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Background: Atrial fibrillation (AF) is the most common arrhythmia diagnosed at an older age. AF is associated with frailty, a condition possibly justifying the higher rate of complications and mortality in aged individuals. This study was aimed at describing the characteristics correlated to frailty in older AF subjects., Methods: After having excluded a < 3 months major surgery procedure, cancer or other conditions associated with activation of inflammation, and a life expectancy < 12 months, we consecutively enrolled patients ≥ 65 years with persistent AF. They underwent a Comprehensive Geriatric Assessment evaluation. In particular, Mini-Mental State Examination, 15-item Geriatric Depression Scale and Short-Physical Performance Battery (SPPB) described, respectively, cognitive profile, depressive symptoms and physical performance. A venous blood sample was collected to measure interleukin-6 (IL-6; marker of low-grade inflammation) and acylcarnitines, expression of mitochondrial dysfunction and abnormal energy production., Results: Overall, 49 patients (mean age: 76 ± 6 years; women 30.6 %) were studied. Cluster analysis described two different patterns; the second (N = 18, 36.7 %), when compared to the first one (N = 31, 63.3 %), was characterized by a worse phenotype, identified by the simultaneous presence of lower body mass index, higher CHA 2 DS 2 -VASc score (index of clinical complexity), worse SPPB functional performance, and high IL-6 levels. Second cluster patients had a higher concentration of 13 of the 35 acylcarnitines evaluated and increased 5-year mortality. All these features can outline a frail condition., Conclusions: Body size, clinical complexity, physical performance and low-grade inflammation seem to rapidly and adequately describe frailty., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Study Objectives: The umbrella term "Disorders of Arousal" (DoA), encompassing sleepwalking, confusional arousals, and sleep terrors, refers to parasomnias manifesting during non-rapid eye movement (NREM) sleep, commonly thought to arise from an aberrant arousal process. While previous studies have detailed EEG changes linked to DoA episodes, it remains uncertain how these alterations differ from a physiological arousal process. This study directly compared brain activity between DoA episodes and arousals associated with physiological movements (motor arousal) in individuals with DoA and healthy sleepers., Methods: Fifty-three adult patients with DoA (25 males, 32.2±15.5years) and 33 control subjects (14 males, 31.4±11.4years) underwent one or more home-EEG recordings. A semiparametric regression model was employed to elucidate the complex relationship between EEG activity across channels, within and across different groups, including motor arousals in DoA (n=169), parasomnia episodes in DoA (n=361), and motor arousals in healthy sleepers (n=137)., Results: Parasomnia episodes and motor arousals in both groups were preceded by a diffuse increase in slow-wave activity (SWA) and beta power, and a widespread decrease in sigma power. However, motor arousals in DoA displayed lower beta and central sigma than in healthy sleepers. Within DoA patients, episodes were preceded by lower beta, frontal sigma, and higher SWA than motor arousals., Conclusions: Our findings suggest that the arousal process is altered in DOA patients, and that specific EEG patterns are required for DOA episodes to emerge. These insights will help guide future research into the underlying circuits and objective markers of DOA., (© The Author(s) 2024. Published by Oxford University Press on behalf of Sleep Research Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: SARS-CoV-2 pandemic still poses a significant burden on global health and economy, especially for symptoms persisting beyond the acute disease. COVID-19 manifests with various degrees of severity and the identification of early biomarkers capable of stratifying patient based on risk of progression could allow tailored treatments., Methods: We longitudinally analyzed 67 patients, classified according to a WHO ordinal scale as having Mild, Moderate, or Severe COVID-19. Peripheral blood samples were prospectively collected at hospital admission and during a 6-month follow-up after discharge. Several subsets and markers of the innate and adaptive immunity were monitored as putative factors associated with COVID-19 symptoms., Results: More than 50 immunological parameters were associated with disease severity. A decision tree including the main clinical, laboratory, and biological variables at admission identified low NK-cell precursors and CD14 + CD91 + monocytes, and high CD8 + Effector Memory T cell frequencies as the most robust immunological correlates of COVID-19 severity and reduced survival. Moreover, low regulatory B-cell frequency at one month was associated with the susceptibility to develop long COVID at six months, likely due to their immunomodulatory ability., Discussion: These results highlight the profound perturbation of the immune response during COVID-19. The evaluation of specific innate and adaptive immune-cell subsets allows to distinguish between different acute and persistent COVID-19 symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Noviello, De Lorenzo, Chimienti, Maugeri, De Lalla, Siracusano, Lorè, Rancoita, Cugnata, Tassi, Dispinseri, Abbati, Beretta, Ruggiero, Manfredi, Merolla, Cantarelli, Tresoldi, Pastori, Caccia, Sironi, Marzinotto, Saliu, Ghezzi, Lampasona, Vicenzi, Cinque, Manfredi, Scarlatti, Dellabona, Lopalco, Di Serio, Malnati, Ciceri, Rovere-Querini and Bonini.)

Celiac disease (CD) is an autoimmune enteropathy resulting from an interaction between diet, genome, and immunity. Although many patients respond to a gluten-free diet, in a substantive number of individuals, the intestinal injury persists. Thus, other factors might amplify the ongoing inflammation. Candida albicans is a commensal fungus that is well adapted to the intestinal life. However, specific conditions increase Candida pathogenicity. The hypothesis that Candida may be a trigger in CD has been proposed after the observation of similarity between a fungal wall component and two CD-related gliadin T-cell epitopes. However, despite being implicated in intestinal disorders, Candida may also protect against immune pathologies highlighting a more intriguing role in the gut. Herein, we postulated that a state of chronic inflammation associated with microbial dysbiosis and leaky gut are favorable conditions that promote C. albicans pathogenicity eventually contributing to CD pathology via a mast cells (MC)-IL-9 axis. However, the restoration of immune and microbial homeostasis promotes a beneficial C. albicans -MC cross-talk favoring the attenuation of CD pathology to alleviate CD pathology and symptoms., (© 2024 Renga et al.)

