According to previous reports, intranasal administration of the Cry1Ac protein alone or with amoebic lysates increases protection against Naegleria fowleri meningoencephalitis in mice, apparently by eliciting IgA responses in the nasal mucosa. In the current study, we performed an immunohistochemical analysis of IgA in the nasal mucosa of mice immunized intranasally with Cry1Ac, and amoebic lysates or a combination of both. The animals were sacrificed 24 h after the last immunization or after an intranasal lethal challenge with N. fowleri. Our results indicate that all of the intranasal immunizations provoked an increase in areas with metaplasia in the olfactory epithelium, allowing for secretion of IgA. As a result, IgA antibodies were found interacting with trophozoites in the nasal lumen, and there was a marked increase of IgA in the metaplasic epithelium. On the other hand in nonimmunized mice trophozoites were observed invading the nasal mucosa, which was not the case for immunized mice. Our results suggest that intranasal immunization provokes cellular changes in the olfactory epithelium, leading to greater protection against N. fowleri that is probably caused by an increased secretion of IgA. The increased IgA response induced in the nasal mucosa by immunization probably impedes both amoebic adhesion and subsequent invasion of the parasite to the nasal epithelium.

Intranasal immunization with Naegleria fowleri lysates and Cry1Ac induces metaplasia in the olfactory epithelium and increases IgA secretion.

Parasite Immunology

Acute kidney injury (AKI) is a common clinical syndrome characterized by a sudden decline in or loss of kidney function. AKI is not only associated with substantial morbidity and mortality but also with increased risk of chronic kidney disease (CKD). AKI is classically defined and staged based on serum creatinine concentration and urine output rates. The etiology of AKI is conceptually classified into three general categories: prerenal, intrarenal, and postrenal. Although this classification may be useful for establishing a differential diagnosis, AKI has mostly multifactorial, and pathophysiologic features that can be divided into different categories. Acute tubular necrosis, caused by either ischemia or nephrotoxicity, is common in the setting of AKI. The timely and accurate identification of AKI and a better understanding of the pathophysiological mechanisms that cause kidney dysfunction are essential. In this review, we consider various medical causes of AKI and summarize the most recent updates in the pathogenesis of AKI.

Acute Kidney Injury: Medical Causes and Pathogenesis.

Journal of Clinical Medicine

Hemorrhagic shock (HS) management is based on a timely, rapid, definitive source control of bleeding/s and on blood loss replacement. Stopping the hemorrhage from progressing from any named and visible vessel is the main stem fundamental praxis of efficacy and effectiveness and an essential, obligatory, life-saving step. Blood loss replacement serves the purpose of preventing ischemia/reperfusion toxemia and optimizing tissue oxygenation and microcirculation dynamics. The "physiological classification of HS" dictates the timely management and suits the 'titrated hypotensive resuscitation' tactics and the 'damage control surgery' strategy. In any hypotensive but not yet critical shock, the body's response to a fluid load test determines the cut-off point between compensation and progression between the time for adopting conservative treatment and preparing for surgery or rushing to the theater for rapid bleeding source control. Up to 20% of the total blood volume is given to refill the unstressed venous return volume. In any critical level of shock where, ab initio, the patient manifests signs indicating critical physiology and impending cardiac arrest or cardiovascular accident, the balance between the life-saving reflexes stretched to the maximum and the insufficient distal perfusion (blood, oxygen, and substrates) remains in a liable and delicate equilibrium, susceptible to any minimal change or interfering variable. In a cardiac arrest by exsanguination, the core of the physiological issue remains the rapid restoration of a sufficient venous return, allowing the heart to pump it back into systemic circulation either by open massage via sternotomy or anterolateral thoracotomy or spontaneously after aorta clamping in the chest or in the abdomen at the epigastrium under extracorporeal resuscitation and induced hypothermia. This is the only way to prevent ischemic damage to the brain and the heart. This is accomplishable rapidly and efficiently only by a direct approach, which is a crush laparotomy if the bleeding is coming from an abdominal +/- lower limb site or rapid sternotomy/anterolateral thoracotomy if the bleeding is coming from a chest +/- upper limbs site. Without first stopping the bleeding and refilling the heart, any further exercise is doomed to failure. Direct source control via laparotomy/thoracotomy, with the concomitant or soon following venous refilling, are the two essential, initial life-saving steps.

Management of Hemorrhagic Shock: Physiology Approach, Timing and Strategies.

