Half a century after the introduction of Amphotericin B the management of cryptococcosis remains unsatisfactory. The disease, caused primarily by the two fungal species Cryptococcus neoformans and Cryptococcus gattii, remains responsible for considerable morbidity and mortality despite standard medical care. Current therapeutic options are limited to Amphotericin B, azoles and 5-flucytosine. However, this organism has numerous well-characterized virulence mechanisms that are amenable to pharmacological interference and are thus potential therapeutic targets. Here, we discuss existing approved antifungal drugs, resistance mechanisms to these drugs and non-standard antifungal drugs that have potential in treatment of cryptococcosis, including immunomodulatory strategies that synergize with antifungal drugs, such as cytokine administration or monoclonal antibodies. Finally, we summarize attempts to target well-described virulence factors of Cryptococcus, the capsule or fungal melanin. This review emphasizes the pressing need for new therapeutic alternatives for cryptococcosis.

Cryptococcal therapies and drug targets: the old, the new and the promising.

Cellular Microbiology

Circulatory shock is a common and important diagnosis in the critical care environment. Hemodynamic monitoring is quintessential in the management of shock. The currently used hemodynamic monitoring devices not only measure cardiac output but also provide data related to the prediction of fluid responsiveness, extravascular lung water, and also pulmonary vascular permeability. Additionally, these devices are minimally invasive and associated with fewer complications. The area of hemodynamic monitoring is progressively evolving with a trend toward the use of minimally invasive devices in this area. The critical care physician should be well-versed with current hemodynamic monitoring limitations and stay updated with the upcoming advances in this field so that optimal therapy can be delivered to patients in circulatory shock.

Monitoring Macro- and Microcirculation in the Critically Ill: A Narrative Review.

Avicenna Journal of Medicine

Membranous nephropathy is an autoimmune disease affecting the glomeruli and is one of the most common causes of nephrotic syndrome. In the absence of any therapy, 35% of patients develop end-stage renal disease. The discovery of autoantibodies such as phospholipase A2 receptor 1, antithrombospondin and neural epidermal growth factor-like 1 protein has greatly helped us to understand the pathogenesis and enable the diagnosis of this disease and to guide its treatment. Depending on the complications of nephrotic syndrome, patients with this disease receive supportive treatment with diuretics, ACE inhibitors or angiotensin-receptor blockers, lipid-lowering agents and anticoagulants. After assessing the risk of progression of end-stage renal disease, patients receive immunosuppressive therapy with various drugs such as cyclophosphamide, steroids, calcineurin inhibitors or rituximab. Since immunosuppressive drugs can cause life-threatening side effects and up to 30% of patients do not respond to therapy, new therapeutic approaches with drugs such as adrenocorticotropic hormone, belimumab, anti-plasma cell antibodies or complement-guided drugs are currently being tested. However, special attention needs to be paid to the choice of therapy in secondary forms or in specific clinical contexts such as membranous disease in children, pregnant women and patients undergoing kidney transplantation.

How to Choose the Right Treatment for Membranous Nephropathy.

Medicina

ANCA-associated Vasculitides (AAV) are characterized by small vessel necrotizing inflammation and prior to the advent of immunosuppressive therapy frequently had a fatal outcome. Treatment has transformed AAV into a relapsing/remitting disease with increased drug-related toxicities and organ damage. The use of glucocorticoids, cyclophosphamide and immunosuppressives (including azathioprine, mycophenolate, methotrexate) was optimised through a sequence of clinical trials establishing a standard of care against which subsequent targeted therapies could be developed. Improved understanding of pathophysiology has supported the development of B cell depletion and complement inhibition, in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), and interleukin 5 inhibition for eosinophilic granulomatosis with polyangiitis (EGPA), leading to the approval of newer agents for these conditions. There has been an increased attention on minimising the adverse effects of treatment and of understanding the epidemiology of co-morbidities in AAV. This review will focus on recent evidence from clinical trials, especially with respect to glucocorticoids, avacopan, plasma exchange, rituximab and mepolizumab, and their interpretation in the 2022 management recommendations by the European League of Associations of Rheumatology (EULAR).

ANCA-associated vasculitis - Treatment Standard.

Nephrology, Dialysis, Transplantation

ASA Consensus-based Guidance on Preoperative Management of Patients on Glucagon-like Peptide-1 Receptor Agonists.

Anesthesiology

The field of bariatric and metabolic surgery has changed rapidly over the past two decades, with an exponential increase in case volumes being performed because of its proven efficacy for morbid obesity and obesity-related comorbidities. Although this increased volume of procedures has been accompanied by significant decrease in postoperative complication rates, there are numerous potential complications after bariatric surgery that may require urgent or emergent surgical evaluation or interventions. Many of these risks extend well beyond the early postoperative period and can present months to years after the index procedure. Acute care surgeons are increasingly covering most or all of the emergency general surgery services at many centers and must be familiar with the numerous bariatric surgical procedures being performed and their individual complication profile to provide optimal care for these frequently challenging patients. This article provides a focused and concise review of the common bariatric procedures being performed, their early and late complication profiles, and a practical guide to the optimal diagnostic evaluations, surgical interventions, and perioperative management options. The author group includes both acute care surgeons and bariatric surgeons with significant experience in the emergency management of the complicated postbariatric surgical patient.

