Patient-level meta-analysis of the EDITION 1, 2 and 3 studies : glycaemic control and hypoglycaemia with new insulin glargine 300 U/ml versus glargine 100 U/ml in people with type 2 diabetes

AimsTo conduct a patient-level meta-analysis of the EDITION 1, 2 and 3 studies, which compared the efficacy and safety of new insulin glargine 300 U/ml (Gla-300) with insulin glargine 100 U/ml (Gla-100) in people with type 2 diabetes (T2DM) on basal and mealtime insulin, basal insulin and oral antihyperglycaemic drugs, or no prior insulin, respectively. MethodsThe EDITION studies were multicentre, randomized, open-label, parallel-group, phase IIIa studies, with similar designs and endpoints. A patient-level meta-analysis of the studies enabled these endpoints to be examined over 6 months in a large population with T2DM (Gla-300, n = 1247; Gla-100, n = 1249). ResultsNo significant study-by-treatment interactions across studies were found, enabling them to be pooled. The mean change in glycated haemoglobin was comparable for Gla-300 and Gla-100 [each -1.02 (standard error 0.03)%; least squares (LS) mean difference 0.00 (95% confidence interval (CI) -0.08 to 0.07)%]. Annualized rates of confirmed (3.9 mmol/l) or severe hypoglycaemia were lower with Gla-300 than with Gla-100 during the night (31% difference in rate ratio over 6 months) and at any time (24 h, 14% difference). Consistent reductions were observed in percentage of participants with 1 hypoglycaemic event. Severe hypoglycaemia at any time (24 h) was rare (Gla-300: 2.3%; Gla-100: 2.6%). Weight gain was low ( ConclusionGla-300 provides comparable glycaemic control to Gla-100 in a large population with a broad clinical spectrum of T2DM, with consistently less hypoglycaemia at any time of day and less nocturnal hypoglycaemia.Peer reviewe

Livestock Selective Behaviour in Natural Grasslands Challenges the Concept of Plant Preference in the Elaboration of a Successful Diet

Conciliating livestock production and conservation of grassland biodiversity is now an imperative. We propose that a way to reach that goal is to take advantage of the natural tendency of herbivores to exploit environmental heterogeneity. However, it would go against the well-rooted concept that mammalian herbivores have invariable preference for some plants. Preference was defined as being “what the animal selects when given the minimum of physical constraints” (Parsons et al. 1994). But after decades of studies, the concept of preference remains particularly inefficient in predicting observed patterns of selection by herbivores (e.g. Newman et al. 1992; Parsons et al. 1994; Provenza 2006). We performed detailed descriptions of cattle diet composition and foraging strategy in highly diversified natural pasture of South Brazil. We present here preliminary results that seriously question the concept of plant preference

Similar glycaemic control and less hypoglycaemia during active titration after insulin initiation with glargine 300 units/mL and degludec 100 units/mL: A subanalysis of the BRIGHT study

Aim: To further investigate glycaemic control and hypoglycaemia in BRIGHT, focusing on the titration period. Materials and Methods: BRIGHT was a multicentre, open-label, randomized, active-controlled, two-arm, parallel-group, 24-week study in insulin-naïve patients with uncontrolled type 2 diabetes initiated on glargine 300 U/mL (Gla-300) (N = 466) or degludec (IDeg-100) (N = 463). Predefined efficacy and safety outcomes were investigated during the initial 12-week titration period. In addition, patients’ characteristics and clinical outcomes were assessed descriptively, stratified by confirmed (≤3.9 mmol/L) hypoglycaemia incidence during the initial titration period. Results: At week 12, HbA1c was comparable between Gla-300 (7.32%) and IDeg-100 (7.23%), with similar least squares (LS) mean reductions from baseline (−1.37% and − 1.39%, respectively; LS mean difference of 0.02; 95% confidence interval: −0.08 to 0.12). Patients who experienced hypoglycaemia during the initial titration period had numerically greater HbA1c reductions by week 12 than patients who did not (−1.46% vs. −1.28%), and higher incidence of anytime (24 hours; 73.3% vs. 35.7%) and nocturnal (00:00–06:00 hours; 30.0% vs. 11.9%) hypoglycaemia between weeks 13–24. Conclusions: The use of Gla-300 resulted in similar glycaemic control as IDeg-100 during the initial 12-week titration period of the BRIGHT study, when less anytime (24 hours) hypoglycaemia with Gla-300 versus IDeg-100 has been reported. Experiencing hypoglycaemia shortly after initiating Gla-300 or IDeg-100 may be associated with hypoglycaemia incidence in the longer term, potentially impacting glycaemic management

