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Abstract Excessive peripheral microvascular constriction during acute psychological stress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing. Digital pulse wave amplitude was continuously measured and the stress/rest (sPAT) ratio of pulse wave amplitude was calculated. Race stratified genome-wide association studies (GWAS) of sPAT-ratio were conducted using linear regression of additive genetic models. A trans-ethnic meta-analysis integrated the four sets of GWAS results. Participants were followed for the outcome of recurrent cardiovascular events (myocardial infarction, heart failure, revascularization, and CV death) for a median of 5 years. We used Wei-Lin-Weissfeld (WLW) model to assess the association between sPAT-ratio with recurrent events. Mean age was 63 ± 9. We identified three SNPs in linkage disequilibrium, closely related to chr7:111,666,943 T > C (rs6466396) that were associated with sPAT-ratio (p = 6.68E-09). Participants homozygous for the T allele had 80% higher risk of incident adverse events (HR 1.8, 95% CI, 1.4–2.2). Also, participants with a lower sPAT-ratio (

Abstract This paper presents a detailed characterization of the positron beam delivered by the Beam Test Facility at Laboratori Nazionali of Frascati to the PADME experiment during Run III, which took place from October to December 2022. It showcases the methodology used to measure the main beam parameters such as the position in space, the absolute momentum scale, the beam energy spread, and its intensity through a combination of data analysis and Monte Carlo simulations. The results achieved include an absolute precision in the momentum of the beam to within ~1–2 MeV/c, a relative beam energy spread below 0.25%, and an absolute precision in the intensity of the beam at the level of 2%.

Abstract Background Mindfulness practice has gained interest in the management of Chronic Migraine associated with Medication Overuse Headache (CM-MOH). Mindfulness is characterized by present-moment self-awareness and relies on attention control and emotion regulation, improving headache-related pain management. Mindfulness modulates the Default Mode Network (DMN), Salience Network (SN), and Fronto-Parietal Network (FPN) functional connectivity. However, the neural mechanisms underlying headache-related pain management with mindfulness are still unclear. In this study, we tested neurofunctional changes after mindfulness practice added to pharmacological treatment as usual in CM-MOH patients. Methods The present study is a longitudinal phase-III single-blind Randomized Controlled Trial (MIND-CM study; NCT03671681). Patients had a diagnosis of CM-MOH, no history of neurological and severe psychiatric comorbidities, and were attending our specialty headache centre. Patients were divided in Treatment as Usual (TaU) and mindfulness added to TaU (TaU + MIND) groups. Patients underwent a neuroimaging and clinical assessment before the treatment and after one year. Longitudinal comparisons of DMN, SN, and FPN connectivity were performed between groups and correlated with clinical changes. Vertex-wise analysis was performed to assess cortical thickness changes. Results 177 CM-MOH patients were randomized to either TaU group or TaU + MIND group. Thirty-four patients, divided in 17 TaU and 17 TaU + MIND, completed the neuroimaging follow-up. At the follow-up, both groups showed an improvement in most clinical variables, whereas only TaU + MIND patients showed a significant headache frequency reduction (p = 0.028). After one year, TaU + MIND patients showed greater SN functional connectivity with the left posterior insula (p-FWE = 0.007) and sensorimotor cortex (p-FWE = 0.026). In TaU + MIND patients only, greater SN-insular connectivity was associated with improved depression scores (r = -0.51, p = 0.038). A longitudinal increase in cortical thickness was observed in the insular cluster in these patients (p = 0.015). Increased anterior cingulate cortex thickness was also reported in TaU + MIND group (p-FWE = 0.02). Conclusions Increased SN-insular connectivity might modulate chronic pain perception and the management of negative emotions. Enhanced SN-sensorimotor connectivity could reflect improved body-awareness of painful sensations. Expanded cingulate cortex thickness might sustain improved cognitive processing of nociceptive information. Our findings unveil the therapeutic potential of mindfulness and the underlying neural mechanisms in CM-MOH patients. Trial Registration Name of Registry; MIND-CM study; Registration Number ClinicalTrials.gov identifier: NCT0367168; Registration Date: 14/09/2018

Background & Aims: Among the reprogrammed metabolic pathways described in cancer stem cells, aberrant lipid metabolism has recently drawn increasing attention. Our study explored the contribution of fatty acids (FA) in the regulation of stem-like features in intrahepatic cholangiocarcinoma (iCCA). Methods: We previously identified a functional stem-like subset in human iCCA by using a three-dimensional sphere (SPH) model in comparison to parental cells grown as monolayers (MON). In this study, quantification of intracellular free FA and lipidomic analysis (triacylglycerol [TAG] composition, de novo synthesis products) was performed by Liquid chromatography–mass spectrometry (LC–MS); quadrupole time-of-flight liquid chromatography/mass spectrometry (Q-TOF LC/MS), respectively, in both SPH and MON cultures. Results: Stem-like SPH showed a superior content of free FA (citric, palmitic, stearic, and oleic acids) and unsaturated TAG. Molecularly, SPH showed upregulation of key metabolic enzymes involved in de novo FA biosynthesis (AceCS1, ACLY, ACAC, FASN, ACSL1) and the mTOR signalling pathway. In patients with iCCA (n = 68), tissue expression of FASN, a key gene involved in FA synthesis, correlated with 5-year overall survival. Interference with FASN activity in SPH cells through both specific gene silencing (siRNA) or pharmacological inhibition (orlistat) decreased sphere-forming ability and expression of stem-like markers. In a murine xenograft model obtained by injection of iCCA-SPH cells, FASN inhibition by orlistat or injection of FASN-silenced cells significantly reduced tumour growth and expression of stem-like genes. Conclusion: Altered FA metabolism contributes to the maintenance of a stem-like phenotype in iCCA. FASN inhibition may represent a new approach to interfere with the progression of this deadly disease. Impact and implications: Recent evidence indicates that metabolic disorders correlate with an increased susceptibility to intrahepatic cholangiocarcinoma (iCCA). Our investigation emphasises the pivotal involvement of lipid metabolism in the tumour stem cell biology of iCCA, facilitated by the upregulation of crucial enzymes and the mTOR signalling pathway. From a clinical perspective, this underscores the dual role of FASN as both a prognostic indicator and a therapeutic target, suggesting that FASN inhibitors could enhance patient outcomes by diminishing stemness and tumour aggressiveness. These findings pave the way for novel therapeutic strategies for iCCA and shed light on its relationship with metabolic disorders such as diabetes, obesity, metabolic syndrome, and metabolic dysfunction-associated steatotic liver disease.

