Voltage-gated sodium channel NaV 1.7 plays essential roles in pain and odor perception. NaV 1.7 variants cause pain disorders. Accordingly, NaV 1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human NaV 1.7/&#x3b2;1/&#x3b2;2 complexed with inhibitors XEN907, TC-N1752 and NaV 1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes &#x3b1;- to &#x3c0;-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces &#x3c0;-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. NaV 1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize NaV 1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for NaV 1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics.

Structural basis for Na V 1.7 inhibition by pore blockers.

Nature Structural & Molecular Biology

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

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

Recent randomized controlled trials (RCTs) have shown no benefit but&#xa0; dose-dependent harm by early full nutritional support in critically ill patients. Lack of benefit may be explained by anabolic resistance, suppression of cellular repair processes, and aggravation of hyperglycemia and insulin needs. Also early high amino acid doses did not provide benefit, but instead associated with harm in patients with organ dysfunctions. However, most studies focused on nutritional interventions initiated during the first days after intensive care unit admission. Although the intervention window of some RCTs extended into the post-acute phase of critical illness, no large RCTs studied nutritional interventions initiated beyond the first week. Hence, clear evidence-based guidance on when and how to initiate and advance nutrition is lacking. Prolonged underfeeding will come at a price as there is no validated metabolic monitor that indicates readiness for medical nutrition therapy, and an adequate response to nutrition, which likely varies between patients. Also micronutrient status cannot be assessed reliably, as inflammation can cause redistribution, so that plasma micronutrient concentrations are not necessarily reflective of total body stores. Moreover, high doses of individual micronutrients have not proven beneficial. Accordingly, current evidence provides clear guidance on which nutritional strategies to avoid, but the ideal nutritional regimen for individual patients remains unclear. In this narrative review, we summarize the findings of recent studies, discuss possible mechanisms explaining the results, point out pitfalls in interpretation of RCTs and their effect on clinical practice, and formulate suggestions for future research.

Nutrition in the intensive care unit: from the acute phase to beyond.

Intensive Care Medicine

In this comprehensive state-of-the-art review, we provide an evidence-based analysis of current drug therapies for patients with heart failure with preserved ejection fraction (HFpEF) in the acute and chronic phases with concurrent hypertension. Additionally, we explore the latest developments and emerging evidence on the efficacy, safety, and clinical outcomes of common and novel drug treatments in the management of HFpEF with concurrent hypertension. During the acute phase of HFpEF, intravenous diuretics, mineralocorticoid receptor antagonists (MRAs), and vasodilators are pivotal, while in the chronic phase, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have proven effective in enhancing clinical outcomes. However, the use of calcium channel blockers in HFpEF with hypertension should be approached with caution, owing to their potential negative inotropic effects. We also explored emerging drug therapies for HFpEF, such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, angiotensin receptor-neprilysin inhibitor (ARNI), soluble guanylate cyclase (sGC) stimulators, novel MRAs, and ivabradine. Notably, SGLT2 inhibitors have shown promise in reducing heart failure hospitalizations and cardiovascular mortality in patients with HFpEF, regardless of their diabetic status. Additionally, ARNI and sGC stimulators have demonstrated potential in improving symptoms, functional capacity, and quality of life. Nonetheless, additional research is necessary to pinpoint optimal treatment strategies for HFpEF with concurrent hypertension. Furthermore, long-term studies are essential to assess the durability and sustained benefits of emerging drug therapies. Identification of novel targets and mechanisms underlying HFpEF pathophysiology will pave the way for innovative drug development approaches in the management of HFpEF with concurrent hypertension.

Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction with Hypertension: A State-of-the-Art Review.

American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions

Diabetes is associated with high risks of premature chronic kidney disease (CKD), cardiovascular diseases, cardiovascular death and impaired quality of life. People with diabetes are more likely to develop kidney impairment, and approximately one in three adults with diabetes have CKD. People with CKD and diabetes experience a substantially higher risk of cardiovascular outcomes. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors have shown potential effects in preventing kidney and cardiovascular outcomes in people with CKD and diabetes. However, new trials are emerging rapidly, and evidence synthesis is essential to summarising cumulative evidence.

This review aimed to assess the benefits and harms of SGLT2 inhibitors for people with CKD and diabetes.

We searched the Cochrane Kidney and Transplant Register of Studies up to 17 November 2023 using a search strategy designed by an Information Specialist. Studies in the Register are continually identified through regular searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov.

Randomised controlled studies were eligible if they evaluated SGLT2 inhibitors versus placebo, standard care or other glucose-lowering agents in people with CKD and diabetes. CKD includes all stages (from 1 to 5), including dialysis patients.

Two authors independently extracted data and assessed the study risk of bias. Treatment estimates were summarised using random effects meta-analysis and expressed as a risk ratio (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. The primary review outcomes were all-cause death, 3-point and 4-point major adverse cardiovascular events (MACE), fatal or nonfatal myocardial infarction (MI), fatal or nonfatal stroke, and kidney failure.

