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Land-based nutrient inputs to the ocean have been linked to increased coastal productivity, subsurface acidification and O2 loss, even in upwelling systems like the Southern California Bight. However, whether eutrophication alters the [environment’s] capacity to support key taxa has yet to be evaluated for this region. Here, we assess the impact of land-based nutrient inputs on the availability of aerobic and calcifying habitat for key pelagic taxa using ocean model simulations. We find that acute, lethal conditions are not commonly induced in epipelagic surface waters, but that sublethal, ecologically relevant changes are pervasive. Land-based nutrient inputs reduce the potential aerobic and calcifier habitat during late summer, when viable habitat is at its seasonal minimum. A region of annually recurring habitat compression is predicted 30 – 90 km from the mainland, southeast of Santa Catalina Island. Here, both aerobic and calcifier habitat is vertically compressed by, on average, 25%, but can be as much as 60%. This effect can be traced to enhanced remineralization of organic matter that originates from the coast. These findings suggest that effects of land-based nutrients are not restricted to chemistry but extend to habitat capacity for multiple taxa of ecological and economic importance. Considerable uncertainty exists, however, in how this habitat compression translates to population-level effects.

There are many potential approaches to marine carbon dioxide removal (mCDR), of which ocean iron fertilization (OIF) has the longest history of study. However, OIF studies to date were not primarily designed to quantify the durability of carbon (C) storage, nor how wise OIF might be as an mCDR approach. To quantify C sequestration, we introduce a metric called the “centennial tonne,” defined as 1,000 kg of C isolated from atmospheric contact for on average at least 100 years. We present the activities needed to assess OIF from a scientific and technological perspective, and additionally, how it might be responsibly studied and potentially deployed. The five activities include: field studies in the Northeast Pacific; improved modeling for field studies, data assimilation and predictions at larger scales; improvements in monitoring, reporting and verification (MRV) for C, and also MRV for tracking ecological and environmental impacts; and developing new iron sources and their delivery, to increase efficiencies and reduce costs. The fifth activity is to understand whether public and community support exists for OIF, and what governance structures might support further research and possible deployment of OIF. This article is written by a multidisciplinary experts group called Exploring Ocean Iron Solutions (ExOIS) that is organized around a responsible code of conduct. Of the mCDR approaches, OIF has the potential to be low cost, scalable, and rapidly deployable. Reducing CO2 emissions must lead the way, but there is also an urgency to decide under what conditions and whether OIF might be deployed or not.

Bifidobacteria are well known as common and abundant colonizers of the human gut and are able to exert multiple beneficial effects on their host, although the cooperative and competitive relationships that may occur among bifidobacterial strains are still poorly investigated. Therefore, to dissect possible molecular interactions among bifidobacterial species that typically colonize the human gut, three previously identified bifidobacterial prototypes, i.e., B. bifidum PRL2010, B. breve PRL2012, and B. longum PRL2022 were cultivated individually as well as in bi- and tri-association in a human gut-simulating medium. Transcriptomic analyses of these co-associations revealed up-regulation of genes predicted to be involved in the production of extracellular structures including pili (i.e., flp pilus assembly TadE protein gene), exopolysaccharides (i.e., GtrA family protein gene) and teichoic acids (i.e., ABC transporter permease), along with carbohydrate, amino acid and vitamin metabolism-related genes (i.e., exo-alpha-sialidase; beta-galactosidase and pyridoxamine kinase), suggesting that co-cultivation of bifidobacteria induces a response, in individual bifidobacterial strains, aimed at enhancing their proliferation and survival, as well as their ability to cooperate with their host to promote their persistence. Furthermore, exposure of the selected prototypes to human cell line monolayers unveiled the ability of the bifidobacterial tri-association to communicate with their host by increasing the expression of genes involved in adherence to/interaction with intestinal human cells. Lastly, bifidobacterial tri-association promoted the transcriptional upregulation of genes responsible for maintaining the integrity and homeostasis of the intestinal epithelial barrier.

BackgroundThis phenomenological-hermeneutic study is about the experiences of physicians in the Oncology Intensive Care Unit of the Careggi University Hospital, in Florence. The Oncology Intensive Care Unit is a place of great emotional impact and can be create stressful situations. The emotional labor can lead to the development of cynicism, depersonalization and emotional exhaustion. The objective of the study was to learn about and come into contact with the experiences of operators who operate in a highly specialized and critical context.MethodA semi-structured interview was conducted on 11 physicians in the Oncology Intensive Care Unit of careggi hospital. The interviews were transcribed and subjected to content analysis using the phenomenological-hermeneutic method. The results concerning the emotional involvement of doctors were placed in three macro categories: difficulties, what helps and needs.ResultsThe interviews highlight the difficulty doctors have in coming into contact with the potentially deadly disease and a further aggravating element appears to be the identification with the patient himself. This condition of difficulty can lead doctors to commit medical errors or to reduce the quality of care.ConclusionThe results that emerged provide a more detailed understanding of the landscape of emotional reactions of working with the cancer patient in the intensive care unit. In light of the high emotional burden and the inherent possibility of developing burnout in this target population of health care workers, knowing the main critical issues and needs reported may facilitate a more effective tailored intervention.

BackgroundSkeletal fragility is characterized by increased frequency of vertebral fractures (VFs) in acromegaly. Several trials were conducted to identify modifiable risk factors and predictors of VFs, with limited data on the prognostic role of GH receptor (GHR) isoforms. In this study, we investigated the potential role of GHR polymorphism on the occurrence of incidental VFs (i-VFs), in patients treated with second-line medical therapies.MethodsA longitudinal, retrospective, observational study was conducted on a cohort of 45 acromegalic patients not-responsive to first-generation somatostatin receptor ligands (fg-SRLs) and treated with GHR antagonist (Pegvisomant) or with the second-generation SRLs (Pasireotide long-acting release).ResultsSecond line treatments were Pegvisomant plus fg-SRLs in 26 patients and Pasireotide LAR in 19 patients. From the group treated with fg-SRLs+Peg-V, the fl-GHR isoform was identified in 18 patients (69.2%) and the d3-GHR isoform in 8 patients (30.8%). I-VFs arose exclusively in fl-GHR isoform carriers (p=0.039). From the group treated with Pasireotide LAR, the fl-GHR isoform was identified in 11 patients (57.9%), and the d3-GHR isoform in 8 patients (42.1%). I-VFs arose exclusively in d3-GHR isoform carriers (p=0.018). Patients with fl-GHR isoform had a higher risk for i-VFs if treated with fg-SRL+Peg-V (OR: 1.6 95%IC: 1.1-2.3, p=0.04), and a lower risk if treated with Pasi-LAR (OR: 0.26 IC95%: 0.11-0.66, p=0.038).ConclusionsOur data support a predictive role of the GHR isoforms for the occurrence of i-VFs in acromegalic patients treated with second-line drugs, tailored to the individual patient. The knowledge of the GHR polymorphism may facilitate the choice of second-line therapies, improving the therapeutic approach, in the context of personalized medicine.

