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Abstract Iron homoeostasis is tightly regulated, with hepcidin and soluble transferrin receptor (sTfR) playing significant roles. However, the genetic determinants of these traits and the biomedical consequences of iron homoeostasis variation are unclear. In a meta-analysis of 12 cohorts involving 91,675 participants, we found 43 genomic loci associated with either hepcidin or sTfR concentration, of which 15 previously unreported. Mapping to putative genes indicated involvement in iron-trait expression, erythropoiesis, immune response and cellular trafficking. Mendelian randomisation of 292 disease outcomes in 1,492,717 participants revealed associations of iron-related loci and iron status with selected health outcomes across multiple domains. These associations were largely driven by HFE, which was associated with the largest iron variation. Our findings enhance understanding of iron homoeostasis and its biomedical consequences, suggesting that lifelong exposure to higher iron levels is likely associated with lower risk of anaemia-related disorders and higher risk of genitourinary, musculoskeletal, infectious and neoplastic diseases.

Background Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome‐wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results We performed genome‐wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2‐stage analysis (genome‐wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single‐stage genome‐wide meta‐analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2‐degrees of freedom joint main and interaction and 1‐degree of freedom interaction P values. In 2‐stage and single‐stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2‐degrees of freedom joint main and interaction P value

(1) Background: Granulicatella adiacens is a former nutritionally variant streptococci (NVS). NVS infective endocarditis (IE) is generally characterized by a higher rate of morbidity and mortality, partially due to difficulties in choosing the most adequate microbiological culture method and the most effective treatment strategy, and partially due to higher rates of complications, such as heart failure, peripheral septic embolism, and peri-valvular abscess, as well as a higher rate of valve replacement. Depending on the affected valve (native valve endocarditisNVE, or prosthetic valve endocarditisPVE), the American Heart Association (AHA) 2015 treatment guidelines (GLs) suggest penicillin G, ampicillin, or ceftriaxone plus gentamicin (2 weeks for NVE and up to 6 weeks for PVE), while vancomycin alone may be a reasonable alternative in patients who are intolerant of β-lactam therapy. The European Society of Cardiology (ESC) 2023 GLs recommend treating NVE with penicillin G, ceftriaxone, or vancomycin for 6 weeks, suggesting combined with an aminoglycoside (AG) for at least the first 2 weeks only for PVE; likewise, the same recommendations for IE due to Enterococcus faecalis. (2) Methods: Starting from the case of a 51-year-old man with G. adiacens aortic bio-prosthesis IE who was successfully treated with aortic valve replacement combined with double beta-lactams, an AG-sparing regimen, we performed microbiology tests in order to validate this potential treatment change. (3) Results: As for E. faecalis IE, we found that the combination of ampicillin plus cephalosporines (like ceftriaxone or ceftobiprole) showed a synergistic effect in vitro, probably due to wider binding to penicillin-binding proteins (PBPs), thus contributing to enhanced bacterial killing and good clinical outcome, as well as avoiding the risk of nephrotoxicity due to AG association therapy. (4) Conclusions: Further studies are required to confirm this hypothesis, but double beta-lactams and an adequate sourcecontrol could be a choice in treating G. adiacens IE.

In this paper, we report the scientific experience of HELMeTO 2020, the second edition of the International Workshop on Higher Education Learning Methodologies and Technologies Online, held virtually in Bari (Italy) in September 2020 because of the COVID-19 pandemic. The call received 59 proposals from nine countries, 39 papers were accepted to the virtual workshop and 26 full papers were finally selected to be published in the proceedings. The workshop illustrated a fast-developing scenario in which the epidemic emergency accelerated the dissemination and consolidation of online learning in higher education. A specific focus of the workshop can be identified as students' learning experience, with studies on tutoring and active learning approaches, personalized solutions supported by data analysis, virtual reality and an in-depth analysis of human-computer interactions.

