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BackgroundHigh dietary sodium intake is a major cardiovascular risk factor and adversely affects blood pressure control. Patients with primary aldosteronism (PA) are at increased cardiovascular risk, even after medical treatment, and high dietary sodium intake is common in these patients. Here, we analyze the impact of a moderate dietary sodium restriction on microbiome composition and immunophenotype in patients with PA.MethodsProspective two-stage clinical trial including two subgroups: 15 treatment-naive PA patients compared to matched normotensive controls; and 31 PA patients on mineralocorticoid receptor antagonist treatment before and three months after sodium restriction. Patients underwent blood pressure measurements, laboratory tests, analysis of peripheral blood mononuclear cells via flow cytometry and microbiome analysis.ResultsWe observed a higher percentage of Tregs in treatment-naive PA patients (p = 0.0303), while the abundance of Bacteroides uniformis was higher in PA patients compared to normotensive controls (p = 0.00027) and the abundance of Lactobacillus species however was higher in the subgroup of normotensive controls (p = 0.0290). Sodium restriction was accompanied by a decrease in pro-inflammatory Tc17 cells in male patients (p = 0.0081, females p = 0.3274). Bacteroides uniformis abundance was higher in female patients (0.01230, p = 0.0016) and decreased upon sodium restriction (0.002309, p = 0.0068).ConclusionDietary sodium restriction in patients with PA modulates the peripheral immune cell composition toward a less inflammatory phenotype. This suggests a potential mechanism by which sodium reduction modulates immune cell composition, leading to blood pressure reduction and positively impacting cardiovascular risk.

Introduction: The competency-based catalogue of learning objectives “Principal Relevant Objectives and Framework for Integrative Learning and Education in Switzerland” (PROFILES) based on Entrustable Professional Activities (EPAs) was newly introduced in 2018 in undergraduate medical education in Switzerland. Clerkships provide opportunities for students to train clinical skills and competencies within the curriculum. This study aims to assess the students’ experiences during paediatric clerkships and whether they achieve the expected competency level of certain EPAs by the end of their training.Methods: An online survey was conducted among all 316 students in their last year of medical school (3 year master) enrolled at the University of Zurich. A total of 113 students who had completed a clerkship in paediatrics in different hospitals, were asked about their general expectations and experiences, and to rate their achievement of competency levels in 26 selected EPAs. An EPA was considered accomplished if a minimum of 2/3 of all students reached at least level 3.Results: Paediatric clerkship was generally viewed as positive experience by most students. However, a desire for more integration into clinical teams, increased training in clinical skills, and feedback was expressed. The expected level 3 of competency (indirect supervision) was achieved in 14 out of 26 EPAs by at least 2/3 of students. Level 3 was however not reached for more specific EPAs such as neonatal examination, rating of psychomotor and pubertal development, and clinical reasoning. Conclusion: Paediatric clerkships are regarded as valuable clinical training opportunities. To enhance the learning of competencies, integration into clinical teams and faculty training is crucial. The implementation of EPAs in the clinical context aligns with these goals.

Non-Helicobacter pylori Helicobacters (NHPHs) represent a group of bacteria distinct from H. pylori. They are commonly found in the gastrointestinal tracts of animals, such as poultry, swine, and domestic pets. Recent studies have demonstrated that these organisms have implications beyond animal hosts, indicating a potential role in human gastric diseases and raising concerns about the possibility of zoonotic transmission. Different NHPH species can cause gastritis, ulcerations, and even systemic effects like bacteremia in human individuals. A comprehensive literature search protocol on MEDLINE (PubMed) from the last twelve months was employed, resulting in the identification of 24 articles and case studies on NHPHs in animals and 12 in humans, respectively. Furthermore, we conducted a search for Helicobacter species other than H. pylori that are referenced individually in the National Library of Medicine database. The most recent studies have focused on the clinical manifestations and diagnostic challenges of NHPHs-related diseases in animal models and human cases. An important subject was the transmission of disease between different species, particularly those associated with livestock farming. The results suggest that NHPHs, especially H. pullorum, H. suis, and H. cinaedi, may be a significant contributing factor in the development of gastrointestinal diseases in humans, particularly in instances where H. pylori is not present. Although there has been a significant improvement in the overall awareness regarding NHPH infections, it remains a challenge to identify new species and distinguish between low and high pathogenicity levels. Further research is needed to understand how NHPH impacts human health, with a focus on improved diagnostic tools and treatment strategies.