Abstract: CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, because it improves survival and outcome of patients who received hematopoietic stem cell transplant compared with the continuous infusion of cytarabine plus daunorubicin (referred to as "7 + 3" combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily affects the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 vs "7 + 3" combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and "7 + 3" combination on mucosal barrier function, gut microbial composition and function, and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with "7 + 3" combination, protected from gut dysbiosis, mucosal damage, and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor-interleukin-22 (IL-22)-IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34 + cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34 + cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34 + cells infused and younger age at GT affected positively the plateau of CD3 + transduced cells, lymphocytes and CD4 + CD45RA + naive T cells, whereas the cell dose positively influenced the final plateau of CD15 + transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Although CO2 field-flooding was first used during cardiac surgery more than 60 years ago, its efficacy is still disputed. The invisible nature of the gas and the difficulty in determining the "safe" quantity to protect the patient are two of the main obstacles to overcome for its validation. Moreover, CO2 concentration in the chest cavity is highly sensitive to procedural aspects, such suction and hand movements. Based on our review of the existing literature, we identified four major factors that influence the intra-cavity CO2 concentration during open-heart surgery: type of delivery device (diffuser), delivery CO2 flow rate, diffuser position around the wound cavity, and its orientation inside the cavity. In this initial study, only steady state conditions were considered to establish a basic understanding on the effect of the four above-mentioned factors. Transient factors, such as suction or hand movements, will be reported separately., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Puthettu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Atrial fibrillation (AF) is associated with chronic inflammation, a hallmark of ageing process. The aim of this study was to determine interleukin-6 (IL-6)-associated variables, also exploring acylcarnitines, expression of mitochondrial abnormalities., Methods: We evaluated 22 controls and 50 patients with persistent AF. IL-6 and acylcarnitines were measured with ELISA kits and mass spectrometry techniques., Results: IL-6 concentration (mean: 3.9 ± 3.1 pg/mL) was lower in controls and increased in AF patients, especially with heart failure. The CHA 2 DS 2 -VASc, the MMSE and the SPPB scores were 3.8 ± 1.6, 28 ± 2 and 9.4 ± 2.1. Thirteen acylcanitines correlated with IL-6. At multivariable analysis, IL-6 was directly associated with C4-OH-a short-chain acylcarnitine, fibrinogen and alanine aminotransferase values, and with hyperuricemia. An inverse association existed with calcium concentration and SPPB score., Conclusions: In older AF patients, IL-6 correlated with acylcarnitines and lower physical performance. Alterations in energy production, reduced physical function and inflammation could contribute to frailty development., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Whether clinical practice guidelines have a significant impact on practice is unclear. The effect of guideline recommendations on clinical practice often a lags behind the date of publication. We evaluated by means of a data-driven approach if and when the guidelines on red blood cell transfusions (RBCTs) issued by Swiss Smarter Medicine in 2016 had an impact on RBCTs practice within a hospital network, where awareness of guidelines was promoted mainly among internal medicine specialties. Data on RBCTs performed in a Swiss hospital network from January 2014 to April 2021 were analyzed by hospital site and specialty to assess whether guidelines led to a decrease in inappropriate RBCTs. RBCTs were defined as "inappropriate" if patients had a hemoglobin level ≥ 70 g/L without or ≥ 80 g/L with significant cardiovascular comorbidities. Changes in the rate of inappropriate transfusions were analyzed with an advanced statistical approach that included generalized additive models. Overall prior to March 2017 there were more inappropriate than appropriate RBCTs, but after October 2017 the opposite could be observed. A change-point in the time trend was estimated from transfusion data to occur in the time interval between March and October 2017. This change was mainly driven by practice changes in the medical wards, while no significant change was observed in the critical care, surgical and oncology wards. Change in practice varied by hospital site. In conclusion, our results show that a significant change in the RBCTs practice at the hospital level occurred approximately 18 months after national guidelines were issued., (© 2023. The Author(s).)

A full understanding of the characteristics of Covid-19 patients with a better chance of experiencing poor vital outcomes is critical for implementing accurate and precise treatments. In this paper, two different advanced data-driven statistical approaches along with standard statistical methods have been implemented to identify groups of patients most at-risk for death or severity of respiratory distress. First, the tree-based analysis allowed to identify profiles of patients with different risk of in-hospital death (by Survival Tree-ST analysis) and severity of respiratory distress (by Classification and Regression Tree-CART analysis), and to unravel the role on risk stratification of highly dependent covariates (i.e., demographic characteristics, admission values and comorbidities). The ST analysis identified as the most at-risk group for in-hospital death the patients with age > 65 years, creatinine [Formula: see text] 1.2 mg/dL, CRP [Formula: see text] 25 mg/L and anti-hypertensive treatment. Based on the CART analysis, the subgroups most at-risk of severity of respiratory distress were defined by patients with creatinine level [Formula: see text] 1.2 mg/dL. Furthermore, to investigate the multivariate dependence structure among the demographic characteristics, the admission values, the comorbidities and the severity of respiratory distress, the Bayesian Network analysis was applied. This analysis confirmed the influence of creatinine and CRP on the severity of respiratory distress., (© 2023. The Author(s).)

Acute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts., (© 2023. The Author(s).)

This paper is based on a retrospective longitudinal study on people living with HIV under antiretroviral treatment (ART) where allelic variants (either heterozygous CT genotype or homozygous CC genotype) have been evaluated at position -168 of the promoter region of the protein kinase R (-168/PKR). In general, antiviral effects of interferon are partially mediated by a RNA-dependent protein kinase (PKR) that, once activated, inhibits protein synthesis. Indeed, activation of PKR response can inhibit HIV replication. To explore the role of allelic variants in shaping dynamics of commonly monitored HIV biomarkers, CD4 cells, CD8 cells and HIV-load were modelled within a latent class mixed model (LCMM) to account for participants' heterogeneity over time. The estimated models identified two sub-groups from CD4 and HIV-load dynamics, revealing better outcomes for subgroups of participants with the heterozygous CT genotype. Heterozygous CT subjects in one of the two identified subgroups exhibited higher increase of CD4 cells and more marked decrease of HIV-load, over time, with respect to the homozygous CC subjects assigned to the same group., (© 2022. The Author(s).)

Purpose: To develop and validate an effective and user-friendly AI platform based on a few unbiased clinical variables integrated with advanced CT automatic analysis for COVID-19 patients' risk stratification., Material and Methods: In total, 1575 consecutive COVID-19 adults admitted to 16 hospitals during wave 1 (February 16-April 29, 2020), submitted to chest CT within 72 h from admission, were retrospectively enrolled. In total, 107 variables were initially collected; 64 extracted from CT. The outcome was survival. A rigorous AI model selection framework was adopted for models selection and automatic CT data extraction. Model performances were compared in terms of AUC. A web-mobile interface was developed using Microsoft PowerApps environment. The platform was externally validated on 213 COVID-19 adults prospectively enrolled during wave 2 (October 14-December 31, 2020)., Results: The final cohort included 1125 patients (292 non-survivors, 26%) and 24 variables. Logistic showed the best performance on the complete set of variables (AUC = 0.839 ± 0.009) as in models including a limited set of 13 and 5 variables (AUC = 0.840 ± 0.0093 and AUC = 0.834 ± 0.007). For non-inferior performance, the 5 variables model (age, sex, saturation, well-aerated lung parenchyma and cardiothoracic vascular calcium) was selected as the final model and the extraction of CT-derived parameters was fully automatized. The fully automatic model showed AUC = 0.842 (95% CI: 0.816-0.867) on wave 1 and was used to build a 0-100 scale risk score (AI-SCoRE). The predictive performance was confirmed on wave 2 (AUC 0.808; 95% CI: 0.7402-0.8766)., Conclusions: AI-SCoRE is an effective and reliable platform for automatic risk stratification of COVID-19 patients based on a few unbiased clinical data and CT automatic analysis., (© 2022. The Author(s).)

Background and Objectives: Data on the clinical efficacy of EUS-guided ablation using the HybridTherm-Probe (EUS-HTP) in locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) are lacking. The aim of the study was to assess the impact of EUS-HTP added to chemotherapy (CT) on overall survival (OS) and progression-free survival (PFS) of LA-PDAC patients with local disease progression (DP) after first-line therapy, compared to CT alone in controls., Methods: LA-PDAC cases, prospectively treated by EUS-HTP, were retrospectively compared to matched controls (1:2) receiving standard treatment. Study endpoints were the OS and PFS from local DP after first-line therapy, compared through log-rank test calculating hazard ratios and differences in restricted mean OS/PFS time (RMOST/RMPFST) within prespecified time points (4, 6, and 12 months)., Results: Thirteen cases and 26 controls were included. Clinical, tumor, and therapy features before and after first-line therapy were case-control balanced. The median OS and PFS were not significantly improved in cases over controls (months: 7 vs. 5 and 5 vs. 3, respectively). At 4 and 6 months, the RMPFST difference was in favor of cases (P = 0.0001 and P = 0.003, respectively). In cases and controls not candidate to further CT (N = 5 and N = 9), the median OS and PFS were not significantly improved in cases over controls (months: 6 vs. 3 and 4 vs. 2, respectively), but the RMPFST difference was in favor of cases at 4 months (P = 0.002)., Conclusions: In locally progressive PDAC patients experiencing failure of first-line therapy, EUS-HTP achieves a significantly better RMPFST up to 6 months compared to standard treatment, although without a significant impact on OS., Competing Interests: None

The COVID-19 pandemic cast a dramatic spotlight on the use of data as a fundamental component of good decision-making. Evaluating and comparing alternative policies required information on concurrent infection rates and insightful analysis to project them into the future. Statisticians in Israel were involved in these processes early in the pandemic in some silos as an ad-hoc unorganized effort. Informal discussions within the statistical community culminated in a roundtable, organized by three past presidents of the Israel Statistical Association, and hosted by the Samuel Neaman Institute in April 2021. The meeting was designed to provide a forum for exchange of views on the profession's role during the COVID-19 pandemic, and more generally, on its influence in promoting evidence-based public policy. This paper builds on the insights and discussions that emerged during the roundtable meeting and presents a general framework, with recommendations, for involving statisticians and statistics in decision-making., (© 2022. The Author(s).)

