Linking metabolic dysfunction with cardiovascular diseases: Brn-3b/POU4F2 transcription factor in cardiometabolic tissues in health and disease.

Metabolic and cardiovascular diseases are highly prevalent and chronic conditions that are closely linked by complex molecular and pathological changes. Such adverse effects often arise from changes in the expression of genes that control essential cellular functions, but the factors that drive such effects are not fully understood. Since tissue-specific transcription factors control the expression of multiple genes, which affect cell fate under different conditions, then identifying such regulators can provide valuable insight into the molecular basis of such diseases. This review explores emerging evidence that supports novel and important roles for the POU4F2/Brn-3b transcription factor (TF) in controlling cellular genes that regulate cardiometabolic function. Brn-3b is expressed in insulin-responsive metabolic tissues (e.g. skeletal muscle and adipose tissue) and is important for normal function because constitutive Brn-3b-knockout (KO) mice develop profound metabolic dysfunction (hyperglycaemia; insulin resistance). Brn-3b is highly expressed in the developing hearts, with lower levels in adult hearts. However, Brn-3b is re-expressed in adult cardiomyocytes following haemodynamic stress or injury and is necessary for adaptive cardiac responses, particularly in male hearts, because male Brn-3b KO mice develop adverse remodelling and reduced cardiac function. As a TF, Brn-3b regulates the expression of multiple target genes, including GLUT4, GSK3β, sonic hedgehog (SHH), cyclin D1 and CDK4, which have known functions in controlling metabolic processes but also participate in cardiac responses to stress or injury. Therefore, loss of Brn-3b and the resultant alterations in the expression of such genes could potentially provide the link between metabolic dysfunctions with adverse cardiovascular responses, which is seen in Brn-3b KO mutants. Since the loss of Brn-3b is associated with obesity, type II diabetes (T2DM) and altered cardiac responses to stress, this regulator may provide a new and important link for understanding how pathological changes arise in such endemic diseases

Supervision, scheduling, satisfaction and shared working: how experiences of junior doctors relate to excess mortality within the NHS.

BACKGROUND: We sought to explore associations between trainee doctor perception and excess patient mortality. METHODS: Data from two publicly available databases reflecting mortality and components of trainee satisfaction within 81 NHS healthcare institutions between the years 2012 and 2019 were analysed. Pearson's correlation coefficients were calculated. RESULTS: All domains of trainee perception were correlated with excess mortality. Clinical supervision out of hours (R=-0.44; p<0.0001), teamwork (R=-0.36; p<0.0001) and clinical supervision at any time (R=-0.35; p<0.0001) were most strongly correlated. Most associations remained consistent year on year. CONCLUSION: Trainee doctor perceptions of clinical supervision, rota design and teamwork within the NHS are consistently correlated with excess patient mortality. Further exploration of these associations could identify opportunities for interventions to reduce excess patient mortality. Given the clinical significance of our findings, organisations should consider rapid implementation of evidence-based interventions where they exist

Establishing surrogate kidney endpoints for lupus nephritis clinical trials: development and validation of a novel approach to predict future kidney outcomes

Objective: Endpoints currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long‐term kidney survival. The objective of this investigation was to identify short‐term endpoints that predict long‐term kidney outcomes for use in clinical trials. Methods: A database of 944 LN patients was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long‐term outcomes in a 36 month follow‐up period. The long‐term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). Hazard Index Tools (HITs) to predict risk for each outcome were derived using multivariable analysis with Cox proportional hazards regression. Results: Among 550 eligible subjects 54 CKD, 55 SKI and 22 RRT events occurred. Variables in the final CKD HIT were prediction period CKD status, 12‐month proteinuria and12‐month serum creatinine (SCr). The SKI HIT included prediction period CKD status, ISN Class, 12‐month proteinuria, 12‐month SCr, race and an interaction between ISN Class and 12‐month proteinuria. The RRT HIT included age at diagnosis, 12‐month proteinuria and 12‐month SCr. Each HIT validated well internally (c‐indices 0.84‐0.92) and in an independent LN cohort (c‐indices 0.83‐0.92). Conclusion: HITs, derived from short‐term kidney responses to treatment correlate with long‐term kidney outcomes, and now must be validated as surrogate endpoints for LN clinical trials.</p

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

OBJECTIVE: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials. METHODS: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression. RESULTS: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92). CONCLUSION: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials

The Development of Augmented Reality Applications for Chemistry Learning

This chapter describes the use of Augmented Reality (AR) technology in chemistry education. The chapter begins with definition analysis, development, component, working principles, steps in making AR media, and supporting applications that are related with AR in education particularly for chemistry teaching and learning process. The proposed AR system consists of three parts: computers, Head Mounted Display (HMD), and markers that use AR toolkit working principles as follows:making AR through Vuforia setting stage, making the target management, managing assets, and running processes. Additionally, Unity application also supports in AR making. There were researches in the field of education especially in chemistry teaching and learning that had used AR technology, such as the concept of crystal structure, molecular geometry, molecular chirality, and molecular hybridization