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Background: Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of the whole-brain effects of intracortical stimulation, as well as their relationships to the EEG responses evoked by non-invasive stimuli. Objective: To demonstrate that CCEPs recorded by high-density electroencephalography (hd-EEG) provide additional information with respect SEEG alone and to provide an open, curated dataset to allow for further exploration of their potential. Methods: The dataset encompasses SEEG and hd-EEG recordings simultaneously acquired during Single Pulse Electrical Stimulation (SPES) in drug-resistant epileptic patients (N = 36) in whom stimulations were delivered with different physical, geometrical, and topological parameters. Differences in CCEPs were assessed by amplitude, latency, and spectral measures. Results: While invasively and non-invasively recorded CCEPs were generally correlated, differences in pulse duration, angle and stimulated cortical area were better captured by hd-EEG. Further, intracranial stimulation evoked site-specific hd-EEG responses that reproduced the spectral features of EEG responses to transcranial magnetic stimulation (TMS). Notably, SPES, albeit unperceived by subjects, elicited scalp responses that were up to one order of magnitude larger than the responses typically evoked by sensory stimulation in awake humans. Conclusions: CCEPs can be simultaneously recorded with SEEG and hd-EEG and the latter provides a reliable descriptor of the effects of SPES as well as a common reference to compare the whole-brain effects of intracortical stimulation to those of non-invasive transcranial or sensory stimulations in humans.

Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The changes in Stereo-Electroencephalographic (SEEG) activity after Radiofrequency-Thermocoagulation (RFTC) recorded in 21 epileptic subjects were assessed with respect to baseline resting wakefulness and sleep activity. In addition, Cortico-Cortical Evoked Potentials (CCEPs) recorded before the lesion were employed to interpret these changes with respect to individual long-range connectivity patterns. We found that small structural ablations lead to the generation and large-scale propagation of sleep-like slow waves within the awake brain. These slow waves match those recorded in the same subjects during sleep, are prevalent in perilesional areas, but can percolate up to distances of 60 mm through specific long-range connections, as predicted by CCEPs. Given the known impact of slow waves on information processing and cortical plasticity, demonstrating their intrusion and percolation within the awake brain add key elements to our understanding of network dysfunction after cortical injuries.

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On the one hand, TMEM176B promotes antigen cross-presentation to CD8 + T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, it inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. We speculated that formulating BayK8644 in PEGylated chitosan nanoparticles (NP-PEG-BayK8644) should slowly release the compound and by that mean avoid cross-presentation inhibition (which happens with a fast 30 min kinetics) while still triggering inflammasome activation. Chitosan nanocarriers were successfully obtained, exhibiting a particle size within the range of 200 nm; they had a high positive surface charge and a 99 % encapsulation efficiency. In in vitro studies, NP-PEG-BayK8644 did not inhibit antigen cross-presentation by DCs, unlike the free compound. The NP-PEG-BayK8644 activated the inflammasome in a Tmem176b-dependent manner in DCs. We administered either empty (eNP-PEG) or NP-PEG-BayK8644 to mice with established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and improved mice survival compared to both eNP-PEG and free BayK8644 in melanoma and lymphoma models. This effect was associated with enhanced inflammasome activation by DCs in the tumor-draining lymph node and infiltration of the tumor by CD8 + T cells. Thus, encapsulation of BayK8644 in chitosan NPs improves the anti-tumoral properties of the compound by avoiding inhibition of antigen cross-presentation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MH is founder and CSO of ARDAN Pharma. One patent application related to this work has been filed at the USA Patent and Trademark Office., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background and Study Aims: Balanced propofol sedation (BPS) administered by adequately trained non-anaesthesiologist personnel has gained popularity in GI endoscopy because of its shorter procedure and recovery time, high patient satisfaction, and low rate of adverse events (AEs), despite being considered controversial. We report data from an audit of endoscopist-directed (ED) nurse-administered sedation in an Italian referral hospital., Patients and Methods: Consecutive endoscopic procedures performed between 2020 and 2022 were considered. Under the guidance of the endoscopist, the nurse administered midazolam/fentanyl, followed by a progressive top-up dosage of a 10-20 mg bolus of propofol to achieve moderate to deep sedation. The endoscopists and nurses were all certified in our hospital with a continuous and scheduled training from 2006., Results: During the study period, a total of 19,407 examinations (7,803 EGDS, 10,439 colonoscopies, 77 PEG, 697 EUS, and 365 ERCP) and 14,415 patients were included. Of these, 29.4 % of patients were classified as ASA I, 66.5 % as ASA II, and 5.1 % as ASA III. Hypotension was recorded in 1,293 (6 %) examinations and bradycardia in 176 (0.9 %) patients. Eleven patients (0.06 %) had minor respiratory adverse events. Two patients (0.01 %) had major AEs requiring orotracheal intubation., Conclusions: ED-BPS is safe in low-risk patients. Major AEs occurred in 0.01 % of procedures., Competing Interests: Conflicts of interest No conflict of interest, (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Endoscopic surgery is a minimally invasive procedure that has been shown to relieve intradiscal pressure, irrigation of inflammatory factors, and visual debridement, which are crucial for the successful treatment of spondylodiscitis. This study proposes a systematic review and meta-analysis to evaluate the effectiveness and safety of endoscopic treatment of thoracolumbar spondylodiscitis., Methods: Multiple databases were searched for studies involving thoracolumbar spondylodiscitis treated by endoscopic disc drainage with or without additional posterior fixation over the last 20 years. Studies that met the inclusion criteria, which included outcomes related to the percentage of cured infections, patient satisfaction, regression of inflammatory markers, and/or the percentage of adverse event rates, were included in the analysis. For each study, the percentage of patients who showed improvement or experienced an adverse event was abstracted and pooled in a meta-analysis., Results: Based on the search strategy and inclusion criteria, our systematic review and meta-analysis included 20 studies with 546 participants. The success rate was 89.4% (95% CI 83.1%-94.5%). The rate of major adverse events was 0.3%, while that of postoperative transient paresthesia was 2.6% (95% CI 0.8%-5.1%). The recurrence rate was 1.7% (95% CI 0.3%-4.0%), and revision surgery was 8.5% (95% CI 3.8%-14.6%). The causative pathogen diagnosis rate was 73.9% (95% CI 67.7%-79.8%), while progression of deformity was 3.7% (95% CI 0.2%-9.8%), and spontaneous fusion was 40.1% (95% CI 11.0%-73.3%)., Conclusions: Endoscopic discectomy for thoracolumbar spondylodiscitis has been shown to be a safe technique with satisfactory clinical outcomes and a high causative pathogen identification rate., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present the case of a 53-year-old Caucasian man with a history of intravenous drug use who presented with fever and multiple pustules predominantly affecting hairy areas of the body, with no clinical improvement despite previous antibiotic treatment. Culture of the pustules confirmed Candida albicans infection and histological examination of skin biopsies revealed suppurative granulomas compatible with candidomycetic folliculitis. The patient was successfully treated with systemic antifungals and discharged with resolution of symptoms. Candidomycetic folliculitis is a condition typically associated with brown heroin consumption due to the use of acidic solvent that promotes Candida growth. Clinical manifestations include fever followed by skin lesions, with possible systemic involvement if untreated. Extensive folliculitis with associated fever in an IVDU should raise suspicion of this pathology since early diagnosis and appropriate treatment are crucial to prevent complications., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