Background: Effective treatment for metachromatic leukodystrophy (MLD) remains a substantial unmet medical need. In this study we investigated the safety and efficacy of atidarsagene autotemcel (arsa-cel) in patients with MLD., Methods: This study is an integrated analysis of results from a prospective, non-randomised, phase 1/2 clinical study and expanded-access frameworks. 29 paediatric patients with pre-symptomatic or early-symptomatic early-onset MLD with biochemical and molecular confirmation of diagnosis were treated with arsa-cel, a gene therapy containing an autologous haematopoietic stem and progenitor cell (HSPC) population transduced ex vivo with a lentiviral vector encoding human arylsulfatase A (ARSA) cDNA, and compared with an untreated natural history (NHx) cohort of 31 patients with early-onset MLD, matched by age and disease subtype. Patients were treated and followed up at Ospedale San Raffaele, Milan, Italy. The coprimary efficacy endpoints were an improvement of more than 10% in total gross motor function measure score at 2 years after treatment in treated patients compared with controls, and change from baseline of total peripheral blood mononuclear cell (PBMC) ARSA activity at 2 years after treatment compared with values before treatment. This phase 1/2 study is registered with ClinicalTrials.gov, NCT01560182., Findings: At the time of analyses, 26 patients treated with arsa-cel were alive with median follow-up of 3·16 years (range 0·64-7·51). Two patients died due to disease progression and one due to a sudden event deemed unlikely to be related to treatment. After busulfan conditioning, all arsa-cel treated patients showed sustained multilineage engraftment of genetically modified HSPCs. ARSA activity in PBMCs was significantly increased above baseline 2 years after treatment by a mean 18·7-fold (95% CI 8·3-42·2; p<0·0001) in patients with the late-infantile variant and 5·7-fold (2·6-12·4; p<0·0001) in patients with the early-juvenile variant. Mean differences in total scores for gross motor function measure between treated patients and age-matched and disease subtype-matched NHx patients 2 years after treatment were significant for both patients with late-infantile MLD (66% [95% CI 48·9-82·3]) and early-juvenile MLD (42% [12·3-71·8]). Most treated patients progressively acquired motor skills within the predicted range of healthy children or had stabilised motor performance (maintaining the ability to walk). Further, most displayed normal cognitive development and prevention or delay of central and peripheral demyelination and brain atrophy throughout follow-up; treatment benefits were particularly apparent in patients treated before symptom onset. The infusion was well tolerated and there was no evidence of abnormal clonal proliferation or replication-competent lentivirus. All patients had at least one grade 3 or higher adverse event; most were related to conditioning or to background disease. The only adverse event related to arsa-cel was the transient development of anti-ARSA antibodies in four patients, which did not affect clinical outcomes., Interpretation: Treatment with arsa-cel resulted in sustained, clinically relevant benefits in children with early-onset MLD by preserving cognitive function and motor development in most patients, and slowing demyelination and brain atrophy., Funding: Orchard Therapeutics, Fondazione Telethon, and GlaxoSmithKline., Competing Interests: Declaration of interests FFu, VC, MGNS, AA, CB, FB, FFe, MM, FT, VG, SR, ESF, MPC, and MEB are investigators of gene therapy clinical trials for MLD sponsored by Orchard Therapeutics, the licence holder of investigational medicinal product arsa-cel. FFu and VC have acted as ad-hoc consultants for an Orchard Therapeutics advisory board. The MLD gene therapy was licensed to GlaxoSmithKline in 2014, and then to Orchard Therapeutics in 2018. Telethon and Ospedale San Raffaele are entitled to receive milestone payments and royalties for such a therapy. MSe and AB left San Raffaele Hospital and their role as principal investigators of the pivotal study on November, 2014, and September, 2015, respectively. AA subsequently became study principal investigator and responsible physician for treatment under expanded access frameworks. AB is currently a member of the scientific advisory board of Orchard Therapeutics and holds stock in Orchard Therapeutics. PMVR and CDS have a contract with Orchard Therapeutics to perform statistical analyses of gene therapy clinical trials for MLD. SMa and FM have a service contract with Ospedale San Raffaele. SMa has a contract with Orchard Therapeutics to perform ARSA activity on CSF in the clinical trial NCT03392987. JG-S, LCS, and GFD are former employees and hold stock in Orchard Therapeutics, which sponsored the clinical trial. All other authors declare that they have no financial interest related to the work described in the manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Plants and their associated microbiota share ecological and evolutionary traits that are considered to be inseparably woven. Their coexistence foresees the use of similar metabolic pathways, leading to the generation of molecules that can cross-regulate each other's metabolism and ultimately influence plant phenotype. However, the extent to which the microbiota contributes to the overall plant metabolic landscape remains largely unexplored. Due to their early presence in the seed, seed-borne endophytic bacteria can intimately colonize the plant's endosphere while conferring a series of phytobeneficial services to their host. Understanding the dynamics of these endophytic communities is a crucial step toward the formulation of microbial inoculants that can modulate the functionality of the plant-associated microbiota for improved plant fitness. In this work, wheat ( Triticum aestivum ) roots non-inoculated and inoculated with the bacterium Herbaspirillum seropedicae strain RAM10 were analyzed to explore the impact of inoculant-endophyte-wheat interrelationships on the regulation of tryptophan (Trp) metabolism in the endosphere environment. Root inoculation with H. seropedicae led to phylum-specific changes in the cultivable seed-borne endophytic community. This modulation shifted the metabolic potential of the community in light of its capacity to modulate the levels of key Trp-related metabolites involved in both indole-3-acetic acid (IAA) biosynthesis and in the kynurenine pathway. Our results support a mode of action of H. seropedicae relying on a shift in both the composition and functionality of the seed-borne endophytic community, which may govern important processes such as root growth. We finally provide a conceptual framework illustrating that interactions among roots, inoculants, and seed-borne endophytes are critical to fine-tuning the levels of IAA in the endosphere. Understanding the outcomes of these interactions is a crucial step toward the formulation of microbial inoculants based on their joint action with seed-borne endophytic communities to promote crop growth and health in a sustainable manner., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Carril, Cruz, di Serio, Pieraccini, Ait Bessai, Tenreiro and Cruz.)

