Sphingosine-1-phosphate (S1P) regulates numerous important physiological functions, including immune response and vascular integrity, via its cognate receptors (S1PR1 to S1PR5); however, it remains unclear how S1P activates S1PRs upon binding. Here, we determined the crystal structure of the active human S1PR3 in complex with its natural agonist S1P at 3.2-Å resolution. S1P exhibits an unbent conformation in the long tunnel, which penetrates through the receptor obliquely. Compared with the inactive S1PR1 structure, four residues surrounding the alkyl tail of S1P (the "quartet core") exhibit orchestrating rotamer changes that accommodate the moiety, thereby inducing an active conformation. In addition, we reveal that the quartet core determines G protein selectivity of S1PR3. These results offer insight into the structural basis of activation and biased signaling in G protein-coupled receptors and will help the design of biased ligands for optimized therapeutics.

Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias.

Science Advances

Contrast-induced acute kidney injury (CI-AKI) has become the third leading cause of hospital-acquired AKI, which seriously threatens the health of patients. To date, the precise pathogenesis of CI-AKI has remained not clear and may be related to the direct cytotoxicity, hypoxia and ischemia of medulla, and oxidative stress caused by iodine contrast medium, which have diverse physicochemical properties, including cytotoxicity, permeability and viscosity. The latest research shows that microRNAs (miRNAs) are also involved in apoptosis, pyroptosis, and autophagy which caused by iodine contrast medium (ICM), which may be implicated in the pathogenesis of CI-AKI. Unfortunately, effective therapy of CI-AKI is very limited at present. Therefore, effective prevention of CI-AKI is of great significance, and several preventive options, including hydration, antagonistic vasoconstriction, and antioxidant drugs, have been developed. Here, we review current knowledge about the features of iodine contrast medium, the definition, pathogenesis, molecular mechanism, risk factors, prevention and treatment of CI-AKI.

Contrast-induced acute kidney injury: a review of definition, pathogenesis, risk factors, prevention and treatment.

BMC Nephrology

Hemodynamic Support in Sepsis.

Anesthesiology

In recent years, obesity has become one of the major diseases that affect human health and consume human health resources, especially when it causes comorbidities such as hypertension, diabetes, cardiovascular disease and kidney disease. Many studies have demonstrated that obesity is associated with the development of chronic kidney disease and can exacerbate the progression of end-stage renal disease. This review described the mechanisms associated with the development of obesity-associated nephropathy and the current relevant therapeutic modalities, with the aim of finding new therapeutic targets for obesity-associated nephropathy. The mechanisms of obesity-induced renal injury include, in addition to the traditional alterations in renal hemodynamics, the involvement of various mechanisms such as macrophage infiltration in adipose tissue, alterations in adipokines (leptin and adiponectin), and ectopic deposition of lipids. At present, there is no "point-to-point" treatment for obesity-induced kidney injury. The renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-dependent glucose transporter 2 (SGLT-2) inhibitors and bariatric surgery described in this review can reduce urinary protein to varying degrees and delay the progression of kidney disease. In addition, recent studies on the therapeutic effects of intestinal flora on obesity may reduce the incidence of obesity-related kidney disease from the perspective of primary prevention. Both of these interventions have their own advantages and disadvantages, so the continuous search for the mechanism of obesity-induced related kidney disease will be extremely helpful for the future treatment of obesity-related kidney disease.

The New Challenge of Obesity - Obesity-Associated Nephropathy.

