium.