Humoral immune response to glutamic acid decarboxylase (GAD) has been implicated in the pathogenesis of stiff-man syndrome and cerebellar ataxia, but the underlying pathomechanism is unclear. Using a whole-cell patch-clamp technique with rat cerebellar slices, we found that immunoglobulins present in the cerebrospinal fluid of an ataxic patient acted presynaptically to cause a selective suppression of GABAergic transmission. This synaptic depression was most likely elicited by an autoantibody to GAD.

Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase.

Annals of Neurology

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

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

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

A great proportion of neuromuscular diseases are immune-mediated, included myasthenia gravis, Lambert-Eaton myasthenic syndrome, acute- and chronic-onset autoimmune neuropathies (anti-MAG neuropathy, multifocal motor neuropathy, Guillain-Barr&#xe9; syndromes, chronic inflammatory demyelinating polyradiculoneuropathy, CANDA and autoimmune nodopathies), autoimmune neuronopathies, peripheral nerve hyperexcitability syndromes and idiopathic inflammatory myopathies. The detection of autoantibodies against neuromuscular structures has many diagnostic and therapeutic implications and, over time, allowed a better understanding of the physiopathology of those disorders. In this paper, we will review the main autoantibodies described in neuromuscular diseases and focus on their use in clinical practice.

Autoantibodies in neuromuscular disorders: a review of their utility in clinical practice.

Frontiers in Neurology

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

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

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.

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

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.

Selective suppression of cerebellar GABAergic transmission by an autoantibody to glutamic acid decarboxylase.

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