Pneumonia is frequently encountered in clinical practice, and Gram-negative bacilli constitute a significant proportion of its aetiology, especially when it is acquired in a hospital setting. With the alarming global rise in multidrug resistance in Gram-negative bacilli, antibiotic therapy for treating patients with pneumonia is challenging and must be guided by in vitro susceptibility results. In this review, we provide an overview of antibiotics newly approved for the treatment of pneumonia caused by Gram-negative bacilli. Ceftazidime-avibactam, imipenem-relebactam and meropenem-vaborbactam have potent activity against some of the carbapenem-resistant Enterobacterales, especially Klebsiella pneumoniae carbapenemase producers. Several novel antibiotics have potent activity against multidrug-resistant Pseudomonas aeruginosa , such as ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relabactam and cefiderocol. Cefiderocol may also play an important role in the management of pneumonia caused by Acinetobacter baumannii , along with plazomicin and eravacycline.

New antibiotics for Gram-negative pneumonia.

European Respiratory Review : An Official Journal of the European Respiratory Society

Migraine affects about 1 billion people worldwide, and up to 15% of adults in the United States have migraine attacks in any given year. Migraine is associated with substantial adverse socioeconomic and personal effects. It is the second leading cause of years lived with disability worldwide for all ages and the leading cause in women aged 15 to 49 years. Diagnostic uncertainty increases the likelihood of unnecessary investigations and suboptimal management. This article advises clinicians about diagnosing migraine, ruling out secondary headache disorders, developing acute and preventive treatment plans, and deciding when to refer the patient to a specialist.

Migraine.

Annals of Internal Medicine

Iron deficiency (ID) is the most common nutritional disorder worldwide. It is often observed in patients with chronic diseases, such as heart failure (HF), chronic kidney disease (CKD), inflammatory bowel disease (IBD) and cancer. ID is associated with poor clinical outcome, including poor performance, reduced quality of life, as well as increased hospitalization and mortality. The aim of this review is to provide an overview about the role of ID in chronic diseases (HF, CKD, IBD, cancer) regarding their current definitions and clinical relevance; diagnostic accuracy of iron parameters in chronic inflammatory conditions and its potential as prognostic markers. Due to different definitions and guideline recommendations of ID, various laboratory parameters for ID diagnostic exist and there is no general consensus about the definition of ID and its treatment. Still, a general trend can be observed across all investigated indications of this review (HF, CKD, IBD, cancer) that serum ferritin and transferrin saturation (TSAT) are the two parameters mentioned most often and emphasized in all guidelines to define ID and guide treatment. The most commonly used threshold values for the diagnosis of ID are TSAT of&#x2009;&lt;&#x2009;20% and serum ferritin of&#x2009;&lt;&#x2009;100-300&#xa0;&#xb5;g/L. Noteworthy, both TSAT and particularly ferritin are frequently applied, but both may vary due to inflammatory conditions. Studies showed that TSAT is less affected by inflammatory processes and may therefore be more accurate and reliable than serum ferritin, particularly in conditions with elevated inflammatory state. A low iron status and particularly a low TSAT value was associated with a poor outcome in all investigated indications, with the strongest evidence in HF patients. Routine surveillance of iron status in these groups of patients with chronic conditions is advisable to detect ID early. Depending on the inflammatory state, TSAT&#x2009;&lt;&#x2009;20% may be the more accurate diagnostic marker of ID than ferritin. Moreover, TSAT may also be the more reliable estimate for the prognosis, particularly in HF.

How to diagnose iron deficiency in chronic disease: A review of current methods and potential marker for the outcome.

European Journal of Medical Research

Obesity is a chronic disease associated with serious complications and increased mortality. Weight loss through lifestyle changes results in modest weight loss long-term possibly due to compensatory biological adaptations (increased appetite and reduced energy expenditure) promoting weight gain. Bariatric surgery was until recently the only intervention that consistently resulted in&#x2009;&#x2265;&#x2009;15% weight loss and maintenance. Our better understanding of the endocrine regulation of appetite has led to the development of new medications over the last decade for treatment of obesity with main target the reduction of appetite. The efficacy of semaglutide 2.4&#x2005;mg/week - the latest glucagon like peptide-1 (GLP-1) receptor analogue - on weight loss for people with obesity suggests that we are entering a new era in obesity pharmacotherapy where &#x2265;15% weight loss is feasible. Moreover, the weight loss achieved with the dual agonist tirzepatide (GLP-1/glucose-dependent insulinotropic polypeptide) for people with type 2 diabetes and most recently also obesity, indicate that combining the GLP-1 with other gut hormones may lead to additional weight loss compared to GLP-1 receptor analogues alone and in the future, multi-agonist molecules may offer the potential to bridge further the efficacy gap between bariatric surgery and the currently available pharmacotherapies. This article provides a review of the currently available interventions for weight loss and weight maintenance with a focus on pharmacological therapies for obesity approved over the last decade, as well as the emerging development of new obesity pharmacotherapies.