OBJECTIVES:. Continuous renal replacement therapy (CRRT) and shock are both associated with high morbidity and mortality in the ICU. Adult data suggest renoprotective effects of vasopressin vs. catecholamines (norepinephrine and epinephrine). We aimed to determine whether vasopressin use during CRRT was associated with improved kidney outcomes in children and young adults. DESIGN:. Secondary analysis of Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK), a multicenter, retrospective cohort study. SETTING:. Neonatal, cardiac, PICUs at 34 centers internationally from January 1, 2015, to December 31, 2021. PATIENTS/SUBJECTS:. Patients younger than 25 years receiving CRRT for acute kidney injury and/or fluid overload and requiring vasopressors. Patients receiving vasopressin were compared with patients receiving only norepinephrine/epinephrine. The impact of timing of vasopressin relative to CRRT start was assessed by categorizing patients as: early (on or before day 0), intermediate (days 1–2), and late (days 3–7). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 1016 patients, 665 (65%) required vasopressors in the first week of CRRT. Of 665, 248 (37%) received vasopressin, 473 (71%) experienced Major Adverse Kidney Events at 90 days (MAKE-90) (death, renal replacement therapy dependence, and/or > 125% increase in serum creatinine from baseline 90 days from CRRT initiation), and 195 (29%) liberated from CRRT on the first attempt within 28 days. Receipt of vasopressin was associated with higher odds of MAKE-90 (adjusted odds ratio [aOR], 1.80; 95% CI, 1.20–2.71; p = 0.005) but not liberation success. In the vasopressin group, intermediate/late initiation was associated with higher odds of MAKE-90 (aOR, 2.67; 95% CI, 1.17–6.11; p = 0.02) compared with early initiation. CONCLUSIONS:. Nearly two-thirds of children and young adults receiving CRRT required vasopressors, including over one-third who received vasopressin. Receipt of vasopressin was associated with more MAKE-90, although earlier initiation in those who received it appears beneficial. Prospective studies are needed to understand the appropriate timing, dose, and subpopulation for use of vasopressin.

Access to land is one of the key factors of farm growth, while at the same time, related research is characterised by important gaps, in particular facing the change over time in the nature and role of drivers of the land market. The objective of this research is to identify the endogenous and exogenous factors that affect the decision to purchase land in Italy between 2013 and 2020. Five probit regression models were implemented to understand the role of a set of different determinants in land investment decisions. The results show that factors related to capital in machinery and equipment, energy production and the presence of a successor are endogenous factors that positively influence the purchase decision. The ratio of rented land to utilised agricultural area and of family work units to total work units are endogenic factors that negatively influence the purchase decision. Exogenous factors related to the cost of capital and inflation rate affect the purchase of land in an opposite way, negatively and positively respectively. The role of Utilised Agricultural Area and Gross Saleable Production per hectare varies depending on the specialisation considered. The research can support policymakers in designing policies to promote the survival and growth of farms, as well as to facilitate land investment by reducing barriers to land acquisition.

Abstract Background Metabolic dysfunction-associated Steatotic Liver Disease (MASLD) displays a worse prognosis in subjects with type 2 diabetes (T2D); effective treatments are, so far, scanty. Semaglutide showed efficacy in improving steatohepatitis. We longitudinally observed a MASLD cohort of T2D subjects starting semaglutide, to detect an improvement of non-invasive surrogates of steatosis and fibro-inflammatory liver involvement, evaluating the role of mild alcohol consumption. Patients and methods In 62 overweight/obese T2D subjects with MASLD (36 non-drinker and 26 mild alcohol consumers), anthropometric, bio-humoral and transient elastography (TE) data were collected before (T0) and after an average time of 6.4 month (T1) from injective semaglutide prescription. Circulating levels of hormones (GIP, GLP-1, glucagon, insulin) and inflammatory markers (TNFα, MCP-1, IL-18, IL-10) were measured. Steatotic and necro-inflammatory liver involvement was evaluated with FibroScan controlled attenuation parameter (CAP) and liver stiffness (LS), respectively. Results Significant (p

Abstract Selective binding of TCR-like antibodies that target a single tumour-specific peptide antigen presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive modeling. We developed an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. As proof of concept, we confirm the target epitope of a MAGE-A4-specific TCR-like antibody. We further determine cross-reactive peptide sequences for ESK1, a TCR-like antibody with known off-target activity, in human liver tissue. We confirm off-target-induced T cell activation and ESK1-mediated liver spheroid killing. Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application.

Abstract The NA48/2 experiment at CERN reports the first observation of the K ± → π 0 π 0 μ ± ν decay based on a sample of 2437 candidates with 15% background contamination collected in 2003–2004. The decay branching ratio in the kinematic region of the squared dilepton mass above 0.03 GeV2/c 4 is measured to be (0.65 ± 0.03) × 10 −6. The extrapolation to the full kinematic space, using a specific model, is found to be (3.45 ± 0.16) × 10 −6, in agreement with chiral perturbation theory predictions.

Abstract Salinity poses a significant challenge to global crop productivity, affecting approximately 20% of cultivated and 33% of irrigated farmland, and this issue is on the rise. Negative impact of salinity on plant development and metabolism leads to physiological and morphological alterations mainly due to high ion concentration in tissues and the reduced water and nutrients uptake. Common bean (Phaseolus vulgaris L.), a staple food crop accounting for a substantial portion of consumed grain legumes worldwide, is highly susceptible to salt stress resulting in noticeable reduction in dry matter gain in roots and shoots even at low salt concentrations. In this study we screened a common bean panel of diversity encompassing 192 homozygous genotypes for salt tolerance at seedling stage. Phenotypic data were leveraged to identify genomic regions involved in salt stress tolerance in the species through GWAS. We detected seven significant associations between shoot dry weight and SNP markers. The candidate genes, in linkage with the regions associated to salt tolerance or harbouring the detected SNP, showed strong homology with genes known to be involved in salt tolerance in Arabidopsis. Our findings provide valuable insights onto the genetic control of salt tolerance in common bean and represent a first contribution to address the challenge of salinity-induced yield losses in this species and poses the ground to eventually breed salt tolerant common bean varieties.

Abstract Background The burden and disability associated with headaches are conceptualized and measured differently at patients’ and populations’ levels. At the patients’ level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0–1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients’ disability which might inform future GBD definitions of DW for headache disorders. Methods We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females’ percentage in the sample, and age). We developed a 0–1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium. Results A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake. Conclusions Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels.

IntroductionCrop Wild Relatives (CWR) have great socioeconomic importance for humans harbouring a broad spectrum of diversity and being important elements of different habitats. Beta vulgaris subsp. maritima ((L.) Arcangeli), also known as sea beet, is an important CWR of cultivated beets (GP-1). The high adaptability of this taxon to different environmental conditions, as well as its tolerance/resistance to different biotic and abiotic stresses, makes it a vital source for sugar beet improvement. Aim of this work was to analyse the in situ and ex situ status of sea beet population conservation in Italy, so as to guide protection activities and new collecting missions.MethodsGeographical distribution data of populations were that occur in the wild and conserved in genebanks were assembled from different databases and submitted to data quality control. Distribution, habitat characterization, land cover and use of the involved sites were then evaluated to provide insight into the current condition of areas hosting this CWR diversity. The presence of populations within vs. outside Italian protected areas was also evaluated. A density analysis of the records was performed and the adequateness of sea beet ex situ conservation, in terms of number of conserved accessions, was finally estimated.ResultsA collection of 138 B. vulgaris subsp. maritima high quality georeferenced records were obtained, mainly distributed into Mediterranean Biogeographic Region. About 22% of the considered populations occurs in protected sites of the Natura 2000 Network, while about 15% in areas recorded in the Official list of protected natural areas (EUAP). Occurrences within protected areas are founded primarily in natural environments, whereas those outside are mainly located in urban and cultivated areas. The comparison of distribution and density analysis results revealed the presence of several gaps between sites hosting in situ populations and sites where ex situ conserved accessions were originally collected.DiscussionHere presented data indicates that the protection status for sea beet in Italy can be considered only partially adequate; more proactive protection measures should be foreseen to increase the role of protected areas in safeguarding in situ conservation. “Out of reserve management” for populations outside protected areas should also be developed, as well as new collecting missions carried out.