Em busca de uma proposta metodológica para o desenvolvimento de software educativo colaborativo

Apesar da existência de metodologias para especificação de sistemas computacionaisconsolidadas na área de Computação e Informática, o caráter diferenciado do softwareeducativo vem impulsionado a investigação nesta área, em busca de uma proposta quecontemple, além dos aspectos computacionais, também os aspectos educacionais, deinterface e colaboração. O presente artigo apresenta uma proposta metodológica para odesenvolvimento de software educativo colaborativo. Este estudo considera a análisedas especificidades dos softwares educativos em relação aos de aplicação comercial eindustrial, bem como as diferentes metodologias de desenvolvimento propostas pelaárea de engenharia de software. Esta metodologia está sendo validada na construção doambiente PALCO (Portal Acessível para Linguagem Colaborativa), atualmente emdesenvolvimento pelo Grupo de Pesquisa de Tecnologias de Informação do CentroUniversitário Feevale

Glycaemic control and hypoglycaemia risk with insulin glargine 300 U/mL versus glargine 100 U/mL: A patient-level meta-analysis examining older and younger adults with type 2 diabetes

Abstract Aim Older people with type 2 diabetes (T2DM) are at an increased risk of hypoglycaemia and its consequences. However, efficacy and safety data for basal insulin therapy are limited in these individuals. This patient-level meta-analysis assessed the treatment effects of insulin glargine 300 U/mL (Gla-300) versus glargine 100 U/mL (Gla-100) in people with T2DM ≥ 65 years old. Methods Data were pooled for patients randomised to receive Gla-300 or Gla-100 in the Phase 3a, treat-to-target EDITION 1, 2 and 3 trials. Glycaemic efficacy, hypoglycaemia, changes in body weight and insulin dosage and adverse events were examined over 6 months' treatment with Gla-300 versus Gla-100 for participants aged ≥ 65 and  Results Of 2496 participants randomised, 662 were ≥ 65 years (Gla-300, n = 329; Gla-100, n = 333). Glycaemic control was comparable for Gla-300 and Gla-100 in participants ≥ 65 years (LS mean [95% CI] difference in HbA1c change from baseline to month 6: 0.00 [−0.14 to 0.15] %; 0.00 [−1.53 to 1.64] mmol/mol) and  Conclusion Gla-300 was associated with a reduced risk of nocturnal hypoglycaemia versus Gla-100, accompanied by comparable glycaemic improvement, for people aged ≥ 65 an

CD200-CD200R1 inhibitory signaling prevents spontaneous bacterial infection and promotes resolution of neuroinflammation and recovery after stroke