Background: In patient with a complete or near-complete clinical response after neoadjuvant treatment for locally advanced rectal cancer, the organ-sparing approach [watch & wait (W&W) or local excision (LE)] is a possible alternative to major rectal resection. Although, in case of local recurrence or regrowth, after these treatments, a total mesorectal excision (TME) can be operated. Method: In this retrospective study, we selected 120 patients with locally advanced rectal cancer (LARC) who had a complete or near-complete clinical response after neoadjuvant treatment, from June 2011 to June 2021. Among them, 41 patients were managed by W&W approach, whereas 79 patients were managed by LE. Twenty-three patients underwent salvage TME for an unfavorable histology after LE (11 patients) or a local recurrence/regrowth (seven patients in LE group – five patients in W&W group), with a median follow-up of 42 months. Results: Following salvage TME, no patients died within 30 days; serious adverse events occurred in four patients; 8 (34.8%) patients had a definitive stoma; 8 (34.8%) patients undergone to major surgery for unfavorable histology after LE – a complete response was confirmed. Conclusion: Notably active surveillance after rectal sparing allows prompt identifying signs of regrowth or relapse leading to a radical TME. Rectal sparing is a possible strategy for LARC patients although an active surveillance is necessary.

The aim of this informative review was to investigate the application of radiomics in cancer imaging and to summarize the results of recent studies to support oncological imaging with particular attention to breast cancer, rectal cancer and primitive and secondary liver cancer. This review also aims to provide the main findings, challenges and limitations of the current methodologies. Clinical studies published in the last four years (2019–2022) were included in this review. Among the 19 studies analyzed, none assessed the differences between scanners and vendor-dependent characteristics, collected images of individuals at additional points in time, performed calibration statistics, represented a prospective study performed and registered in a study database, conducted a cost-effectiveness analysis, reported on the cost-effectiveness of the clinical application, or performed multivariable analysis with also non-radiomics features. Seven studies reached a high radiomic quality score (RQS), and seventeen earned additional points by using validation steps considering two datasets from two distinct institutes and open science and data domains (radiomics features calculated on a set of representative ROIs are open source). The potential of radiomics is increasingly establishing itself, even if there are still several aspects to be evaluated before the passage of radiomics into routine clinical practice. There are several challenges, including the need for standardization across all stages of the workflow and the potential for cross-site validation using real-world heterogeneous datasets. Moreover, multiple centers and prospective radiomics studies with more samples that add inter-scanner differences and vendor-dependent characteristics will be needed in the future, as well as the collecting of images of individuals at additional time points, the reporting of calibration statistics and the performing of prospective studies registered in a study database.

IntroductionEndocrine hypertension (EHT) due to pheochromocytoma/paraganglioma (PPGL), Cushing’s syndrome (CS), or primary aldosteronism (PA) is linked to a variety of metabolic alterations and comorbidities. Accordingly, patients with EHT and primary hypertension (PHT) are characterized by distinct metabolic profiles. However, it remains unclear whether the metabolomic differences relate solely to the disease-defining hormonal parameters. Therefore, our objective was to study the association of disease defining hormonal excess and concomitant adrenal steroids with metabolomic alterations in patients with EHT.MethodsRetrospective European multicenter study of 263 patients (mean age 49 years, 50% females; 58 PHT, 69 PPGL, 37 CS, 99 PA) in whom targeted metabolomic and adrenal steroid profiling was available. The association of 13 adrenal steroids with differences in 79 metabolites between PPGL, CS, PA and PHT was examined after correction for age, sex, BMI, and presence of diabetes mellitus.ResultsAfter adjustment for BMI and diabetes mellitus significant association between adrenal steroids and metabolites – 18 in PPGL, 15 in CS, and 23 in PA – were revealed. In PPGL, the majority of metabolite associations were linked to catecholamine excess, whereas in PA, only one metabolite was associated with aldosterone. In contrast, cortisone (16 metabolites), cortisol (6 metabolites), and DHEA (8 metabolites) had the highest number of associated metabolites in PA. In CS, 18-hydroxycortisol significantly influenced 5 metabolites, cortisol affected 4, and cortisone, 11-deoxycortisol, and DHEA each were linked to 3 metabolites.DiscussionsOur study indicates cortisol, cortisone, and catecholamine excess are significantly associated with metabolomic variances in EHT versus PHT patients. Notably, catecholamine excess is key to PPGL’s metabolomic changes, whereas in PA, other non-defining adrenal steroids mainly account for metabolomic differences. In CS, cortisol, alongside other non-defining adrenal hormones, contributes to these differences, suggesting that metabolic disorders and cardiovascular morbidity in these conditions could also be affected by various adrenal steroids.