The present document constitutes Part 2 of the EoETALY Consensus Statements guideline on the diagnosis and management of eosinophilic esophagitis (EoE) developed by experts in the field of EoE across Italy (i.e., EoETALY Consensus Group). Part 1 was published as a different document, and included three chapters discussing 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history and 3) diagnosis of EoE. The present work provides guidelines on the management of EoE in two final chapters: 4) treatment and 5) monitoring and follow-up, and also includes considerations on knowledge gaps and a proposed research agenda for the coming years. The guideline was developed through a Delphi process, with grading of the strength and quality of the evidence of the recommendations performed according to accepted GRADE criteria.This document has received the endorsement of three Italian national societies including the Italian Society of Gastroenterology (SIGE), the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). The guidelines also involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To assess the clinical complications reported after the ingestion of magnetic foreign bodies (FBs) in pediatric age, along with their incidence among all FB ingestions and clinical presentation., Study Design: We've consecutively recruited all children aged 0-14 years who were admitted for single or multiple magnet ingestion from May 2015 to December 2022. Patient demographics, admission sources and discharge status were accurately recorded, along with their clinical management and outcomes., Results: Sixty-one children were enrolled, of whom 49/61 (80.3%) had ingested a single magnet and 12/61 (19.7%) multiple magnets. Only 1/49 children with single magnet required endoscopic removal due to esophageal retention. Among children having ingested multiple magnets, 5/12 (41.7%) undergo endoscopic removal since magnets were amenable to endoscopic retrieval whereas in 7/12 (58.3%) magnets could not be promptly removed. Among these, 4/12 (33.3%) later developed intestinal ischemia/necrosis or perforation and required FB surgical intervention whereas 3/12 (25%) uneventfully evacuated magnets., Conclusions: Our data confirm that multiple magnet ingestion, unlike single magnet ingestion, pose a serious health hazard. Parents and caregivers should remove them from the reach of children. Medical providers should maintain a high index of suspicion of their ingestion since prompt evaluation and likely removal may be lifesaving and intestine saving., Competing Interests: Conflict of interest The authors Paolo Quitadamo, Piergiorgio Gragnaniello, Sara Isoldi, Cristina Bucci, Francesco Esposito, Silvana Russo, Giovanna Grella, Mariano Caldore have no conflicts of interest to declare related to the manuscript., (Copyright © 2023 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Eosinophilic esophagitis (EoE) is a chronic type 2-mediated inflammatory disease of the esophagus that represents the most common eosinophilic gastrointestinal disease. Experts in the field of EoE across Italy (i.e., EoETALY Consensus Group) including gastroenterologists, endoscopists, allergologists/immunologists, and paediatricians conducted a Delphi process to develop updated consensus statements for the management of patients with EoE and update the previous position paper of the Italian Society of Gastroenterology (SIGE) in light of recent evidence. Grading of the strength and quality of the evidence of the recommendations was performed using accepted GRADE criteria. The guideline is divided in two documents: Part 1 includes three chapters, namely 1) definition, epidemiology, and pathogenesis; 2) clinical presentation and natural history, and 3) diagnosis, while Part 2 includes two chapters: 4) treatment and 5) monitoring and follow-up. This document has received the endorsement of three Italian national societies including the SIGE, the Italian Society of Neurogastroenterology and Motility (SINGEM), and the Italian Society of Allergology, Asthma, and Clinical Immunology (SIAAIC). With regards to patients' involvement, these guidelines involved the contribution of members of ESEO Italia, the Italian Association of Families Against EoE., Competing Interests: Declaration of competing interest Nicola de Bortoli: Advisory board member for: AlfaSigma, Sanofi Genzyme, Dr Falk; Lecture grants from Reckitt-Benkiser, Malesci, Dr. Flak, Sofar, Alfa-Sigma, Pharma-Line. Pierfrancesco Visaggi: Has served as speaker for Dr Falk, JB Pharmaceuticals, Malesci. Roberto Penagini: Has served as speaker for Dr Falk, Sanofi. Edda Battaglia: has served as consultant for NZP, GUNA Gaia Pellegatta has served as speaker for Dr Falk, Sanofi Genzyme, Malesci. Paola Iovino: Has served as consultant for Dr Falk Giovanni Marasco: Served as an advisory board member for AlfaSigma, EG Pharma, Monteresearch srl, Recordati, Cineca. Received lecture grants from Agave, AlfaSigma, Bromatech, Clorofilla, Echosens, Ferring, Mayoly Spindler, Menarini and Schwabe Pharma. Salvatore Oliva: Has served as speaker for Sanofi, Medtronic; Has served as consultant for: Sanofi, Medtronic, Brystol; Has received research support from Alfa Sigma, Medtronic. Francesca Racca: has served as speaker for Sanofi; has served as consultant for Dr Falk, Sanofi, GSK Erminia Ridolo: has served as consultant for Dr Falk Edoardo Vincenzo Savarino: has served as speaker for Abbvie, Agave, AGPharma, Alfasigma, Aurora Pharma, CaDiGroup, Celltrion, Dr Falk, EG Stada Group, Fenix Pharma, Fresenius Kabi, Galapagos, Janssen, JB Pharmaceuticals, Innovamedica/Adacyte, Malesci, Mayoly Biohealth, Omega Pharma, Pfizer, Reckitt Benckiser, Sandoz, SILA, Sofar, Takeda, Tillots, Unifarco; has served as consultant for Abbvie, Agave, Alfasigma, Biogen, Bristol-Myers Squibb, Celltrion, Diadema Farmaceutici, Dr. Falk, Fenix Pharma, Fresenius Kabi, Janssen, JB Pharmaceuticals, Merck & Co, Nestlè, Reckitt Benckiser, Regeneron, Sanofi, SILA, Sofar, Synformulas GmbH, Tssakeda, Unifarco; he received research support from Pfizer, Reckitt Benckiser, SILA, Sofar, Unifarco, Zeta Farmaceutici. Bruno Annibale, Federica Baiano Svizzero, Giovanni Barbara, Brigida Barberio, Ottavia Bartolo, Antonio Di Sabatino, Ludovico Docimo, Marzio Frazzoni, Manuele Furnari, Matteo Ghisa, Andrea Iori, Marco Vincenzo Lenti, Elisa Marabotto, Aurelio Mauro, Marcella Pesce, Antonino Carlo Privitera, Ilaria Puxeddu, Mentore Ribolsi, Salvatore Russo, Giovanni Sarnelli, Salvatore Tolone, Patrizia Zentilin, Fabiana Zingone: None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Intermittent treatment with tyrosine kinase inhibitors (TKIs) is an option for elderly chronic myeloid leukemia (CML) patients who are often candidates for life-long treatment., Materials and Methods: The Italian phase III multicentric randomized Optimize TKIs Multiple Approaches (OPTkIMA) study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the molecular remission (MR) 3.0 and to improve Health-Related Quality of Life (HRQoL) in CML elderly patients., Results: A