This contribution explores in a new statistical perspective the antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 141 coronavirus disease 2019 (COVID-19) patients exhibiting a broad range of clinical manifestations. This cohort accurately reflects the characteristics of the first wave of the SARS-CoV-2 pandemic in Italy. We determined the IgM, IgA, and IgG levels towards SARS-CoV-2 S1, S2, and NP antigens, evaluating their neutralizing activity and relationship with clinical signatures. Moreover, we longitudinally followed 72 patients up to 9 months postsymptoms onset to study the persistence of the levels of antibodies. Our results showed that the majority of COVID-19 patients developed an early virus-specific antibody response. The magnitude and the neutralizing properties of the response were heterogeneous regardless of the severity of the disease. Antibody levels dropped over time, even though spike reactive IgG and IgA were still detectable up to 9 months. Early baseline antibody levels were key drivers of the subsequent antibody production and the long-lasting protection against SARS-CoV-2. Importantly, we identified anti-S1 IgA as a good surrogate marker to predict the clinical course of COVID-19. Characterizing the antibody response after SARS-CoV-2 infection is relevant for the early clinical management of patients as soon as they are diagnosed and for implementing the current vaccination strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Siracusano, Brombin, Pastori, Cugnata, Noviello, Tassi, Princi, Cantoni, Malnati, Maugeri, Bozzi, Saretto, Clementi, Mancini, Uberti-Foppa, Temperton, Bonini, Di Serio and Lopalco.)

During the last year, mass screening campaigns have been carried out to identify immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and establish a possible seroprevalence. The obtained results gained new importance with the beginning of the SARS-CoV-2 vaccination campaign, as the lack of doses has persuaded several countries to introduce different policies for individuals who had a history of COVID-19. Lateral flow assays (LFAs) may represent an affordable tool to support population screening in low-middle-income countries, where diagnostic tests are lacking and epidemiology is still widely unknown. However, LFAs have demonstrated a wide range of performance, and the question of which one could be more valuable in these settings still remains. We evaluated the performance of 11 LFAs in detecting SARS-CoV-2 infection, analyzing samples collected from 350 subjects. In addition, samples from 57 health care workers collected at 21 to 24 days after the first dose of the Pfizer-BioNTech vaccine were also evaluated. LFAs demonstrated a wide range of specificity (92.31% to 100%) and sensitivity (50% to 100%). The analysis of postvaccination samples was used to describe the most suitable tests to detect IgG response against S protein receptor binding domain (RBD). Tuberculosis (TB) therapy was identified as a potential factor affecting the specificity of LFAs. This analysis identified which LFAs represent a valuable tool not only for the detection of prior SARS-CoV-2 infection but also for the detection of IgG elicited in response to vaccination. These results demonstrated that different LFAs may have different applications and the possible risks of their use in high-TB-burden settings. IMPORTANCE Our study provides a fresh perspective on the possible employment of SARS-CoV-2 LFA antibody tests. We developed an in-depth, large-scale analysis comparing LFA performance to enzyme-linked immunosorbent assay (ELISA) and electrochemiluminescence immunoassay (ECLIA) and evaluating their sensitivity and specificity in identifying COVID-19 patients at different time points from symptom onset. Moreover, for the first time, we analyzed samples of patients undergoing treatment for endemic poverty-related diseases, especially tuberculosis, and we evaluated the impact of this therapy on test specificity in order to assess possible performance in TB high-burden countries.

Background: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment., Methods: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers., Results: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital., Conclusions: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19., (© 2021. The Author(s).)

Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in progressive destruction of β-cells. Several factors affecting lymphocyte and antigen-presenting cells, including dendritic cells (DCs), contribute to defective maintenance of tolerance in T1D. DC-10 are a subset of human DCs involved in IL-10-mediated tolerance. A precise monitoring of DC-10 in the peripheral blood is possible thanks to the discovery of specific biomarkers. DC-10, being cells that naturally express HLA-G, may be used for the appropriate staging of the disease. By enumerating and phenotypically characterizing DC-10 in the peripheral blood of subjects at different stages of T1D development-first-degree relatives (FDRs) of T1D patients, without (Ab neg ) or with (Ab pos ) autoantibodies, T1D patients at onset, and age-matched healthy controls (HCs)-we showed that DC-10 contain a high proportion of HLA-G-expressing cells as compared with monocytes. We reported that a low frequency of DC-10 during disease development is paralleled with the increased proportion of pro-inflammatory cDC2 cells. Moreover, DC-10 number and phenotype differ from Ab neg FDRs, Ab pos FDRs, and T1D patients compared with HCs, and DC-10 from T1D patients express low levels of CD83. Finally, multiple regression analysis, considering DC-10 and HLA-G-related parameters, showed that Ab neg FDRs are more similar to subjects with autoimmunity than to HCs. This is the first demonstration that impairment in DC-10 number and phenotype, specifically CD83 expression, is associated with risk of developing T1D, suggesting a possible use of CD83 + DC-10 to stratify individuals at risk of T1D in conjunction with classical prognostic factors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Amodio, Mandelli, Curto, Rancoita, Stabilini, Bonfanti, de Pellegrin, Bosi, Di Serio, Battaglia and Gregori.)

Background: The aim of this study was to quantify COVID-19 pneumonia features using CT performed at time of admission to emergency department in order to predict patients' hypoxia during the hospitalization and outcome., Methods: Consecutive chest CT performed in the emergency department between March 1st and April 7th 2020 for COVID-19 pneumonia were analyzed. The three features of pneumonia (GGO, semi-consolidation and consolidation) and the percentage of well-aerated lung were quantified using a HU threshold based software. ROC curves identified the optimal cut-off values of CT parameters to predict hypoxia worsening and hospital discharge. Multiple Cox proportional hazards regression was used to analyze the capability of CT quantitative features, demographic and clinical variables to predict the time to hospital discharge., Results: Seventy-seven patients (median age 56-years-old, 51 men) with COVID-19 pneumonia at CT were enrolled. The quantitative features of COVID-19 pneumonia were not associated to age, sex and time-from-symptoms onset, whereas higher number of comorbidities was correlated to lower well-aerated parenchyma ratio (rho = -0.234, p = 0.04) and increased semi-consolidation ratio (rho = -0.303, p = 0.008). Well-aerated lung (≤57%), semi-consolidation (≥17%) and consolidation (≥9%) predicted worst hypoxemia during hospitalization, with moderate areas under curves (AUC 0.76, 0.75, 0.77, respectively). Multiple Cox regression identified younger age (p < 0.01), female sex (p < 0.001), longer time-from-symptoms onset (p = 0.049), semi-consolidation ≤17% (p < 0.01) and consolidation ≤13% (p = 0.03) as independent predictors of shorter time to hospital discharge., Conclusion: Quantification of pneumonia features on admitting chest CT predicted hypoxia worsening during hospitalization and time to hospital discharge in COVID-19 patients., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late-infantile, 14 early-juvenile, 5 late-juvenile, and 4 adult MLD patients. Thirty-four were prospectively evaluated (median FU time 43 months). In late-infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early-juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late-infantile and early-juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late-infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease-related milestones (except death) between early-juvenile and late-juvenile patients. Late-juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late-infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants., (© 2021 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Objectives: Enlarged main pulmonary artery diameter (MPAD) resulted to be associated with pulmonary hypertension and mortality in a non-COVID-19 setting. The aim was to investigate and validate the association between MPAD enlargement and overall survival in COVID-19 patients., Methods: This is a cohort study on 1469 consecutive COVID-19 patients submitted to chest CT within 72 h from admission in seven tertiary level hospitals in Northern Italy, between March 1 and April 20, 2020. Derivation cohort (n = 761) included patients from the first three participating hospitals; validation cohort (n = 633) included patients from the remaining hospitals. CT images were centrally analyzed in a core-lab blinded to clinical data. The prognostic value of MPAD on overall survival was evaluated at adjusted and multivariable Cox's regression analysis on the derivation cohort. The final multivariable model was tested on the validation cohort., Results: In the derivation cohort, the median age was 69 (IQR, 58-77) years and 537 (70.6%) were males. In the validation cohort, the median age was 69 (IQR, 59-77) years with 421 (66.5%) males. Enlarged MPAD (≥ 31 mm) was a predictor of mortality at adjusted (hazard ratio, HR [95%CI]: 1.741 [1.253-2.418], p < 0.001) and multivariable regression analysis (HR [95%CI]: 1.592 [1.154-2.196], p = 0.005), together with male gender, old age, high creatinine, low well-aerated lung volume, and high pneumonia extension (c-index [95%CI] = 0.826 [0.796-0.851]). Model discrimination was confirmed on the validation cohort (c-index [95%CI] = 0.789 [0.758-0.823]), also using CT measurements from a second reader (c-index [95%CI] = 0.790 [0.753;0.825])., Conclusion: Enlarged MPAD (≥ 31 mm) at admitting chest CT is an independent predictor of mortality in COVID-19., Key Points: • Enlargement of main pulmonary artery diameter at chest CT performed within 72 h from the admission was associated with a higher rate of in-hospital mortality in COVID-19 patients. • Enlargement of main pulmonary artery diameter (≥ 31 mm) was an independent predictor of death in COVID-19 patients at adjusted and multivariable regression analysis. • The combined evaluation of clinical findings, lung CT features, and main pulmonary artery diameter may be useful for risk stratification in COVID-19 patients.

