SUMMARYInfectious bacteria have both intrinsic and acquired mechanisms to combat harmful biocides that enter the cell. Through adaptive pressures, many of these pathogens have become resistant to many, if not all, of the current antibiotics used today to treat these often deadly infections. One prominent mechanism is the upregulation of efflux systems, especially the resistance-nodulation-cell division class of exporters. These tripartite systems consist of an inner membrane transporter coupled with a periplasmic adaptor protein and an outer membrane channel to efficiently transport a diverse array of substrates from inside the cell to the extracellular space. Detailed mechanistic insight into how these inner membrane transporters recognize and shuttle their substrates can ultimately inform both new antibiotic and efflux pump inhibitor design. This review examines the structural basis of substrate recognition of these pumps and the molecular mechanisms underlying multidrug extrusion, which in turn mediate antimicrobial resistance in bacterial pathogens.

Structural analysis of resistance-nodulation cell division transporters.

Microbiology and Molecular Biology Reviews : MMBR

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.

Hyperkalemia management: a multidisciplinary expert panel's perspective on the role of new potassium binders.

Heart Failure Reviews

Immunosuppressed patients, particularly those with cancer, represent a momentous and increasing portion of the population, especially as cancer incidence rises with population growth and aging. These patients are at a heightened risk of developing severe infections, including sepsis and septic shock, due to multiple immunologic defects such as neutropenia, lymphopenia, and T and B-cell impairment. The diverse and complex nature of these immunologic profiles, compounded by the concomitant use of immunosuppressive therapies (e.g., corticosteroids, cytotoxic drugs, and immunotherapy), superimposed by the breakage of natural protective barriers (e.g., mucosal damage, chronic indwelling catheters, and alterations of anatomical structures), increases the risk of various infections. These and other conditions that mimic sepsis pose substantial diagnostic and therapeutic challenges. Factors that elevate the risk of progression to septic shock in these patients include advanced age, pre-existing comorbidities, frailty, type of cancer, the severity of immunosuppression, hypoalbuminemia, hypophosphatemia, Gram-negative bacteremia, and type and timing of responses to initial treatment. The management of vulnerable cancer patients with sepsis or septic shock varies due to biased clinical practices that may result in delayed access to intensive care and worse outcomes. While septic shock is typically associated with poor outcomes in patients with malignancies, survival has significantly improved over time. Therefore, understanding and addressing the unique needs of cancer patients through a new paradigm, which includes the integration of innovative technologies into our healthcare system (e.g., wireless technologies, medical informatics, precision medicine), targeted management strategies, and robust clinical practices, including early identification and diagnosis, coupled with prompt admission to high-level care facilities that promote a multidisciplinary approach, is crucial for improving their prognosis and overall survival rates.

Septic shock in the immunocompromised cancer patient: a narrative review.

Critical Care : the Official Journal of the Critical Care Forum

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

Interstitial lung disease (ILD) encompasses a diverse group of parenchymal lung diseases characterized by varying degrees of inflammation and/or fibrosis. Patients with ILD frequently require hospitalization, with many needing intensive care unit (ICU) admission, most often due to respiratory failure. The diagnosis and management of ILD in the ICU present unique challenges. Diagnosis primarily relies on chest CT imaging to identify fibrosis and inflammation. Acute exacerbations, whether in idiopathic pulmonary fibrosis (IPF) or non-IPF ILD, require careful evaluation of potential triggers and differential diagnoses. Bronchoalveolar lavage may provide valuable information, such as the identification of infections, but carries risks of complications. Biopsies, whether transbronchial or surgical, can also be informative but pose significant procedural risks. Corticosteroids are the cornerstone of treatment for acute exacerbations of IPF, with higher doses potentially benefiting non-IPF ILD. Additional immunosuppressive agents may be used in cases with evidence of inflammation. Oxygen supplementation, particularly with high-flow nasal cannula, is often employed to manage severe hypoxemia, while noninvasive ventilation can be useful for worsening hypoxemia and/or hypercapnia. When mechanical ventilation is used, it is recommended to target low tidal volumes to minimize lung injury; high PEEP may be less effective and even associated with increased mortality. Prone positioning can improve oxygenation in severely hypoxemic patients. In addition to ventilatory strategies, careful fluid management and addressing concomitant pulmonary hypertension are essential components of care. Extracorporeal membrane oxygenation is a high-risk intervention reserved for the most severe cases. Lung transplantation may be considered for end-stage ILD patients in the ICU, with outcomes dependent on the urgency of transplantation and the patient's overall condition. Managing ILD in the ICU requires a multidisciplinary approach, and despite recent advances, mortality remains high, emphasizing the need for continued research and individualized treatment strategies.