total of 215 patients in stable MR 3.0 /MR 4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n = 111) vs. a progressive de-escalation TKI dose up to one-third of the starting dose at the 3rd year (PROGRESSIVE arm; n = 104). Two hundred three patients completed the 3rd year of OPTkIMA study. At the last follow-up, MR 3.0 loss was 27% vs. 46% (P = .005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3-year probability of maintaining the MR 3.0 was 59% vs. 53%, respectively (P = .13). HRQoL globally improved from the baseline to the 3rd year, without any significant difference between the 2 arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the 2 arms was 36% (FIXED) vs. 58% (PROGRESSIVE) (P = .03)., Conclusions: The intensification of intermittent TKI therapy is associated with a higher incidence of MR 3.0 loss, but those patients who maintain the MR 3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms., Competing Interests: Disclosures AI: Speaker honoraria – AOP, BMS, GSK, Incyte, Novartis and Pfizer. CB: Speaker's Bureau – Novartis, Incyte and Pfizer AB: Advisory Board and Consultancy - Novartis, Incyte, BMS, Pfizer. GR: Speaker's Bureau and Advisory Boards - Incyte, Novartis and Pfizer. MT: Speaker's Bureau – Novartis, Incyte and BMS. AMR: research funding - AstraZeneca, European Hematology Association, Transcan2-ERANET and Italian Association for Cancer Research (Fondazione AIRC); honoraria - Amgen, Celgene, Janssen and Takeda. All the other Authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: To reduce the risk of viral transmission, guidelines recommend the use of designated haemodialysis machines and patient isolation for patients with chronic hepatitis B virus (HBV). These practices are without a strong evidence base, and may no longer be necessary in the setting of heat disinfection programs and standard precautions., Methods: An online cross-sectional survey was developed for renal clinicians across Australia and New Zealand to explore infection prevention policy concerning patients with chronic HBV in haemodialysis units. We sought to determine whether psychosocial and cultural impacts might result from the mandatory use of machine designation and patient isolation practices, as perceived by multidisciplinary healthcare workers with experience working with this patient population., Results: Sixty-seven responses from 27 health districts across all states of Australia and one New Zealand district were received. Most respondents were from urban areas (65%), and were nurses (87%). 50% of health districts reported using designated machines, while 32% isolate patients. Lack of necessary resources limited the use of designated machines (57%), and patient isolation (78%). Respondents not routinely using these precautions were more likely to express concerns regarding patient psychosocial wellbeing and cultural appropriateness. Overall, 30% of respondents expressed concerns regarding the cultural appropriateness of these recommendations., Conclusion: We demonstrate wide variation in haemodialysis infection prevention and control policy and practice with regards to managing patients with chronic HBV. While use of standard precautions and machine disinfection are consistently applied, resource availability and concerns for patient psychosocial wellbeing limit adherence to international guidelines., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a threat to public health and the global economy, necessitating the development of various vaccination strategies. Mutations in the SPIKE protein gene, a crucial component of mRNA and adenovirus-based vaccines, raised concerns about vaccine efficacy, prompting the need for rapid vaccine updates. To address this, we leveraged PeptiCRAd, an oncolytic vaccine based on tumor antigen decorated oncolytic adenoviruses, creating a vaccine platform called PeptiVAX. First, we identified multiple CD8 T-cell epitopes from highly conserved regions across coronaviruses, expanding the range of T-cell responses to non-SPIKE proteins. We designed short segments containing the predicted epitopes presented by common HLA-Is in the global population. Testing the immunogenicity, we characterized T-cell responses to candidate peptides in peripheral blood mononuclear cells (PBMCs) from pre-pandemic healthy donors and ICU patients. As a proof of concept in mice, we selected a peptide with epitopes predicted to bind to murine MHC-I haplotypes. Our technology successfully elicited peptide-specific T-cell responses, unaffected by the use of unarmed adenoviral vectors or adeno-based vaccines encoding SPIKE. In conclusion, PeptiVAX represents a fast and adaptable SARS-CoV-2 vaccine delivery system that broadens T-cell responses beyond the SPIKE protein, offering potential benefits for vaccine effectiveness., Competing Interests: Declaration of competing interest Vincenzo Cerullo is a co-founder and shareholder at VALO Therapeutics. Sari Pesonen is co-founder, an employee, and a shareholder at VALO Therapeutics. The other authors have no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

First experiences with rhythm occur in the womb, with different rhythmic sources being available to the human fetus. Among sensory modalities, vestibular, tactile, and somatosensory perception plays a crucial role in early processing. However, a limited number of studies so far have specifically focused on VTS rhythms in language development. The present work investigated VTS rhythmic abilities and their role in language acquisition through two experiments with 45 infants (21 females, sex assigned at birth; M age = 661.6 days, SD = 192.6) with middle/high socioeconomic status. Specifically, 37 infants from the original sample completed Experiment 1, assessing VTS rhythmic abilities through a vibrotactile tool for music perception. In Experiment 2, linguistic abilities were evaluated in 40 participants from the same cohort, specifically testing phonological and prosodic processing. Discrimination abilities for rhythmic and linguistic stimuli were inferred from changes in pupil diameter to contingent visual stimuli over time, through a Tobii X-60 eye-tracker. The predictive effect of VTS rhythmic abilities on linguistic processing and the developmental changes occurring across ages were explored in the 32 infants who completed both Experiments 1 and 2 by means of generalized, additive and linear, mixed-effect models. Results are discussed in terms of cross-sensory (i.e., haptic to hearing) and cross-domain (i.e., music to language) effects of rhythm on language acquisition, with implications for typical and atypical development., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: This study explored the trajectories of patient-centered orientation in a sample of Italian medical students throughout medical school., Methods: Four consecutive student cohorts were longitudinally assessed at the second (T0) and fifth year (T1) of medical school. Students completed a questionnaire including demographics and the Italian validated version of the Patient-Practitioner Orientation Scale., Results: 352 students completed both administrations. Students became more patient-centered in terms of Sharing along the course of their clinical curriculum, whereas there were no significant changes in Caring. Groups with distinct developmental trajectory patterns of both Caring and Sharing were identified. Students high in patient-centeredness at T0 reported significantly lower scores at T1 while students with lower scores at T0 significantly increased from the first to the last measurement. Female students significantly outscored their male colleagues on Caring and Sharing in both administrations., Conclusions: Findings call for innovative education strategies to sustain patient-centeredness attitudes in medical students entering hospital-based clinical medicine. Further research is needed to identify characteristics of the medical curriculum that are