Vaccinium myrtillus berry extract (VME) and a recombined standard mixture (RSM) of its main native phenolic compounds were investigated for cell growth inhibition and pro-apoptotic activity on hormone-dependent (LNCaP) and hormone-independent (PC3 and DU-145) prostate cancer (PCa) cell lines. Normal prostate epithelial cells (PrEC) were also studied in comparison. VME hindered anchorage-dependent PCa cell proliferation in a dose-dependent manner, that is, at 1/800 (v/v) dilution for LNCaP and PC3, and 1/100 (v/v) dilution for DU-145 (corresponding to 14.15 and 113.2 μg cyanidin-3-O-glucoside equivalents per ml of culture medium), respectively. VME had a growth inhibitory effect towards PrEC at the same dilution of DU-145 cells although the IC50 values indicated that PrEC are more resistant than PCa cell lines. VME also reduced the anchorage-independent growth of PCa cells. The study of the apoptotic profile (i.e., non-apoptotic, early apoptotic, late apoptotic and necrotic cells) evidenced that the apoptotic rate (early+late) was statistically higher in all three cell lines exposed to VME compared to control. Anchorage-dependent and anchorage-independent growth inhibition of RSM was very similar to that displayed by VME. Moreover, RSM exerted its growth inhibitory effect also under hypoxia, the latter representing a biological condition known to sustain PCa proliferation and aggressiveness., (© 2020 John Wiley & Sons Ltd.)

As the COVID-19 pandemic is spreading around the world, increasing evidence highlights the role of cardiometabolic risk factors in determining the susceptibility to the disease. The fragmented data collected during the initial emergency limited the possibility of investigating the effect of highly correlated covariates and of modeling the interplay between risk factors and medication. The present study is based on comprehensive monitoring of 576 COVID-19 patients. Different statistical approaches were applied to gain a comprehensive insight in terms of both the identification of risk factors and the analysis of dependency structure among clinical and demographic characteristics. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells by binding to the angiotensin-converting enzyme 2 (ACE2), but whether or not renin-angiotensin-aldosterone system inhibitors (RAASi) would be beneficial to COVID-19 cases remains controversial. The survival tree approach was applied to define a multilayer risk stratification and better profile patient survival with respect to drug regimens, showing a significant protective effect of RAASi with a reduced risk of in-hospital death. Bayesian networks were estimated, to uncover complex interrelationships and confounding effects. The results confirmed the role of RAASi in reducing the risk of death in COVID-19 patients. De novo treatment with RAASi in patients hospitalized with COVID-19 should be prospectively investigated in a randomized controlled trial to ascertain the extent of risk reduction for in-hospital death in COVID-19., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Chronic granulomatous disease (CGD) is a rare inherited disorder due to loss-of-function mutations in genes encoding the NADPH oxidase subunits. Hematopoietic stem and progenitor cell (HSPC) gene therapy (GT) using regulated lentiviral vectors (LVs) has emerged as a promising therapeutic option for CGD patients. We performed non-clinical Good Laboratory Practice (GLP) and laboratory-grade studies to assess the safety and genotoxicity of LV targeting myeloid-specific Gp91 phox expression in X-linked chronic granulomatous disease (XCGD) mice. We found persistence of gene-corrected cells for up to 1 year, restoration of Gp91 phox expression and NADPH oxidase activity in XCGD phagocytes, and reduced tissue inflammation after LV-mediated HSPC GT. Although most of the mice showed no hematological or biochemical toxicity, a small subset of XCGD GT mice developed T cell lymphoblastic lymphoma (2.94%) and myeloid leukemia (5.88%). No hematological malignancies were identified in C57BL/6 mice transplanted with transduced XCGD HSPCs. Integration pattern analysis revealed an oligoclonal composition with rare dominant clones harboring vector insertions near oncogenes in mice with tumors. Collectively, our data support the long-term efficacy of LV-mediated HSPC GT in XCGD mice and provide a safety warning because the chronic inflammatory XCGD background may contribute to oncogenesis., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Pancreatic neuroendocrine neoplasms (PanNEN) are ideal entities for minimally invasive surgery. The advantage of the laparoscopic approach in terms of complications, length of stay (LOS) and cosmetic results has been previously demonstrated. However, scarce data are available on long-term oncological outcomes. Aim of this study was to compare short-term postoperative outcomes, pathological findings and long-term oncological results of minimally invasive distal pancreatectomy (MIDP) and open distal pancreatectomy (ODP) for PanNEN., Methods: Patients who underwent ODP or MIDP for nonfunctioning PanNEN (NF-PanNEN) were retrospectively analyzed. Inverse probability of treatment weighting using propensity score was performed to compare the outcomes of MIDP and ODP., Results: Overall, 124 patients were included in the study: 84 underwent OPD, whereas 40 were submitted to MIDP. The rate of high-grade postoperative complications was significantly lower in the MIDP group (p = 0.005, grade of complication with highest estimated probability 0 vs 2) and the postoperative LOS was significantly shorter after MIDP (p < 0.001, estimated days 8 versus 10). The number of examined lymph nodes (ELN) in the ODP group was significantly higher (p = 0.0036, estimated number of ELN 13 vs 10). Similar disease-free survival and overall survival were reported for the two groups (p = 0.234 and p = 0.666, respectively)., Conclusions: Although MIDP for PanNEN seems to be associated with a lower number of ELN, long-term survival is not influenced by the type of surgical approach. MIDP is advantageous in terms of postoperative complications and LOS, but prospective studies are needed to confirm the overall oncological quality of resection in this group of neoplasms.