Background Pharmacological treatment options for patients with dementia owing to Alzheimer's disease are limited to symptomatic therapy. Recently, the US Food and Drug Administration approved the monoclonal antibody lecanemab for the treatment of amyloid-positive patients with mild cognitive impairment (MCI) and early Alzheimer´s dementia. European approval is expected in 2024. Data on the applicability and eligibility for treatment with anti-amyloid monoclonal antibodies outside of a study population are lacking. Aims This study examined eligibility criteria for lecanemab in a real-world memory clinic population between 1 January 2022 and 31 July 2023. Method We conducted a retrospective, single-centre study applying the clinical trial eligibility criteria for lecanemab to out-patients of a specialised psychiatric memory clinic. Eligibility for anti-amyloid treatment was assessed following the phase 3 inclusion and exclusion criteria and the published recommendations for lecanemab. Results The study population consisted of 587 out-patients. Two-thirds were diagnosed with Alzheimer's disease (probable or possible Alzheimer's disease dementia in 43.6% of cases, n = 256) or MCI (23%, n = 135), and 33.4% (n = 196) were diagnosed with dementia or neurocognitive disorder owing to another aetiology. Applying all lecanemab eligibility criteria, 11 (4.3%) patients with dementia and two (1.5%) patients with MCI would have been eligible for treatment with this compound, whereas 13 dementia (5.1%) and 14 (10.4%) MCI patients met clinical inclusion criteria, but had no available amyloid status. Conclusions Even in a memory clinic with a good infrastructure and sufficient facilities for dementia diagnostics, most patients do not meet the eligibility criteria for treatment with lecanemab.

Abstract Background Thyroid physiology is closely related to oxidative changes. The aim of this controlled study was to evaluate the levels of nutritional anti-oxidants such as vitamin C, zinc (Zn) and selenium (Se), and to investigate any association of them with parameters of thyroid function and pathology including benign and malignant thyroid diseases. Methods This controlled evaluation of Se included a total of 1401 subjects (1186 adults and 215 children) distributed as follows: control group (n = 687), benign thyroid disease (85 children and 465 adults); malignant thyroid disease (2 children and 79 adults). Clinical evaluation of patients with benign thyroid disease included sonography, scintigraphy, as well as the determination of fT3, fT4, TSH, thyroid antibodies levels, Se, Zn, and vitamin C. Besides the routine oncological parameters (TG, TSH, fT4, ultrasound) Se was also determined in the cases of malignant disease. The local control groups for the evaluation of Se levels were taken from a general practice (WOMED) as well as from healthy active athletes. Blood samples were collected between 8:00 and 10:30 a.m. All patients lived in Innsbruck. Statistical analysis was done using SPSS 14.0. The Ho stated that there should be no differences in the levels of antioxidants between controls and thyroid disease patients. Results Among the thyroid disease patients neither vitamin C, nor Zn nor Se correlated with any of the following parameters: age, sex, BMI, body weight, thyroid scintigraphy, ultrasound pattern, thyroid function, or thyroid antibodies. The proportion of patients with benign thyroid diseases having analyte concentrations below external reference cut off levels were 8.7% of cases for vitamin C; 7.8% for Zn, and 20.3% for Se. Low Se levels in the control group were found in 12%. Se levels were significantly decreased in cases of sub-acute and silent thyroiditis (66.4 ± 23.1 μg/l and 59.3 ± 20.1 μg/l, respectively) as well as in follicular and papillary thyroid carcinoma. The mean Se level in the control group was 90.5 ± 20.8 μg/l. Conclusion The H0 can be accepted for vitamin C and zinc levels whereas it has to be rejected for Se. Patients with benign or malignant thyroid diseases can present low Se levels as compared to controls. Low levels of vitamin C were found in all subgroups of patients.