Abstract The World Health Organization (WHO) Intersectoral Global Action Plan on Epilepsy and Other Neurological Disorders was developed by WHO to address the worldwide challenges and gaps in provision of care and services for people with epilepsy and other neurological disorders and to ensure a comprehensive, coordinated response across sectors to the burden of neurologic diseases and to promote brain health across life-course. Headache disorders constitute the second most burdensome of all neurological diseases after stroke, but the first if young and midlife adults are taken into account. Despite the availability of a range of treatments, disability associated with headache disorders, and with migraine, remains very high. In addition, there are inequalities between high-income and low and middle income countries in access to medical care. In line with several brain health initiatives following the WHOiGAP resolution, herein we tailor the main pillars of the action plan to headache disorders: (1) raising policy prioritization and strengthen governance; (2) providing effective, timely and responsive diagnosis, treatment and care; (3) implementing strategies for promotion and prevention; (4) fostering research and innovation and strengthen information systems. Specific targets for future policy actions are proposed. The Global Action Plan triggered a revolution in neurology, not only by increasing public awareness of brain disorders and brain health but also by boosting the number of neurologists in training, raising research funding and making neurology a public health priority for policy makers. Reducing the burden of headache disorders will not only improve the quality of life and wellbeing of people with headache but also reduce the burden of neurological disorders increasing global brain health and, thus, global population health.

Chest pain/discomfort (CP) is a common symptom and can be a diagnostic dilemma for many clinicians. The misdiagnosis of an acute or progressive chronic cardiac etiology may carry a significant risk of morbidity and mortality. This review summarizes the different options and modalities for establishing the diagnosis and severity of coronary artery disease. An effective test selection algorithm should be individually tailored to each patient to maximize diagnostic accuracy in a timely fashion, determine short- and long-term prognosis, and permit implementation of evidence-based treatments in a cost-effective manner. Through collaboration, a decision algorithm was developed (www.chowmd.ca/cadtesting) that could be adopted widely into clinical practice. Résumé: La douleur ou la gêne thoracique sont des symptômes fréquents qui peuvent poser un dilemme diagnostique pour de nombreux médecins. Les erreurs de diagnostic d’une cause aiguë ou chronique progressive d’origine cardiaque peuvent d'ailleurs entraîner un risque considérable de morbidité et de mortalité. La présente synthèse porte sur les différentes options et modalités d’établissement du diagnostic et de la gravité d’une coronaropathie. Un algorithme efficace pour le choix des tests doit être adapté à chaque patient afin de maximiser l’exactitude diagnostique dans les plus brefs délais, de déterminer le pronostic à court et à long terme, et de permettre une mise en œuvre de traitements fondés sur des données probantes tout en tenant compte des coûts. Un algorithme décisionnel a donc été conjointement mis au point (www.chowmd.ca/cadtesting) et pourrait être largement adopté dans la pratique clinique.

Abstract Particle physics today faces the challenge of explaining the mystery of dark matter, the origin of matter over anti-matter in the Universe, the origin of the neutrino masses, the apparent fine-tuning of the electro-weak scale, and many other aspects of fundamental physics. Perhaps the most striking frontier to emerge in the search for answers involves new physics at mass scales comparable to familiar matter, below the GeV-scale, or even radically below, down to sub-eV scales, and with very feeble interaction strength. New theoretical ideas to address dark matter and other fundamental questions predict such feebly interacting particles (FIPs) at these scales, and indeed, existing data provide numerous hints for such possibility. A vibrant experimental program to discover such physics is under way, guided by a systematic theoretical approach firmly grounded on the underlying principles of the Standard Model. This document represents the report of the FIPs 2022 workshop, held at CERN between the 17 and 21 October 2022 and aims to give an overview of these efforts, their motivations, and the decadal goals that animate the community involved in the search for FIPs.

Developing accurate in vitro models that replicate the in vivo tumor environment is essential for advancing cancer research and therapeutic development. Traditional 2D cell cultures often fail to capture the complex structural and functional heterogeneity of tumors, limiting the translational relevance of findings. In contrast, 3D culture systems, such as spheroids, provide a more physiologically relevant context by replicating key aspects of the tumor microenvironment. This study aimed to compare the metabolism of three intrahepatic cholangiocarcinoma cell lines in 2D and 3D cultures to identify metabolic shifts associated with spheroid formation. Cells were cultured in 2D on adhesion plates and in 3D using ultra-low attachment plates. Metabolic exchange rates were measured using NMR, and intracellular metabolites were analyzed using LC-MS. Significant metabolic differences were observed between 2D and 3D cultures, with notable changes in central carbon and glutathione metabolism in 3D spheroids. The results suggest that 3D cultures, which more closely mimic the in vivo environment, may offer a more accurate platform for cancer research and drug testing.

The impact of common and rare variants in COVID-19 host genetics has been widely studied. In particular, in Fallerini et al. (Human genetics, 2022, 141, 147–173), common and rare variants were used to define an interpretable machine learning model for predicting COVID-19 severity. First, variants were converted into sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. After that, the Boolean features, selected by these logistic models, were combined into an Integrated PolyGenic Score (IPGS), which offers a very simple description of the contribution of host genetics in COVID-19 severity.. IPGS leads to an accuracy of 55%–60% on different cohorts, and, after a logistic regression with both IPGS and age as inputs, it leads to an accuracy of 75%. The goal of this paper is to improve the previous results, using not only the most informative Boolean features with respect to the genetic bases of severity but also the information on host organs involved in the disease. In this study, we generalize the IPGS adding a statistical weight for each organ, through the transformation of Boolean features into “Boolean quantum features,” inspired by quantum mechanics. The organ coefficients were set via the application of the genetic algorithm PyGAD, and, after that, we defined two new integrated polygenic scores (IPGSph1 and IPGSph2). By applying a logistic regression with both IPGS, (IPGSph2 (or indifferently IPGSph1) and age as inputs, we reached an accuracy of 84%–86%, thus improving the results previously shown in Fallerini et al. (Human genetics, 2022, 141, 147–173) by a factor of 10%.

Crop Wild Relatives (CWR) are wild plant taxa genetically close to a crop. Being a precious source of genetic variability and of traits for crop improvement, CWR have a high socio-economic value and are identified among the main plant genetic resources. Alarming enough, the inter- and intraspecific diversity, as well as their habitat diversity, is under threat of irremediable loss. Italy is the second richest country in Europe in terms of plant species number; applying the taxon group concept 5712 have been recently identified as CWR. The aims of the present research are to identify the best sites for: i) the institution of genetic reserves to actively protect CWR species of the key crop genera as Allium, Brassica and Triticum and ii) performing new collection missions to reach adequate ex situ conservation of target species. Georeferenced data were retrieved from different online databases. CAPFITOGEN tools were initially used to develop an ecogeographic land characterisation map (ELC) of Italy. Geographical distribution data were assembled for 379 populations of 18 CWR taxa. Results of the complementarity analysis showed that 10 protected areas provide coverage of the 46.4% of the target conservation units and include 66.7% of the priority CWR taxa investigated. Alarming enough, only 7.4% of the 379 populations are currently conserved ex situ; among the 18 ecogeographic land characterisation categories only 3 are covered by ex situ conservation. This is the first study where most suitable protected areas for the institution of genetic reserves are proposed for Italy for the protection of multiple CWR taxa of key genera; this is relevant also considering the global value of many of the related crop such as different wheat species, cabbages, rape, garlic and onion. Being already dedicated to habitat and species conservation, the identified sites are optimal candidates for the institution of genetic reserves. Results will hopefully also guide new collecting missions that are urgently needed to strength ex situ conservation of such precious genetic resources.

