Structure-Based Optimization of Pyridone α-Ketoamides as Inhibitors of the SARS-CoV-2 Main Protease.

The main protease M is a clinically validated target to treat infections by the coronavirus SARS-CoV-2. Among the first reported M inhibitors was the peptidomimetic α-ketoamide , whose cocrystal structure with M paved the way for multiple lead-finding studies. We established structure-activity relationships for the series by modifying residues at the P1', P3, and P4 sites.

AI-powered fraud and the erosion of online survey integrity: an analysis of 31 fraud detection strategies.

The proliferation of AI-powered bots and sophisticated fraudsters poses a significant threat to the integrity of scientific studies reliant on online surveys across diverse disciplines, including health, social, environmental and political sciences. We found a substantial decline in usable responses from online surveys from 75 to 10% in recent years due to survey fraud. Monetary incentives attract sophisticated fraudsters capable of mimicking genuine open-ended responses and verifying information submitted months prior, showcasing the advanced capabilities of online survey fraud today.

The prognostic impact of the Stress Hyperglycemia Ratio on End-Stage Renal Disease among patients with Diabetic Kidney Disease.

Background: The Stress Hyperglycemia Ratio (SHR), a new biomarker calculated from glucose and HbA1c levels, has been linked to significant clinical outcomes in diabetes. This study investigates the potential of the SHR to predict End-Stage Renal Disease (ESRD) among patients with Diabetic Kidney Disease (DKD).

Methods: We included 316 participants from the West China Hospital T2DM-DKD cohort (January 2008-September 2020), divided into three SHR tertiles: T1 (SHR <0.

Lipoxin A improves cardiac remodeling and function in diabetes-associated cardiac dysfunction.

Background: Diabetic heart disease may eventually lead to heart failure, a leading cause of mortality in diabetic individuals. The lack of effective treatments for diabetes-induced heart failure may result from a failure to address the underlying pathological processes, including chronic, low-grade inflammation. Previous studies have reported that lipoxin A (LXA), known to promote resolution of inflammation, attenuates diabetes-induced atherosclerosis, but its impact on diabetic hearts has not been sought.

Altered oxidant and antioxidant levels are associated with vascular stiffness and diabetic kidney disease in type 1 diabetes after exposure to acute and chronic hyperglycemia.

Background: Hyperglycemia-induced oxidative stress is a well-established pathological mediator of vascular complications in diabetes. We assessed plasma oxidant and antioxidant levels in response to acute and chronic hyperglycemia in relation to vascular stiffness and varying degrees of kidney disease in type 1 diabetes individuals.

Methods: The acute hyperglycemia study included 22 type 1 diabetic individuals with normal albumin excretion rate (AER) and 13 non-diabetic controls.

Exploring the benefits and limitations of using telemedicine in unscheduled care.

Telemedicine is increasingly used in healthcare settings, including in unscheduled care. This article details the findings of a literature review that aimed to determine the benefits and limitations of using telemedicine in unscheduled care. The findings suggest that the use of telemedicine can be cost-effective for patients and healthcare providers and may reduce hospital transfer and admission rates.

A Fully Decentralized Randomized Controlled Study of As-Needed Albuterol-Budesonide Fixed-Dose Inhaler in Mild Asthma: The BATURA Study Design.

Purpose: Decentralized clinical trials, where trial-related activities occur at locations other than traditional clinical sites(eg participant homes, local healthcare facilities), have the potential to improve trial access for people for whom time and/or distance constraints may impede participation. Albuterol-budesonide 180/160 µg pressurized metered-dose inhaler (pMDI) is FDA approved for the as-needed treatment or prevention of bronchoconstriction and to reduce the risk of exacerbations in patients with asthma 18 years or older. BATURA (NCT05505734) is a fully decentralized study, investigating as-needed albuterol-budesonide in participants with mild asthma.

A scoping review exploring people's perceptions of healthcare uniforms.

Background: Healthcare staff uniforms are a subject of debate in the UK, and this is particularly true in the case of less understood roles such as advanced nurse practitioners. Aim: This review explores what is known about people's perceptions of health professionals' uniforms.

Method: A mixed methods scoping review following the Joanna Briggs Institute (JBI) methodology.

To target cellular senescence in diabetic kidney disease: the known and the unknown.

Cellular senescence represents a condition of irreversible cell cycle arrest, characterized by heightened senescence-associated beta-galactosidase (SA-β-Gal) activity, senescence-associated secretory phenotype (SASP), and activation of the DNA damage response (DDR). Diabetic kidney disease (DKD) is a significant contributor to end-stage renal disease (ESRD) globally, with ongoing unmet needs in terms of current treatments. The role of senescence in the pathogenesis of DKD has attracted substantial attention with evidence of premature senescence in this condition.

The Role of Activator Protein-1 Complex in Diabetes-Associated Atherosclerosis: Insights From Single-Cell RNA Sequencing.

Despite advances in treatment, atherosclerotic cardiovascular disease remains the leading cause of death in patients with diabetes. Even when risk factors are mitigated, the disease progresses, and thus, newer targets need to be identified that directly inhibit the underlying pathobiology of atherosclerosis in diabetes. A single-cell sequencing approach was used to distinguish the proatherogenic transcriptional profile in aortic cells in diabetes using a streptozotocin-induced diabetic Apoe-/- mouse model.

Targeting the sympathetic nervous system with the selective imidazoline receptor agonist moxonidine for the management of hypertension: an international position statement.

Hypertension is often linked with metabolic risk factors that share common pathophysiological pathways. Despite wide-spread availability of multiple drug classes, optimal blood pressure (BP) control remains challenging. Increased central sympathetic outflow is frequently neglected as a critical regulator of both circulatory and metabolic pathways and often remains unopposed therapeutically.