Background: Laparoscopic distal pancreatectomy (LDP) is a challenging operation due to technical complexity and tumor-related factors. Aim of this study was to identify preoperative risk factors affecting LDP difficulty., Methods: Consecutive patients who underwent LDP between 2015 and 2018 at San Raffaele Hospital and Policlinico S.Orsola-Malpighi Hospital were enrolled retrospectively. Three variables were used to define surgical difficulty: conversion to open, duration of surgery >3rd quartile and intraoperative blood loss >3rd quartile. The presence of ≥1 of these 3 variables was considered as another measure of difficulty., Results: Overall, 191 patients were included. Conversion to open was required in 25 patients (13%). At multiple regression analysis, tumor proximity to major vessels was the only independent predictor of conversion from laparoscopic to open (p < 0.001). No variables independently predicted an excessive duration of surgery. Male gender (p = 0.033) and increasing parenchymal thickness at resection line (p = 0.018) were independent predictors of excessive blood loss. Increasing parenchymal thickness at resection line (p = 0.014) and tumor proximity to major vessels (p = 0.002) were significant risk factors for the presence of ≥1 outcome of surgical difficulty., Conclusion: Male gender, increasing parenchymal thickness at resection line and tumor proximity to major vessels represent preoperative risk factors of LDP difficulty., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate toxicity and clinical outcome in synchronous bone only oligometastatic (≤2 lesions) prostate cancer patients, simultaneously irradiated to prostate/prostatic bed, lymph nodes and bone metastases., Methods: From 2/2009 to 6/2015, 39 bone only prostate cancer patients underwent radiotherapy (RT) at "radical" doses to bone metastases (median 2 Gy equivalent dose, EQD2>40Gy, α/β = 1,5), nodes, and prostate/prostatic bed, within the same RT course, in association with androgen deprivation therapy (ADT).Biochemical relapse-free survival, clinical relapse-free survival, freedom from distant metastases and overall survival were evaluated., Results: After a median follow-up of 46.5 (1.2-103.6) months, 5 patients died from disease progression, 10 experienced biochemical relapse, 19, still in ADT, presented undetectable prostate-specific antigen (PSA) at the last follow-up. Five patients who discontinued ADT after a median of 34 months (5.8-41) are free from biochemical relapse.The 4 year Kaplan-Meier estimates of biochemical relapse-free survival, clinical relapse-free survival, freedom from distant metastases and overall survival were 53.3%, 65.7%, 73.4% and 82.4% respectively.No Grade > 2 acute events and only two severe late urinary events were recorded, not due to the concomitant treatment of primary and metastatic disease., Conclusion: Our results suggest that "radical" and synchronous irradiation of primitive tumor and metastatic disease may be a valid approach in synchronous bone only prostate cancer patients, showing mild toxicity profile and promising survival results., Advances in Knowledge: To the best of our knowledge, this is the first analysis of clinical outcome in synchronous bone-only metastasis (neither nodal nor visceral) patients at diagnosis, treated with radical RT to all disease, associated to ADT.

Background and Aims: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline., Methods: 50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features., Results: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression., Conclusions: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

In economics, models of decision-making under risk are widely investigated. Since many empirical studies have shown patterns in choice behavior that classical models fail to predict, several descriptive theories have been developed. Due to an evident phenotypic heterogeneity, obsessive compulsive disorder (OCD) patients have shown a general deficit in decision making when compared to healthy control subjects (HCs). However, the direction for impairment in decision-making in OCD patients is still unclear. Hence, bridging decision-making models widely used in the economic literature with mental health research may improve the understanding of preference relations in severe patients, and may enhance intervention designs. We investigate the behavior of OCD patients with respect to HCs by means of decision making economic models within a typical neuropsychological setting, such as the Cambridge Gambling Task. In this task subjects have to decide the amount of their initial wealth to invest in each risky decision. To account for heterogenous preferences, we have analyzed the micro-level data for a more informative analysis of the choices made by the subjects. We consider two influential models in economics: the expected value (EV), which assumes risk neutrality, and a multiple reference points model, an alternative formulation of Disappointment theory. We find evidence that (medicated) OCD patients are more consistent with EV than HCs. The former appear to be more risk neutral, namely, less sensitive to risk than HCs. They also seem to base their decisions on disappointment avoidance less than HCs., Competing Interests: The authors have declared that no competing interests exist.

Correctly recognizing emotions is an essential skill to manage interpersonal relationships in everyday life. Facial expression represents the most powerful mean to convey important information on emotional and cognitive states during interactions with others. In this paper, we analyze physiological responses triggered by an emotion recognition test, which requires the processing of facial cues. In particular, we evaluate the modulation of several Heart Rate Variability indices, collected during the Reading the Mind in the Eyes Test, accounting for test difficulty (derived from a Rasch analysis), test performances, demographic and psychological characteristics of the participants. The main idea is that emotion recognition is associated with the Autonomic Nervous System and, as a consequence, with the Heart Rate Variability. The principal goal of our study was to explore the complexity of the collected measures and their possible interactions by applying a class of flexible models, i.e., the latent class mixed models. Actually, this modelling strategy allows for the identification of clusters of subjects characterized by similar longitudinal trajectories. Both univariate and multivariate latent class mixed models were used. In fact, while the interpretation of the Heart Rate Variability indices is very difficult when considered individually, a joint evaluation provides a better description of the Autonomic Nervous System state., Competing Interests: The authors have declared that no competing interests exist.

Arbuscular mycorrhizal (AM) fungi are very widespread, forming symbiotic associations with ∼80% of land plant species, including almost all crop plants. These fungi are considered of great interest for their use as biofertilizer in low-input and organic agriculture. In addition to an improvement in plant nutrition, AM fungi have been reported to enhance plant tolerance to important abiotic and biotic environmental conditions, especially to a reduced availability of resources. These features, to be exploited and applied in the field, require a thorough identification of mechanisms involved in nutrient transfer, metabolic pathways induced by single and multiple stresses, physiological and eco-physiological mechanisms resulting in improved tolerance. However, cooperation between host plants and AM fungi is often related to the specificity of symbiotic partners, the environmental conditions and the availability of resources. In this study, the impact of two AM fungal species ( Funneliformis mosseae and Rhizophagus intraradices ) on the water stress tolerance of a commercial tomato cultivar (San Marzano nano) has been evaluated in pots. Biometric and eco-physiological parameters have been recorded and gene expression analyses in tomato roots have been focused on plant and fungal genes involved in inorganic phosphate (Pi) uptake and transport. R. intraradices , which resulted to be more efficient than F. mosseae to improve physiological performances, was selected to assess the role of AM symbiosis on tomato plants subjected to combined stresses (moderate water stress and aphid infestation) in controlled conditions. A positive effect on the tomato indirect defense toward aphids in terms of enhanced attraction of their natural enemies was observed, in agreement with the characterization of volatile organic compound (VOC) released. In conclusion, our results offer new insights for understanding the molecular and physiological mechanisms involved in the tolerance toward water deficit as mediated by a specific AM fungus. Moreover, they open new perspectives for the exploitation of AM symbiosis to enhance crop tolerance to abiotic and biotic stresses in a scenario of global change.

Selecting visual stimuli for inducing specific emotional states is very challenging, since the choice relies on specific conceptualization of emotions. In this work, we present a set of 55 stimuli, realized integrating discrete and dimensional theories of emotions, and specifically selected to investigate anger, fear, and disgust reactions in non-clinical and clinical contexts. Our set of stimuli presents several aspects of novelty since (1) a large and heterogeneous sample of subjects from the general population was involved in the labelling task, and (2) bivariate and multivariate statistical techniques were applied to integrate emotion models. The proposed set of stimuli could be useful for researchers and other professionals in the affective sciences to address negative emotion recognition issues within a broader perspective both in general population and in psychiatric samples. The obtained comprehensive characterization of the stimuli allowed us to confirm the sexual dimorphism in emotional processing.