Introduction Fifty per cent of patients with cancer require radiotherapy during their disease course, however, only 10%–40% of patients in low-income and middle-income countries (LMICs) have access to it. A shortfall in specialised workforce has been identified as the most significant barrier to expanding radiotherapy capacity. Artificial intelligence (AI)-based software has been developed to automate both the delineation of anatomical target structures and the definition of the position, size and shape of the radiation beams. Proposed advantages include improved treatment accuracy, as well as a reduction in the time (from weeks to minutes) and human resources needed to deliver radiotherapy.Methods ARCHERY is a non-randomised prospective study to evaluate the quality and economic impact of AI-based automated radiotherapy treatment planning for cervical, head and neck, and prostate cancers, which are endemic in LMICs, and for which radiotherapy is the primary curative treatment modality. The sample size of 990 patients (330 for each cancer type) has been calculated based on an estimated 95% treatment plan acceptability rate. Time and cost savings will be analysed as secondary outcome measures using the time-driven activity-based costing model. The 48-month study will take place in six public sector cancer hospitals in India (n=2), Jordan (n=1), Malaysia (n=1) and South Africa (n=2) to support implementation of the software in LMICs.Ethics and dissemination The study has received ethical approval from University College London (UCL) and each of the six study sites. If the study objectives are met, the AI-based software will be offered as a not-for-profit web service to public sector state hospitals in LMICs to support expansion of high quality radiotherapy capacity, improving access to and affordability of this key modality of cancer cure and control. Public and policy engagement plans will involve patients as key partners.

BACKGROUND: RET mutations occur in 70% of medullary thyroid cancers, and RET fusions occur rarely in other thyroid cancers. In patients with RET-altered thyroid cancers, the efficacy and safety of selective RET inhibition are unknown. METHODS: We enrolled patients with RET-mutant medullary thyroid cancer with or without previous vandetanib or cabozantinib treatment, as well as those with previously treated RET fusion-positive thyroid cancer, in a phase 1-2 trial of selpercatinib. The primary end point was an objective response (a complete or partial response), as determined by an independent review committee. Secondary end points included the duration of response, progression-free survival, and safety. RESULTS: In the first 55 consecutively enrolled patients with RET-mutant medullary thyroid cancer who had previously received vandetanib, cabozantinib, or both, the percentage who had a response was 69% (95% confidence interval [CI], 55 to 81), and 1-year progression-free survival was 82% (95% CI, 69 to 90). In 88 patients with RET-mutant medullary thyroid cancer who had not previously received vandetanib or cabozantinib, the percentage who had a response was 73% (95% CI, 62 to 82), and 1-year progression-free survival was 92% (95% CI, 82 to 97). In 19 patients with previously treated RET fusion-positive thyroid cancer, the percentage who had a response was 79% (95% CI, 54 to 94), and 1-year progression-free survival was 64% (95% CI, 37 to 82). The most common adverse events of grade 3 or higher were hypertension (in 21% of the patients), increased alanine aminotransferase level (in 11%), increased aspartate aminotransferase level (in 9%), hyponatremia (in 8%), and diarrhea (in 6%). Of all 531 patients treated, 12 (2%) discontinued selpercatinib owing to drug-related adverse events. CONCLUSIONS: In this phase 1-2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with medullary thyroid cancer with and without previous vandetanib or cabozantinib treatment. (Funded by Loxo Oncology and others; LIBRETTO-001 ClinicalTrials.gov number, NCT03157128.).

Background: High dietary sodium intake is a major cardiovascular risk factor and adversely affects blood pressure control. Patients with primary aldosteronism (PA) are at increased cardiovascular risk, even after medical treatment, and high dietary sodium intake is common in these patients. Here, we analyze the impact of a moderate dietary sodium restriction on microbiome composition and immunophenotype in patients with PA. Methods: Prospective two-stage clinical trial including two subgroups: 15 treatment-naive PA patients compared to matched normotensive controls; and 31 PA patients on mineralocorticoid receptor antagonist treatment before and three months after sodium restriction. Patients underwent blood pressure measurements, laboratory tests, analysis of peripheral blood mononuclear cells via flow cytometry and microbiome analysis. Results: We observed a higher percentage of Tregs in treatment-naive PA patients (p = 0.0303), while the abundance of Bacteroides uniformis was higher in PA patients compared to normotensive controls (p = 0.00027) and the abundance of Lactobacillus species however was higher in the subgroup of normotensive controls (p = 0.0290). Sodium restriction was accompanied by a decrease in pro-inflammatory Tc17 cells in male patients (p = 0.0081, females p = 0.3274). Bacteroides uniformis abundance was higher in female patients (0.01230, p = 0.0016) and decreased upon sodium restriction (0.002309, p = 0.0068). Conclusion: Dietary sodium restriction in patients with PA modulates the peripheral immune cell composition toward a less inflammatory phenotype. This suggests a potential mechanism by which sodium reduction modulates immune cell composition, leading to blood pressure reduction and positively impacting cardiovascular risk. [ABSTRACT FROM AUTHOR]