ObjectiveThe prevalence of anxiety and depression in patients diagnosed with Alopecia Areata (AA) is very high and this significant burden of psychological symptoms threatens the Health-Related Quality of Life (HRQoL) of affected patients. Indeed, AA often does not produce significant physical symptoms, but it nonetheless disrupts many areas of mental health. Clinical assessment of disease severity may not reliably predict patient's HRQoL, nor may it predict the patient's perception of illness. For this reason, considerable effort has been made to apply and develop measures that consider patient's perception and assess the HRQoL of individuals affected by AA. The aim of this multicentric study was to provide the Italian version of the Skindex-16AA and to evaluate its psychometric properties in a clinical sample of consecutive patients with moderate-to-severe AA.MethodsThis is a longitudinal, multicenter, observational study. Patients returned for follow-up visits at 4-, 12-, and 24-weeks. The analyses of the current work aimed to confirm the factorial structure of the Skindex-16AA. In the case of non-fit, an alternative structure for the model was proposed, using an Exploratory Graph Analysis and the Bayesian approach.ResultsThe sample was composed of 106 patients with AA. Alopecia Universalis was the most frequently diagnosed type of alopecia at all time points. The analyses on the Skindex-16AA revealed that a two-factor structure with eight items fit the data best (Bayesian Posterior Predictive Checking using 95% Confidence Interval for the Difference Between the Observed and the Replicated Chi-Square values = −6.246/56.395, Posterior Predictive P-value = 0.06), and reported satisfactory psychometric properties (i.e., internal consistency and convergent validity).ConclusionThe Skindex-8AA demonstrated optimal psychometric properties (i.e., convergent and construct validity, and test-retest reliability) measured in a sample of patients with AA, that may suggest that it is an appropriate tool to measure the HRQoL in AA patients. However, further studies are needed in order to confirm and tested other psychometric features of this tool.

IntroductionN-glycosylation is a post-translational modification that is highly important for the development of monoclonal antibodies (mAbs), as it regulates their biological activity, particularly in terms of immune effector functions. While typically added at the Fc level, approximately 15-25% of circulating antibodies exhibit glycosylation in the Fab domains as well. To the best of our knowledge, cetuximab (Erbitux®) is the only therapeutic antibody presenting Fab glycosylation approved world-wide targeting the epidermal growth factor receptor for the treatment of metastatic-colorectal and head and neck cancers. Additionally, it can trigger antibody-dependent cell cytotoxicity (ADCC), a response that typically is influenced by N-glycosylation at Fc level. However, the role of Fab glycosylation in cetuximab remains poorly understood. Hence, this study aims to investigate the structural role of Fab glycosylation on the conformational behavior of cetuximab.MethodsThe study was performed in silico via accelerated molecular dynamics simulations. The commercial cetuximab was compared to its form without Fab glycosylation and structural descriptors were evaluated to establish conformational differences.ResultsThe results clearly show a correlation between the Fab glycosylation and structural descriptors that may modulate the conformational freedom of the antibody, potentially affecting Fc effector functions, and suggesting a negative role of Fab glycosylation on the interaction with FcγRIIIa.ConclusionFab glycosylation of cetuximab is the most critical challenge for biosimilar development, but the differences highlighted in this work with respect to its aglycosylated form can improve the knowledge and represent also a great opportunity to develop novel strategies of biotherapeutics.

Understanding the complex dynamics of heart rate variability (HRV) during pregnancy is crucial for monitoring both maternal well-being and fetal health. In this study, we use the Multifractal Detrended Fluctuations Analysis approach to investigate HRV patterns in pregnant individuals during sleep based on RR interval maxima (MM fluctuations). In addition, we study the type of multifractality within MM fluctuations, that is, if it arises from a broad probability density function or from varying long-range correlations. Furthermore, to provide a comprehensive view of HRV changes during sleep in pregnancy, classical temporal and spectral HRV indices were calculated at quarterly intervals during sleep. Our study population consists of 21 recordings from nonpregnant women, 18 from the first trimester (early-pregnancy) and 18 from the second trimester (middle-pregnancy) of pregnancy. Results. There are statistically significant differences (p-value < 0.05) in mean heart rate, rms heart rate, mean MM fluctuations, and standard deviation of MM fluctuations, particularly in the third and fourth quarter of sleep between pregnant and non-pregnant states. In addition, the early-pregnancy group shows significant differences (p-value < 0.05) in spectral indices during the first and fourth quarter of sleep compared to the non-pregnancy group. Furthermore, the results of our research show striking similarities in the average multifractal structure of MM fluctuations between pregnant and non-pregnant states during normal sleep. These results highlight the influence of different long-range correlations within the MM fluctuations, which could be primarily associated with the emergence of sleep cycles on multifractality during sleep. Finally, we performed a separability analysis between groups using temporal and spectral HRV indices as features per sleep quarter. Employing only three features after Principal Component Analysis (PCA) to the original feature set, achieving complete separability among all groups appears feasible. Using multifractal analysis, our study provides a comprehensive understanding of the complex HRV patterns during pregnancy, which holds promise for maternal and fetal health monitoring. The separability analysis also provides valuable insights into the potential for group differentiation using simple measures such as mean heart rate, rms heart rate, and mean MM fluctuations or in the transformed feature space based on PCA.

IntroductionIntrauterine transfusion is the treatment for fetal anemia resulting from maternal alloimmunization, infections (parvovirus B19 and cytomegalovirus), single demise of a monochorionic twin, chorioangioma, and other rare conditions. Fetal analgesia is mandatory to reduce movement and pain perception during the procedure. This study aims to evaluate perinatal outcomes for such procedures, following the routine use of fetal analgesia in our clinical practice.Materials and methodsRetrospective analysis of cases from 2009 to 2022, including all confirmed fetal anemia with fetal blood sampling. After fetal analgesia, Rh-negative concentrated red blood cells were transfused, with ultrasonographic follow-up 24 h and 1 week later. In case of suspected brain lesion, magnetic resonance imaging was performed. Elective delivery was considered in case of persistent anemia after 34 weeks. Post-natal follow-up and comprehensive obstetric and perinatal outcomes data were collected.ResultsAltogether 59 anemic fetuses were included, with 34 (57.6%) being hydropic. The causes of anemia were maternal alloimmunization (22, 37.3%), infections (13, 22%), monochorionicity (10, 16.9%), rare conditions (9, 15.3%), and two chorioangiomas (3.4%). The median gestational age at the procedure was 25.2 weeks (18–32 weeks), with no related preterm premature rupture of membranes (

More than 650 reversible and irreversible post-translational modifications (PTMs) of proteins have been listed so far. Canonical PTMs of proteins consist of the covalent addition of functional or chemical groups on target backbone amino-acids or the cleavage of the protein itself, giving rise to modified proteins with specific properties in terms of stability, solubility, cell distribution, activity, or interactions with other biomolecules. PTMs of protein contribute to cell homeostatic processes, enabling basal cell functions, allowing the cell to respond and adapt to variations of its environment, and globally maintaining the constancy of the milieu interieur (the body’s inner environment) to sustain human health. Abnormal protein PTMs are, however, associated with several disease states, such as cancers, metabolic disorders, or neurodegenerative diseases. Abnormal PTMs alter the functional properties of the protein or even cause a loss of protein function. One example of dramatic PTMs concerns the cellular prion protein (PrPC), a GPI-anchored signaling molecule at the plasma membrane, whose irreversible post-translational conformational conversion (PTCC) into pathogenic prions (PrPSc) provokes neurodegeneration. PrPC PTCC into PrPSc is an additional type of PTM that affects the tridimensional structure and physiological function of PrPC and generates a protein conformer with neurotoxic properties. PrPC PTCC into PrPSc in neurons is the first step of a deleterious sequence of events at the root of a group of neurodegenerative disorders affecting both humans (Creutzfeldt–Jakob diseases for the most representative diseases) and animals (scrapie in sheep, bovine spongiform encephalopathy in cow, and chronic wasting disease in elk and deer). There are currently no therapies to block PrPC PTCC into PrPSc and stop neurodegeneration in prion diseases. Here, we review known PrPC PTMs that influence PrPC conversion into PrPSc. We summarized how PrPC PTCC into PrPSc impacts the PrPC interactome at the plasma membrane and the downstream intracellular controlled protein effectors, whose abnormal activation or trafficking caused by altered PTMs promotes neurodegeneration. We discussed these effectors as candidate drug targets for prion diseases and possibly other neurodegenerative diseases.