Albuterol-budesonide fixed-dose combination rescue inhaler for asthma: a plain language summary of the MANDALA study.

This summary describes the results of a clinical study called MANDALA that was published in the in 2022. In the MANDALA study, researchers looked at a new asthma rescue inhaler that contains both and in a single inhaler (known as , AIRSUPRA™). This summary describes the results for people aged 18 yearsand older who took part in the study.

Endothelial NOX5 Obliterates the Reno-Protective Effect of Nox4 Deletion by Promoting Renal Fibrosis via Activation of EMT and ROS-Sensitive Pathways in Diabetes.

Chronic hyperglycemia induces intrarenal oxidative stress due to the excessive production of reactive oxygen species (ROS), leading to a cascade of events that contribute to the development and progression of diabetic kidney disease (DKD). NOX5, a pro-oxidant NADPH oxidase isoform, has been identified as a significant contributor to renal ROS in humans. Elevated levels of renal ROS contribute to endothelial cell dysfunction and associated inflammation, causing increased endothelial permeability, which can disrupt the renal ecosystem, leading to progressive albuminuria and renal fibrosis in DKD.

Set7 Methyltransferase and Phenotypic Switch in Diabetic Glomerular Endothelial Cells.

Key Points: Set7 knockout improves diabetic glomerular structure and function and prevents diabetes-induced endothelial–mesenchymal transition (EDMT) by regulating Igfbp5. Set7 knockdown prevents, and (R)-PFI-2 hydrochloride reverses, diabetes-induced EDMT by regulating insulin growth factor binding protein 5. Set7 regulates the phenotypic EDMT switch, and inhibiting the methyltransferase attenuates glomerular injury in diabetic kidney disease.

Urine Albumin-Creatinine Ratio Variability in People With Type 2 Diabetes: Clinical and Research Implications.

Rationale & Objective: Evidence has demonstrated that albuminuria is a key diagnostic and prognostic marker of diabetic chronic kidney disease, but the impact of its day-to-day variability has not been adequately considered. This study quantified within-individual variability of albuminuria in people with type 2 diabetes to inform clinical albuminuria monitoring.

Study Design: Descriptive cross-sectional analysis.

Empagliflozin and Rapid Kidney Function Decline Incidence in Type 2 Diabetes: An Exploratory Analysis From the EMPA-REG OUTCOME Trial.

Rationale & Objective: Kidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression.

Contrasting leaf-scale photosynthetic low-light response and its temperature dependency are key to differences in crop-scale radiation use efficiency.

Radiation use efficiency (RUE) is a key crop adaptation trait that quantifies the potential amount of aboveground biomass produced by the crop per unit of solar energy intercepted. But it is unclear why elite maize and grain sorghum hybrids differ in their RUE at the crop level. Here, we used a non-traditional top-down approach via canopy photosynthesis modelling to identify leaf-level photosynthetic traits that are key to differences in crop-level RUE.

YB-1: the Jekyll and Hyde of kidney disease?

Y-box-binding protein 1 is a well-described and important regulator of gene transcription, which is linked to various pathologic conditions, including inflammation and fibrosis of the kidney. The identification of a novel and protective crosstalk pathway between podocytes and tubular cells in the kidney with Y-box-binding protein 1 acting as a paracrine messenger sheds new light and provides novel opportunities for renoprotection.

Hypoglycemia and Cardiovascular Outcomes in the CARMELINA and CAROLINA Trials of Linagliptin: A Secondary Analysis of Randomized Clinical Trials.

Importance: Previous studies have reported an association between hypoglycemia and cardiovascular (CV) events in people with type 2 diabetes (T2D), but it is unclear if this association is causal or identifies a high-risk patient phenotype.

Objective: To evaluate the associations between hypoglycemia and CV outcomes.

Design, Setting, And Participants: This secondary analysis was a post hoc assessment of the multinational, double-blind CARMELINA (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; 2013-2016) and CAROLINA (Cardiovascular Outcome Trial of Linagliptin vs Glimepiride in Type 2 Diabetes; 2010-2018) randomized clinical trials of the antihyperglycemic drug, linagliptin, a dipeptidyl peptidase 4 inhibitor.

Glucagon-like peptide-1 receptor signaling modifies the extent of diabetic kidney disease through dampening the receptor for advanced glycation end products-induced inflammation.

Glucagon like peptide-1 (GLP-1) is a hormone produced and released by cells of the gastrointestinal tract following meal ingestion. GLP-1 receptor agonists (GLP-1RA) exhibit kidney-protective actions through poorly understood mechanisms. Here we interrogated whether the receptor for advanced glycation end products (RAGE) plays a role in mediating the actions of GLP-1 on inflammation and diabetic kidney disease.

Novel pharmacological interventions for diabetic kidney disease.

Purpose Of Review: The purpose of this review is to summarize the latest evidence on the prevention and progression of diabetic kidney disease (DKD), as well as novel pharmacological interventions from preclinical and early clinical studies with promising findings in the reduction of this condition's burden.

Recent Findings: We will cover the latest evidence on the reduction of proteinuria and kidney function decline in DKD achieved through established renin-angiotensin-aldosterone system (RAAS) system blockade and the more recent addition of SGLT2i, nonsteroidal mineralocorticoid receptor antagonists (MRAs) and GLP1-RA, that combined will most likely integrate the mainstay for current DKD treatment. We also highlight evidence from new mechanisms of action in DKD, including other haemodynamic anti-inflammatory and antifibrotic interventions, oxidative stress modulators and cell identity and epigenetic targets.