BackgroundOccupational e–mental health (OeMH) interventions significantly reduce the burden of mental health conditions. The successful implementation of OeMH interventions is influenced by many implementation strategies, barriers, and facilitators across contexts, which, however, are not systematically tracked. One of the reasons is that international consensus on documenting and reporting the implementation of OeMH interventions is lacking. There is a need for practical guidance on the key factors influencing the implementation of interventions that organizations should consider. Stakeholder consultations secure a valuable source of information about these key strategies, barriers, and facilitators that are relevant to successful implementation of OeMH interventions. ObjectiveThe objective of this study was to develop a brief checklist to guide the implementation of OeMH interventions. MethodsBased on the results of a recently published systematic review, we drafted a comprehensive checklist with a wide set of strategies, barriers, and facilitators that were identified as relevant for the implementation of OeMH interventions. We then used a 2-stage stakeholder consultation process to refine the draft checklist to a brief and practical checklist comprising key implementation factors. In the first stage, stakeholders evaluated the relevance and feasibility of items on the draft checklist using a web-based survey. The list of items comprised 12 facilitators presented as statements addressing “elements that positively affect implementation” and 17 barriers presented as statements addressing “concerns toward implementation.” If a strategy was deemed relevant, respondents were asked to rate it using a 4-point Likert scale ranging from “very difficult to implement” to “very easy to implement.” In the second stage, stakeholders were interviewed to elaborate on the most relevant barriers and facilitators shortlisted from the first stage. The interview mostly focused on the relevance and priority of strategies and factors affecting OeMH intervention implementation. In the interview, the stakeholders’ responses to the open survey’s questions were further explored. The final checklist included strategies ranked as relevant and feasible and the most relevant facilitators and barriers, which were endorsed during either the survey or the interviews. ResultsIn total, 26 stakeholders completed the web-based survey (response rate=24.8%) and 4 stakeholders participated in individual interviews. The OeMH intervention implementation checklist comprised 28 items, including 9 (32.1%) strategies, 8 (28.6%) barriers, and 11 (39.3%) facilitators. There was widespread agreement between findings from the survey and interviews, the most outstanding exception being the idea of proposing OeMH interventions as benefits for employees. ConclusionsThrough our 2-stage stakeholder consultation, we developed a brief checklist that provides organizations with a guide for the implementation of OeMH interventions. Future research should empirically validate the effectiveness and usefulness of the checklist.

A sample of 3984 candidates of the K+→π+γγ decay, with an estimated background of 291±14 events, was collected by the NA62 experiment at CERN during 2017–2018. In order to describe the observed di-photon mass spectrum, the next-to-leading order contribution in chiral perturbation theory was found to be necessary. The decay branching ratio in the full kinematic range is measured to be (9.61±0.17)×10−7. The first search for production and prompt decay of an axion-like particle with gluon coupling in the process K+→π+a, a→γγ is also reported.

Abstract Measurement of the ultra-rare K + → π + ν ν ¯ $$ {K}^{+}\to {\pi}^{+}\nu \overline{\nu} $$ decay at the NA62 experiment at CERN requires high-performance particle identification to distinguish muons from pions. Calorimetric identification currently in use, based on a boosted decision tree algorithm, achieves a muon misidentification probability of 1.2 × 10 −5 for a pion identification efficiency of 75% in the momentum range of 15–40 GeV/c. In this work, calorimetric identification performance is improved by developing an algorithm based on a convolutional neural network classifier augmented by a filter. Muon misidentification probability is reduced by a factor of six with respect to the current value for a fixed pion-identification efficiency of 75%. Alternatively, pion identification efficiency is improved from 72% to 91% for a fixed muon misidentification probability of 10 −5.

Abstract The 2030 Agenda for Sustainable Development sets out, through 17 Sustainable Development Goals (SDGs), a path for the prosperity of people and the planet. SDG 3 in particular aims to ensure healthy lives and promote well-being for all at all ages and includes several targets to enhance health. This review presents a “headache-tailored” perspective on how to achieve SDG 3 by focusing on six specific actions: targeting chronic headaches; reducing the overuse of acute pain-relieving medications; promoting the education of healthcare professionals; granting access to medication in low- and middle-income countries (LMIC); implementing training and educational opportunities for healthcare professionals in low and middle income countries; building a global alliance against headache disorders. Addressing the burden of headache disorders directly impacts on populations’ health, as well as on the possibility to improve the productivity of people aged below 50, women in particular. Our analysis pointed out several elements, and included: moving forward from frequency-based parameters to define headache severity; recognizing and managing comorbid diseases and risk factors; implementing a disease management multi-modal management model that incorporates pharmacological and non-pharmacological treatments; early recognizing and managing the overuse of acute pain-relieving medications; promoting undergraduate, postgraduate, and continuing medical education of healthcare professionals with specific training on headache; and promoting a culture that favors the recognition of headaches as diseases with a neurobiological basis, where this is not yet recognized. Making headache care more sustainable is an achievable objective, which will require multi-stakeholder collaborations across all sectors of society, both health-related and not health-related. Robust investments will be needed; however, considering the high prevalence of headache disorders and the associated disability, these investments will surely improve multiple health outcomes and lift development and well-being globally.

Abstract Background Acute kidney injury (AKI) is among the most common complications following cardiac surgery in adult and pediatric patients, significantly affecting morbidity and mortality. Artificial Intelligence (AI) with Machine Learning (ML) can be used to predict outcomes. AKI diagnosis anticipation may be an ideal target of these methods. The scope of the study is building a Machine Learning (ML) train model with Random Forest (RF) algorithm, based on electronic health record (EHR) data, able to forecast AKI continuously after 48 h in post-cardiac surgery children, and to test its performance. Four hundred nineteen consecutive patients out of 1115 hospital admissions were enrolled in a single-center retrospective study. Patients were younger than 18 years and admitted from August 2018 to February 2020 in a pediatric cardiac intensive care unit (PCICU) undergoing cardiac surgery, invasive procedure (hemodynamic studies), and medical conditions with complete EHR records and discharged after 48 h or more. Results Thirty-six variables were selected to build the algorithm according to commonly described cardiac surgery-associated AKI clinical predictors. We evaluated different models for different outcomes: binary AKI (no AKI vs. AKI), severe AKI (no-mild vs severe AKI), and multiclass classification (maximum AKI and the most frequent level of AKI, mode AKI). The algorithm performance was assessed with the area under the curve receiver operating characteristics (AUC ROC) for binary classification, with accuracy and K for multiclass classification. AUC ROC for binary AKI was 0.93 (95% CI 0.92–0.94), and for severe AKI was 0.99 (95% CI 0.98–1). Mode AKI accuracy was 0.95, and K was 0.80 (95% CI 0.94–0.96); maximum AKI accuracy was 0.92, and K was 0.71 (95% CI 0.91–0.93). The importance matrix plot demonstrated creatinine, basal creatinine, platelets count, adrenaline support, and lactate dehydrogenase for binary AKI with the addition of cardiopulmonary bypass duration for severe AKI as the most relevant variables of the model. Conclusions We validated a ML model to detect AKI occurring after 48 h in a retrospective observational study that could help clinicians in individuating patients at risk of AKI, in which a preventive strategy can be determinant to improve the occurrence of renal dysfunction.