BackgroundPure red cell aplasia (PRCA) is a possible complication after allogeneic hematopoietic stem cell transplantation (HSCT) with major ABO incompatibility. Patients experience delayed engraftment of the erythroid series, with prolonged transfusion-dependent anemia and iron overload.MethodsWe performed a revision of the most recent literature about post-HSCT PRCA treatment procedures. Moreover, we conducted a retrospective study, over the last 13-years, which included all consecutive major ABO mismatched HSCT performed in our unit, with the aim to assess PRCA incidence, risk factors, and response to different treatments. Overall, 194 patients received a major ABO mismatched transplant from 2010 to 2022. For each patient, data about demographic and transplant characteristics, engraftment, blood transfusion, and possible treatment received were collected.ResultsThe literature review returned 23 eligible papers on PRCA treatment, with high success rate using plasma-exchange (PEX) and immunoadsorption procedures, daratumumab, and eltrombopag. Our study identified a total of 24 cases of PRCA. Among risk factors for PRCA development, we have found older recipient age (p=0.01), high pre-HSCT IgG and IgM IHA titer (p

A recent development in deep learning techniques has attracted attention to the decoding and classification of electroencephalogram (EEG) signals. Despite several efforts to utilize different features in EEG signals, a significant research challenge is using time-dependent features in combination with local and global features. Several attempts have been made to remodel the deep learning convolution neural networks (CNNs) to capture time-dependency information. These features are usually either handcrafted features, such as power ratios, or splitting data into smaller-sized windows related to specific properties, such as a peak at 300 ms. However, these approaches partially solve the problem but simultaneously hinder CNNs' capability to learn from unknown information that might be present in the data. Other approaches, like recurrent neural networks, are very suitable for learning time-dependent information from EEG signals in the presence of unrelated sequential data. To solve this, we have proposed an encoding kernel (EnK), a novel time-encoding approach, which uniquely introduces time decomposition information during the vertical convolution operation in CNNs. The encoded information lets CNNs learn time-dependent features in addition to local and global features. We performed extensive experiments on several EEG data sets—physical human-robot collaborations, P300 visual-evoked potentials, motor imagery, movement-related cortical potentials, and the Dataset for Emotion Analysis Using Physiological Signals. The EnK outperforms the state of the art with an up to 6.5% reduction in mean squared error (MSE) and a 9.5% improvement in F1-scores compared to the average for all data sets together compared to base models. These results support our approach and show a high potential to improve the performance of physiological and non-physiological data. Moreover, the EnK can be applied to virtually any deep learning architecture with minimal effort.

BackgroundCardiovascular diseases (CVDs) pose a significant global health challenge, necessitating innovative approaches for primary prevention. Personalized prevention, based on genetic risk scores (PRS) and digital technologies, holds promise in revolutionizing CVD preventive strategies. However, the clinical efficacy of these interventions requires further investigation. This study presents the protocol of the INNOPREV randomized controlled trial, aiming to evaluate the clinical efficacy of PRS and digital technologies in personalized cardiovascular disease prevention.MethodsThe INNOPREV trial is a four-arm RCT conducted in Italy. A total of 1,020 participants, aged 40–69 with high 10-year CVD risk based on SCORE 2 charts, will be randomly assigned to traditional CVD risk assessment, genetic testing (CVD PRS), digital intervention (app and smart band), or a combination of genetic testing and digital intervention. The primary objective is to evaluate the efficacy of providing CVD PRS information, measured at baseline, either alone or in combination with the use of an app and a smart band, on two endpoints: changes in lifestyle patterns, and modification in CVD risk profiles. Participants will undergo a comprehensive assessment and cardiovascular evaluation at baseline, with follow-up visits at one, five, and 12 months. Lifestyle changes and CVD risk profiles will be assessed at different time points beyond the initial assessment, using the Life's Essential 8 and SCORE 2, respectively. Blood samples will be collected at baseline and at study completion to evaluate changes in lipid profiles. The analysis will employ adjusted mixed-effect models for repeated measures to assess significant differences in the data collected over time. Additionally, potential moderators and mediators will be examined to understand the underlying mechanisms of behavior change.DiscussionAs the largest trial in this context, the INNOPREV trial will contribute to the advancement of personalized cardiovascular disease prevention, with the potential to positively impact public health and reduce the burden of CVDs on healthcare systems. By systematically examining the clinical efficacy of PRS and digital interventions, this trial aims to provide valuable evidence to guide future preventive strategies and enhance population health outcomes.

BackgroundLeptomeningeal enhancement (LME) is considered an MRI marker of leptomeningeal inflammation in inflammatory neurological disorders, including multiple sclerosis (MS). To our knowledge, no disease-modifying therapies (DMTs) have been demonstrated to affect LME number or morphology so far.MethodsMonocentric study investigating the frequency and number of LME in a cohort of people with (pw)MS who performed a 3 T brain MRI with a standardized protocol (including a post-contrast FLAIR sequence), and exploring the impact of autologous hematopoietic stem cell transplantation (AHSCT) on this marker. In a longitudinal pilot study, consecutive MRIs were also analyzed in a subgroup of pwMS, including patients evaluated both pre- and post-AHSCT.ResultsFifty-five pwMS were included: 24/55 (44%) had received AHSCT (AHSCT group) and 31 other treatments (CTRL group). At least one LME was identified in 19/55 (35%) cases (42 and 29% in the AHSCT and CTRL groups, respectively; p = 0.405). In the AHSCT group, LME number correlated with age at AHSCT (R = 0.50; p = 0.014), but not with age at post-treatment MRI. In the longitudinal pilot study (n = 8), one LME disappeared following AHSCT in 1/4 patients, whereas LME number was unchanged in the remaining four pwMS from the CTRL group.DiscussionThese results suggest that AHSCT may affect development and persistence of LME, strengthening the indication for early use of effective therapies bioavailable within the central nervous system (CNS), and therefore potentially targeting compartmentalized inflammation.

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%.

IntroductionProstate-specific membrane antigen (PSMA) is a transmembrane protein expressed by normal prostatic tissue. Therefore, molecular imaging targeting PSMA (PSMA-PET) has gained particular interest and diffusion for PCa staging and restaging. Several factors may affect PSMA-PET results, and many tools have been proposed to improve patient selection. Furthermore, PSMA expression is not homogeneous among different tissues and within the prostate itself. The aims of this study were to evaluate immunohistochemistry (IHC) features of prostate biopsy samples and to assess their correlation with whole-mount specimens and PSMA-PET parameters.MethodsWe included consecutive high-risk PCa patients who underwent PSMA-PET for staging proposal at our institution from January 2022 to December 2022. The PET parameters selected were SUVmax, total volume (TV), and total lesion activity (TL). Each patient underwent multiparametric MRI (mpMRI) and fusion-targeted prostate biopsy prior to surgery. IHC analyses were performed on the index lesion cores. IHC visual score (VS) (1, 2, 3) and visual pattern (VP) (membranous, cytoplasmic, and combined) and the percentage of PSMA-negative tumor areas (PSMA%neg) within biopsy cores were evaluated.ResultsForty-three patients who underwent robotic radical prostatectomy after PSMA-PET were available for analyses. Concordance between VS and VP at biopsy and final pathology showed a Cohen’s kappa coefficient of 0.39 and 0.38, respectively. Patients with PSMA%neg 20% on biopsy cores in terms of SUVmax, PSMA-TL, and PSMA-TV (p = 0.5, p = 0.5, and p = 0.9 respectively).ConclusionsWe found a correlation between IHC VS and VP on targeted biopsy cores and SUVmax at PSMA-PET. However, the correlation between the IHC parameters of biopsy cores and final pathology was not as high as expected. Nevertheless, the presence of PSMA%neg

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is widely recognized to play important, but complex, modulatory roles in a variety of tumor types. In this review, we comprehensively summarize the increasingly controversial role of AhR as a tumor regulator and the mechanisms by which it alters tumor progression based on the cancer cell type. Finally, we discuss new and emerging strategies to therapeutically modulate AhR, focusing on novel agents that hold promise in current human clinical trials as well as existing FDA-approved drugs that could potentially be repurposed for cancer therapy.