primarily involved in fostering students' patient-centeredness., Practice Implications: Including the assessment and monitoring of patient-centeredness throughout the medical school can inform tailored education aiming to foster this dimension., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy., Patients and Methods: Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m 2 intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population., Results: The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab., Conclusions: The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way., Competing Interests: Role of the funder The sponsor of the study is Fondazione Michelangelo, a non-profit organization, who collaborated in the study design. Fondazione Michelangelo had no primary roles in the collection, analysis or interpretation of the data. Hoffman-La Roche, Ltd, and Celgene, had no role in the study design, or in the interpretation of the data or in writing the report. Disclosure LG has received consulting fees from Novartis and Odonate Therapeutics; honoraria for lecture from Roche; support for attending meetings from Pfizer; is co-inventor of ‘European patent Application N. 12195182.6 and 12196177.5 titled PDL-1 expression in anti-HER2 therapy’—Roche—Issued (no compensation provided); has served on Advisory Boards for Astra Zeneca, Celgene, Genentech, Merk Sharp & Dohme, Roche, Pfizer and Sanofi Aventis; and is Chair of the Breast Cancer Research Committee of Fondazione Michelangelo. CSH has received research grants for his institution from Daiichi Sankyo, Astra Zeneca, EirGenix, Eli Lilly, MSD, OBI Pharma, Pfizer, Roche and Novartis; honoraria for speakers’ bureaus from Amgen, Astra Zeneca, Pfizer, Roche and Novartis; support for attending meetings from Astra Zeneca, Pfizer and Roche; and has served on Advisory Boards for Amgen, Astra Zeneca, Eli Lilly, Pfizer, Roche and Novartis. DE has received consulting fees from Astra Zeneca, Daichii Sankyo, Gilead, Novartis, MSD, Roche, Pfizer and Seagen; honoraria for lectures from Amgen, AstraZeneca, Daichii Sankyo, Novartis, MSD, Roche and Pfizer; and support for attending meetings from Pfizer and Roche. BB has received honoraria for speaker bureaus from MDS, Roche, Novartis, Pfizer, Palex, Astra Zeneca and Lilly; and has served on Advisory Boards for MSD, Roche and Daichii Sankyo. CZ has received grants from Eisai, Pharmamar, Eli Lilly, Celgene, MSD, GSK, Amgen and Daichii Sankyo and for him and his institution from Roche, Novartis, Astra Zeneca, Pfizer, Tesaro, Pierre Fabre, Ist. Gentili, Teva and Seagen; support for attending meetings from Roche, Novartis, Pfizer, Pharmamar, Tesaro, Pierre Fabre, Ist. Gentili and Celgene; has served on Advisory Boards for Roche, Eisai, Novartis, Astrazeneca, Pfizer, Pharmamar, Amgen, Tesaro, QuintilesIMS, Eli Lilly, Celgene, MSD, GSK and Daichii Sankyo; and has received other financial and non-financial interests from Roche, Novartis, Astra Zeneca, Pfizer, Amgen, Tesaro, QuintilesIMS, MSD, GSK and Daichii Sankyo. MT has received research grants from Roche and Exact Sciences; consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche and Seagen; honoraria for speakers’ bureaus from Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, Seagen and VIfor; support for attending meetings from Amgen, AstraZeneca, Connect Medica, Daiichi Sankyo, Eisai, Exact Sciences, Hexal, I-Med-Institute, Lilly, MSD, Novartis, Pfizer, pfm Medical and Roche; has served on Advisory Board for Roche; is Chair of Board of Directors AWOgyn; and has received other services from Celgene. AA has received consulting fees from Daichii Sankyo, Roche, Pfizer and Bayer Spain; payment for expert testimony from Pfizer; has served on Advisory Boards for Lilly and Gilead; and has received other services from GSK. GB has received consulting fee from Roche, AstraZeneca, Novartis, MSD, Sanofi, Daiichi Sankyo and Exact Science; honoraria for speakers’ bureaus from Roche, Pfizer, AstraZeneca, Lilly, Novartis, Neopharm Israel, MSD, Chugai, Daiichi Sankyo, EISAI and Exact Science; support for attending meetings from Roche, Pfizer and AstraZeneca; and has served on Advisory Board for Roche, Pfizer, Daiichi Sankyo, Lilly, MSD, Novartis, AstraZeneca, Genomic Health, EISAI, Gilead and Seagen. EMC has received consulting fee from Roche, Lilly, Astra Zeneca, Daiichi Sankyo, Novartis, Pfizer and MSD; honoraria for speakers’ bureaus from Lilly and Roche; and support for attending meetings from Pfizer and Roche. RG has received consulting fees from Celgene, Novartis, Roche, BMS, Takeda, Abbvie, Astra Zeneca, Jaanssen, MSD, Merk, Gilead, Daiichi Sankyo and Sanofi; support for attending meetings from Roche, Amgen, Janssen, Astra Zeneca, Novartis, MSD, Celgene, Gilead, BMS, Abbvie and Daiichi Sankyo; has served on Advisory Boards for Celgene, Novartis, Roche, BMS, Takeda, Abbvie, Astra Zeneca, Jaanssen, MSD, Merk, Gilead, Daiichi Sankyo and Sanofi; and has received other financial or non-financial interests from Celgene, Roche, Merk, Takeda, Astra Zeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead and Daiichi Sankyo. MC has received research grant from Roche. CK has received grants from Mater Foundation and HRB Grant/Hospital Co investment and from Irish Cancer Society; honoraria for educational events from Exact Sciences, Astra Zeneca and Daiichi Sanyko; support for attending meetings from Roche; and has participated in Steering Committees for PALLAS trial, PenelopeB trial and Destiny Breast 11. LDM has received honoraria for speakers’ bureaus from Roche, Novartis, Eli Lilly, MDS, Pfizer, Ipsen and from Novartis for her institution; support for attending meetings from Roche, Pfizer and Celgene; and has served on Advisory Boards for Roche, Eli Lilly, Novartis, MSD, Genomic Health, Pierre Fabre, Daiichi Sanyko and Seagen. GV has received grants from Roche/Genentech and Astra Zeneca for his institution; consulting fees from Roche/Genentech, Astra Zeneca, MDS Oncology and Daiichi Sanyko; honoraria for lectures from Roche/Genentech, Astra Zeneca and Daiichi Sanyko; support for attending meetings from Roche/Genentech; and has served on Advisory Boards for Roche/Genentech, Astra Zeneca, Pfizer, MDS Oncology and Novartis. All other authors have declared no conflicts of interest. Data sharing Qualified researchers can address requests to the datasets generated during and/or analysed during the current study to the corresponding author or to segreteria@fondazionemichelangelo.org and the request will be examined by the members of the Protocol Steering Committee., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: Cortico-cortical evoked potentials (CCEPs) recorded by stereo-electroencephalography (SEEG) are a valuable tool to investigate brain reactivity and effective connectivity. However, invasive recordings are spatially sparse since they depend on clinical needs. This sparsity hampers systematic comparisons across-subjects, the detection of the whole-brain effects of intracortical stimulation, as well as their relationships to the EEG responses evoked by non-invasive stimuli., Objective: To demonstrate that CCEPs recorded by high-density electroencephalography (hd-EEG) provide additional information with respect SEEG alone and to provide an open, curated dataset to allow for further exploration of their potential., Methods: The dataset encompasses SEEG and hd-EEG recordings simultaneously acquired during Single Pulse Electrical Stimulation (SPES) in drug-resistant epileptic patients (N = 36) in whom stimulations were delivered with different physical, geometrical, and topological parameters. Differences in CCEPs were assessed by amplitude, latency, and spectral measures., Results: While invasively and non-invasively recorded CCEPs were generally correlated, differences in pulse duration, angle and stimulated cortical area were better captured by hd-EEG. Further, intracranial stimulation evoked site-specific hd-EEG responses