IRES mediated translation initiation requires a different repertoire of factors than canonical cap-dependent translation. Treatments that inhibit the canonical translation factor EIF4G1 have little or no effect on the ability of the Insr and Igf1r cellular IRESes to promote translation. Transcripts for two cellular receptors contain RNA elements that facilitate translation initiation without intact EIF4G1. Cellular IRES mechanisms may resemble viral type III IRESes allowing them to promote translate with a limited number of initiation factors allowing them to work under stress conditions when canonical translation is repressed.

The Insulin Receptor and Insulin like Growth Factor Receptor 5' UTRs Support Translation Initiation Independently of EIF4G1.

Molecular and Cellular Biology

In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4&#xa0;mg once weekly administered for 1&#xa0;year decreased body weight and significantly improved quality of life and the 6&#xa0;min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

2024 update in heart failure.

ESC Heart Failure

Background Subclinical thyroid diseases are often the subject of debate concerning their clinical significance, the appropriateness of diagnostic testing and possible treatment. This systematic review addresses the variation in international guidelines for subclinical hyperthyroidism, focusing on diagnostic work-up, treatment, and follow-up recommendations. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched PubMed, Embase, and guideline-specific databases, and included clinical practice guidelines with recommendations on subclinical hyperthyroidism. Guideline recommendations were extracted, and quality assessment was performed using selected questions of the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Results Of the 2,624 records screened, 22 guidelines were included, which were published between 2007 and 2021. Guideline quality was generally intermediate to low. Diagnostic approaches differed substantially, particularly in the extent of recommended testing. Treatment initiation depended on TSH levels, age, and comorbidities, but the level of detail regarding defining precise comorbidities varied. Recommendations for monitoring intervals for follow-up ranged from three to twelve months. Conclusions This review underscores the existing variability in (inter)national guidelines concerning subclinical hyperthyroidism. There is need for clear recommendations in guidelines considering diagnostic work-up, treatment and follow-up of subclinical hyperthyroidism. In order to establish this, future research should focus on determining clear and evidence-based intervention thresholds.

A Systematic Review of Subclinical Hyperthyroidism Guidelines: a Remarkable Range of Recommendations.

European Thyroid Journal

Antibiotics have played a pivotal role in modern medicine, drastically reducing mortality rates associated with bacterial infections. Despite their significant contributions, the emergence of antibiotic resistance has become a formidable challenge, necessitating a re-evaluation of antibiotic use practices. The widespread belief in clinical practice that bactericidal antibiotics are inherently superior to bacteriostatic ones lacks consistent support from evidence in randomized controlled trials (RCTs). With the latest evidence, certain infections have demonstrated equal or even superior efficacy with bacteriostatic agents. Furthermore, within clinical practice, there is a tendency to indiscriminately order urine cultures for febrile patients, even in cases where alternative etiologies might be present. Consequently, upon obtaining a positive urine culture result, patients often receive antimicrobial prescriptions despite the absence of clinical indications warranting such treatment.&#xa0;Furthermore, it is a prevailing notion among physicians that extended durations of antibiotic therapy confer potential benefits and mitigate the emergence of antimicrobial resistance. Contrary to this belief, empirical evidence refutes such assertions. This article aims to address common myths and misconceptions within the field of infectious diseases.

''Myth Busting in Infectious Diseases'': A Comprehensive Review.

Curēus

Guillain-Barr&#xe9; syndrome (GBS) is a potentially devastating yet treatable disorder. A classically postinfectious, immune-mediated, monophasic polyradiculoneuropathy, it is the leading global cause of acquired neuromuscular paralysis. In most cases, the immunopathological process driving nerve injury is ill-defined. Diagnosis of GBS relies on clinical features, supported by laboratory findings and electrophysiology. Although previously divided into primary demyelinating or axonal variants, this dichotomy is increasingly challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma exchange remain the primary modalities of treatment, regardless of the electrophysiological subtype. Most patients recover, but approximately one-third require mechanical ventilation, and 5% die. Disease activity and treatment response are currently monitored through interval neurological examination and outcome measures, and the potential role of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being explored but none have yet modified clinical practice. This review provides a comprehensive update on the pathological and clinical aspects of GBS for clinicians and scientists.

Guillain-Barré syndrome: A comprehensive review.

European Journal of Neurology

The 6th International Conference, "Controversies in Vitamin D," was convened to discuss controversial topics, such as vitamin D metabolism, assessment, actions, and supplementation. Novel insights into vitamin D mechanisms of action suggest links with conditions that do not depend only on reduced solar exposure or diet intake and that can be detected with distinctive noncanonical vitamin D metabolites. Optimal 25-hydroxyvitamin D (25(OH)D) levels remain debated. Varying recommendations from different societies arise from evaluating different clinical or public health approaches. The lack of assay standardization also poses challenges in interpreting data from available studies, hindering rational data pooling and meta-analyses. Beyond the well-known skeletal features, interest in vitamin D's extraskeletal effects has led to clinical trials on cancer, cardiovascular risk, respiratory effects, autoimmune diseases, diabetes, and mortality. The initial negative results are likely due to enrollment of vitamin D-replete individuals. Subsequent post hoc analyses have suggested, nevertheless, potential benefits in reducing cancer incidence, autoimmune diseases, cardiovascular events, and diabetes. Oral administration of vitamin D is the preferred route. Parenteral administration is reserved for specific clinical situations. Cholecalciferol is favored due to safety and minimal monitoring requirements. Calcifediol may be used in certain conditions, while calcitriol should be limited to specific disorders in which the active metabolite is not readily produced in vivo. Further studies are needed to investigate vitamin D effects in relation to the different recommended 25(OH)D levels and the efficacy of the different supplementary formulations in achieving biochemical and clinical outcomes within the multifaced skeletal and extraskeletal potential effects of vitamin D.

Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows.

Endocrine Reviews

Diabetic kidney disease (DKD) is a major microvascular complication of both type 1 and type 2 diabetes. DKD is characterised by injury to both glomerular and tubular compartments, leading to kidney dysfunction over time. It is one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Persistent high blood glucose levels can damage the small blood vessels in the kidneys, impairing their ability to filter waste and fluids from the blood effectively. Other factors like high blood pressure (hypertension), genetics, and lifestyle habits can also contribute to the development and progression of DKD. The key features of renal complications of diabetes include morphological and functional alterations to renal glomeruli and tubules leading to mesangial expansion, glomerulosclerosis, homogenous thickening of the glomerular basement membrane (GBM), albuminuria, tubulointerstitial fibrosis and progressive decline in renal function. In advanced stages, DKD may require treatments such as dialysis or kidney transplant to sustain life. Therefore, early detection and proactive management of diabetes and its complications are crucial in preventing DKD and preserving kidney function.

Diabetes and Renal Complications: An Overview on Pathophysiology, Biomarkers and Therapeutic Interventions.

Biomedicines

The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP.

This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading of Recommendations, Assessment, Development and Evaluations). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations.

The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis.

With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made.

The Insulin Receptor and Insulin like Growth Factor Receptor 5' UTRs Support Translation Initiation Independently of EIF4G1.

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The Insulin Receptor and Insulin like Growth Factor Receptor 5' UTRs Support Translation Initiation Independently of EIF4G1.

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