IntroductionSleep-wake cycle disruption caused by shift work may lead to cardiovascular stress, which is observed as an alteration in the behavior of heart rate variability (HRV). In particular, HRV exhibits complex patterns over different time scales that help to understand the regulatory mechanisms of the autonomic nervous system, and changes in the fractality of HRV may be associated with pathological conditions, including cardiovascular disease, diabetes, or even psychological stress. The main purpose of this study is to evaluate the multifractal-multiscale structure of HRV during sleep in healthy shift and non-shift workers to identify conditions of cardiovascular stress that may be associated with shift work.MethodsThe whole-sleep HRV signal was analyzed from female participants: eleven healthy shift workers and seven non-shift workers. The HRV signal was decomposed into intrinsic mode functions (IMFs) using the empirical mode decomposition method, and then the IMFs were analyzed using the multiscale-multifractal detrended fluctuation analysis (MMF-DFA) method. The MMF-DFA was applied to estimate the self-similarity coefficients, α(q, τ), considering moment orders (q) between –5 and +5 and scales (τ) between 8 and 2,048 s. Additionally, to describe the multifractality at each τ in a simple way, a multifractal index, MFI(τ), was computed.ResultsCompared to non-shift workers, shift workers presented an increase in the scaling exponent, α(q, τ), at short scales (τ < 64 s) with q < 0 in the high-frequency component (IMF1, 0.15–0.4 Hz) and low-frequency components (IMF2–IMF3, 0.04–0.15 Hz), and with q> 0 in the very low frequencies (IMF4, < 0.04 Hz). In addition, at large scales (τ> 1,024 s), a decrease in α(q, τ) was observed in IMF3, suggesting an alteration in the multifractal dynamic. MFI(τ) showed an increase at small scales and a decrease at large scales in IMFs of shift workers.ConclusionThis study helps to recognize the multifractality of HRV during sleep, beyond simply looking at indices based on means and variances. This analysis helps to identify that shift workers show alterations in fractal properties, mainly on short scales. These findings suggest a disturbance in the autonomic nervous system induced by the cardiovascular stress of shift work.

Constraining the primary growth channel of supermassive black holes (SMBHs) remains one the most actively debated questions in the context of cosmological structure formation. Owing to the expected connection between SMBH spin parameter evolution and the accretion and merger history of individual black holes, population spin measurements offer a rare observational window into the cosmic growth of SMBHs. As of today, the most common method for estimating SMBH spin relies on modeling the relativistically broaden atomic profiles in the reflection spectrum observed in X-rays. In this paper, we study the observational requirements needed to confidently distinguish between the primary SMBH growth channels based on their distinct spin-mass distributions predicted by the Horizon-AGN cosmological simulation. Indoing so, we characterize outstanding limitations associated with the existing measurements and discuss the landscape of future observational campaigns which could be planned and executed with future X-ray observatories. We focus our attention on the High-Energy X-ray Probe (HEX-P), a proposed probe-class mission designed to serve the high-energy community in the 2030s.

Objectives: The aim of this study was to characterize the reimbursement policy for orphan drugs (ODs) in Central and Eastern European (CEE) countries in relation to the availability and impact of clinical evidence, health technology assessment (HTA) procedure, selected economic indicators, and the drug type according to indications.Materials and methods: A list of authorized medicines with orphan designation and information about active substance, Anatomical Therapeutic Chemical (ATC) classification, and therapeutic area was extracted from the web-based register of the European Medicines Agency (EMA). A country-based questionnaire survey was performed between September 2021 and January 2022 in a group of selected experts from nine CEE countries (an invitation was sent to 11 countries). A descriptive and statistical analysis was conducted to determine statistical significance, correlations, between the drug or country characteristic and the positive recommendation or reimbursement of ODs.Results: The proportion of reimbursed orphan drugs differed between countries, ranging from 17.7% in Estonia to 49.6% in Hungary (p < 0.001). The odds that ODs were reimbursed were reduced in countries with a “strong” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), the presence of other additional specific clinical aspects (e.g., genomic data) considered in the reimbursement decision (p < 0.001) and mandatory (without exception) safety assessments (p=0.004). The probability that ODs were reimbursed was increased in countries with a “moderate” level of impact of drug safety and efficacy on reimbursement decisions (p=0.018), when reimbursement decisions are dependent on the EMA registration status and orphan drug designation (p < 0.001), the presence of the “positive HTA recommendation guarantees reimbursement” policy (p < 0.001), higher GDP per inhabitant (p=0.003), and higher healthcare expenditure (p < 0.001).Conclusion: We found that there are differences among CEE countries in the reimbursement of orphan drugs, and we identified aspects that may influence these differences. Safety, efficacy, and specific clinical aspect issues significantly influenced reimbursement decisions. Antineoplastic and immunomodulating agents drugs were the largest group of ODs and increased the chance of getting a positive recommendation. The higher GDP per inhabitant and healthcare expenditures per inhabitant were positively linked to the chance that an OD receives reimbursement.

The first aim of this study is to investigate the relationship between bullying victimization and social anxiety in native and migrant adolescents in Italy. Specifically, it was hypothesized that migrant adolescents (in comparison with natives) experience more frequent episodes of bullying victimization, which in turn, may be a risk factor for the development of social anxiety symptoms. The second aim of the study is to explore the relationships from reflected minority categorization to perceived ethnic discrimination at school and social anxiety symptoms, in the subgroup of migrant students. Results showed that the migrant (vs. native) status was predictive of higher scores in social anxiety dimensions (Fear of Negative Evaluation, Social Avoidance and Distress in New Situations, and General Social Avoidance Distress), via the mediating effect of increased peer victimization. Moreover, in the subgroup of migrant participants, an indirect effect of reflected minority categorization on social anxiety was observed, mediated by perceived ethnic discrimination at school. These findings may contribute to the understanding of health inequalities among migrant and native people in the Italian context. Limitations and practical implications of the study were discussed.

During touch, mechanical forces are converted into electrochemical signals by tactile organs made of neurons, accessory cells, and their shared extracellular spaces. Accessory cells, including Merkel cells, keratinocytes, lamellar cells, and glia, play an important role in the sensation of touch. In some cases, these cells are intrinsically mechanosensitive; however, other roles include the release of chemical messengers, the chemical modification of spaces that are shared with neurons, and the tuning of neural sensitivity by direct physical contact. Despite great progress in the last decade, the precise roles of these cells in the sense of touch remains unclear. Here we review the known and hypothesized contributions of several accessory cells to touch by incorporating research from multiple organisms including C. elegans, D. melanogaster, mammals, avian models, and plants. Several broad parallels are identified including the regulation of extracellular ions and the release of neuromodulators by accessory cells, as well as the emerging potential physical contact between accessory cells and sensory neurons via tethers. Our broader perspective incorporates the importance of accessory cells to the understanding of human touch and pain, as well as to animal touch and its molecular underpinnings, which are underrepresented among the animal welfare literature. A greater understanding of touch, which must include a role for accessory cells, is also relevant to emergent technical applications including prosthetics, virtual reality, and robotics.

