A new study by Longo, Roy et al. has solved the structure of the RAD51C-XRCC3 (CX3) heterodimer with a bound ATP analog, identifying two main structural interfaces and defining separable replication fork stability roles. One function relates to the ability of RAD51C to bind and assemble CX3 on nascent DNA, with impact on the ability of forks to restart upon replication stress. The other relates to effective CX3 heterodimer formation, required for 5' RAD51 filament capping, with effects on RAD51 filament disassembly, fork protection and influencing the persistence of reversed forks.

Hot on RAD51C: structure and functions of RAD51C-XRCC3.

Molecular Oncology

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM), affecting over one-third of type 1 and nearly half of type 2 diabetes patients. As the leading cause of end-stage renal disease (ESRD) globally, DKD develops through a complex interplay of chronic hyperglycemia, oxidative stress, and inflammation. Early detection is crucial, with diagnosis based on persistent albuminuria and reduced estimated glomerular filtration rate (eGFR). Treatment strategies emphasize comprehensive management, including glycemic control, blood pressure regulation, and the use of nephroprotective agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Ongoing research explores novel therapies targeting molecular pathways and non-coding RNAs. Preventive measures focus on rigorous control of hyperglycemia and hypertension, aiming to mitigate disease progression. Despite therapeutic advances, DKD remains a leading cause of ESRD, highlighting the need for continued research to identify new biomarkers and innovative treatments.

Novel Insights into Diabetic Kidney Disease.

International Journal of Molecular Sciences

Fluid therapy is an integral component of perioperative management. In light of emerging evidence in this area, the Perioperative Quality Initiative (POQI) convened an international multiprofessional expert meeting to generate evidence-based consensus recommendations for fluid management in patients undergoing surgery. This article provides a summary of the recommendations for perioperative fluid management of surgical patients from the preoperative period until hospital discharge and for all types of elective and emergency surgery, apart from burn injuries and head and neck surgery. Where evidence was lacking, recommendations for future research were generated. Specific recommendations are made for fluid management in elective major noncardiac surgery, cardiopulmonary bypass, thoracic surgery, neurosurgery, minor noncardiac surgery under general anaesthesia, and critical illness. There are ongoing gaps in knowledge resulting in variation in practice and some disagreement with our consensus recommendations. Perioperative fluid management should be individualised, taking into account the type of surgery and important patient factors, including intravascular volume status and acute and chronic comorbidities. Recommendations are made for further research in perioperative fluid management to address important gaps.

Perioperative fluid management: evidence-based consensus recommendations from the international multidisciplinary PeriOperative Quality Initiative.

British Journal of Anaesthesia

What is the impact of sodium-glucose cotransporter-2 (SGLT-2) inhibitors on survival and on cardiovascular and kidneyoutcomes for adults living with chronic kidney disease (CKD)?

Few therapies slow kidney disease progression and improve long term prognosis for adults living with CKD. SGLT-2 inhibitors have demonstrated cardiovascular and kidney benefits in adults with CKD with and without type 2 diabetes. Existing guidance for SGLT-2 inhibitors does not account for the totality of current best evidence for adults with CKD and does not provide fully stratified treatment effects and recommendations across all risk groups based on risk of CKD progression and complications.

The guideline panel considered evidence regarding benefits and harms of SGLT-2 inhibitor therapy for adults with CKD over a five year period, along with contextual factors, and provided the following recommendations:1. For adults at low risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)2. For adults at moderate risk of CKD progression and complications, we suggest administering SGLT-2 inhibitors (weak recommendation in favour)3. For adults at high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour)4. For adults at very high risk of CKD progression and complications, we recommend administering SGLT-2 inhibitors (strong recommendation in favour).Recommendations are applicable to all adults with CKD, irrespective of type 2 diabetes status.

An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified typical risk strata of adults with CKD (from low to very high risk of CKD progression and related complications) using the classification system developed by Kidney Disease Improving Global Outcomes (KDIGO), and applied an individual patient perspective in moving from evidence to recommendations. Effects of SGLT-2 inhibitors were interpreted in absolute terms applicable to different risk strata with varying baseline risks for outcomes of benefit over a five year period. The panel explicitly considered the balance of benefits, harms, and burdens of starting an SGLT-2 inhibitor, incorporating the values and preferences of adults with different risk profiles. Interactive evidence summaries and decision aids accompany multilayered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that allows reuse and adaptation.