New therapies for obesity.

Cardiovascular Research

Diabetic kidney disease is highly prevalent in patients with type 2 diabetes and is a major cause of end-stage renal disease in Switzerland. Patients with diabetic kidney disease are among the most complex patients in diabetes care. They require a multifactorial and multidisciplinary approach with the goal to slow the decline in glomerular filtration rate (GFR) and cardiovascular morbidity. With this consensus we propose an evidence-based guidance to health care providers involved in the care of type 2 diabetic patients with diabetic kidney disease.First, there is a need to increase physician awareness and improve screening for diabetic kidney disease as early intervention may improve clinical outcomes and the financial burden. Evaluation of estimated GFR (eGFR) and spot urine albumin/creatinine ratio is recommended at least annually. Once it is diagnosed, glucose control and optimisation of blood pressure control with renin-angiotensin system blockers have been recommended as mainstay management of diabetic kidney disease for more than 20 years. Recent, high quality randomised controlled trials have shown that sodium-glucose cotransporter-2 (SGLT2) inhibition slows eGFR decline and cardiovascular events beyond glucose control. Likewise, mineralocorticoid receptor antagonism with finerenone has cardiorenal protective effects in diabetic kidney disease. Glucagon-like peptide-1 (GLP1) receptor agonists improve weight loss if needed, and decrease albuminuria and cardiovascular morbidity. Lipid control is also important to decrease cardiovascular events. All these therapies are included in the treatment algorithms proposed in this consensus. With advancing kidney failure, other challenges may rise, such as hyperkalaemia, anaemia and metabolic acidosis, as well as chronic kidney disease-mineral and bone disorder. These different topics and treatment strategies are discussed in this consensus. Finally, an update on diabetes management in renal replacement therapy such as haemodialysis, peritoneal dialysis and renal transplantation is provided. With the recent developments of efficient therapies for diabetic kidney disease, it has become evident that a consensus document is necessary. We are optimistic that it will significantly contribute to a high-quality care for patients with diabetic kidney disease in Switzerland in the future.

Diabetic kidney disease in type 2 diabetes: a consensus statement from the Swiss Societies of Diabetes and Nephrology.

Swiss Medical Weekly

Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus&#xa0;2 (SARS-CoV-2) infections. More than 200 symptoms have been identified with impacts on multiple organ systems. At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily. Biomedical research has made substantial progress in identifying various pathophysiological changes and risk factors and in characterizing the illness; further, similarities with other viral-onset illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome have laid the groundwork for research in the field. In this Review, we explore the current literature and highlight key findings, the overlap with other conditions, the variable onset of symptoms, long COVID in children and the impact of vaccinations. Although these key findings are critical to understanding long COVID, current diagnostic and treatment options are insufficient, and clinical trials must be prioritized that address leading hypotheses. Additionally, to strengthen long COVID research, future studies must account for biases and SARS-CoV-2 testing issues, build on viral-onset research, be inclusive of marginalized populations and meaningfully engage patients throughout the research process.

Long COVID: major findings, mechanisms and recommendations.

Nature Reviews. Microbiology

The association of chronic heart failure (CHF) and iron deficiency (ID) with or without anemia is frequently encountered in current medical practice and has a negative prognostic impact, worsening patients' exercise capacity and increasing hospitalization costs. Moreover, anemia is common in patients with chronic kidney disease (CKD) and CHF, an association known as cardio-renal anemia syndrome (CRAS) possessing a significantly increased risk of death.

This review aims to provide an illustrative survey on the impact of ID in CHF patients-based on physiopathological traits, clinical features, and the correlation between functional and absolute ID with CHF-and the benefit of iron supplementation in CHF.

We selected the most recent publications with important scientific content covering the association of CHF and ID with or without anemia.

An intricate physiopathological interplay is described in these patients-decrease in erythropoietin levels, activation of the renin-angiotensin-aldosterone system, systemic inflammation, and increases in hepcidin levels. These mechanisms amplify anemia, CHF, and CKD severity and worsen patients' outcomes.

Anemia is frequently encountered in CHF and represents a negative prognostic factor. Data from randomized controlled trials have underlined the administration of intravenous iron therapy (ferric carboxymaltose) as the only viable treatment option, with beneficial effects on quality of life and exercise capacity in patients with ID and systolic heart failure.

Intranasal immunization with Naegleria fowleri lysates and Cry1Ac induces metaplasia in the olfactory epithelium and increases IgA secretion.

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Intranasal immunization with Naegleria fowleri lysates and Cry1Ac induces metaplasia in the olfactory epithelium and increases IgA secretion.

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