Members of the genus Bifidobacterium are among the first microorganisms colonizing the human gut. Among these species, strains of Bifidobacterium breve are known to be commonly transmitted from mother to her newborn, while this species has also been linked with activities supporting human wellbeing. In the current study, an in silico approach, guided by ecology- and phylogenome-based analyses, was employed to identify a representative strain of B. breve to be exploited as a novel health-promoting candidate. The selected strain, i.e., B. breve PRL2012, was found to well represent the genetic content and functional genomic features of the B. breve taxon. We evaluated the ability of PRL2012 to survive in the gastrointestinal tract and to interact with other human gut commensal microbes. When co-cultivated with various human gut commensals, B. breve PRL2012 revealed an enhancement of its metabolic activity coupled with the activation of cellular defense mechanisms to apparently improve its survivability in a simulated ecosystem resembling the human microbiome.

IntroductionHomonymous visual field defects (HVFDs) following acquired brain lesions affect independent living by hampering several activities of everyday life. Available treatments are intensive and week- or month-long. Transcranial Direct current stimulation (tDCS), a plasticity-modulating non-invasive brain stimulation technique, could be combined with behavioral trainings to boost their efficacy or reduce treatment duration. Some promising attempts have been made pairing occipital tDCS with visual restitution training, however less is knows about which area/network should be best stimulated in association with compensatory approaches, aimed at improving exploratory abilities, such as multisensory trainings.MethodsIn a proof-of-principle, sham-controlled, single-blind study, 15 participants with chronic HVFDs underwent four one-shot sessions of active or sham anodal tDCS applied over the ipsilesional occipital cortex, the ipsilesional or contralesional posterior parietal cortex. tDCS was delivered during a compensatory multisensory (audiovisual) training. Before and immediately after each tDCS session, participants carried out a visual detection task, and two visual search tasks (EF and Triangles search tests). Accuracy (ACC) and response times (RTs) were analyzed with generalized mixed models. We investigated differences in baseline performance, clinical-demographic and lesion factors between tDCS responders and non-responders, based on post-tDCS behavioral improvements. Lastly, we conducted exploratory analyses to compare left and right brain-damaged participants.ResultsRTs improved after active ipsilesional occipital and parietal tDCS in the visual search tasks, while no changes in ACC were detected. Responders to ipsilesional occipital tDCS (Triangle task) had shorter disease duration and smaller lesions of the parietal cortex and the superior longitudinal fasciculus. On the other end, on the EF test, those participants with larger damage of the temporo-parietal cortex or the fronto-occipital white matter tracts showed a larger benefit from contralesional parietal tDCS. Overall, the visual search RTs improvements were larger in participants with right-sided hemispheric lesions.ConclusionThe present result shows the facilitatory effects of occipital and parietal tDCS combined with compensatory multisensory training on visual field exploration in HVFDs, suggesting a potential for the development of new neuromodulation treatments to improve visual scanning behavior in brain-injured patients.

BackgroundSkin cancer is one of the most common forms worldwide, with a significant increase in incidence over the last few decades. Early and accurate detection of this type of cancer can result in better prognoses and less invasive treatments for patients. With advances in Artificial Intelligence (AI), tools have emerged that can facilitate diagnosis and classify dermatological images, complementing traditional clinical assessments and being applicable where there is a shortage of specialists. Its adoption requires analysis of efficacy, safety, and ethical considerations, as well as considering the genetic and ethnic diversity of patients.ObjectiveThe systematic review aims to examine research on the detection, classification, and assessment of skin cancer images in clinical settings.MethodsWe conducted a systematic literature search on PubMed, Scopus, Embase, and Web of Science, encompassing studies published until April 4th, 2023. Study selection, data extraction, and critical appraisal were carried out by two independent reviewers. Results were subsequently presented through a narrative synthesis.ResultsThrough the search, 760 studies were identified in four databases, from which only 18 studies were selected, focusing on developing, implementing, and validating systems to detect, diagnose, and classify skin cancer in clinical settings. This review covers descriptive analysis, data scenarios, data processing and techniques, study results and perspectives, and physician diversity, accessibility, and participation.ConclusionThe application of artificial intelligence in dermatology has the potential to revolutionize early detection of skin cancer. However, it is imperative to validate and collaborate with healthcare professionals to ensure its clinical effectiveness and safety.

Paratuberculosis (Johne’s disease) is a globally widespread infectious disease affecting domestic and wild ruminants, caused by Mycobacterium avium subsp. paratuberculosis (MAP). The bacterium is excreted in the feces and is characterized by high environmental resistance. The new Animal Health Law (Regulation EU 2016/429) on transmissible animal diseases, recently in force throughout the European Union, includes paratuberculosis within the diseases requiring surveillance in the EU, listing some domestic and wild Bovidae, Cervidae, and Camelidae as potential reservoirs. Taking advantage of a culling activity conducted in the Stelvio National Park (Italy), this study investigated MAP infection status of red deer (Cervus elaphus) between 2018 and 2022, and evaluated the probability of being MAP-positive with respect to individual and sampling-level variables. A total of 390 subjects were examined macroscopically and tested for MAP, using different diagnostic tools: IS900 qPCR, culture, histopathology, and serology. Twenty-three of them were found positive for MAP by at least one test, with an overall prevalence of 5.9% (95% CI 4.0–8.7), that, respectively, ranged from 12.4% in the first culling season to 2.0 and 2.1% in the 2019–2020 and 2021–2022 culling seasons. Quantitative PCR assay on ileocecal valve and mesenteric lymph nodes detected the highest number of MAP positive animals. The results of the study showed the increased probability of being MAP-positive with increasing age and that red deer with lower body mass values were more likely to be infected with MAP. Overall, the absence of signs of clinical paratuberculosis and gross lesions together with the low level of shedding witness early phases of the disease among the positive red deer and support an improvement of the paratuberculosis status of this population, as shown by the decreased prevalence of the disease over the years.

The hard X-ray emission in active galactic nuclei (AGN) and black hole X-ray binaries is thought to be produced by a hot cloud of electrons referred to as the corona. This emission, commonly described by a power law with a high-energy cutoff, is suggestive of Comptonization by thermal electrons. While several hypotheses have been proposed to explain the origin, geometry, and composition of the corona, we still lack a clear understanding of this fundamental component. NuSTAR has been playing a key role improving our knowledge of X-ray coronæ thanks to its unprecedented sensitivity above 10 keV. However, these constraints are limited to bright, nearby sources. The High Energy X-ray Probe (HEX-P) is a probe-class mission concept combining high spatial resolution X-ray imaging and broad spectral coverage (0.2–80 keV) with a sensitivity superior to current facilities. In this paper, we highlight the major role that HEX-P will play in further advancing our insights of X-ray coronæ notably in AGN. We demonstrate how HEX-P will measure key properties and track the temporal evolution of coronæ in unobscured AGN. This will allow us to determine their electron distribution and test the dominant emission mechanisms. Furthermore, we show how HEX-P will accurately estimate the coronal properties of obscured AGN in the local Universe, helping address fundamental questions about AGN unification. In addition, HEX-P will characterize coronæ in a large sample of luminous quasars at cosmological redshifts for the first time and track the evolution of coronæ in transient systems in real time. We also demonstrate how HEX-P will enable estimating the coronal geometry using spectral-timing techniques. HEX-P will thus be essential to understand the evolution and growth of black holes over a broad range of mass, distance, and luminosity, and will help uncover the black holes’ role in shaping the Universe.