that reproduced the spectral features of EEG responses to transcranial magnetic stimulation (TMS). Notably, SPES, albeit unperceived by subjects, elicited scalp responses that were up to one order of magnitude larger than the responses typically evoked by sensory stimulation in awake humans., Conclusions: CCEPs can be simultaneously recorded with SEEG and hd-EEG and the latter provides a reliable descriptor of the effects of SPES as well as a common reference to compare the whole-brain effects of intracortical stimulation to those of non-invasive transcranial or sensory stimulations in humans., Competing Interests: Declarations of competing interest None of the authors have conflicts of interest to disclose in relationship with the current work., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Context: A novel remote volunteer program was implemented in response to the initial COVID-19 surge in New York City, allowing out-of-state palliative care specialists to serve patients and families in need. No study has detailed the perceptions of these consultants., Objectives: To understand the experiences of remote volunteer palliative care consultants during the initial COVID-19 surge., Methods: This qualitative study utilized a thematic analysis approach. During January and February 2021, we conducted one-on-one semi-structured interviews with 15 board-certified palliative care physicians who participated in the program. Codes and emerging themes were identified through iterative discussion and comparison., Results: Five overarching themes (with sub-themes in parentheses) were identified: 1) motivations for participating in the program, 2) logistical evaluation of the program (integration, telehealth model, dyad structure and debriefing sessions), 3) barriers to delivery (language and cultural differences, culture of high-intensity care, legal and administrative differences), 4) emotional burden (moral distress, burnout), and 5) ideas for improvements. Notably, participants observed institutional and cultural differences that posed challenges to delivery of care. Many expressed feelings of distress related to the uncertainty and scarcity caused by the pandemic, although volunteering may have been protective against burnout., Conclusion: This study provides an in-depth look at the experiences of remote volunteer palliative care consultants during the initial COVID-19 surge from the unique perspectives of the consultants themselves. Participants expressed overall positive and meaningful experiences and felt that the model was appropriate given the circumstances. Additionally, participants provided recommendations that could guide future implementations of similar programs., (Copyright © 2021 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: We examined the feasibility of using cortico-cortical evoked potentials (CCEPs) to monitor the major cortical white matter tract involved in language, the arcuate fasciculus (AF), during surgery under general anaesthesia., Methods: We prospectively recruited nine patients undergoing surgery for lesions in the left peri-sylvian cortex, for whom awake surgery was not indicated. High angular resolution diffusion imaging (HARDI) tractography was used to localise frontal and temporal AF terminations, which guided intraoperative cortical strip placement., Results: CCEPs were successfully evoked in 5/9 patients, showing a positive potential (P1) at 12 ms and a negative component (N1) at 21 ms when stimulating from the frontal lobe and recording in the temporal lobe. CCEP responses peaked in the posterior middle temporal gyrus. No CCEPs were evoked when stimulating temporal sites and recording from frontal contacts., Conclusion: For the first time, we show that CCEPs can be evoked from the peri-sylvian cortices also in adult patients who are not candidates for awake procedures. Our results are akin to those described in the awake setting and suggest the recorded activity is conveyed by the arcuate fasciculus., Significance: This intraoperative approach may have promising implications in reducing deficits in patients that require surgery in language areas under general anesthesia., 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 © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Cyclothone braueri (Stomiiformes, Gonostomatidae) is a widely distributed fish inhabiting the mesopelagic zone of marine tropical and temperate waters. Constituting one of the largest biomasses of the ocean, C. braueri is a key element in most of the ecological processes occurring in the twilight layer. We focused on the ecological processes linked to early life stages in relation to marine pelagic environmental drivers (temperature, salinity, food availability and geostrophic currents) considering different regions of the Central Mediterranean Sea. A multivariate morphometric analysis was carried out using six parameters with the aim of discerning different larval morphotypes, while a fragment of 367 bp representing the 12S ribosomal RNA gene was used to perform molecular analyses aimed at determining the intraspecific genetic variability. Analysis highlighted two geographically distinct morphotypes not genetically discernible and related to the different nutritional conditions due to spatial heterogeneities in terms of temperature and food availability. The body depth (BD) emerged as an appropriate morphometric parameter to detect the larval condition in this species. Molecular analysis highlighted a moderate genetic divergence in the fish population, showing the recurrence of two phylogroups not geographically separated., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: We evaluated the efficacy and safety of the nontaxane microtubule dynamics inhibitor eribulin plus the humanized anti-VEGF monoclonal antibody bevacizumab in a novel second-line chemotherapy scheme in HER2-negative metastatic breast cancer (MBC) patients progressing after first-line paclitaxel and bevacizumab., Patients and Methods: This is a multicenter, single-arm, Simon's two-stage, phase II study. The primary endpoint was the overall response rate, considered as the sum of partial and complete response based on the best overall response rate (BORR). The secondary endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate., Results: A total of 58 of the 61 patients enrolled in the study were evaluable for efficacy. The BORR was 24.6% (95% CI 14.5-37.3). The clinical benefit rate was 32.8% (95% CI 21.3-46.0). The median PFS was 6.2 months (95% CI 4.0-7.8), and median OS was 14.8 months (95% CI 12.6-22.8). Overall, adverse events (AEs) were clinically manageable and the most common AEs were fatigue, paresthesia, and neutropenia. Quality of life was well preserved in most patients., Conclusions: The results of this study suggest that second-line therapy with bevacizumab in combination with eribulin has a meaningful clinical activity and may represent a potential therapeutic option for patients with HER2-negative MBC., Competing Interests: Disclosure CDA is a consultant/advisory board member for Novartis, Eli Lilly, and Pfizer. FP has received travel, accommodations, expenses supported by Takeda, Ely Lilly, and received honoraria from Merck Sharp & Dohme, Ely Lilly, and Novartis outside the submitted work. AM is a consultant/advisory board member for EISAI, Novartis, Astra Zeneca, Teva, Pfizer, Celgene; has received travel accommodations supported by Eisai, Celgene, Novartis, and Ipsen. LDM is a consultant/advisory board member for Roche, Novartis, Celgene, Pfizer, MSD, Genomic Health, Ipsen, Takeda, Eli Lilly, Seattle Genetics, Pierre Fabre, and Eisai. MG, GA, and SDP have declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen, and Eisai. MDL has declared consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai, and Celgene. The remaining authors have declared no conflicts of interest. Data sharing The data sets obtained and/or analyzed during this study are