Austropuccinia psidii, the causal agent of myrtle rust, has emerged as a significant threat to Myrtaceae in planted and natural woody ecosystems. The first detection of A. puccinia in South Africa was from severely infected ornamental Myrtus communis. This raised concern that M. communis, the sole Myrtaceae species native to Europe and an important component of vegetation in Mediterranean regions, could be threatened by the rust. In light of the potential threat to this unique species, seed was collected from 12 Italian provenances of M. communis, including mainland and island (Sardinia and Sicily) populations. We assessed the susceptibility of these provenances to both the pandemic and South African strains of A. psidii. In Colombia, where the pandemic strain of A. psidii is native, seedlings rapidly became infected by natural inoculum. In South Africa, a preliminary screening of seedlings by artificial inoculation with a single-uredinium isolate produced high levels of disease. Finally, plants of each of the 12 provenances were planted and monitored in Florence, Italy. To date, these showed no signs of disease, but will continue to be monitored. This study highlights the significant threat that both the pandemic and South African strains of A. puccinia pose to M. communis in Europe.

Dutch elm disease (DED) is a destructive tracheomycosis caused by Ophiostoma novo-ulmi, an ascomycete probably originating in East-Asia that is devastating natural elm populations throughout Europe, North America and Asia. The fungus is mainly spread by elm bark beetles that complete their life cycle between healthy and diseased elms. Recently, it has been highlighted that some fungi of the genus Geosmithia, which are similarly well associated with bark beetles, seem to also play a role in the DED pathosystem acting as mycoparasites of O. novo-ulmi. Although some relationship between the fungi is clear, the biological cycle of Geosmithia spp. within the DED cycle is still partly unclear, as is the role of Geosmithia spp. in association with the bark beetles. In this work, we tried to clarify these aspects by developing a qPCR duplex TaqMan assay to detect and quantify DNA of both fungi. The assay is extremely sensitive showing a limit of detection as low as 2 fg μl–1 for both fungi. We collected woody samples from healthy and infected elm trees throughout the beetle life cycle. All healthy elm samples were negative for both Geosmithia spp. and O. novo-ulmi DNA. Geosmithia spp. are never present in infected, but living trees, while they are present in frass of elm bark beetles (EBB – Scolytus spp.) and at each stage of the EBB life cycle in much higher quantities than O. novo-ulmi. This work provides a better understanding of the role and interactions occurring amongst the main players of the DED pathosystem.

Background: Neurally mediated reflex syncope (NMRS) has been recently described as a possible trigger of Takotsubo syndrome (TTS). There are few data in the literature about this association. Methods: In the present meta-summary, 6 case reports describing patients who experienced TTS following an NMRS episode were included. Patient characteristics, triggers and type of syncope were collected. Results: A total of 7 patients with a median age of 63.4 years (interquartile range, IQR: 47.5–76) were evaluated; 71.4% were females, mainly in the menopausal state (80%). The TTS triggers were: vasovagal syncope in 6 patients (85.7%) and situational syncope in 1 patient (14.3%). 2 patients underwent a comprehensive clinical evaluation which showed a cardioinhibitory response. Conclusions: NMRS due to sudden orthostatism and emotional stress, mainly with a cardioinhibitory response, has been associated with the onset of TTS, in particular among female patients in a menopausal state.

Cardiopathy has become one of the predominant global causes of death. The timely identification of different types of heart diseases significantly diminishes mortality risk and enhances the efficacy of treatment. However, fast and efficient recognition necessitates continuous monitoring, encompassing not only specific clinical conditions but also diverse lifestyles. Consequently, an increasing number of studies are striving to automate and progress in the identification of different cardiopathies. Notably, the assessment of electrocardiograms (ECGs) is crucial, given that it serves as the initial diagnostic test for patients, proving to be both the simplest and the most cost-effective tool. This research employs a customized architecture of Convolutional Neural Network (CNN) to forecast heart diseases by analyzing the images of both three bands of electrodes and of each single electrode signal of the ECG derived from four distinct patient categories, representing three heart-related conditions as well as a spectrum of healthy controls. The analyses are conducted on a real dataset, providing noteworthy performance (recall greater than 80% for the majority of the considered diseases and sometimes even equal to 100%) as well as a certain degree of interpretability thanks to the understanding of the importance a band of electrodes or even a single ECG electrode can have in detecting a specific heart-related pathology.

The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and TAS1R and TAS2R38 (TAS2Rs member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the TAS1R3 gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26–51.99) and shortness of breath (OR 4.83, 95% CI 1.71–17.32) in comparison with T/C carriers. Finally, no significant associations between the TAS2R38 haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed TAS1R3 gene involvement in determining COVID-19 symptom severity independently of TAS2R38 activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.