Infection-related mortality (IRM) is a substantial component of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). No scores have been developed to predict IRM before transplantation. Pretransplantation clinical and biochemical data were collected from a study cohort of 607 adult patients undergoing allo-HSCT between January 2009 and February 2017. In a training set of 273 patients, multivariate analysis revealed that age >60 years (P = .003), cytomegalovirus host/donor serostatus different from negative/negative (P < .001), pretransplantation IgA level <1.11 g/L (P = .004), and pretransplantation IgM level <.305 g/L (P = .028) were independent predictors of increased IRM. Based on these results, we developed and subsequently validated a 3-tiered weighted prognostic index for IRM in a retrospective set of patients (n = 219) and a prospective set of patients (n = 115). Patients were assigned to 3 different IRM risk classes based on this index score. The score significantly predicted IRM in the training set, retrospective validation set, and prospective validation set (P < .001, .044, and .011, respectively). In the training set, 100-day IRM was 5% for the low-risk group, 11% for the intermediate-riak group, and 16% for the high-risk groups. In the retrospective validation set, the respective 100-day IRM values were 7%, 17%, and 28%, and in the prospective set, they were 0%, 5%, and 7%. This score predicted also overall survival (P < .001 in the training set, P < 041 in the retrospective validation set, and P < .023 in the prospective validation set). Because pretransplantation levels of IgA/IgM can be modulated by the supplementation of enriched immunoglobulins, these results suggest the possibility of prophylactic interventional studies to improve transplantation outcomes., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background and Aim: Antibodies against hepatitis B core antigen (anti-HBc) are found in 14-44% of patients with HIV infection, but it is still unclear whether hepatitis B virus (HBV) vaccination should be recommended for HIV-positive subjects with isolated anti-HBc (IAHBc). We examined the rate of anamnestic and primary responses (ARs and PRs) and associated factors in a group of HIV-infected patients with an IAHBc profile., Methods: This prospective study recruited 25 HIV-positive patients with anti-HBc alone who were vaccinated against HBV infection. Those without an AR (anti-hepatitis B envelope antigen [anti-HBs] levels of <10 U/L) or who were hypo-responsiveness (anti-HBs levels of >10 but <100 U/L) four weeks after the first dose of vaccine underwent a full course of vaccinations. Their clinical and virological data, including the presence of occult hepatitis B infection (OBI), were evaluated in accordance with the vaccination schedule., Results: Six of the 25 patients (24%) showed an AR, four of whom had anti-HBs levels of <100 U/L. Ten of 19 (52.6%) remaining patients became seroprotected after the third dose. OBI was detected in four of the six patients with an AR, two of the 10 patients with a PR, and none of the nine patients who did not respond. Multivariate analysis showed that an AR was associated with the presence of OBI (P = 0.0162), and a PR was associated with HCV antibody status. (P = 0.0191)., Conclusions: Our data suggest that testing for anti-HBc alone may not be a reliable means of assessing protection from HBV infection in HIV-positive patients. OBI-positive patients may benefit from a single vaccine dose. Anti-HCV serostatus may affect PRs.

The aim of this work is to evaluate the factor structure and psychometric properties of the Italian version of the Disgust Propensity and Sensitivity Scale-Revised (DPSS-R, 16 items) in two samples taken from the general population. In the first study, 285 participants completed the DPSS-R questionnaire through a web-based survey. Exploratory factor analysis for ordinal Likert-type data supported the existence of four underlying factors, reflecting self-focused disgust , disgust propensity , somatic anxiety and disgust sensitivity . In the second study, an independent sample of 293 participants was enrolled as a test set to validate the factor structure obtained in the exploratory phase. The factor solution was confirmed, but showed quite highly correlated latent factors. We fitted the model and tested whether or not the bifactor structure was better than the previous one (four correlated factors). Actually, we had evidence supporting the presence of a general factor, providing a measure of disgust susceptibility, along with the four specific factors previously defined. This result could be useful also from the clinical perspective since the DPSS-R questionnaire will be used in clinical context, where underlying factors may be related to different and specific psychopathological profiles. Finally, we examined and visualized the interrelationships among the four DPSS-R factors and the external scales (Anxiety Sensitivity, Disgust Scale and Padua) using a graphical model approach.

Frailty models are here proposed in the tumor dormancy framework, in order to account for possible unobservable dependence mechanisms in cancer studies where a non-negligible proportion of cancer patients relapses years or decades after surgical removal of the primary tumor. Relapses do not seem to follow a memory-less process, since their timing distribution leads to multimodal hazards. From a biomedical perspective, this behavior may be explained by tumor dormancy, i.e., for some patients microscopic tumor foci may remain asymptomatic for a prolonged time interval and, when they escape from dormancy, micrometastatic growth results in a clinical disease appearance. The activation of the growth phase at different metastatic states would explain the occurrence of metastatic recurrences and mortality at different times (multimodal hazard). We propose a new frailty model which includes in the risk function a random source of heterogeneity (frailty variable) affecting the components of the hazard function. Thus, the individual hazard rate results as the product of a random frailty variable and the sum of basic hazard rates. In tumor dormancy, the basic hazard rates correspond to micrometastatic developments starting from different initial states. The frailty variable represents the heterogeneity among patients with respect to relapse, which might be related to unknown mechanisms that regulate tumor dormancy. We use our model to estimate the overall survival in a large breast cancer dataset, showing how this improves the understanding of the underlying biological process., (© 2016, The International Biometric Society.)

Background: A great part of the literature has confirmed the importance of both child and parents reports as source of factual information, especially for childhood emotional syndromes. In our study we aimed at: (i) calculating mother-child agreement and (ii) evaluating factorial structure of the Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire in an Italian clinical sample. The novelty of this contribution is two-fold: first, from a clinical point of view, we investigated the parent-child agreement level and examined separately the factorial structures of both parent and child versions of the SCARED for the first time in an Italian clinical sample. Second, unlike previous studies, we used statistical approaches specifically suited to account for the ordinal nature of the collected variables. Method: In a clinical sample of 171 children and adolescents aged 8-18 and their mothers we evaluated inter-rater agreement using weighted kappa indices to assess agreement for each item belonging to a certain SCARED subscale. Exploratory factor analysis for ordinal data was then performed on the polychoric correlation matrix calculated on SCARED items. Differences in the numbers of symptoms reported by children and parents were evaluated as well. Results and Conclusions: Our results reveal moderate to strong mother-child agreement. A significant age effect is present. Two different factorial solutions emerged for parent and child SCARED versions (a 5 factor structure for parents and a 6 factor solution in the child version, including a new factor "Worry about Parents"). This study confirmed the importance of evaluating both child and parent reports in assessment protocols for anxiety disorders. Our findings could help clinicians to determine which information, and from which rater, must be accounted for in evaluating treatment decisions. Moreover, we find that patients characteristics, such as gender and age, should be taken into account when assessing agreement.

Background and Aims: Atrial fibrillation (AF) is the most frequent arrhythmia of the elderly, and electrical cardioversion (ECV) is a common procedure, although incidence of recurrences remains high. We evaluated the possible association between arterial stiffness (AS) and the persistence or recurrence of AF in elderly patients after ECV., Methods: We enrolled all subjects undergoing ECV over a 9-month period. AS was evaluated with the cardio-ankle vascular index (CAVI). Patients were then visited at follow-up (on average at 6 months)., Results: Thirty-one patients (age 78 ± 7 years; men 67.7 %; CHA 2 DS 2 -VASc 4.1 ± 1.6; AF length >2 months 51.6 %; CAVI 9.9 ± 1.6) underwent ECV. At follow-up, sinus rhythm was recorded in 16 (51.6 %) patients. At multivariate analysis, the presence of AF was directly associated with CHA 2 DS 2 -VASc score and CAVI. Amiodarone therapy reduced the risk of relapsed AF., Conclusions: In elderly AF patients treated with ECV, AS at baseline seems to predict AF at follow-up., Competing Interests: No conflict of interest to declare. Human and animal rights All procedures were performed in accordance with the principles of the Declaration of Helsinki and approved by the appropriate institutional review committee. Informed consent All subjects gave their informed consent to participate in the study.