available from the corresponding author on reasonable request., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting., Patients and Methods: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant., Results: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095)., Conclusions: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials., Competing Interests: Disclosure MG, GA and SDP have declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen and Eisai outside the submitted work. ML acted as consultant for Roche, AstraZenenca, Novartis, and received speaker honoraria from Roche, Takeda, Novartis, Lilly, Pfizer, Sandoz outside the submitted work. LDM has declared honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and Merck Sharp & Dohme (MSD), consulting/advisory role for Roche and Eli Lilly, travels, accommodations and expenses from Roche, Pfizer and Celgene outside the submitted work. MDL has declared consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai, Celgene. FP has declared honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche and Takeda, and research funding from AstraZeneca, Eisai, Roche and Italian Ministry of Health outside the submitted work. PFC reports grants from Merck KGaA, Roche and Bristol-Myers Squibb; grants and personal fees from Novartis and EliLilly; personal fees from AstraZeneca, outside the submitted work. VG reports personal fees from Novartis, Roche, EliLilly, MSD, outside the submitted work. DG has declared consulting fees from Novartis, Lilly and Pfizer, research funding from LILT, Novartis, AstraZeneca and University of Trieste outside the submitted work. GB received honoraria for speaker activities and travel grants from GlaxoSmithKline, Novartis, Pfizer, Roche, Genetic Spa, outside the submitted work. FM declared advisory role for Roche, Novartis, AstraZeneca, Pfizer, Eli Lilly, Pierre Fabre, Daiichi Sankyo, travel grants from Roche and financial support from the Fondazione Piemontese per la Ricerca sul Cancro (FPRC) Onlus 5 x mille funding from the Italian Ministry of Health 2017 outside the submitted work. AF has declared honoraria for advisory board from Roche and Novartis, activity as speaker for Pfizer and Lilly, travel grant from Roche, Novartis, Pfizer, Lilly and AstraZeneca outside the submitted work. The other authors have nothing to declare. Data sharing The anonymized database is available from the corresponding author upon reasonable request. The R codes used are available from the corresponding author upon reasonable request., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The aquifer north of Vicenza, Italy, is one of the main and most studied drinking water reservoirs within the Veneto region. The area is an intensive cropland, and monitoring of s-triazine herbicides and metabolites has been carried out since the late eighties. This study analysed the trends of atrazine (ATR), terbuthylazine (TBZ), deethyl-atrazine (DEA), and deethyl-terbuthylazine (DET) concentrations from 1987 to 2016 and related the variations of agricultural land use, herbicide load, and pesticide regulations to the residence time of pollutants in the aquifer. In total, 785 water samples collected from 82 selected check wells were analysed with high-resolution gas chromatography combined with mass spectrometry. Non-detects were substituted by one-half the limit of detection. Over the 30 years of monitoring, concentrations of all of the pollutants decreased at all sampling sites. Since the beginning, TBZ and DET residues have been systematically lower than ATR and DEA, respectively, with more than 70% of the data below the limit of detection and never exceeding the European Maximum Acceptable Concentration (MAC) for a single pesticide (0.1 μg/L). The highest concentrations of ATR and DEA showed a spatial shift along the flow direction, suggesting an increase in groundwater residence time from the recharge zone to the accumulation zone of the aquifer. The last residues of ATR were found 27 years after its ban. Although all of the concentrations were lower than those found elsewhere in Europe, the sum of s-triazines overcame the MAC in 20% of the samples. Considering the structural and toxicological similarities of s-triazines, these findings confirm the necessity of better characterisation of the toxicological risk posed by mixtures., 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 Elsevier B.V. All rights reserved.)

Microplastics (MPs) are small (<5 mm) plastic particles which pose a threat to marine ecosystems. Identifying MPs is crucial for understanding their fate and effects. Many MP extraction methods exist, but procedural differences prevent meaningful comparisons across datasets. This method comparison examines the efficiency of five methods for extracting MPs (40-710 μm) from marine sediments. Known quantities of MPs were spiked into sediments. The MPs were extracted and enumerated to demonstrate percent recovery. Findings determined that sediment matrix, MP properties, and extraction method affect the percent recovery of MPs from sediments. Average recoveries of spiked microplastics were between 0 and 87.4% and varied greatly by sediment type, microplastic, and method of extraction. In general, larger particle and lower density MPs were more effectively recovered. Marine sediments low in organic matter and with larger grain size also had higher percent recoveries of MPs. These findings support the need for method optimization and unified procedures., (Published by Elsevier Ltd.)

The uterine electromyogram, also named Electrohysterogram (EHG), is a non-invasive technique that has been used for pregnancy and labour monitoring as well as for research work on uterine physiology. This technique is well established in this field. There is however a vast unexplored potential in the EHG that is currently the subject of interdisciplinary research work involving different scientific fields such as medicine, engineering, physics and mathematics. In this paper, an unsupervised clustering method is applied to a previously obtained set of frequency spectral representations of the respective EHG signal contractions that were previously automatically detected and delineated. An innovative approach using the complete spectrum projection is described, rather than a set of relevant points. The feasibility of the method is established despite the concerns of possible computational burden incurred by the processing of the whole spectrum. Given the unsupervised nature of this classification, a validation procedure was performed whereas the obtained clusters were labelled through the correlation with the common knowledge about the most relevant uterine contraction types, as described in the literature. As a result of this study, a spectral description of the Alvarez contractions was obtained where it was possible to breakdown these important events in two different types according to their spectrum. Spectral estimates of Braxton-Hicks contractions were also obtained and associated to one of the clusters. This led to a full spectral characterization of these uterine events., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cornelia de Lange syndrome is a rare autosomal dominant or X-linked developmental disorder characterized by characteristic facial dysmorphism, intellectual disability, growth retardation, upper limb and multiorgan anomalies. Causative mutations have been identified in five genes coding for the cohesion complex structure components or regulatory elements. Among them, RAD21 is associated with a milder phenotype. Very few RAD21 intragenic mutations have been identified so far. Thus, any new patient is a valuable tool to delineate the associated phenotype. We discuss a new patient with RAD21 confirmed molecular diagnosis and compare his clinical features to those of previously described patients carrying different RAD21 intragenic mutations., (Copyright © 2019. Published by Elsevier Masson SAS.)