Literature Synthesis and Expert Opinion; Level V.

Common postbariatric surgery emergencies for the acute care surgeon: What you need to know.

Journal of Trauma and Acute Care Surgery

How we approach titrating PEEP in patients with acute hypoxemic failure.

Critical Care : the Official Journal of the Critical Care Forum

The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.

A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate.

Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

Circulation

Urinary tract infections (UTIs) are some of the most commonly encountered infections in clinical practice. Accurate diagnosis and evidence-based treatment of UTIs will lead to better clinical care for many patients and limit unnecessary antibiotic use. Urinalysis and urine cultures are helpful tools in the diagnosis of UTIs; however, it is important to recognize their limitations. Differentiating between asymptomatic bacteriuria (ASB) and true UTI is important because antibiotics are unnecessary in most nonpregnant patients with ASB and can even potentially cause harm if prescribed. Choice and duration of antibiotics varies across the spectrum of UTI syndromes such as acute uncomplicated cystitis, pyelonephritis, prostatitis, and catheter-associated UTIs. The treatment approach also depends on patients' degree of immunosuppression and their genitourinary anatomy. Therefore, patients with urological obstruction or kidney transplants may require a specialized and multidisciplinary management approach. For individuals prone to frequent UTIs, some preventative measures can be utilized, yet there is often not a "one size fits all" approach.

Urinary Tract Infections: Core Curriculum 2024.

American Journal of Kidney Diseases

Cardiogenic pulmonary edema (CPE) is characterized by the development of acute respiratory failure associated with the accumulation of fluid in the lung's alveolar spaces due to an elevated cardiac filling pressure. All cardiac diseases, characterized by an increasing pressure in the left side of the heart, can cause CPE. High capillary pressure for an extended period can also cause barrier disruption, which implies increased permeability and fluid transfer into the alveoli, leading to edema and atelectasis. The breakdown of the alveolar-epithelial barrier is a consequence of multiple factors that include dysregulated inflammation, intense leukocyte infiltration, activation of procoagulant processes, cell death, and mechanical stretch. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Some studies claim that these patients may have higher levels of surfactant protein B in the bloodstream. The correct approach to patients with CPE should include a detailed medical history and a physical examination to evaluate signs and symptoms of CPE as well as potential causes. Second-level diagnostic tests, such as pulmonary ultrasound, natriuretic peptide level, chest radiograph, and echocardiogram, should occur in the meantime. The identification of the specific CPE phenotype is essential to set the most appropriate therapy for these patients. Non-invasive ventilation (NIV) should be considered early in the treatment of this disease. Diuretics and vasodilators are used for pulmonary congestion. Hypoperfusion requires treatment with inotropes and occasionally vasopressors. Patients with persistent symptoms and diuretic resistance might benefit from additional approaches (i.e., beta-agonists and pentoxifylline). This paper reviews the pathophysiology, clinical presentation, and management of CPE.

Cardiogenic Pulmonary Edema in Emergency Medicine.

Advances in Respiratory Medicine

The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and the cardio-renal system. The classical RAS, mainly mediated by angiotensin I, angiotensin-converting enzyme, and angiotensin II, has been reported to be altered in critically ill patients, such as those in vasodilatory shock. However, recent research has highlighted the role of some components of the counterregulatory axis of the classical RAS, termed the alternative RAS, such as angiotensin-converting Enzyme 2 (ACE2) and angiotensin-(1-7), or peptidases which can modulate the RAS like dipeptidyl-peptidase 3, in many critical situations. In cases of shock, dipeptidyl-peptidase 3, an enzyme involved in the degradation of angiotensin and opioid peptides, has been associated with acute kidney injury and mortality and preclinical studies have tested its neutralization. Angiotensin-(1-7) has been shown to prevent septic shock development and improve outcomes in experimental models of sepsis. In the context of experimental acute lung injury, ACE2 activity has demonstrated a protective role, and its inactivation has been associated with worsened lung function, leading to the use of active recombinant human ACE2, in preclinical and human studies. Angiotensin-(1-7) has been tested in experimental models of acute lung injury and in a recent randomized controlled trial for patients with COVID-19 related hypoxemia. Overall, the alternative RAS appears to have a role in the pathogenesis of disease in critically ill patients, and modulation of the alternative RAS may improve outcomes. Here, we review the available evidence regarding the methods of analysis of the RAS, pathophysiological disturbances of this system, and discuss how therapeutic manipulation may improve outcomes in the critically ill.

Cryptococcal therapies and drug targets: the old, the new and the promising.

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Cryptococcal therapies and drug targets: the old, the new and the promising.

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