Diabetes, Metabolic Syndrome and Obesity

Stroke affects up to one in five people during their lifetime in some high-income countries, and up to almost one in two in low-income countries. Globally, it is the second leading cause of death. Clinically, the disease is characterised by sudden neurological deficits. Vascular aetiologies contribute to the most common causes of ischaemic stroke, including large artery disease, cardioembolism, and small vessel disease. Small vessel disease is also the most frequent cause of intracerebral haemorrhage, followed by macrovascular causes. For acute ischaemic stroke, multimodal CT or MRI reveal infarct core, ischaemic penumbra, and site of vascular occlusion. For intracerebral haemorrhage, neuroimaging identifies early radiological markers of haematoma expansion and probable underlying cause. For intravenous thrombolysis in ischaemic stroke, tenecteplase is now a safe and effective alternative to alteplase. In patients with strokes caused by large vessel occlusion, the indications for endovascular thrombectomy have been extended to include larger core infarcts and basilar artery occlusion, and the treatment time window has increased to up to 24 h from stroke onset. Regarding intracerebral haemorrhage, prompt delivery of bundled care consisting of immediate anticoagulation reversal, simultaneous blood pressure lowering, and prespecified stroke unit protocols can improve clinical outcomes. Guided by underlying stroke mechanisms, secondary prevention encompasses pharmacological, vascular, or endovascular interventions and lifestyle modifications.

Stroke.

Lancet

Over the course of 2023, numerous key clinical trials with valuable contributions to clinical cardiology were published or presented at major international conferences. This review seeks to summarise these trials and reflect on their clinical context.

The authors collated and reviewed clinical trials presented at major cardiology conferences during 2023 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), Transcatheter Cardiovascular Therapeutics (TCT), American Heart Association (AHA), European Heart Rhythm Association (EHRA), Society for Cardiovascular Angiography and Interventions (SCAI), TVT-The Heart Summit (TVT) and Cardiovascular Research Technologies (CRT). Trials with a broad relevance to the cardiology community and those with potential to change current practice were included.

A total of 80 key cardiology clinical trials were identified for inclusion. Key trials in acute coronary syndrome (ACS) and antiplatelet management such as HOST-IDEA, T-PASS and STOP-DAPT3 were included in addition to several pivotal interventional trials such as ORBITA 2, MULTISTARS-AMI, ILUMIEN-IV, OCTIVUS and OCTOBER. Additionally, several trials evaluated new stent design and technology such as BIOSTEMI, PARTHENOPE and TRANSFORM. Structural intervention trials included long-term data from PARTNER 3, new data on the durability of transcatheter aortic valve intervention (TAVI), in addition to major new trials regarding transcatheter tricuspid valve intervention from TRISCEND II. Heart failure (HF) and prevention covered several key studies including DAPA-MI, STEP-HF, ADVOR, DICTATE HF and CAMEO-DAPA. In cardiac devices and electrophysiology, several trial exploring novel ablation strategies in atrial fibrillation (AF) such as PULSED AF and ADVENT were presented with further data evaluating the efficacy of anticoagulation in subclinical AF in NOAH-AFNET 6, FRAIL AF and AZALEA-TIMI 71.

This article presents a summary of key clinical cardiology trials published and presented during the past year and should be of interest to both practising clinicians and researchers.

Advances in Clinical Cardiology 2023: A Summary of Key Clinical Trials.

Advances in Therapy

Atrial fibrillation (AF) is highly prevalent in patients with chronic kidney disease (CKD). It is associated with an increased risk of stroke, which increases as kidney function declines. In the general population and in those with a moderate degree of CKD (creatinine clearance 30-50 mL/min), the use of oral anticoagulation to decrease the risk of stroke has been the standard of care based on a favorable risk-benefit profile that had been established in seminal randomized controlled trials. However, evidence regarding the use of oral anticoagulants for stroke prevention is less clear in patients with severe CKD (creatinine clearance &lt;30 mL/min) and those receiving maintenance dialysis, as these individuals were excluded from such large randomized controlled trials. Nevertheless, the direct oral anticoagulants have invariably usurped vitamin K antagonists as the preferred choice for oral anticoagulation among patients with AF across all strata of CKD based on their well-defined safety and efficacy and multiple pharmacokinetic benefits (e.g., less drug-drug interactions). This review summarizes the current literature on the role of oral anticoagulation in the management of AF among patients with CKD and highlights current deficiencies in the evidence base and how to overcome them.

Oral Anticoagulation Use in Individuals With Atrial Fibrillation and Chronic Kidney Disease: A Review.

Seminars in Nephrology

Appendicitis is an extremely common disease with a variety of medical and surgical treatment approaches. A multidisciplinary expert panel was convened to develop evidence-based recommendations to support clinicians and patients in decisions regarding the diagnosis and treatment of appendicitis.