Background: Ankylosing spondylitis (AS) is a systemic enthesopathy. In its presence, spinal fractures are often unstable. Acknowledging the preinjury level of kyphosis is key in the management of cervical fractures, and placement into a hard collar has been shown to result in life-threatening spinal cord complications., Case Description: This report presents the unique case of a patient with AS who developed a unilateral C5 palsy after the application of a hard collar for a C5/6 fracture, to our knowledge the first such case presented to date. The patient subsequently went on to an anterior fixation and partially recovered from the C5 palsy/injury. After the case report is an examination of the currently available literature and evidence exploring the factors that may contribute to C5 palsy after the application of a collar for acute fracture in AS., Conclusions: We described the first case in the literature of a posttraumatic C5 palsy after application of a hard collar in AS. This report and literature review should act to underscore the importance of respecting a preexisting rigid kyphotic deformity in cervical fractures but also to stimulate further thoughts and investigations into what may contribute to a posttraumatic C5 palsy., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder characterized by growth retardation, skeletal anomalies and intellectual disability, caused by heterozygous mutations in either CREBBP (RSTS1) or EP300 (RSTS2) genes. We characterized 3 iPSC lines generated by Sendai from blood of RSTS1 patients with unique non sense c.4435G > T, p.(Gly1479*), c.3474G > A, p.(Trp1158*) and missense c.4627G > T, p.(Asp1543Tyr) CREBBP mutations. All lines displayed iPSC morphology, pluripotency markers, trilineage differentiation potential, stable karyotype and specific mutations. Western-blot using a CREB-Binding Protein N-terminus antibody demonstrated the same amount of full length protein as control in the missense mutation line and reduced amount in lines with stop mutations., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Research has been mainly focused on how to elicit patient preferences, with less attention on why patients form certain preferences., Objectives: To assess which psychological instruments are currently used and which psychological constructs are known to have an impact on patients' preferences and health-related decisions including the formation of preferences and preference heterogeneity., Methods: A systematic database search was undertaken to identify relevant studies. From the selected studies, the following information was extracted: study objectives, study population, design, psychological dimensions investigated, and instruments used to measure psychological variables., Results: Thirty-three studies were identified that described the association between a psychological construct, measured using a validated instrument, and patients' preferences or health-related decisions. We identified 33 psychological instruments and 18 constructs, and categorized the instruments into 5 groups, namely, motivational factors, cognitive factors, individual differences, emotion and mood, and health beliefs., Conclusions: This review provides an overview of the psychological factors and related instruments in the context of patients' preferences and decisions in healthcare settings. Our results indicate that measures of health literacy, numeracy, and locus of control have an impact on health-related preferences and decisions. Within the category of constructs that could explain preference and decision heterogeneity, health locus of control is a strong predictor of decisions in several healthcare contexts and is useful to consider when designing a patient preference study. Future research should continue to explore the association of psychological constructs with preference formation and heterogeneity to build on these initial recommendations., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival., Patients and Methods: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility., Results: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively., Conclusion: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Eph/ephrin interactions and their bidirectional signaling are integral part of the complex communication system between β-cells, essential for glucose homeostasis. Indeed, Eph/ephrin system was shown to be directly involved in the glucose-stimulated insulin secretion (GSIS) process occurring in the pancreatic islets. Here we tested the Eph antagonist UniPR500 as GSIS enhancer. UniPR500 was validated as EphA5-ephrin-A5 inhibitor in vitro and its efficacy as GSIS enhancer was assessed on EndoC-βH1 cells. The selectivity of UniPR500 was evaluated by testing this compound on a panel of well-known molecular targets responsible for the regulation of glucose homeostasis. Plasmatic levels of UniPR500 were measured by HPLC/MS approach after oral administration. Finally, UniPR500 was tested as hypoglycemic agent in healthy mice, in a non-genetic mouse model of insulin resistance (IR) and in a non-genetic mouse model of type 1 diabetes (T1D). The compound is an orally bioavailable and selective Eph antagonist, able to increase GSIS from EndoC-βH1 cells. When tested in vivo UniPR500 showed to improve glucose tolerance in healthy and IR mice. As expected by a GSIS enhancer acting on healthy β-cells, UniPR500 was ineffective when tested on a non-genetic mouse model of type 1 diabetes, where pancreatic function was severely compromised. In conclusion our findings suggest that Eph targeting is a new and valuable pharmacological strategy in the search of new hypoglycemic agents., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Neutrophil gelatinase-associated lipocalin (NGAL a.k.a lipocalin 2, lnc2) is a secreted protein which can form a complex with matrix metalloproteinase-9 (MMP9). This MMP9/NGAL complex has been associated with metastasis. MMP9 and NGAL are detected in the urine of patients afflicted with many different types of cancer, including prostate cancer. The effects of p53, NF-κB and the androgen receptor (AR) on the expression of NGAL was examined in four prostate cancer cell lines. Prostate cancer cell lines that are AR negative and expressed either mutant or no p53 (DU145 and PC3) displayed higher levels of NGAL expression compared to the prostate cancer cell lines (LNCaP and 22Rv-1) which are AR positive and express wild type (WT) p53. Introduction of WT-p53 into the PC3 prostate cancer cell line, resulted in reduction of the levels of NGAL expression. Conversely, introduction of dominant negative (DN) p53 or a retroviral construct expressing NF-κB into LNCaP cells increased NGAL expression. NGAL expression had functional effects on the ability of the cells to form colonies in soft agar. Whereas suppression of WT-53 in LNCaP cells increased NGAL expression, the introduction of WT-p53 suppressed NGAL transcription activity in PC3 prostate cells which normally express high level of NGAL. NF-κB and p53 were determined to regulate NGAL expression by positive and negative mechanisms, respectively. Our data indicate that prostate cancer growth, progression and sensitivity to chemotherapeutic drugs are regulated in part by NGAL and may involve complex interactions between NGAL, MMP9, NF-κB and p53., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Rubinstein-Taybi syndrome (RSTS) is a neurodevelopmental disorder characterized by growth retardation, skeletal anomalies and intellectual disability, caused by heterozygous mutation in either the CREBBP (RSTS1) or EP300 (RSTS2) genes. We generated an induced pluripotent stem cell line from an RSTS2 patient's blood mononuclear cells by Sendai virus non integrative reprogramming method. The iPSC line (IAIi001RSTS2-65-A) displayed iPSC morphology, expressed pluripotency markers, possessed trilineage differentiation potential and was stable by karyotyping. Mutation and western blot analyses demonstrated in IAIi001RSTS2-65-A the patient's specific non sense mutation in exon 23 c.3829A > T, p.(Lys 1277*) and showed reduced quantity of wild type p300 protein., (Copyright © 2018 ISTITUTO AUXOLOGICO ITALIANO, IRCCS, Milano. Published by Elsevier B.V. All rights reserved.)