Abstract Background Custom-made implants are a valid option in revision total hip arthroplasty to address massive acetabular bone loss. The aim of this study was to assess the accuracy of custom-made acetabular implants between preoperative planning and postoperative positioning using CT scans. Methods In a retrospective analysis, three patients who underwent an acetabular custom-made prosthesis were identified. The custom-made designs were planned through 3D CT analysis considering surgical points of attention. The accuracy of intended implants positioning was assessed by comparing pre- and postoperative CT analyzing the center of rotation (CoR), anteversion, inclination, screws, and implant surface in contact with the bone. Results The three cases presented satisfactory accuracy in positioning. A malpositioning in the third case was observed due to the posterization of the CoR of the implant of more than 10 mm. The other CoR vectors considered in the third patient and all vectors in the other two cases fall within 10 mm. All the cases were positioned with a difference of less than 10° of anteversion and inclination with respect to the planning. Conclusions The current case series revealed promising accuracy in the positioning of custom-made acetabular prosthesis comparing the planned implant in preoperative CT with postoperative CT.

Abstract A sample of 1.3 × 105 K + → π 0 e + νγ candidates with less than 1% background was collected by the NA62 experiment at the CERN SPS in 2017–2018. Branching fraction measurements are obtained at percent relative precision in three restricted kinematic regions, improving on existing results by a factor larger than two. An asymmetry, possibly related to T-violation, is investigated with no evidence observed within the achieved precision.

Abstract The NA62 experiment at CERN, designed to study the ultra-rare decay K + → π + ν ν ¯ $$ \nu \overline{\nu} $$ , has also collected data in beam-dump mode. In this configuration, dark photons may be produced by protons dumped on an absorber and reach a decay volume beginning 80 m downstream. A search for dark photons decaying in flight to μ + μ − pairs is reported, based on a sample of 1.4 × 1017 protons on dump collected in 2021. No evidence for a dark photon signal is observed. A region of the parameter space is excluded at 90% CL, improving on previous experimental limits for dark photon masses between 215 and 550 MeV/c 2.

Abstract Background Mindfulness gained considerable attention for migraine management, but RCTs are lacking. We aimed to assess the efficacy of a six-sessions mindfulness-based treatment added to treatment as usual (TaU) in patients with Chronic Migraine (CM) and Medication Overuse Headache (MOH) on headache frequency, medication intake, quality of life, disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. Methods In this Phase-III single-blind RCT carried out in a specialty Italian headache center, 177 patients with CM and MOH were randomized 1:1 to either TaU (withdrawal from overused drugs, education on proper medication use and lifestyle issues, and tailored prophylaxis) or mindfulness-based intervention added to TaU (TaU + MIND). The mindfulness-based intervention consisted of six group session of mindfulness practice and 7–10 min daily self-practice. The primary endpoint was the achievement of ≥ 50% headache frequency reduction at 12 months compared to baseline, and was analyzed on an intention-to-treat principle using Pearson’s Chi-Squared test. Secondary endpoints included medication intake, quality of life (QoL), disability, depression and anxiety, cutaneous allodynia, awareness of inner states, work-related difficulties, and disease cost. The secondary endpoints were analyzed using per-protocol linear mixed models. Results Out of the 177 participants 89 were randomized to TaU and 88 to TaU + MIND. Patients in the TaU + MIND group outperformed those in TaU for the primary endpoint (78.4% vs. 48.3%; p

The PROpel trial assessed the combination of olaparib + abiraterone acetate (AA) plus prednisone and androgen deprivation therapy (ADT) versus AA plus prednisone and ADT alone as first-line treatment for metastatic castration-resistant prostate cancer (mCPRP). To contextualize the progression free survival (PFS) benefit in PROpel, we performed a systematic review and quasi-individual patient data network meta-analysis on randomized controlled trials of first-line hormonal treatments for mCPRC. Meta-analysis was performed for the PROpel control arm and PREVAIL (enzalutamide) and COU-AA-302 (AA) treatment arms. Kaplan-Meier PFS curves were digitally reconstructed and differences in restricted mean survival time (ΔRMST) were computed. Combination therapy yielded longer PFS (24-mo ΔRMST 1.5 mo, 95% confidence interval 0.6–2.4) in comparison to novel hormonal treatments alone. However, the lack of mature overall survival data, higher complication rates, and higher health care costs are limitations of combination therapy. Ultimately, combining treatments, rather than molecularly targeted sequencing in cases of failure, might not be justified in unselected patients with mCRPC. Patient summary: A recent trial showed that for metastatic prostate cancer that does not respond to hormone treatment, combined therapy with two drugs (olaparib and abiraterone) may prolong survival free from cancer progression. We included these data in an analysis of three trials that confirmed a small benefit. This combination approach has higher complication rates and is more expensive, and longer-term results for overall survival are needed.

Background: Patients receiving dialysis have high cardiovascular risk in part due to extensive vascular calcification. In the CaLIPSO study, infusion of hexasodium fytate (SNF472), the hexasodium salt of inositol hexaphosphate, for 52 weeks thrice weekly during hemodialysis significantly reduced progression of coronary artery calcification (CAC). This report examines pharmacokinetic/pharmacodynamic (PK/PD) and exposure-efficacy in CaLIPSO.Methods: We measured hexasodium fytate plasma concentrations (PK) by validated liquid chromatography-mass spectroscopy, and hydroxyapatite crystallization in plasma (PD) by validated spectrophotometry. Analyses included patients evaluable for PK, PD, and CAC change (per-protocol analysis). We developed a simple Emax model for maximum concentration (Cmax) and PD effect, and linear and non-linear Emax models for exposure-efficacy among individual average Cmax and absolute and percent changes in CAC score from baseline to week 52.Results: Among evaluable patients receiving placebo (n = 15), 300 mg (n = 20), or 600 mg (n = 20), average Cmax across visits was not quantifiable (21.9 µM and a plateau in exposure-efficacy above the third quartile of Cmax (≥32 µM).Conclusion: Hexasodium fytate has exposure-dependent effects on hydroxyapatite crystallization and progression of cardiovascular calcification. Simple Emax models show robust relations among exposure, inhibition of hydroxyapatite crystallization, and change in CAC volume.Clinical Trial Registration:https://www.clinicaltrials.gov; identifier NCT02966028.

BackgroundDietary fat consumption, involved in the pathogenesis of insulin resistance and impaired glucose metabolism, is linked with decline in cognitive functions, dementia, and development of Parkinson’s disease and Alzheimer’s disease. Mature IL-1β, requiring the activation of the P2X7 receptor (P2X7R)-inflammasome complex, is an important mediator of neuroinflammation. The aim of the study was to test whether P2X7R activation might interfere with systemic and cerebral metabolic homeostasis.MethodsWe treated WT and P2X7R KO mice with a high-fat diet (HFD) for 16 weeks, evaluating the effects on the Substantia Nigra and Hippocampus, target areas of damage in several forms of cognitive impairment.ResultsHFD-treated WT and P2X7R KO mice showed a different brain mRNA profile of Insulin and Igf-1, with these genes and relative receptors, more expressed in KO mice. Unlike P2X7R KO mice, WT mice treated with HFD displayed a diameter reduction in dopaminergic neurons in the Substantia Nigra, accompanied by an increased IBA1 expression in this area; they also showed poor performances during Y-Maze and Morris Water Maze, tasks involving Hippocampus activity. Conversely, Parkin, whose reduction might promote neuronal cell death, was increased in the brain of P2X7R KO animals.ConclusionWe report for the first time that HFD induces damage in dopaminergic neurons of the Substantia Nigra and a Hippocampus-related worse cognitive performance, both attenuated in the absence of P2X7R. The involved mechanisms might differ in the two brain areas, with a predominant role of inflammation in the Substantia Nigra and a metabolic derangement in the Hippocampus.