IntroductionPatients with chronic liver disease are highly prone to acquiring influenza infection diseases and experiencing associated complications. National and international guidelines recommend the influenza vaccine for patients with liver disorders to reduce the risk of influenza complications. Our study aims to evaluate the risk of flu complications faced by patients with liver disease and assess influenza vaccination coverage.MethodsThe archive of hospital discharge forms was used to define the list of Apulian patients with liver disease, considering data from 2017 through 2022. The vaccination status of these patients was assessed via data collected from the Regional Immunization Database. We focused on influenza vaccine shots administered during the 2020/21, 2021/22, and 2022/23 flu seasons.ResultsA declining trend across the flu seasons was observed, with a VC of 49.5% in the 2020/21 flu season, 48.1% in the 2021/22 season, and 45.0% in the 2022/23 season. Subjects with multiple comorbidities have higher vaccination rates. Additionally, the multivariate models demonstrate that vaccination compliance increases with age and is strongly associated with having received a previous influenza vaccine shot.ConclusionThe VC rates reported in our study are unsatisfactory and did not reach the minimum achievable goal (75%) the Italian Ministry of Health set. A multifactorial approach is required to raise the immunization rates and therefore protect the patients from the influenza-associated risk of collateral liver damage; the role of gastroenterologists and hepatologists is crucial, as their responsibilities should extend beyond patient care to the prevention of complications after infectious diseases.

BackgroundThe objective of this study was to assess the impact of age and other patient and treatment characteristics on toxicity in prostate cancer patients receiving adjuvant radiotherapy (RT).Materials and methodsThis observational study (ICAROS-1) evaluated both acute (RTOG) and late (RTOG/EORTC) toxicity. Patient- (age; Charlson’s comorbidity index) and treatment-related characteristics (nodal irradiation; previous TURP; use, type, and duration of ADT, RT fractionation and technique, image-guidance systems, EQD2 delivered to the prostate bed and pelvic nodes) were recorded and analyzed.ResultsA total of 381 patients were enrolled. The median EQD2 to the prostate bed (α/β=1.5) was 71.4 Gy. The majority of patients (75.4%) were treated with intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT). Acute G3 gastrointestinal (GI) and genitourinary (GU) toxicity rates were 0.5% and 1.3%, respectively. No patients experienced >G3 acute toxicity. The multivariable analysis of acute toxicity (binomial logistic regression) showed a statistically significant association between older age (> 65) and decreased odds of G≥2 GI acute toxicity (OR: 0.569; 95%CI: 0.329-0.973; p: 0.040) and decreased odds of G≥2 GU acute toxicity (OR: 0.956; 95%CI: 0.918-0.996; p: 0.031). The 5-year late toxicity-free survival rates for G≥3 GI and GU toxicity were 98.1% and 94.5%, respectively. The only significant correlation found (Cox’s regression model) was a reduced risk of late GI toxicity in patients undergoing hypofractionation (HR: 0.38; 95% CI: 0.18-0.78; p: 0.008).ConclusionsThe unexpected results of this analysis could be explained by a “response shift bias” concerning the protective effect of older age and by treatment in later periods (using IMRT/VMAT) concerning the favorable effect of hypofractionation. However, overall, the study suggests that age should not be a reason to avoid adjuvant RT and that the latter is well-tolerated even with moderately hypofractionated regimens.

BackgroundThis is a systematic review and meta-analysis of emotional and behavioral problems among Italian community adolescents in the last 20 years, as assessed through the ASEBA questionnaires CBCL 6–18, YSR 11–18 and TRF 6–18. Research questions address: (1) pooled means of problems’ scores in questionnaires scales; (2–3) variations in scores according to sociodemographic and time-related factors, and studies’ quality; (4) trends in research with ASEBA instruments along with other outcomes, e.g., psychopathological symptoms.MethodsA systematic literature review of Scopus, EBSCO, PubMed, Web of Science, and ProQuest databases using the PRISMA 2020 guidelines was conducted on November, 2021, and of grey literature on December, 2021. The quality of studies was assessed through the Newcastle-Ottawa Scale.ResultsForty-four studies were eligible for the systematic review, of which 34 were included for meta-analysis. Results showed that: (1) emotional-behavioral problems were higher when assessed by the CBCL and lower when assessed by the YSR compared to normative data; (2) there were no gender and age differences, except for higher scores of Anxious/Depression symptoms, in girls. (3) internalizing and attention problems increased over the last two decades. (4) major trends of Italian research investigate adolescents’ emotional behavioral problems concerning attachment, comorbid symptoms, especially internet addictions, and eating disorders.DiscussionDespite some limitations (e.g., low-medium quality of most studies, no data on the TRF, under-representation of some geographical areas, some search-related choices), these data provides Italian practitioners and international researchers of some parameter to evaluate Italian adolescents emotional-behavioral problems. Registered on PROSPERO N. CRD42022299999.

BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disease involving several articular and extra-articular structures. Despite the important progresses recently made in all of the aspects of this disease, its management is still burdened by unresolved issues. The aim of this exercise was to provide a set of statements that may be helpful for the management of PsA.MethodsA group of 38 Italian rheumatologists with recognized expertise in PsA selected and addressed the following four topics: “early PsA,” “axial-PsA,” “extra-articular manifestations and comorbidities,” “therapeutic goals.” Relevant articles from the literature (2016–2022) were selected by the experts based on a PubMed search. A number of statements for each topic were elaborated.ResultsNinety-four articles were selected and evaluated, 68 out of the 1,114 yielded by the literature search and 26 added by the Authors. Each of the four topic was subdivided in themes as follows: transition from psoriasis to PsA, imaging vs. CASPAR criteria in early diagnosis, early treatment for “early PsA”; axial-PsA vs. axialspondyloarthritis, diagnosis, clinical evaluation, treatment, standard radiography vs. magnetic resonance imaging for “axial PsA”; influence of inflammatory bowel disease on the therapeutic choice, cardiovascular comorbidity, bone damage, risk of infection for “comorbidities and extra-articular manifestations”; target and tools, treat-to-target strategy, role of imaging for “therapeutic goals.” The final document consisted of 49 statements.DiscussionThe final product of this exercise is a set of statements concerning the main issues of PsA management offering an expert opinion for some unmet needs of this complex disease.

IntroductionThe Latinx Advocacy Team & Interdisciplinary Network for COVID-19 (LATIN-19) is a unique multi-sector coalition formed early in the COVID-19 pandemic to address the multi-level health inequities faced by Latinx communities in North Carolina.MethodsWe utilized the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to conduct a directed content analysis of 58 LATIN-19 meeting minutes from April 2020 through October 2021. Application of the NIMHD Research Framework facilitated a comprehensive assessment of complex and multidimensional barriers and interventions contributing to Latinx health while centering on community voices and perspectives.ResultsCommunity interventions focused on reducing language barriers and increasing community-level access to social supports while policy interventions focused on increasing services to slow the spread of COVID-19.DiscussionOur study adds to the literature by identifying community-based strategies to ensure the power of communities is accounted for in policy reforms that affect Latinx health outcomes across the U.S. Multisector coalitions, such as LATIN-19, can enable the improved understanding of underlying barriers and embed community priorities into policy solutions to address health inequities.

