It has long been known from work in both Drosophila and vertebrate systems that the hedgehog signalling pathway is pivotal to embryonic development, but the past 5 years has seen an increase in our understanding of how members of this pathway are crucial to the processes of tumorigenesis. This important link was firmly established with the discovery that mutations in the gene encoding the hedgehog receptor molecule patched are responsible for both familial and sporadic forms of basal cell carcinoma (BCC), as well as a number of other tumour types. It is now known that a number of key members of the hedgehog cascade are involved in tumorigenesis, and dysregulation of this pathway appears to be a key element in the aetiology of a range of tumours.

The role of hedgehog signalling in tumorigenesis.

Cancer Letters

Carvedilol, probably the β-blocker of choice for everyone with cirrhosis and portal hypertension: But not so fast!

Liver International : Official Journal of the International Association for the Study of the Liver

Syncope is a concerning symptom that affects a large proportion of patients. It can be related to a heterogeneous group of pathologies ranging from trivial causes to diseases with a high risk of sudden death. However, benign causes are the most frequent, and identifying high-risk patients with potentially severe etiologies is crucial to establish an accurate diagnosis, initiate effective therapy, and alter the prognosis. The term cardiac syncope refers to those episodes where the cause of the cerebral hypoperfusion is directly related to a cardiac disorder, while arrhythmic syncope is cardiac syncope specifically due to rhythm disorders. Indeed, arrhythmias are the most common cause of cardiac syncope. Both bradyarrhythmia and tachyarrhythmia can cause a sudden decrease in cardiac output and produce syncope. In this review, we summarized the main guidelines in the management of patients with syncope of presumed arrhythmic origin. Therefore, we presented a thorough approach to syncope work-up through different tests depending on the clinical characteristics of the patients, risk stratification, and the management of syncope in different scenarios such as structural heart disease and channelopathies.

Arrhythmic syncope: From diagnosis to management.

World Journal of Cardiology

Glomerulonephritis (GN) is a diverse group of immune-mediated disorders. Currently, GN is classified largely by histological patterns that are difficult to understand and teach and most importantly, do not indicate treatment choices. Indeed, altered systemic immunity is the primary pathogenic process and the key therapeutic target in GN. Here, we apply a conceptual framework of immune-mediated disorders to GN guided by immunopathogenesis and hence immunophenotyping: 1) Infection-related GN require pathogen identification and control, 2) Autoimmunity-related GN, defined by presence of autoantibodies, and 3) Alloimmunity-related GN in transplant recipients both require the suppression of adaptive immunity in lymphoid organs and bone marrow, 4) Autoinflammation-related GN, e.g. inborn errors of immunity diagnosed by genetic testing, requires suppression of single cytokine or complement pathways, and 5) Monoclonal gammopathy-related GN requires B or plasma cell clone-directed therapy. A new GN classification should include a) disease category, b) immunological activity to tailor the use of the increasing number of immunomodulatory drugs, and c) chronicity to trigger standard CKD care including the evolving spectrum of cardio-renoprotective drugs. Certain biomarkers allow diagnosis and the assessment of immunological activity and disease chronicity without kidney biopsy. These five GN categories and a therapy-focused GN classification is likely to overcome some of the existing hurdles in GN research, management, and teaching by reflecting disease pathogenesis and guiding the therapeutic approach.

The five types of glomerulonephritis classified by pathogenesis, activity, and chronicity (GN-AC).

Nephrology, Dialysis, Transplantation

Chronic idiopathic constipation (CIC) is a common disorder associated with significant impairment in quality of life. This clinical practice guideline, jointly developed by the American Gastroenterological Association and the American College of Gastroenterology, aims to inform clinicians and patients by providing evidence-based practice recommendations for the pharmacological treatment of CIC in adults.

The American Gastroenterological Association and the American College of Gastroenterology formed a multidisciplinary guideline panel that conducted systematic reviews of the following agents: fiber, osmotic laxatives (polyethylene glycol, magnesium oxide, lactulose), stimulant laxatives (bisacodyl, sodium picosulfate, senna), secretagogues (lubiprostone, linaclotide, plecanatide), and serotonin type 4 agonist (prucalopride). The panel prioritized clinical questions and outcomes and used the Grading of Recommendations Assessment, Development, and Evaluation framework to assess the certainty of evidence for each intervention. The Evidence to Decision framework was used to develop clinical recommendations based on the balance between the desirable and undesirable effects, patient values, costs, and health equity considerations.

The panel agreed on 10 recommendations for the pharmacological management of CIC in adults. Based on available evidence, the panel made strong recommendations for the use of polyethylene glycol, sodium picosulfate, linaclotide, plecanatide, and prucalopride for CIC in adults. Conditional recommendations were made for the use of fiber, lactulose, senna, magnesium oxide, and lubiprostone.