Abstract Background The WHODAS-2 is a disability assessment instrument based on the conceptual framework of the International Classification of Functioning, Disability, and Health (ICF). It provides a global measure of disability and 7 domain-specific scores. The aim of this study was to assess WHODAS-2 conceptual model and metric properties in a set of chronic and prevalent clinical conditions accounting for a wide scope of disability in Europe. Methods 1,119 patients with one of 13 chronic conditions were recruited in 7 European centres. Participants were clinically evaluated and administered the WHODAS-2 and the SF-36 at baseline, 6 weeks and 3 months of follow-up. The latent structure was explored and confirmed by factor analysis (FA). Reliability was assessed in terms of internal consistency (Cronbach's alpha) and reproducibility (intra-class correlation coefficients, ICC). Construct validity was evaluated by correlating the WHODAS-2 and SF-36 domains, and comparing known groups based on the clinical-severity and work status. Effect size (ES) coefficient was used to assess responsiveness. To assess reproducibility and responsiveness, subsamples of stable (at 6 weeks) and improved (after 3 moths) patients were defined, respectively, according to changes in their clinical-severity. Results The satisfactory FA goodness of fit indexes confirmed a second order factor structure with 7 dimensions, and a global score for the WHODAS-2. Cronbach's alpha ranged from 0.77 (self care) to 0.98 (life activities: work or school), and the ICC was lower, but achieved the recommended standard of 0.7 for four domains. Correlations between global WHODAS-2 score and the different domains of the SF-36 ranged from -0.29 to -0.65. Most of the WHODAS-2 scores showed statistically significant differences among clinical-severity groups for all pathologies, and between working patients and those not working due to ill health (p < 0.001). Among the subsample of patients who had improved, responsiveness coefficients were small to moderate (ES = 0.3-0.7), but higher than those of the SF-36. Conclusions The latent structure originally designed by WHODAS-2 developers has been confirmed for the first time, and it has shown good metric properties in clinic and rehabilitation samples. Therefore, considerable support is provided to the WHODAS-2 utilization as an international instrument to measure disability based on the ICF model.

Abstract Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy.

Abstract The NA62 experiment at CERN targets the measurement of the ultra-rare K + → π + ν ν ¯ $$ {K}^{+}\to {\pi}^{+}\nu \overline{\nu} $$ decay, and carries out a broad physics programme that includes probes for symmetry violations and searches for exotic particles. Data were collected in 2016–2018 using a multi-level trigger system, which is described highlighting performance studies based on 2018 data.

Abstract The workshop “Shedding light on X17” brings together scientists looking for the existence of a possible new light particle, often referred to as X17. This hypothetical particle can explain the resonant structure observed at $$\sim $$ ∼ 17 MeV in the invariant mass of electron-positron pairs, produced after excitation of nuclei such as $$^8\hbox {Be}$$ 8 Be and $$^4\hbox {He}$$ 4 He by means of proton beams at the Atomki Laboratory in Debrecen. The purpose of the workshop is to discuss implications of this anomaly, in particular theoretical interpretations as well as present and future experiments aiming at confirming the result and/or at providing experimental evidence for its interpretation.

Sustained attention is pivotal for tasks like studying and working for which focus and low distractions are necessary for peak productivity. This study explores the effectiveness of adaptive transcranial direct current stimulation (tDCS) in either the frontal or parietal region to enhance sustained attention. The research involved ten healthy university students performing the Continuous Performance Task-AX (AX-CPT) while receiving either frontal or parietal tDCS. The study comprised three phases. First, we acquired the electroencephalography (EEG) signal to identify the most suitable metrics related to attention states. Among different spectral and complexity metrics computed on 3 s epochs of EEG, the Fuzzy Entropy and Multiscale Sample Entropy Index of frontal channels were selected. Secondly, we assessed how tDCS at a fixed 1.0 mA current affects attentional performance. Finally, a real-time experiment involving continuous metric monitoring allowed personalized dynamic optimization of the current amplitude and stimulation site (frontal or parietal). The findings reveal statistically significant improvements in mean accuracy (94.04 vs. 90.82%) and reaction times (262.93 vs. 302.03 ms) with the adaptive tDCS compared to a non-stimulation condition. Average reaction times were statistically shorter during adaptive stimulation compared to a fixed current amplitude condition (262.93 vs. 283.56 ms), while mean accuracy stayed similar (94.04 vs. 93.36%, improvement not statistically significant). Despite the limited number of subjects, this work points out the promising potential of adaptive tDCS as a tailored treatment for enhancing sustained attention.

Background: Chronic migraine (CM) is a disabling and hard-to-treat condition, associated with high disability and high cost. Among the preventive treatments, botulinum toxin A (BoNT-a) and monoclonal antibodies against the calcitonin gene-related protein (anti-CGRP mAbs) are the only disease-specific ones. The assessment of the disease burden is complex, and among others, tools such as the allodynia symptoms checklist (ASC-12) and headache impact test (HIT-6) are very useful. This exploratory study analysed the impact of these two therapies on migraine burden. Methods: The RAMO study was a multicentre, observational, retrospective investigation conducted in two headache centres: the Fondazione IRCCS Istituto Neurologico Carlo Besta (Milan) and the Fondazione Policlinico Campus Bio-Medico (Rome). This study involved patients with chronic migraine treated with mAbs or BoNT-A. We conducted a subgroup exploratory analysis on HIT-6 and ASC-12 scores in the two groups. The Wilcoxon rank-sum test, Fisher’s exact test, and ANOVA were performed. Results: Of 126 patients, 36 on mAbs and 90 on BoNT-A had at least one available follow-up. mAbs resulted in a mean reduction of −11.1 and −11.4 points, respectively, in the HIT-6 at 6 and 12 months, while BoNT-A was reduced −3.2 and −3.6 points, respectively; the mAbs arm resulted in mean reductions in ASC-12 at 6 and 12 months of follow-up of −5.2 and −6.0 points, respectively, while BoNT-A showed lesser mean changes of −0.5 and −0.9 points, respectively. The adjusted analysis confirmed our results. Conclusions: In this exploratory analysis, anti-CGRP mAbs showed superior effectiveness for HIT-6 and ASC12 compared to BoNT-A. Reductions in terms of month headache days (MHD), migraine disability assessment test (MIDAS), and migraine acute medications (MAM) were clinically relevant for both treatments.

In response to concerns over land concentration and access within the European Union, this study seeks to elucidate the factors influencing farmers’ decisions to invest in land and the consequent growth of farm size. Employing a systematic literature review utilizing the PRISMA method, we delve into theoretical and empirical studies to bridge the gap between agricultural management practices and land market dynamics. Our analysis reveals a complex interplay of endogenous and exogenous factors, including technological advancements, farm characteristics, demographic factors, macroeconomic conditions, and policy environment, significantly impacting investment behaviours and farm growth trajectories. The research highlights the underexplored impact of external factors like policy and land regulation, which are scarcely addressed in empirical studies despite their substantial influence on farm-size evolution and investment decisions. Furthermore, the study emphasizes the need for future research to incorporate a more comprehensive framework that integrates internal farm dynamics with broader economic and policy contexts, thereby facilitating a deeper understanding of the agricultural sector’s resilience and sustainability. The findings underscore the critical role of adopting innovative methodologies and approaches to fully understand the dynamics of farm growth and land investments, aiming to support policymakers, stakeholders, and researchers in fostering sustainable agricultural practices.