The Management of Interstitial Lung Disease in the ICU: A Comprehensive Review.

Journal of Clinical Medicine

Heart failure is defined as increased intracardiac pressures, either alone or combined with reduced cardiac output. Clinically, it is presented with signs and symptoms of congestion and compensated perfusion. Cardiogenic shock, on the other hand, is the spectrum of hemodynamic disturbances that lead to hypoperfusion or need for circulatory support, due to cardiac disease. Both entities affect millions of people worldwide, have a dismal prognosis, and constitute a severe socioeconomic burden. Heart failure can be the aftermath of ischemic heart disease, hypertension, arrhythmias, or cardiomyopathies. It undergoes multiple classifications, facilitating its investigation and treatment. The pathogenetic mechanisms differ in various types of heart failure, regarding the affected ventricles, the duration of symptoms, and their primary/secondary onset. These mechanisms reflect the complex interactions between cardiopulmonary, vascular, and hepatorenal systems. Acute deterioration of cardiac function can lead to cardiogenic shock. Myocardial infarction accounts for 81% of such cases. Healthy lifestyle and timely management of coronary artery disease are paramount, as they can prevent this life-threatening situation and reduce mortality and the economic burden for healthcare systems. Irrespective of the etiology, cardiogenic shock is interpreted using the pressure-volume loop. This can be modified for each ventricle, the underlying pathophysiology, and the time since symptoms' onset. It therefore provides valuable information about the native circulation and the expected alterations under mechanical or pharmacological support, facilitating the decision-making progress. In 2019, given the phenotypical heterogeneity of cardiogenic shock, the Society for Cardiovascular Angiography and Interventions introduced a classification system. According to this, patients are stratified in five stages proportionally to the severity of their condition. Aside from this classification, various biochemical, imaging, and hemodynamic monitoring indices are used to assess coagulation pathway and cardiac, hepatorenal, and pulmonary function, enabling the heart team to tailor therapy. Additionally, the prognostication progress is facilitated by scores, such as the Observatoire Regional Breton sur l'Infarctus (ORBI) score, the intra-aortic balloon pump (IABP) SHOCK-II score, and the CardShock score, indicating suitable escalation or de-escalation strategies. Despite the current progress, there are several areas of advancement regarding the role of vasoactive drugs in cardiogenic shock, revascularization options, mechanical ventilation patterns, hypothermia treatment, and mechanical circulatory support protocols.

Cardiac Failure and Cardiogenic Shock: Insights Into Pathophysiology, Classification, and Hemodynamic Assessment.

Curēus

The integrity of the glomerular filtration barrier maintains protein excretion below 150 mg/day. When urinary proteins increase, this indicates damage to the filtration barrier. However, proteinuria is not only a marker of kidney damage but also exacerbates it through various mechanisms involving the glomerular and tubulointerstitial compartments. Therefore, it is essential to intervene with renoprotective action that reduces the proteinuria. In this context, Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are cornerstone treatments. Recent advancements include sodium-glucose cotransporter 2 inhibitors, initially used for glycemic control, now recognized for their renoprotective properties in both diabetic and non-diabetic populations. Another drug, Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has emerged as a promising agent, offering anti-inflammatory and antifibrotic benefits with fewer side effects than traditional steroidal options. Finally, dual inhibition of angiotensin II and endothelin-1 receptors through agents like Sparsentan presents a novel approach with significant antiproteinuric effects in IgA nephropathy and focal segmental glomerulosclerosis. This brief review summarizes the mechanisms by which proteinuria promotes kidney damage and the renoprotective therapeutic approaches available, which can be combined with lifestyle modifications and specific treatments for underlying diseases to mitigate the progression of chronic kidney disease.

Proteinuria and Progression of Renal Damage: The Main Pathogenetic Mechanisms and Pharmacological Approach.