One of the most intriguing and still pending questions in radiobiology is to understand whether and how natural environmental background radiation has shaped Life over millions of years of evolution on Earth. Deep Underground Laboratories (DULs) represent the ideal below-background exposure facilities where to address such a question. Among the few worldwide DULs, INFN-Laboratorio Nazionale del Gran Sasso (LNGS) is one of the largest in terms of size and infrastructure. Designed and built to host neutrino and dark matter experiments, since the 1990 s the LNGS has been one of the first DULs to systematically host radiobiology experiments. Here we present the DISCOVER22 (DNA Damage and Immune System Cooperation in VEry low Radiation environment 2022) experiment recently started at LNGS. DISCOVER22 aims at investigating how the low radiation background modulates the Immune System (IS) response in in vitro and in vivo models. Underground radiobiology experiments are particularly complex and tricky to design and perform. In these studies, the accurate characterization of exposure scenarios is mandatory, but a challenging aspect is to understand how the very few ionizing tracks in the ultra-Low Radiation Environment (LRE) interact with the living matter in space and time in order to trigger different biological responses. In this Perspective, we describe these challenges and how we address them through a microdosimetric and a radiobiological approaches. We aim at linking physical microdosimetric measurements and the corresponding biological radiation responses by using radiation biophysical models that could shed light on many as yet unresolved questions.

IntroductionThe humoral response after SARS-CoV-2 vaccination and boosters in kidney transplant recipients (KTRs) is heterogeneous and depends on immunosuppression status. There is no validated immune measurement associated with serological response in clinical practice. Multicolor flow cytometric immunophenotyping could be useful for measuring immune response. This study aimed to study B- and T-cell compartments through Standardized EuroFlow PID Orientation after SARS-CoV-2 vaccination and their association with IgG SARS-CoV-2 seropositivity status after two doses or boosters.MethodsWe conducted a multicenter prospective study to evaluate humoral response after SARS-CoV-2 vaccination in KTRs. Heterologous regimen: two doses of inactivated SARS-CoV-2 and two boosters of BNT162b2 mRNA (n=75). Homologous vaccination: two doses of BNT162b2 mRNA and one BNT162b2 mRNA booster (n=13). Booster doses were administrated to KTRs without taking into account their IgG SARS-CoV-2 seropositivity status. Peripheral blood samples were collected 30 days after the second dose and after the last heterologous or homologous booster. A standardized EuroFlow PID Orientation Tube (PIDOT) and a supervised automated analysis were used for immune monitoring cellular subsets after boosters.ResultsA total of 88 KTRs were included and divided into three groups according to the time of the first detected IgG SARS-CoV-2 seropositivity: non-responders (NRs, n=23), booster responders (BRs, n=41), and two-dose responders (2DRs, n=24). The NR group was more frequent on mycophenolate than the responder groups (NRs, 96%; BRs, 80%; 2DRs, 42%; p=0.000). Switched memory B cells in the 2DR group were higher than those in the BR and NR groups (medians of 30, 17, and 10 cells/ul, respectively; p=0.017). Additionally, the absolute count of central memory/terminal memory CD8 T cells was higher in the 2DR group than in the BR and NR groups. (166, 98, and 93 cells/ul, respectively; p=0.041). The rest of the T-cell populations studied did not show a statistical difference.Conclusionswitched memory B cells and memory CD8 T-cell populations in peripheral blood were associated with the magnitude of the humoral response after SARS-CoV-2 vaccination. Boosters increased IgG anti-SARS-CoV-2 levels, CM/TM CD8 T cells, and switched MBCs in patients with seropositivity after two doses. Interestingly, no seropositivity after boosters was associated with the use of mycophenolate and a lower number of switched MBCs and CM/TM CD8 T cells in peripheral blood.

IntroductionVaccination against SARS-CoV-2 has been used to reduce the severity of COVID-19 disease and the incidence of new cases. However, a significant proportion of people have shown vaccination hesitancy.MethodsThis study explored psychological factors related to vaccination hesitancy in a sample of Italian COVID-19 patients (N = 54), hospitalized during 2021, after vaccines had been made available and while the vaccination campaign was on-going. Consecutive patients, aged 18 or older, admitted to the hospital with a diagnosis of COVID-19 were assessed with a set of standardized measures.ResultsIn our sample, 48.1% was not vaccinated and 7.4% died within 6months after hospitalization, with a preponderance of deaths among non-vaccinated patients. Non-vaccinated participants had higher resilience scores at the CD-RISC-10 scale than vaccinated ones (33.6 ± 5.50 vs 28.6 ± 6.61; t40.2=+ 2.94, p = 0.005). No statistically significant differences were found between the two groups for any other measures.DiscussionHigher levels of resilience among non-vaccinated patients may reflect greater identity worth and self-esteem, in turn resulting in a decrease in vaccination likelihood. This finding may have important public health implications, as it indicates that specific psychological aspects, such as resilience, may result in vaccination hesitancy, with implications for hospitalization rates, and thus healthcare costs, as well as loss of lives.

The subduction of continental lithosphere is a complex process because the buoyancy of the crust is higher than the oceanic and should resist sinking into the mantle. Anyway, studies on the Alpine-Himalayan collision system indicate that a large portion of the continental crust is subducted, while some material is accreted in the orogens. The Apennine is a perfect case for studying how such processes evolve, thanks to high quality seismic images that illuminate a critical depth range not commonly resolved in many collisional settings. In this paper, we show the structure of the Apennines orogen, as jointly revealed by seismicity and deep structure from regional and teleseismic tomography and receiver function profiles. The westward subducting Adria lithosphere is well defined along the orogen showing a mid-crustal delamination. Seismicity within the underthrusting lower crust and velocity anomalies in the mantle wedge highlight how the subduction evolution is entangled with the liberation of fluids. The eclogitization of subducted material enhances the fluid release into the wedge, the delamination and retreat of the Adria plate. This delamination/subduction generates a coupled compression and extension system that migrates eastward following the retreat of the lithosphere, with broad sets of normal faults that invert or interfere with pre-existing compressional structures all over the roof plate. The sparseness and non-ubiquity of intermediate depth earthquakes along the subduction panel suggest that the brittle response of the subducting crust is governed by its different composition and fluid content. Therefore, the lower crust composition appears essential in conditioning the evolution of continental subduction.

IntroductionAtrial fibrillation (AF) is the main cause of cardioembolic stroke. In high-bleeding-risk patients, long-life anticoagulation therapy is not permitted, and left atrial appendage (LAA) closure may be considered. LAA is also a critical substrate for AF. Epicardial LAA occlusion has several advantages: LAA ligation results in a favorable electrical and structural atrial remodeling, which decreases AF recurrence. Endocardial ablation alone is not efficient for all patients, and new evidence shows better outcomes in patients affected by persistent AF after a combined hybrid endo-epicardial ablation. Considering the synergic potential of these techniques, in this case series, they were both combined in a single procedure.Methods and resultsWe describe the treatment of 5 patients referred for refractory AF ablation and LAA closure. All patients had high thrombotic and previous major hemorrhage, with relative contraindication to life-long therapy with anticoagulation. A combined procedure of LAA ligation and endo-epicardial ablation was scheduled with short-term anticoagulation. LAA closure was performed with an epicardial approach using the LARIAT system. Then, LA mapping and ablation were performed, endocardially and then epicardially.All procedures were concluded without complications.At follow-up, in all patients, transesophageal echocardiography showed the complete occlusion of the LAA; therefore, anticoagulation therapy was interrupted. All patients were asymptomatic, and in the sinus rhythm, no hemorrhage or ischemic events occurred.ConclusionThe combination of percutaneous LAA ligation and endo-epicardial ablation was revealed to be feasible and safe and might represent a new approach for the treatment of refractory AF in patients with indication of LAA occlusion.