Endocrine-disrupting compounds are chemicals that alter the normal functioning of the endocrine system of living organisms. They can be natural (N-EDCs) or synthetic compounds (S-EDCs). N-EDCs can belong to different groups, such as phytoestrogens (PEs), including flavonoids, or mycotoxins originating from plants or fungi, and cyanotoxins, derived from bacteria. Humans encounter these substances in their daily lives. The aim of this rapid review (RR) is to provide a fine mapping of N-EDCs and their toxicological effects on human health in terms of various medical conditions or adverse consequences. This work is based on an extensive literature search and follows a rigorous step-by-step approach (search strategy, analysis strategy and data extraction), to select eligible papers published between 2019 and 2023 in the PubMed database, and to define a set of aspects characterizing N-EDCs and the different human target systems. Of the N-EDCs identified in this RR, flavonoids are the most representative class. Male and female reproductive systems were the targets most affected by N-EDCs, followed by the endocrine, nervous, bone and cardiovascular systems. In addition, the perinatal, pubertal and pregnancy periods were found to be particularly susceptible to natural endocrine disruptors. Considering their current daily use, more toxicological research on N-EDCs is required.

Background Inflammation is a key mediator in the development and progression of the atherosclerotic disease process as well as its resultant complications, like myocardial infarction (MI), stroke and cardiovascular (CV) death, and is emerging as a novel treatment target. Trials involving anti-inflammatory medications have demonstrated outcome benefit in patients with known CV disease. In this regard, colchicine appears to hold great promise. However, there are potential drawbacks to colchicine use, as some studies have identified an increased risk of infection, and a non-significant trend for increased all-cause mortality. Thus, a more thorough understanding of the underlying mechanism of action of colchicine is needed to enable a better patient selection for this novel CV therapy.Objective The primary objective of the Canadian Study of Arterial Inflammation in Patients with Diabetes and Recent Vascular Events, Evaluation of Colchicine Effectiveness (CADENCE) trial is to assess the effect of colchicine on vascular inflammation in the carotid arteries and ascending aorta measured with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with type 2 diabetes mellitus (T2DM) or pre-diabetes who have experienced a recent vascular event (acute coronary syndrome (ACS)/MI, transient ischaemic attack (TIA) or stroke). Secondary objectives include determining colchicine’s effect on inflammatory biomarkers (high-sensitivity C reactive protein (hs-CRP) and interleukin-6 (IL-6)). Additionally, we will assess if baseline inflammation imaging or biomarkers are associated with a treatment response to colchicine determined by imaging. Exploratory objectives will look at: (1) the difference in the inflammatory response to colchicine in patients with coronary events compared with patients with cerebral events; (2) the difference in the inflammatory response to colchicine in different vascular beds; (3) the relationship of FDG-PET imaging markers with serum biomarkers and (4) assessment of quality-of-life changes.Methods and design CADENCE is a multicentre, prospective, randomised, double-blinded, placebo-controlled study to determine the effect of colchicine on arterial inflammation as assessed with imaging and circulatory biomarkers, specifically carotid arteries and aortic FDG uptake as well as hs-CRP and IL-6 among others. Patients with T2DM or pre-diabetes who have recently experienced a CV event (within 30–120 days after an ACS (ie, ST-elevation MI (STEMI) or non-STEMI)) or TIA/stroke with documented large vessel atherosclerotic disease will be randomised to treatment with either colchicine 0.6 mg oral daily or placebo. Participants will undergo baseline clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan of the ascending aorta and left and right carotid arteries. Patients will undergo treatment for 6 months and have repeat clinical evaluation including EQ5D assessment, blood work for inflammatory markers and FDG PET/CT scan at the conclusion of the study. The primary outcome will be the change in the maximum target to background ratio (TBRmax) in the ascending aorta (or carotid arteries) from baseline to follow-up on FDG PET/CT imaging.Discussion Colchicine is an exciting potential new therapy for CV risk reduction. However, its use is associated with side effects and greater understanding of its underlying mechanism of action is needed. Importantly, the current study will determine whether its anti-inflammatory action is an indirect systemic effect, or a more local plaque action that decreases inflammation. The results will also help identify patients who will benefit most from such therapy.Trial registration number NCT04181996.

Background Mental stress–induced myocardial ischemia is a frequent phenomenon in patients with coronary artery disease and is associated with a greater risk of future cardiovascular events. The association between chronic symptoms of psychological distress and mental stress–induced ischemia is not clear. Methods and Results We used a composite score of psychological distress derived from symptoms of depression, posttraumatic stress disorder, anxiety, anger, and perceived general stress. Participants underwent myocardial perfusion imaging with both mental (public speaking task) and conventional (exercise or pharmacological) stress testing. Overall, 142 (15.9%) patients experienced mental stress–induced myocardial ischemia. After adjusting for demographic factors, medical history, and medication use, patients in the highest tertile of psychological distress score had 35% higher odds of having mental stress–induced ischemia compared to those in the lowest tertile (odds ratio [OR], 1.35 [95% CI, 1.06–2.22]). Stratified analyses showed that the association between psychological distress score and mental stress–induced myocardial ischemia was significantly associated only within the subgroup of patients with a prior myocardial infraction, with patients with a prior myocardial infarction in the highest tertile having a 93% higher odds of developing myocardial ischemia with mental stress (95% CI, 1.07–3.60). There was no significant association between psychological distress and conventional stress–induced ischemia (OR, 1.19 [95% CI, 0.87–1.63]). Conclusions Among patients with a history of myocardial infarction, a higher level of psychosocial distress is associated with mental stress–induced myocardial ischemia but not with ischemia induced by a conventional stress test.

The first search for ultra-rare K+ decays into the π+e+e−e+e− final state is reported, using a dataset collected by the NA62 experiment at CERN in 2017–2018. An upper limit of 1.4×10−8 at 90% CL is obtained for the branching ratio of the K+→π+e+e−e+e− decay, predicted in the Standard Model to be (7.2±0.7)×10−11. Upper limits at 90% CL are obtained at the level of 10−9 for the branching ratios of two prompt decay chains involving pair-production of hidden-sector mediators: K+→π+aa, a→e+e− and K+→π+S, S→A′A′, A′→e+e−.