Disease process over time results from the combination of event history information and longitudinal process. Commonly, separate analyses of longitudinal and survival outcomes are performed. However, discharging the dependence between these components may cause misleading results. Separate analyses are difficult to interpret whenever one deals with observational retrospective multicenter cohort studies where the biomarkers are poorly monitored over time, while the survival component may be affected by several sources of bias, such as multiple endpoints, multiple time-scales, and informative censoring. We discuss how joint modeling of longitudinal and survival data represents an effective strategy to incorporate all information simultaneously and to provide valid and efficient inferences, thus allowing to produce a better insight into the biological mechanisms underlying the phenomenon under study. Accounting for the whole dynamics of the disease process is crucial in retrospective longitudinal studies. In this work, we present different approaches for modeling longitudinal and time-to-event data, retrieved from 648 HIV-infected patients enrolled in the Italian cohort of the CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe) study, one of the largest AIDS collaborative cohort studies. In particular, we evaluate CD4 lymphocyte evolution over time (from the date of seroconversion) and overall survival, CD4 being one of the most important immunologic biomarker for HIV progression. Besides a standard separate modeling approach, we consider two alternative joint models: the traditional joint model and the joint latent class mixed model. Advantages and disadvantages of the different approaches are discussed. To compare the performances of these models, cross-validation procedures are also performed., (© The Author(s) 2014.)

We validated the Italian version of the rapid eye movement sleep behavior disorder (RBD) screening questionnaire (RBDSQ) and calculated its cut-off value for discriminating RBD group from other sleep disorders and healthy controls (HC). 380 patients with sleep disorders and 101 HC were enrolled. RBDSQ achieved an acceptable Cronbach's α value of 0.787 and item 10 was the only one with a very low item-total biserial correlation (0.141). At ROC analysis, we obtained an AUC of 0.888, denoting a good performance of the RBDSQ total score for predicting the RBD status. The optimal cut-off value was 8 and it achieved good values of both sensitivity and specificity (0.842 and 0.780, respectively). Due to the poor performance of item 10 in our sample, we analyzed the RBDSQ without this item (called "revised RBDSQ"). We obtained a good Cronbach's α of 0.802. When evaluating the performance of the revised score in predicting the RBD status, we obtained an increased value of AUC (0.899). The optimal cut-off value was still 8 (sensitivity = 0.829; specificity = 0.820). The Italian version of RBDSQ is a sensitive tool for the identification of RBD patients. An improvement of the instrument could be obtained by removing item 10 and define a higher cut-off value of 8. The "revised RBDSQ" represents a reliable screening questionnaire for primary care physicians and neurologists and its employment may facilitate the choice of subjects that should undergo a PSG that confirms the diagnosis of RBD, thus avoiding polysomnographic exams when not needed.

Identifying latently infected individuals is crucial for the elimination of tuberculosis (TB). We evaluated for the first time the performance of a new type of interferon-γ release assay, QuantiFERON-TB Plus (QFT-Plus), which includes an additional antigen tube (TB2), stimulating both CD4 + and CD8 + T-cells in contacts of TB patients.Contacts were screened for latent TB infection by tuberculin skin test, QFT-Plus and QuantiFERON-TB Gold in Tube (QFT-GIT).In 119 TB contacts, the overall agreement between QFT-Plus and QFT-GIT was high, with a Cohen's κ of 0.8. Discordant results were found in 12 subjects with negative QFT-GIT and positive QFT-Plus results. In analyses of markers of TB exposure and test results, the average time spent with the index case was the strongest risk factor for positivity in each of these tests. The difference in interferon-γ production between the two antigen tubes (TB2-TB1) was used as an estimate of CD8 + stimulation provided by the TB2. TB2-TB1 values >0.6 IU·mL -1 were significantly associated with proximity to the index case and European origin.QFT-Plus has a stronger association with surrogate measures of TB exposure than QFT-GIT in adults screened for latent TB infection. Interferon-γ response in the new antigen tube used an indirect estimate of specific CD8 + response correlates with increased Mycobacterium tuberculosis exposure, suggesting a possible role in identifying individuals with recent infection., (Copyright ©ERS 2016.)

Chronic granulomatous disease (CGD) is a primary immunodeficiency due to a deficiency in one of the subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. CGD patients are characterized by an increased susceptibility to bacterial and fungal infections, and to granuloma formation due to the excessive inflammatory responses. Several gene therapy approaches with lentiviral vectors have been proposed but there is a lack of in vivo data on the ability to control infections and inflammation. We set up a mouse model of acute infection that closely mimic the airway infection in CGD patients. It involved an intratracheal injection of a methicillin-sensitive reference strain of S. aureus. Gene therapy, with hematopoietic stem cells transduced with regulated lentiviral vectors, restored the functional activity of NADPH oxidase complex (with 20-98% of dihydrorhodamine positive granulocytes and monocytes) and saved mice from death caused by S. aureus, significantly reducing the bacterial load and lung damage, similarly to WT mice even at low vector copy number. When challenged, gene therapy-treated XCGD mice showed correction of proinflammatory cytokines and chemokine imbalance at levels that were comparable to WT. Examined together, our results support the clinical development of gene therapy protocols using lentiviral vectors for the protection against infections and inflammation.

Background: In biomedical research a relevant issue is to identify time intervals or portions of a n-dimensional support where a particular event of interest is more likely to occur than expected. Algorithms that require to specify a-priori number/dimension/length of clusters assumed for the data suffer from a high degree of arbitrariness whenever no precise information are available, and this may strongly affect final estimation on parameters. Within this framework, spatial scan-statistics have been proposed in the literature, representing a valid non-parametric alternative., Results: We adapt the so called Bernoulli-model scan statistic to the genomic field and we propose a multivariate extension, named Relative Scan Statistics, for the comparison of two series of Bernoulli r.v. defined over a common support, with the final goal of highlighting unshared event rate variations. Using a probabilistic approach based on success probability estimates and comparison (likelihood based), we can exploit an hypothesis testing procedure to identify clusters and relative clusters. Both the univariate and the novel multivariate extension of the scan statistic confirm previously published findings., Conclusion: The method described in the paper represents a challenging application of scan statistics framework to problem related to genomic data. From a biological perspective, these tools offer the possibility to clinicians and researcher to improve their knowledge on viral vectors integrations process, allowing to focus their attention to restricted over-targeted portion of the genome.

Objectives: Adiponectin (AD) promotes insulin sensitivity and has anti-atherogenic properties. However, the role of AD on clinical outcomes in coronary artery disease (CAD) is controversial. We analyzed whether AD was an independent predictor of all-cause mortality and hospitalization in patients with CAD., Method: We prospectively enrolled 138 patients with stable CAD, with or without type 2 diabetes and with or without left ventricular dysfunction. A telephone follow-up was conducted to register long term outcomes. Sensitivity/specificity ratio for AD was investigated with ROC analysis and the independent role of AD on outcome was evaluated with Cox regression model of analysis. The survival rate was represented by Kaplan Meyer curves., Results: Of 138 patients, 61 had type 2 diabetes and 71 left ventricular systolic dysfunction (EF<40%). Median time of follow-up was 1384days; mortality rate was 18.8% (26 deaths) and hospitalization rate was 47.1% (65 events). Mean concentration of AD was 9.87±7.53ng/ml; the analysis of the ROC curve identified an AD cut-off level of 13.2ng/ml (AUC 0.779; p<0.0001). Patients with AD >13.2ng/ml had a significantly higher risk of death (HR=6.50; 95% CI: 2.40-17.70), but not of cardiovascular hospitalization (HR=0.87; 95% CI: 0.31-2.44). AD predictivity remained significant also in patients with type 2 diabetes and with left ventricular systolic dysfunction., Conclusion: In stable CAD, an AD value of >13.2ng/ml independently predicts a 6-fold increased risk of all-cause mortality., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)