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder characterized by distinctive facial features, growth retardation, broad thumbs and toes and mild to severe intellectual disability, caused by heterozygous mutations in either CREBBP or EP300 genes, encoding the homologous CBP and p300 lysine-acetyltransferases and transcriptional coactivators. No RSTS in vitro induced Pluripotent Stem Cell (iPSC)-neuronal model is available yet to achieve mechanistic insights on cognitive impairment of RSTS patients. We established iPSC-derived neurons (i-neurons) from peripheral blood cells of three CREBBP- and two EP300-mutated patients displaying different levels of intellectual disability, and four unaffected controls. Pan neuronal and cortical-specific markers were expressed by all patients' i-neurons. Altered morphology of patients' differentiating neurons, showing reduced branch length and increased branch number, and hypoexcitability of differentiated neurons emerged as potential disease biomarkers. Anomalous neuronal morphology and reduced excitability varied across different RSTS patients' i-neurons. Further studies are needed to validate these markers and assess whether they reflect cognitive and behavioural impairment of the donor patients., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The factors influencing new markers of gastro-esophageal reflux disease detected by impedance-pH monitoring - mean nocturnal baseline impedance (MNBI) and post-reflux swallow-induced peristaltic wave (PSPW) index - need to be evaluated., Aim: To compare endoscopy-negative heartburn with chronic autoimmune atrophic gastritis (CAAG)., Materials and Methods: 24 patients with CAAG, 25 with non-erosive reflux disease (NERD) and 25 with functional heartburn (FH) were included. In all patients the main impedance-pH monitoring parameters were calculated., Results: CAAG and NERD patients had a number of reflux events (non-acid ones being more common among the former group) which was higher than that found in FH (p<0.001). MNBI decreased progressively in FH (>3000Ohm), CAAG (>2000Ohm) and NERD (<1000Ohm) patients (p=0.0046). The PSPW index was similar between CAAG and NERD patients but significantly lower in comparison to FH (p<0.0001)., Conclusion: Patients with CAAG have evidence of non-acid reflux based on the high number of reflux events and confirmed by low values of MNBI and PSPW index. MNBI is a strong marker of acid/non-acid reflux-induced mucosal damage, whereas the PSPW index can reliably discriminate patients with reflux from those with FH, independently of the acidity of refluxate., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Heat waves represent one of the most significant climatic stressors for ecosystems, economies and societies. A main topic of debate is whether they have increased or not in intensity and/or their duration due to the observed climate change. Firstly, this is because of the lack of reliable long-term daily temperature data at the global scale; secondly, because of the intermittent nature of such phenomena. Long datasets are required to produce a reliable and meaningful assessment. In this study, we provide a global estimate of heat wave magnitudes based on the three most appropriate datasets currently available, derived from models and observations (i.e. the 20th Century Reanalyses from NOAA and ECMWF), spanning the last century and before. The magnitude of the heat waves is calculated by means of the Heat Wave Magnitude Index daily (HWMId), taking into account both duration and amplitude. We compare the magnitude of the most severe heat waves occurred across different regions of the world and we discuss the decadal variability of the larger events since the 1850s. We concentrate our analysis from 1901 onwards, where all datasets overlap. Our results agree with other studies focusing on heat waves that have occurred in the recent decades, but using different data. In addition, we found that the percentage of global area covered by heat wave exceeding a given magnitude has increased almost three times, in the last decades, with respect to that measured in the early 20th century. Finally, we discuss the specific implications of the heat waves on the river runoff generated in the Alps, for which comparatively long datasets exist, affecting the water quality and availability in a significant portion of the European region in summer., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Beckwith-Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth-cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association (www.aibws.org) proposed these recommendations for the diagnosis, molecular testing, clinical management, follow-up and tumor surveillance of patients with BWS. The recommendations are intended to allow a timely and appropriate diagnosis of the disorder, to assist patients and their families, to provide clinicians and caregivers optimal strategies for an adequate and satisfactory care, aiming also at standardizing clinical practice as a national uniform approach. They also highlight the direction of future research studies in this setting. With recent advances in understanding the disease (epi)genetic mechanisms and in describing large cohorts of BWS patients, the natural history of the disease will be dissected. In the era of personalized medicine, the emergence of specific (epi)genotype-phenotype correlations in BWS will likely lead to differentiated follow-up approaches for the molecular subgroups, to the development of novel tools to evaluate the likelihood of cancer development and to the refinement and optimization of current tumor screening strategies., Conclusions: In this article, we provide the first comprehensive recommendations on the complex management of patients with Beckwith-Wiedemann syndrome., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: Oesophageal clearance has been scarcely studied., Aims: Oesophageal clearance in endoscopy-negative heartburn was assessed to detect differences in bolus clearance time among patients sub-grouped according to impedance-pH findings., Methods: In 118 consecutive endoscopy-negative heartburn patients impedance-pH monitoring was performed off-therapy. Acid exposure time, number of refluxes, baseline impedance, post-reflux swallow-induced peristaltic wave index and both automated and manual bolus clearance time were calculated. Patients were sub-grouped into pH/impedance positive (abnormal acid exposure and/or number of refluxes) and pH/impedance negative (normal acid exposure and number of refluxes), the former further subdivided on the basis of abnormal/normal acid exposure time (pH+/-) and abnormal/normal number of refluxes (impedance+/-)., Results: Poor correlation (r=0.35) between automated and manual bolus clearance time was found. Manual bolus clearance time progressively decreased from pH+/impedance+ (42.6s), pH+/impedance- (27.1s), pH-/impedance+ (17.8s) to pH-/impedance- (10.8s). There was an inverse correlation between manual bolus clearance time and both baseline impedance and post-reflux swallow-induced peristaltic wave index, and a direct correlation between manual bolus clearance and acid exposure time. A manual bolus clearance time value of 14.8s had an accuracy of 93% to differentiate pH/impedance positive from pH/impedance negative patients., Conclusions: When manually measured, bolus clearance time reflects reflux severity, confirming the pathophysiological relevance of oesophageal clearance in reflux disease., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: The purpose of the study was to evaluate the feasibility of irradiation after prostatectomy in the presence of asymptomatic pelvic lymphocele., Patients and Methods: The inclusion criteria for this study were: (1) patients referred for postoperative (adjuvant or salvage) intensity modulated radiotherapy (IMRT; 66-69 Gy in 30 fractions); (2) detection of postoperative pelvic lymphocele at the simulation computed tomography [CT] scan; (3) no clinical symptoms; and (4) written informed consent. Radiotherapy toxicity and occurrence of symptoms or complications of lymphocele were analyzed. Dosimetric data (IMRT plans) and the modification of lymphocele volume during radiotherapy (cone beam CT [CBCT] scan) were evaluated., Results: Between January 2011 and July 2013, in 30 of 308 patients (10%) treated with radiotherapy after prostatectomy, pelvic lymphocele was detected on the simulation CT. The median lymphocele volume was 47 cm(3) (range, 6-467.3 cm(3)). Lymphocele was not included in planning target volume (PTV) in 8 cases (27%). Maximum dose to lymphocele was 57 Gy (range, 5.7-73.3 Gy). Radiotherapy was well tolerated. In all but 2 patients, lymphoceles remained asymptomatic. Lymphocele drainage-because of symptom occurrence-had to be performed in 2 patients during IMRT and in one patient, 7 weeks after IMRT. CBCT at the end of IMRT showed reduction in lymphocele volume and position compared with the initial data (median reduction of 37%), more pronounced in lymphoceles included in PTV., Conclusion: Radiotherapy after prostatectomy in the presence of pelvic asymptomatic lymphocele is feasible with acceptable acute and late toxicity. The volume of lymphoceles decreased during radiotherapy and this phenomenon might require intermediate radiotherapy plan evaluation., (Copyright © 2015 Elsevier Inc. All rights reserved.)