Abstract Background Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppression after stroke. Methods In this study, we investigated the role of CD200R1-mediated signaling in stroke using CD200 receptor 1-deficient mice. Mice were subjected to a 60-min middle cerebral artery occlusion and evaluated at days 3 and 7, representing the respective peak and early resolution stages of neuroinflammation in this model of ischemic stroke. Infarct size and behavioral deficits were assessed at both time points. Central and peripheral cellular immune responses were measured using flow cytometry. Bacterial colonization was determined in lung tissue homogenates both after acute stroke and in an LPS model of systemic inflammation. Results In wild-type (WT) animals, CD200R1 was expressed on infiltrating monocytes and lymphocytes after stroke but was absent on microglia. Early after ischemia (72 h), CD200R1-knockout (KO) mice had significantly poorer survival rates and an enhanced susceptibility to spontaneous bacterial colonization of the respiratory tract compared to wild-type (WT) controls, despite no difference in infarct or neurological deficits. While the CNS inflammation was resolved by day 7 post-stroke in WT mice, brain-resident microglia and monocyte activation persisted in CD200R1-KO mice, accompanied by a delayed, augmented lymphocyte response. At this time point, CD200R1-KO mice displayed greater weight loss, more severe neurological deficits, and impaired motor function compared to WT. Systemically, CD200R1-KO mice exhibited signs of persistent infection including lymphopenia, T cell activation and memory conversion, and narrowing of the TCR repertoire. These findings were confirmed in a second model of acute neuroinflammation induced by systemic endotoxin challenge. Conclusion This study defines an essential role of CD200-CD200R1 signaling in stroke. Loss of CD200R1 led to high mortality, increased rates of post-stroke infection, and enhanced entry of peripheral leukocytes into the brain after ischemia, with no increase in infarct size. This suggests that the loss of CD200 receptor leads to enhanced peripheral inflammation that is triggered by brain injury.https://deepblue.lib.umich.edu/bitstream/2027.42/148133/1/12974_2019_Article_1426.pd

Δ40 Isoform of p53 Controls β-Cell Proliferation and Glucose Homeostasis in Mice

Objective: Investigating the dynamics of pancreatic $\beta$-cell mass is critical for developing strategies to treat both type 1 and type 2 diabetes. p53, a key regulator of the cell cycle and apoptosis, has mostly been a focus of investigation as a tumor suppressor. Although p53 alternative transcripts can modulate p53 activity, their functions are not fully understood. We hypothesized that $\beta$-cell proliferation and glucose homeostasis were controlled by $\Delta$40p53, a p53 isoform lacking the transactivation domain of the full-length protein that modulates total p53 activity and regulates organ size and life span in mice. Research Design and Methods: We phenotyped metabolic parameters in $\Delta$40p53 transgenic (p44tg) mice and used quantitative RT-PCR, Western blotting, and immunohistochemistry to examine $\beta$-cell proliferation. Results: Transgenic mice with an ectopic p53 gene encoding $\Delta$40p53 developed hypoinsulinemia and glucose intolerance by 3 months of age, which worsened in older mice and led to overt diabetes and premature death from $\sim$14 months of age. Consistent with a dramatic decrease in $\beta$-cell mass and reduced $\beta$-cell proliferation, lower expression of cyclin D2 and pancreatic duodenal homeobox-1, two key regulators of proliferation, was observed, whereas expression of the cell cycle inhibitor p21, a p53 target gene, was increased. Conclusions: These data indicate a significant and novel role for $\Delta$40p53 in $\beta$-cell proliferation with implications for the development of age-dependent diabetes

An Analysis by Synthesis Approach for Automatic Vertebral Shape Identification in Clinical QCT

Quantitative computed tomography (QCT) is a widely used tool for osteoporosis diagnosis and monitoring. The assessment of cortical markers like cortical bone mineral density (BMD) and thickness is a demanding task, mainly because of the limited spatial resolution of QCT. We propose a direct model based method to automatically identify the surface through the center of the cortex of human vertebra. We develop a statistical bone model and analyze its probability distribution after the imaging process. Using an as-rigid-as-possible deformation we find the cortical surface that maximizes the likelihood of our model given the input volume. Using the European Spine Phantom (ESP) and a high resolution \mu CT scan of a cadaveric vertebra, we show that the proposed method is able to accurately identify the real center of cortex ex-vivo. To demonstrate the in-vivo applicability of our method we use manually obtained surfaces for comparison.Comment: Presented on German Conference on Pattern Recognition (GCPR) 2018 in Stuttgar