Fifty-three studies randomising 65,241 people with CKD and diabetes were included. SGLT2 inhibitors with or without other background treatments were compared to placebo, standard care, sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, or insulin. In the majority of domains, the risks of bias in the included studies were low or unclear. No studies evaluated the treatment in children or in people treated with dialysis. No studies compared SGLT2 inhibitors with glucagon-like peptide-1 receptor agonists or tirzepatide. Compared to placebo, SGLT2 inhibitors decreased the risk of all-cause death (20 studies, 44,397 participants: RR 0.85, 95% CI 0.78 to 0.94; I2 = 0%; high certainty) and cardiovascular death (16 studies, 43,792 participants: RR 0.83, 95% CI 0.74 to 0.93; I2 = 29%; high certainty). Compared to placebo, SGLT2 inhibitors probably make little or no difference to the risk of fatal or nonfatal MI (2 studies, 13,726 participants: RR 0.95, 95% CI 0.80 to 1.14; I2 = 24%; moderate certainty), and fatal or nonfatal stroke (2 studies, 13,726 participants: RR 1.07, 95% CI 0.88 to 1.30; I2 = 0%; moderate certainty). Compared to placebo, SGLT2 inhibitors probably decrease 3-point MACE (7 studies, 38,320 participants: RR 0.89, 95% CI 0.81 to 0.98; I2 = 46%; moderate certainty), and 4-point MACE (4 studies, 23,539 participants: RR 0.82, 95% CI 0.70 to 0.96; I2 = 77%; moderate certainty), and decrease hospital admission due to heart failure (6 studies, 28,339 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 17%; high certainty). Compared to placebo, SGLT2 inhibitors may decrease creatinine clearance (1 study, 132 participants: MD -2.63 mL/min, 95% CI -5.19 to -0.07; low certainty) and probably decrease the doubling of serum creatinine (2 studies, 12,647 participants: RR 0.70, 95% CI 0.56 to 0.89; I2 = 53%; moderate certainty). SGLT2 inhibitors decrease the risk of kidney failure (6 studies, 11,232 participants: RR 0.70, 95% CI 0.62 to 0.79; I2 = 0%; high certainty), and kidney composite outcomes (generally reported as kidney failure, kidney death with or without &#x2265; 40% decrease in estimated glomerular filtration rate (eGFR)) (7 studies, 36,380 participants: RR 0.68, 95% CI 0.59 to 0.78; I2 = 25%; high certainty) compared to placebo. Compared to placebo, SGLT2 inhibitors incur less hypoglycaemia (16 studies, 28,322 participants: RR 0.93, 95% CI 0.89 to 0.98; I2 = 0%; high certainty), and hypoglycaemia requiring third-party assistance (14 studies, 26,478 participants: RR 0.75, 95% CI 0.65 to 0.88; I2 = 0%; high certainty), and probably decrease the withdrawal from treatment due to adverse events (15 studies, 16,622 participants: RR 0.94, 95% CI 0.82 to 1.08; I2 = 16%; moderate certainty). The effects of SGLT2 inhibitors on eGFR, amputation and fracture were uncertain. No studies evaluated the effects of treatment on fatigue, life participation, or lactic acidosis. The effects of SGLT2 inhibitors compared to standard care alone, sulfonylurea, DPP-4 inhibitors, or insulin were uncertain.

SGLT2 inhibitors alone or added to standard care decrease all-cause death, cardiovascular death, and kidney failure and probably decrease major cardiovascular events while incurring less hypoglycaemia compared to placebo in people with CKD and diabetes.

Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes.

Cochrane Database of Systematic Reviews

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

Formerly regarded as a rare disease, bronchiectasis is increasingly recognised. A renewed interest in this disease has led to significant progress in bronchiectasis research. Randomised clinical trials have demonstrated the benefits of airway clearance techniques, inhaled antibiotics and long-term macrolide therapy in bronchiectasis patients. However, the heterogeneity of bronchiectasis remains one of the most challenging aspects of management. Phenotypes and endotypes of bronchiectasis have been identified to help find "treatable traits" and partially overcome disease complexity. The goals of therapy for bronchiectasis are to reduce the symptom burden, improve quality of life, reduce exacerbations and prevent disease progression. We review the pharmacological and non-pharmacological treatments that can improve mucociliary clearance, reduce airway inflammation and tackle airway infection, the key pathophysiological features of bronchiectasis. There are also promising treatments in development for the management of bronchiectasis, including novel anti-inflammatory therapies. This review provides a critical update on the management of bronchiectasis focusing on treatable traits and recent randomised clinical trials.

Bronchiectasis management in adults: state of the art and future directions.

European Respiratory Journal

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease.

Biomedicines

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.

Structural basis for Na V 1.7 inhibition by pore blockers.

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