The aim of this study is to report the clinical outcomes of oral supplementation with curcumin-phospholipid in addition to hyaluronic acid-based tear substitute for the management of dry eye disease (DED). Patients with a diagnosis of DED confirmed by pathological values of both NIKBUT 12 were included. Patients were randomized to receive 2 different treatments: 0.25% hyaluronic acid-based tear substitute 3 time daily (Group 1) or as above plus curcumin-phosphatidylcholine complex tablets once a day (Group 2). Patients were evaluated at baseline (T0) and after 90 days of treatment (T1) by means of Keratograph for the measurement of NIKBUT, TMH, meibomian gland dropout and bulbar redness. Overall, data from 90 eyes of 45 patients were included. Group 1 consisted of 48 eyes of 24 patients, while group 2 included 42 eyes of 21 patients. When comparing median values of both groups at T0, no statistically significant differences were found for all parameters; instead for T1, statistically significant differences were found for redness and OSDI compared to Group 1. In group 1, a statistically significant reduction after the treatment was detected for Nikbut average and OSDI questionnaire; while in group 2, a statistically significant reduction after treatment was recorded for Nikbut average, bulbar redness and OSDI questionnaire. The addition of an oral supplement containing curcumin-phospholipid may help in a greater improvement of bulbar redness and subjective ocular symptoms compared to the treatment with tear substitutes alone for the management of DED.

The COVID-19 pandemic has highlighted the importance in the understanding of the biology of SARS-CoV-2. After more than two years since the first report of COVID-19, it remains crucial to continue studying how SARS-CoV-2 proteins interact with the host metabolism to cause COVID-19. In this review, we summarize the findings regarding the functions of the 16 non-structural, 6 accessory and 4 structural SARS-CoV-2 proteins. We place less emphasis on the spike protein, which has been the subject of several recent reviews. Furthermore, comprehensive reviews about COVID-19 therapeutic have been also published. Therefore, we do not delve into details on these topics; instead we direct the readers to those other reviews. To avoid confusions with what we know about proteins from other coronaviruses, we exclusively report findings that have been experimentally confirmed in SARS-CoV-2. We have identified host mechanisms that appear to be the primary targets of SARS-CoV-2 proteins, including gene expression and immune response pathways such as ribosome translation, JAK/STAT, RIG-1/MDA5 and NF-kβ pathways. Additionally, we emphasize the multiple functions exhibited by SARS-CoV-2 proteins, along with the limited information available for some of these proteins. Our aim with this review is to assist researchers and contribute to the ongoing comprehension of SARS-CoV-2’s pathogenesis.

IntroductionThe use of deep convolutional neural networks for analyzing skin lesion images has shown promising results. The identification of skin cancer by faster and less expensive means can lead to an early diagnosis, saving lives and avoiding treatment costs. However, to implement this technology in a clinical context, it is important for specialists to understand why a certain model makes a prediction; it must be explainable. Explainability techniques can be used to highlight the patterns of interest for a prediction.MethodsOur goal was to test five different techniques: Grad-CAM, Grad-CAM++, Score-CAM, Eigen-CAM, and LIME, to analyze the agreement rate between features highlighted by the visual explanation maps to 3 important clinical criteria for melanoma classification: asymmetry, border irregularity, and color heterogeneity (ABC rule) in 100 melanoma images. Two dermatologists scored the visual maps and the clinical images using a semi-quantitative scale, and the results were compared. They also ranked their preferable techniques.ResultsWe found that the techniques had different agreement rates and acceptance. In the overall analysis, Grad-CAM showed the best total+partial agreement rate (93.6%), followed by LIME (89.8%), Grad-CAM++ (88.0%), Eigen-CAM (86.4%), and Score-CAM (84.6%). Dermatologists ranked their favorite options: Grad-CAM and Grad-CAM++, followed by Score-CAM, LIME, and Eigen-CAM.DiscussionSaliency maps are one of the few methods that can be used for visual explanations. The evaluation of explainability with humans is ideal to assess the understanding and applicability of these methods. Our results demonstrated that there is a significant agreement between clinical features used by dermatologists to diagnose melanomas and visual explanation techniques, especially Grad-Cam.

BackgroundTo date, there are no large studies delineating the clinical correlates of “pure” essential tremor (ET) according to its new definition.MethodsFrom the ITAlian tremor Network (TITAN) database, we extracted data from patients with a diagnosis of “pure” ET and excluded those with other tremor classifications, including ET-plus, focal, and task-specific tremor, which were formerly considered parts of the ET spectrum.ResultsOut of 653 subjects recruited in the TITAN study by January 2022, the data of 208 (31.8%) “pure” ET patients (86M/122F) were analyzed. The distribution of age at onset was found to be bimodal. The proportion of familial cases by the age-at-onset class of 20 years showed significant differences, with sporadic cases representing the large majority of the class with an age at onset above 60 years. Patients with a positive family history of tremor had a younger onset and were more likely to have leg involvement than sporadic patients despite a similar disease duration. Early-onset and late-onset cases were different in terms of tremor distribution at onset and tremor severity, likely as a function of longer disease duration, yet without differences in terms of quality of life, which suggests a relatively benign progression. Treatment patterns and outcomes revealed that up to 40% of the sample was unsatisfied with the current pharmacological options.DiscussionThe findings reported in the study provide new insights, especially with regard to a possible inversed sex distribution, and to the genetic backgrounds of “pure” ET, given that familial cases were evenly distributed across age-at-onset classes of 20 years. Deep clinical profiling of “pure” ET, for instance, according to age at onset, might increase the clinical value of this syndrome in identifying pathogenetic hypotheses and therapeutic strategies.

Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4′,3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.

IntroductionBimekizumab is a monoclonal antibody that targets Interleukin-17 A and F, approved for the treatment of moderate-to-severe plaque psoriasis. While bimekizumab has been evaluated in several phase-III clinical trials, real-world evidence is still very limited.MethodThis multicenter retrospective study included patients affected by plaque psoriasis treated with bimekizumab from May 1, 2022 to April 30, 2023, at 19 Italian referral hospitals. Patients affected by moderate-to-severe plaque psoriasis eligible for systemic treatments were included. The effectiveness of bimekizumab was evaluated in terms of reduction in psoriasis area and severity index (PASI) compared with baseline at weeks 4 and 16. The main outcomes were the percentages of patients achieving an improvement of at least 75% (PASI75), 90% (PASI90) and 100% (PASI100) in PASI score.ResultsThe study included 237 patients who received at least one injection of bimekizumab. One hundred and seventy-one patients and 114 reached four and 16 weeks of follow-up, respectively. Complete skin clearance was achieved by 43.3% and 75.4% of patients at weeks 4 and 16, respectively. At week 16, 86.8% of patients reported no impact on their quality of life. At week 16, there were no significant differences between bio-naïve and bio-experienced patients in terms of PASI75, PASI90 and PASI100. The most commonly reported adverse events (AEs) were oral candidiasis (10.1%). No severe AEs or AEs leading to discontinuation were observed throughout the study.ConclusionOur experience supports the effectiveness and tolerability of bimekizumab in a real-world setting with similar results compared with phase-III clinical trials.