Summary: Background: The causes for immune-mediated inflammatory diseases (IMIDs) are diverse and the incidence trends of IMIDs from specific causes are rarely studied. The study aims to investigate the pattern and trend of IMIDs from 1990 to 2019. Methods: We collected detailed information on six major causes of IMIDs, including asthma, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, psoriasis, and atopic dermatitis, between 1990 and 2019, derived from the Global Burden of Disease study in 2019. The average annual percent change (AAPC) in number of incidents and age standardized incidence rate (ASR) on IMIDs, by sex, age, region, and causes, were calculated to quantify the temporal trends. Findings: In 2019, rheumatoid arthritis, atopic dermatitis, asthma, multiple sclerosis, psoriasis, inflammatory bowel disease accounted 1.59%, 36.17%, 54.71%, 0.09%, 6.84%, 0.60% of overall new IMIDs cases, respectively. The ASR of IMIDs showed substantial regional and global variation with the highest in High SDI region, High-income North America, and United States of America. Throughout human lifespan, the age distribution of incident cases from six IMIDs was quite different. Globally, incident cases of IMIDs increased with an AAPC of 0.68 and the ASR decreased with an AAPC of −0.34 from 1990 to 2019. The incident cases increased across six IMIDs, the ASR of rheumatoid arthritis increased (0.21, 95% CI 0.18, 0.25), while the ASR of asthma (AAPC = −0.41), inflammatory bowel disease (AAPC = −0.72), multiple sclerosis (AAPC = −0.26), psoriasis (AAPC = −0.77), and atopic dermatitis (AAPC = −0.15) decreased. The ASR of overall and six individual IMID increased with SDI at regional and global level. Countries with higher ASR in 1990 experienced a more rapid decrease in ASR. Interpretation: The incidence patterns of IMIDs varied considerably across the world. Innovative prevention and integrative management strategy are urgently needed to mitigate the increasing ASR of rheumatoid arthritis and upsurging new cases of other five IMIDs, respectively. Funding: The Global Burden of Disease Study is funded by the Bill and Melinda Gates Foundation. The project funded by Scientific Research Fund of Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital (2022QN38).

Objective: Crosstalk in surface electromyogram (EMG) is an important open problem and the common strategy of reducing it through spatial filters needs improvements. Methods: We evaluated experimentally the optimal spatio-temporal filter (OSTF), i.e., a recent approach that adapts to the subject, filtering different EMG channels both in time and space to emphasize the signal of a target muscle discarding that of adjacent ones. EMGs were recorded by a high-density recording system from pronator teres (target muscle) and flexor carpi radialis (crosstalk muscle) of 8 healthy subjects. OSTF was tested in different conditions, considering one channel per muscle (either single or double differential, SD and DD, respectively), changing the selectivity of detection (small electrodes close to each other, or large ones with higher inter-electrode distance), the force applied by the muscles (whose EMGs were summed to simulate different levels of crosstalk), and the duration of the signal to train the method. Results: OSTF was less affected by crosstalk than SD and DD filters. Statistically significant improvements were obtained in reducing the crosstalk-induced variations: for example, considering small electrodes, we obtained a percentage error of 157.30±57.11 % and 38.54±10.47 % (mean±std) in the estimation of the average rectified value (ARV), and an error of 23.57±3.92 % and 8.31±0.88 % in the estimation of the median frequency (MDF), for SD and OSTF, respectively. Conclusion: The OSTF can be applied in real-time, is easy to use, and is feasible even when using only few detection channels, as is customary in many applications.

Background Regenerative Medicine (RM) is a branch of medicine that aims to regenerate tissues and organs to overcome the problems transplants entail (poor availability, risk of rejection and intense immunosuppression). To do this, RM makes use of tissue engineering (TE). This fundamental branch deals with creating biological scaffolds capable of performing the role that physiologically belongs to the extracellular matrix (ECM). In this review, we report how specific characteristics of the scaffolds (bio-compatibility, biodegradability and mechanical and conformal properties) can be obtained using 3D printing, which facilitates the emulation of physiological tissues and organs.

Abstract Hematological patients at higher risk of severe COVID‐19 were excluded from the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine trials. In this single‐center observational prospective study (NCT05074706), we evaluate immune response in the hematological patients followed at the Hematological Division of San Gerardo Hospital, Monza (Italy) deemed to be severely immunosuppressed after vaccination with two doses of the BNT162b2 vaccine. Anti‐SARS‐CoV‐2 immunoglobulin G titers above the cutoff value of 33.8 BAU/ml were detected in 303 (80.2%) out of the 378 patients enrolled. Patients with lymphoproliferative disorders had a significant lower probability of immunization (43.2% vs. 88.4%, p

Abstract A sample of 2.8 × 104 K + → π + μ + μ − candidates with negligible background was collected by the NA62 experiment at the CERN SPS in 2017–2018. The model-independent branching fraction is measured to be (9.15 ± 0.08) × 10 −8, a factor three more precise than previous measurements. The decay form factor is presented as a function of the squared dimuon mass. A measurement of the form factor parameters and their uncertainties is performed using a description based on Chiral Perturbation Theory at O $$ \mathcal{O} $$ (p 6).

Objective: The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau (VHL) syndrome. Methods: A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings. Results: VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors. Conclusion: Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up.

Background: Adverse mental health conditions including depression, posttraumatic stress disorder (PTSD), and anxiety are prevalent among patients who survive myocardial infarctions (MI) and are associated with adverse outcomes. The mechanisms underlying these associations, however, are not well understood. Inflammatory pathways may mediate the cardiovascular outcomes of patients with mental health disorders. We examined the bidirectional association between PTSD symptoms and inflammatory biomarkers in a young/middle-aged post MI population. We further examined how this association may differ between women and men as well as between Black and non-Black individuals. Methods: Participants included individuals with early onset MI between the ages 25 and 60. Mental health scores for depression, PTSD, perceived stress, and anxiety as well as inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (hsCRP), were collected at baseline and at six-month follow up. We examined the bidirectional changes in mental health symptoms and inflammatory biomarkers between baseline and follow-up. Results: Among 244 patients in the study (mean age: 50.8, 48.4% female, 64.3% Black), the geometric means for IL-6 level and hsCRP at rest were 1.7 pg/mL and 2.76 mg/L, respectively. Mental health scores at baseline did not consistently predict changes in inflammatory biomarkers at follow-up. However, baseline levels of both IL-6 and hsCRP were robustly associated with an increase in re-experiencing PTSD symptoms at 6 months: in adjusted linear mixed models, there was a 1.58-point increase in re-experiencing PTSD symptoms per unit of baseline hsCRP (p = 0.01) and 2.59-point increase per unit of baseline IL-6 (p = 0.02). Once the analysis was stratified by race, the association was only noted in Black individuals. Baseline inflammation was not associated with change in any of the other mental health symptom scores. Conclusion: Markers of inflammation are associated with an increase in post-event PTSD symptoms in younger or middle-aged patients who experienced an MI, especially Black patients. These results suggest a mechanistic link between inflammation and the development of PTSD among individuals with cardiovascular disease.

Abstract Migraine is a complex condition in which genetic predisposition interacts with other biological and environmental factors determining its course. A hyperresponsive brain cortex, peripheral and central alterations in pain processing, and comorbidities play a role from an individual biological standpoint. Besides, dysfunctional psychological mechanisms, social and lifestyle factors may intervene and impact on the clinical phenotype of the disease, promote its transformation from episodic into chronic migraine and may increase migraine-related disability. Thus, given the multifactorial origin of the condition, the application of a biopsychosocial approach in the management of migraine could favor therapeutic success. While in chronic pain conditions the biopsychosocial approach is already a mainstay of treatment, in migraine the biomedical approach is still dominant. It is instead advisable to carefully consider the individual with migraine as a whole, in order to plan a tailored treatment. In this review, we first reported an analytical and critical discussion of the biological, psychological, and social factors involved in migraine. Then, we addressed the management implications of the application of a biopsychosocial model discussing how the integration between non-pharmacological management and conventional biomedical treatment may provide advantages to migraine care.