The widespread adoption of immune checkpoint inhibitors and small molecule inhibitors of the MAP kinase pathway has transformed the management of locally advanced and metastatic melanoma. Here, we provide a broad overview on the use of these agents in the first-line setting, incorporating a review of the clinical literature as well as the practice patterns of our respective melanoma groups. Throughout, we highlight areas of uncertainty that provide opportunities for future clinical investigation and additional improvement in outcomes for patients with melanoma.

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease.

Cancer Journal

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology. GLP-1RA therapy has shown potential benefits in reducing the risk of major adverse cardiovascular events and improving kidney outcomes in patients with diabetes at high risk for cardiovascular disease. More recent evidence is expanding their benefits to heart failure with preserved ejection fraction and clinically important renal outcomes in patients with and without diabetes. Some sub-analyses of large clinical trials suggest that GLP-1RA and sodium-glucose cotransporter 2 inhibitor combination therapy may provide more significant reductions in heart failure hospitalization and renal composite events than each alone. Moreover, the addition of finerenone to this combination therapy could potentially provide stronger cardiorenal protective benefits. Further studies are needed to assess the potential cardiovascular and renal benefits of combination therapy and to determine suitable patient population for the therapy.

Updated evidence on cardiovascular and renal effects of GLP-1 receptor agonists and combination therapy with SGLT2 inhibitors and finerenone: a narrative review and perspectives.

Cardiovascular Diabetology

Traditional approaches to practice guidelines frequently result in dissociation between strength of recommendation and quality of evidence.

To create a clinical guideline for the diagnosis and management of urinary tract infections that addresses the gap between the evidence and recommendation strength.

This consensus statement and systematic review applied an approach previously established by the WikiGuidelines Group to construct collaborative clinical guidelines. In May 2023, new and existing members were solicited for questions on urinary tract infection prevention, diagnosis, and management. For each topic, literature searches were conducted up until early 2024 in any language. Evidence was reported according to the WikiGuidelines charter: clear recommendations were established only when reproducible, prospective, controlled studies provided hypothesis-confirming evidence. In the absence of such data, clinical reviews were developed discussing the available literature and associated risks and benefits of various approaches.

A total of 54 members representing 12 countries reviewed 914 articles and submitted information relevant to 5 sections: prophylaxis and prevention (7 questions), diagnosis and diagnostic stewardship (7 questions), empirical treatment (3 questions), definitive treatment and antimicrobial stewardship (10 questions), and special populations and genitourinary syndromes (10 questions). Of 37 unique questions, a clear recommendation could be provided for 6 questions. In 3 of the remaining questions, a clear recommendation could only be provided for certain aspects of the question. Clinical reviews were generated for the remaining questions and aspects of questions not meeting criteria for a clear recommendation.

In this consensus statement that applied the WikiGuidelines method for clinical guideline development, the majority of topics relating to prevention, diagnosis, and treatment of urinary tract infections lack high-quality prospective data and clear recommendations could not be made. Randomized clinical trials are underway to address some of these gaps; however further research is of utmost importance to inform true evidence-based, rather than eminence-based practice.

Guidelines for the Prevention, Diagnosis, and Management of Urinary Tract Infections in Pediatrics and Adults: A WikiGuidelines Group Consensus Statement.

JAMA Network Open

There is significant variability in the application of positive end-expiratory pressure (PEEP) in patients undergoing invasive mechanical ventilation. There are numerous studies assessing methods of determining optimal PEEP, but many methods, patient populations, and study settings lack high-quality evidence. Guidelines make no recommendations about the use of a specific method because of equipoise and lack of high-quality evidence. We conducted a scoping review to determine which methods of determining optimal PEEP have been studied and what gaps exist in the literature.

We searched five databases for primary research reports studying methods of determining optimal PEEP among adults undergoing invasive mechanical ventilation. Data abstracted consisted of the titration method, setting, study design, population, and outcomes.

Two hundred and seventy-one studies with 17,205 patients met the inclusion criteria, including 73 randomized controlled trials (RCTs) with 10,733 patients. We identified 22 methods. Eleven were studied with an RCT. Studies enrolled participants within an intensive care unit (ICU) (216/271, 80%) or operating room (55/271, 20%). Most ICU studies enrolled patients with acute respiratory distress syndrome (162/216, 75%). The three most studied methods were compliance (73 studies, 29 RCTs), imaging-based methods (65 studies, 11 RCTs), and use of PEEP-FI O2 tables (52 studies, 20 RCTs). Among ICU RCTs, the most common primary outcomes were mortality or oxygenation. Few RCTs assessed feasibility of different methods (n&#x2009;=&#x2009;3). The strengths and limitations of each method are discussed.