A systematic review was conducted from 2010 to 2022 to answer 8 key questions relating to the diagnosis of appendicitis, operative or nonoperative management, and specific technical and post-operative issues for appendectomy. The results of this systematic review were then presented to a panel of adult and pediatric surgeons. Evidence-based recommendations were formulated using the GRADE methodology by subject experts.

Conditional recommendations were made in favor of uncomplicated and complicated appendicitis being managed operatively, either delayed (&gt;12h) or immediate operation (&lt;12h), either suction and lavage or suction alone, no routine drain placement, treatment with short-term antibiotics postoperatively for complicated appendicitis, and complicated appendicitis previously treated nonoperatively undergoing interval appendectomy. A conditional recommendation signals that the benefits of adhering to a recommendation probably outweigh the harms although it does also indicate uncertainty.

These recommendations should provide guidance with regard to current controversies in appendicitis. The panel also highlighted future research opportunities where the evidence base can be strengthened.

SAGES guideline for the diagnosis and treatment of appendicitis.

Surgical Endoscopy

The CHEST Antithrombotic Therapy for Venous Thromboembolism Disease evidencebased guidelines are now updated in a more frequent, focused manner. Guidance statements from the most recent full guideline and two subsequent updates have not been gathered into a single source. METHODS An international panel of experts with experience in prior Antithrombotic Therapy guideline development reviewed the 2012 CHEST Antithrombotic Therapy guideline and its two subsequent updates. All guideline statements, and their associated Patient, Intervention, Comparator, Outcome questions were assembled. A modified Delphi process was used to select statements considered relevant to current clinical care. The panel further endorsed minor phrasing changes to match the standard language for guidance statements using the modified GRADE format endorsed by the CHEST Guidelines Oversight Committee. The panel appended comments following statements as deemed relevant, including suggesting which statements be updated in future guidelines due to interval evidence. RESULTS We include 58 guidance statements from prior versions of the antithrombotic therapy guidelines, with updated phrasing as needed to adhere to contemporary nomenclature. Statements are classified as strong or weak recommendations based on high, moderate, and low-certainty evidence, using GRADE methodology. The panel suggests that 5 statements are no longer relevant to current practice. CONCLUSION As CHEST continues to update guidance statements relevant to antithrombotic therapy for VTE disease, this manuscript serves as a unified collection of currently relevant statements from the preceding three guidelines. Suggestions are made to update specific statements in future publications.

Antithrombotic Therapy for VTE Disease: Compendium and Review of CHEST Guidelines 2012-2021.

Chest

Obesity is considered the leading public health problem in the medical sector. The phenotype includes overweight conditions that lead to several other comorbidities that drastically decrease health. Glucagon-like receptor agonists (GLP-1RAs) initially designed for treating type 2 diabetes mellitus (T2DM) had demonstrated weight loss benefits in several clinical trials . In vivo studies showed that GLP-1RA encourages reduced food consumption and consequent weight reduction by stimulating brown fat and enhancing energy outlay through the action of the sympathetic nervous system (SNS) pathways. Additionally, GLP-1RAs were found to regulate food intake through stimulation of sensory neurons in the vagus, interaction with the hypothalamus and hindbrain, and through inflammation and intestinal microbiota. However, the main concern with the use of GLP-1RA treatment was weight gain after withdrawal or discontinuation. We could identify three different ways that could lead to weight gain. Potential factors might include temporary hormonal adjustment in response to weight reduction, the central nervous system's (CNS) incompetence in regulating weight augmentation owing to the lack of GLP-1RA, and &#x3b2; -cell malfunction due to sustained exposure to GLP-1RA. Here, we also review the data from clinical studies that reported withdrawal symptoms. Although the use of GLP-1RA could be beneficial in multiple ways, withdrawal after years has the symptoms reversed. Clinical studies should emphasize the downside of these views we highlighted, and mechanistic studies must be carried out for a better outcome with GLP-1RA from the laboratory to the bedside.

Endogenous agonist-bound S1PR3 structure reveals determinants of G protein-subtype bias.

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