Medicina

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are key drugs in the management of patients with cardiovascular diseases (CVD), particularly those with hypertension, diabetes, chronic kidney disease and heart failure (HF), given their demonstrated effectiveness in reducing the risk of both surrogate and hard endpoints. Despite their positive impact on the outcome, patients with RAASi and MRAs are particularly vulnerable to hyperkalaemia, with approximately 50 % of these individuals experiencing two or more recurrences annually. The common practice of reducing the dose or discontinuing the treatment with RAASi and MRAs in conditions of hyperkalaemia results in suboptimal management of these patients, with a potential impact on their mortality and morbidity risk. Recent guidelines from cardiovascular and renal international societies increasingly recognize the need for alternative strategies to manage the risk of hyperkalaemia, allowing the continuation of RAASi and MRA therapies. In this review, we summarise the new potential options available to manage hyperkalaemia in patients with CVD and the recommendations of the most recent guidelines on the topic.

New strategies for the treatment of hyperkalemia.

European Journal of Internal Medicine

The distinction between culture-positive sepsis and culture-negative sepsis regarding clinical characteristics and outcomes remains contentious. We aimed to elucidate these differences using large-scale nationwide data.

This prospective cohort study analyzed data from the Korean Sepsis Alliance registry, comprising 21 intensive care units (ICUs) across 20 hospitals from September 2019 to December 2021. Patients meeting the Sepsis-3 criteria were included.

Among 11,981 sepsis patients, 3501 were analyzed, all of whom were referred to the ICU through the emergency department (mean age: 72&#x2009;&#xb1;&#x2009;13&#xa0;years; 1976 [56%] males). Of these, 2213 (63%) were culture-positive sepsis and 1288 (37%) were culture-negative sepsis. Compared to the culture-positive sepsis group, the culture-negative sepsis group exhibited less severe illness, with lower Sequential Organ Failure Assessment scores and less deteriorated vital signs. While pulmonary-origin sepsis was common in both groups, culture-negative patients primarily presented with pulmonary infections and had a higher incidence of respiratory failure. In comparison to the culture-positive sepsis group, blood cultures and the administration of empirical antibiotics were performed less promptly in the culture-negative sepsis group. Patients with culture-negative sepsis also showed lower compliance with fluid resuscitation (98.4% vs. 96.9%, p&#x2009;=&#x2009;0.038; culture-positive sepsis vs. culture-negative sepsis) and received vasopressors earlier (31.1% vs. 35.9%, p&#x2009;=&#x2009;0.012). In-hospital mortality did not differ significantly between the two groups (31.6% vs. 34.9%, p&#x2009;=&#x2009;0.073); however, in patients with septic shock, culture-negative sepsis had higher mortality rates (37.6% vs. 45.1%, p&#x2009;=&#x2009;0.029). The apparent appropriateness of empirical antibiotics in the culture-negative septic shock was higher than that of the culture-positive septic shock (85.2% vs. 96.8%, p&#x2009;&lt;&#x2009;0.001). Culture-negativity independently predicted poor prognosis in septic shock patients (OR: 1.462, 95% CI [1.060-2.017], p&#x2009;=&#x2009;0.021).

In patients with septic shock, culture-negativity was associated with increased mortality, despite the paradoxically higher appropriateness of empirical antibiotics than culture-positive patients. These contradictory findings suggest that the current criteria for determining the appropriateness of empirical antibiotic therapy may not be valid for culture-negative sepsis.

Culture-negative sepsis may be a different entity from culture-positive sepsis: a prospective nationwide multicenter cohort study.

Patients with chronic kidney disease (CKD) have a high incidence and prevalence of atrial fibrillation (AF). While general treatment strategies for AF may largely be transferred to patients with mild to moderate CKD, patients with advanced CKD-particularly hemodialysis (HD) patients-with AF pose substantial therapeutical challenges to cardiologists and nephrologists. The arguably greatest dilemma is the very limited evidence on appropriate strategies for prevention of stroke and systemic embolism in HD patients with AF, since the risk for both thromboembolic events without oral anticoagulation and severe bleeding events with oral anticoagulation are substantially increased in advanced CKD, compared with the general population. Thus, the benefit to risk ratio of either vitamin K antagonists or direct oral anticoagulants is less evident in HD than in non-CKD patients with AF. As a multidisciplinary panel of clinicians, we here propose 10 tips that may help our colleagues to navigate between the risk of undertreatment-exposing CKD patients with AF to a high stroke risk-and overtreatment-exposing the very same patients to a prohibitively high bleeding risk. These tips include ideas on alternative risk stratification strategies and novel treatment approaches that are currently in clinical studies-such as factor XI inhibitors or left atrial appendage closure-and may become game-changers for HD patients with AF.

Structural analysis of resistance-nodulation cell division transporters.

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