This document provides a comprehensive outline of the various over-the-counter and prescription pharmacological agents available for the treatment of CIC. The guidelines are meant to provide a framework for approaching the management of CIC; clinical providers should engage in shared decision making based on patient preferences as well as medication cost and availability. Limitations and gaps in the evidence are highlighted to help guide future research opportunities and enhance the care of patients with chronic constipation.

American Gastroenterological Association-American College of Gastroenterology Clinical Practice Guideline: Pharmacological Management of Chronic Idiopathic Constipation.

Gastroenterology

The goal of hemodynamic resuscitation is to optimize the microcirculation of organs to meet their oxygen and metabolic needs. Clinicians are currently blind to what is happening in the microcirculation of organs, which prevents them from achieving an additional degree of individualization of the hemodynamic resuscitation at tissue level. Indeed, clinicians never know whether optimization of the microcirculation and tissue oxygenation is actually achieved after macrovascular hemodynamic optimization. The challenge for the future is to have noninvasive, easy-to-use equipment that allows reliable assessment and immediate quantitative analysis of the microcirculation at the bedside. There are different methods for assessing the microcirculation at the bedside; all have strengths and challenges. The use of automated analysis and the future possibility of introducing artificial intelligence into analysis software could eliminate observer bias and provide guidance on microvascular-targeted treatment options. In addition, to gain caregiver confidence and support for the need to monitor the microcirculation, it is necessary to demonstrate that incorporating microcirculation analysis into the reasoning guiding hemodynamic resuscitation prevents organ dysfunction and improves the outcome of critically ill patients.

The future of intensive care: the study of the microcirculation will help to guide our therapies.

Critical Care : the Official Journal of the Critical Care Forum

Renin-angiotensin system inhibitors (RAS) inhibitors include angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors decrease proteinuria, progression of chronic kidney disease (CKD), and protect against heart failure hospitalizations and cardiovascular events. There is uncertainty about the appropriate time for discontinuing ARB and ACE inhibitor treatment in patients with low estimated glomerular filtration rate (eGFR). In the present meta-analysis, we examined the effect of RAS inhibitor discontinuation on clinical outcomes in patients with advanced CKD compared to the continuation of RAS inhibitors. Two authors conducted electronic database searches in PubMed, the Cochrane Library, and Excerpta Medica Database (EMBASE) for relevant studies published from the inception of the databases to March 15th, 2023, using the following combination of keywords or key terms: "Renin-angiotensin-system," "angiotensin-converting-enzyme inhibitors", "Angiotensin receptor blockers," and "advanced chronic kidney disease."&#xa0;Primary outcomes assessed in this meta-analysis included cardiovascular events. Secondary outcomes assessed included all-cause mortality and end-stage kidney disease (ESKD). A total of four studies were included in this meta-analysis.&#xa0;The pooled analysis showed that&#xa0;cardiovascular events&#xa0;were significantly higher in patients in the discontinuation group compared to the continuation group (HR: 1.38, 95% CI: 1.21-1.58), ESKD was also significantly higher in the discontinuation group (HR: 1.29, 95% CI: 1.18-1.41). No significant differences were reported between the two groups in all-cause mortality.&#xa0;In conclusion, our meta-analysis provides evidence that continuation of RAS inhibitors could be beneficial in patients with advanced CKD, as it is associated with less risk of cardiovascular events and ESKD.

Effect of Discontinuation of Renin Angiotensin-System Inhibitors in Patients With Advanced Chronic Kidney Disease: A Meta-Analysis.

Curēus

Invasive candidiasis (IC) is a serious infection caused by several Candida species, and the most common fungal disease in hospitals in high-income countries. Despite overall improvements in health systems and ICU care in the last few decades, as well as the development of different antifungals and microbiological techniques, mortality rates in IC have not substantially improved. The aim of this review is to summarize the main issues underlying the management of adults affected by IC, focusing on specific forms of the infection: IC developed by ICU patients, IC observed in haematological patients, breakthrough candidaemia, sanctuary site candidiasis, intra-abdominal infections and other challenging infections. Several key challenges need to be tackled to improve the clinical management and outcomes of IC patients. These include the lack of global epidemiological data for IC, the limitations of the diagnostic tests and risk scoring tools currently available, the absence of standardized effectiveness outcomes and long-term data for IC, the timing for the initiation of antifungal therapy and the limited recommendations on the optimal step-down therapy from echinocandins to azoles or the total duration of therapy. The availability of new compounds may overcome some of the challenges identified and increase the existing options for management of chronic Candida infections and ambulant patient treatments. However, early identification of patients that require antifungal therapy and treatment of sanctuary site infections remain a challenge and will require further innovations.

The role of hedgehog signalling in tumorigenesis.

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