A linked systematic review and pairwise meta-analysis (13 trials including 29&#x2009;614 participants) of benefits and harms associated with SGLT-2 inhibitors in adults with CKD with or without type 2 diabetes informed guidance. Among individuals at very high risk of CKD progression and complications, moderate to high certainty evidence shows SGLT-2 inhibitors (relative to placebo or standard care without SGLT-2 inhibitors) decrease all-cause and cardiovascular mortality, hospitalisation for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke. Among individuals at high risk, moderate to high certainty evidence shows SGLT-2 inhibitors result in similar benefits across outcomes except demonstrating little or no effect on hospitalisation for heart failure and kidney failure. Among individuals at moderate and low risk, moderate to high certainty evidence shows SGLT-2 inhibitors probably reduce all-cause mortality and non-fatal stroke, with little or no effect for other outcomes of benefit. Risk-stratified estimates were unavailable for outcomes of harm; the panel therefore considered absolute effects summarised across risk strata. SGLT-2 inhibitors are associated with little or no effect on acute kidney injury requiring dialysis, bone fractures, lower limb amputations, ketoacidosis, genital infections, or symptomatic hypovolaemia, although a residual possibility of harms at the individual patient level remains.

In order to apply recommendations, clinicians must appropriately identify adults with CKD, consider the underlying aetiology, and risk stratify them based on glomerular filtration rate (estimated or measured) and degree of albuminuria. In addition to classifying individuals into risk strata, further estimation of a given patient's risk based on the extent of their kidney disease and other comorbidities may be warranted to inform individual-level decisions and shared decision making. Available risk calculators may help estimate a given patient's risk of CKD progression and complications.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors for adults with chronic kidney disease: a clinical practice guideline.

BMJ : British Medical Journal

Thrombotic microangiopathy (TMA) encompasses a range of disorders characterized by blood clotting in small blood vessels, leading to organ damage. It can manifest as various syndromes, including thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome (HUS), and others, each with distinct causes and pathophysiology. Thrombo-inflammation plays a significant role in TMA pathogenesis: inflammatory mediators induce endothelial injury and activation of platelet and coagulation cascade, contributing to microvascular thrombosis. Primary TMA, such as TTP, is primarily caused by deficient ADAMTS13 metalloproteinase activity, either due to antibody-mediated inhibition or intrinsic enzyme synthesis defects. In cancer patients, a significant reduction in ADAMTS13 levels and a corresponding increase in VWF levels is observed. Chemotherapy further decreased ADAMTS13 levels and increased VWF levels, leading to an elevated VWF/ADAMTS13 ratio and increased thrombotic risk. Drug-induced TMA (DITMA) can result from immune-mediated or non-immune-mediated mechanisms. Severe cases of COVID-19 may lead to a convergence of syndromes, including disseminated intravascular coagulation (DIC), systemic inflammatory response syndrome (SIRS), and TMA. Treatment of TMA involves identifying the underlying cause, implementing therapies to inhibit complement activation, and providing supportive care to manage complications. Plasmapheresis may be beneficial in conditions like TTP. Prompt diagnosis and treatment are crucial to prevent serious complications and improve outcomes.

The Phenomenon of Thrombotic Microangiopathy in Cancer Patients.

Acute coronary syndrome (ACS) is associated with high mortality rates. Although the goal was to achieve a missed diagnosis rate of <mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"><mml:mo>&lt;</mml:mo></mml:math> 1%, the actual data showed a rate of <mml:math xmlns:mml="https://www.w3.org/1998/Math/MathML"><mml:mo>&gt;</mml:mo></mml:math> 2%. Chest pain diagnosis has remained unchanged over the years and is based on medical interviews and electrocardiograms (ECG), with biomarkers playing complementary roles. We aimed to summarize the key points of medical interviews, ECG clinics, use of biomarkers, and clinical scores, identify problems, and provide directions for future research. Medical interviews should focus on the character and location of chest pain (is it accompanied by radiating pain?) and the duration, induction, and ameliorating factors. An ECG should be recorded within 10 minutes of the presentation. The serial performance of an ECG is recommended for emergency department (ED) evaluation of suspected ACS. Characteristic ECG traces, such as Wellens syndrome and De Winter T-waves, should be understood. Therefore, troponin levels in all patients with suspected ischemic heart disease should be examined using a highly sensitive assay system. Depending on the ED facility, the patient should be risk stratified by serial measurements of cardiac troponin levels (re-testing at one hour would be preferred) to determine the appropriate time to perform an invasive strategy for a definitive diagnosis. The diagnostics should be based on Bayes' theorem; however, care should be taken to avoid the influence of heuristic bias.

How to Approach Patients with Acute Chest Pain.

Reviews in Cardiovascular Medicine

Venous thromboembolism (VTE), particularly portal vein thrombosis, is common in patients with cirrhosis. Misconceptions around the increased bleeding risk in this patient group may lead to delayed and/or inadequate anticoagulation. This nutshell review focusses on the approach to management including the role of direct oral anticoagulants in the treatment of VTE in patients with cirrhosis.

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