Objective The effects of sex hormones remain largely unexplored in pheochromocytomas and paragangliomas (PPGLs) and gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods We evaluated the effects of estradiol, progesterone, Dehydroepiandrosterone sulfate (DHEAS), and testosterone on human patient-derived PPGL/GEP-NET primary culture cell viability (n = 38/ n = 12), performed next-generation sequencing and immunohistochemical hormone receptor analysis in patient-derived PPGL tumor tissues (n = 36). Results In PPGLs, estradiol and progesterone (1 µ m) demonstrated overall significant antitumor effects with the strongest efficacy in PPGLs with NF1 (cluster 2) pathogenic variants. Estrogen receptor alpha (ERα) positivity was detected in 11/36 PPGLs, including 4/4 head-and-neck paragangliomas (HNPGLs). ERα–positive tumors responded with a significant cell viability decrease to estradiol. DHEAS and testosterone (1 µ m) displayed no effects, but higher doses of testosterone (10 µ m) demonstrated significant antitumor effects, including a pheochromocytoma lung metastasis with strong androgen receptor positivity (30%). Driven by the antitumor effects of estrogen, we evaluated G-protein-coupled estrogen receptor (GPER) agonist G-1 as a potential therapeutic option for PPGLs and found strong significant antitumor potential, with the strongest efficacy in tumors with NF1 pathogenic variants. Moreover, we detected sex-related differences—tumors from male patients showed significantly stronger responsivity to G-1 compared with tumors from female patients. In GEP-NETs, sex hormones showed overall no effects, especially no tumor growth-promoting effects. Conclusion We provide novel data on the effects of elevated sex hormone levels, potentially seen during pregnancy or hormone replacement therapy, on PPGL/GEP-NET tumor growth. G-1 might offer a novel therapeutic approach for some PPGLs depending on patient's sex and the individual tumor's genetic/molecular background. All HNPGLs showed ERα positivity. [ABSTRACT FROM AUTHOR]

Objective Cushing's syndrome (CS) results in increased cardiovascular (CV) morbidity and mortality. Subtype-specific differences and possible reversibility after biochemical cure are not well investigated. Design Prospective cohort study evaluating the CV status in different forms of endogenous cortisol excess. Methods Patients with overt CS (n = 40, 47 ± 13 years, 75% women; 18 pituitary, 13 adrenal, and 9 ectopic), biochemically cured CS (n = 56, 53 ± 12 years, 79% women; 30 pituitary, 21 adrenal, and 5 ectopic), and adrenal incidentalomas with mild autonomous cortisol secretion (MACS) (n = 18, 62 ± 11 years, 56% women) underwent comprehensive biochemical, metabolic, and CV assessment. Results were compared with a representative sample of the general population of Würzburg (n = 4965, 55 ± 12 years, 52% women). Results Overt CS was associated with left ventricular (LV) remodeling along with hypertrophy and impaired longitudinal systolic/diastolic function at echocardiography. In 20 CS patients followed for a median of 8 (quartiles: 6, 11) months after biochemical remission, hypertension, and hyperglycemia were better controlled, while cardiac alterations only partially improved. Patients with previous CS (median time of biochemical remission: 95 [36, 201] months) had worse diastolic function than the general population (LV relaxation velocity e′ 0.08 [0.07, 0.10] ms−1 vs 0.10 [0.08, 0.12] ms−1, P <.001). In MACS, cardiac remodeling was even more pronounced than in individuals with metabolic syndrome. Conclusions In patients with overt CS, cured CS, and MACS, we found a sizable and significant deviation from the general population mean regarding cardiac structure and function. Even mild cortisol excess is associated with glucocorticoid-induced cardiac alterations, which appear to persist despite long-term biochemical remission. [ABSTRACT FROM AUTHOR]