Numerous methods of determining optimal PEEP have been evaluated; however, notable gaps remain in the evidence supporting their use. These include specific populations (normal lungs, patients weaning from mechanical ventilation) and using alternate outcomes (ventilator-free days and feasibility) and they present significant opportunities for future study.

Open Science Framework ( https://osf.io/atzqc ); first posted, 19 July 2022.

Methods for determining optimal positive end-expiratory pressure in patients undergoing invasive mechanical ventilation: a scoping review.

Canadian Journal of Anaesthesia

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF) represents a frequent form of PH related to left ventricular dysfunction. The pathophysiology of PH-HFpEF is intricate, and varied and includes vascular, cardiac, and pulmonary factors that contribute synergistically to developing this clinical syndrome. Improved knowledge of the pathophysiology of PH-HFpEF has paved the way for the use of new drugs such as angiotensin receptor neprilysin inhibitors (ARNIs), non-steroidal mineral corticoid receptor antagonist (nsMRA), sodium-glucose cotransporter inhibitors (SGLT2is), levosimendan, and glucagon-like peptide 1 (GLP-1) agonists. ARNIs are a widely used drug for the treatment of PH associated with heart failure with reduced ejection fraction. They have also recently been used in PH-HFpEF patients with hemodynamic benefits that need to be confirmed in future research. Finerenone is an innovative non-steroidal mineralocorticoid receptor antagonist that exhibits notable cardioprotective and renoprotective properties in individuals suffering from chronic diabetic kidney disease. It also enhances outcomes for patients with heart failure, whether they have mildly reduced or preserved ejection fraction. Moreover, in experimental studies, finerenone has been found to lower pulmonary artery pressure, reduce muscularization, and decrease the wall thickness of pulmonary arteries. SGLT2i have revolutionized the treatment of patients with heart failure irrespective of left ventricular ejection fraction, and their treatment is also associated with an improvement in the hemodynamics profile in patients with PH-HFpEF. Levosimendan is a widely used inodilator in the treatment of acute and advanced heart failure. In addition, its use in patients with PH-HFpEF (supported by the positive effects on pulmonary hemodynamics that levosimendan exerts) has recently demonstrated hemodynamic benefit in a small phase 2 study that paved the way for phase 3 studies and the creation of an oral formulation of levosimendan. Finally, GLP1 agonists are a class of drugs that, in preliminary evidence, have shown a positive effect on cardiac hemodynamics, mainly by facilitating left ventricular unloading. These effects, along with the reduction in insulin resistance and weight loss, likely lead to beneficial outcomes for PH-HFpEF patients, especially those with obesity as a comorbidity.

Pharmacologic Treatment of Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction: Are There More Arrows on Our Bow?

Journal of Clinical Medicine

Hyperkalemia is a potentially life-threatening condition frequently encountered in clinical practice, particularly among patients with chronic kidney disease, heart failure, diabetes, and hypertension and those undergoing treatment with renin-angiotensin-aldosterone system inhibitors (RAASi). The management of chronic and acute hyperkalemia is complex and requires timely intervention to prevent severe complications such as cardiac arrhythmias and sudden death. Traditional therapeutic approaches to chronic hyperkalemia, including dietary potassium restriction, use of diuretics, and administration of cation-exchange resins like sodium polystyrene sulfonate, often suffer from limitations like gastrointestinal side effects, variable efficacy, delayed onset of action, and RAASi treatment discontinuation. In recent years, the development of new potassium binders, specifically patiromer and sodium zirconium cyclosilicate (SZC), has revolutionized the management of hyperkalemia. Patiromer, a non-absorbed polymer, binds potassium in the gastrointestinal tract in exchange for calcium, thus facilitating its excretion. SZC operates by exchanging sodium and hydrogen ions for potassium, leading to efficient potassium removal. Both agents have demonstrated rapid and sustained reductions in serum potassium levels, coupled with favorable safety and tolerability profiles, in multiple clinical trials. This review article, authored by a multidisciplinary group of Portuguese experts in hyperkalemia management, provides an in-depth analysis of the efficacy and safety of current therapeutic strategies and highlights the clinical potential of new potassium binders. The introduction of patiromer and SZC offers significant advantages over traditional therapies, providing effective and better-tolerated options for patients. The review highlights the role of these novel agents in contemporary hyperkalemia management and calls for ongoing research to further refine treatment protocols and improve patient outcomes.

A General Approach to Patients Presenting With Locally Advanced or Distant Metastatic Disease.

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