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Background The aim of the present study was to evaluate early results of thoracic endovascular aortic repair (TEVAR) using the Valiant Navion™ stent graft in a “real-world” scenario. Methods All patients who underwent TEVAR with the Valiant Navion™ endograft between November 2018 and November 2019 were included in this retrospective multicenter study (six European centers). The primary endpoints were technical success, incidence of major adverse events (MAEs), access failure, deployment failure, deployment accuracy, and rate of intraoperative endoleaks (ELs). Results One hundred-sixteen patients with varying thoracic aortic diseases were included. Eighteen patients (15.5%) were treated for an off-label condition. The technical success rate was 100%, without any access or deployment failures. The proximal and distal deployment accuracy rates were 99.1% and 97.4%, respectively. There were no intraoperative MAEs, including death. Two (1.7%) type Ib ELs were detected at the first postoperative CTA, all of which were in off-label procedures and related to the short length of the sealing neck. No type III ELs were detected. The median hospitalization time was 8 days (IQR 4–12), including a median intensive care unit stay of 1 day (IQR 1–2). The in-hospital mortality rate was 4.3%. At a median follow-up time of 98 days (IQR 39–187), there were no aortic-related mortalities or new onset of endoleaks. Conclusion Our initial experience with the Valiant Navion™ endograft in a wide variety of aortic diseases showed safe early outcomes, especially for on-label procedures.

Background and Purpose: The spectrum of brain infarction in patients with embolic stroke of undetermined source (ESUS) has not been well characterized. Our objective was to define the frequency and pattern of brain infarcts detected by magnetic resonance imaging (MRI) among patients with recent ESUS participating in a clinical trial. Methods: In the NAVIGATE ESUS trial (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial Versus ASA to Prevent Embolism in Embolic Stroke of Undetermined Source), an MRI substudy was carried out at 87 sites in 15 countries. Participants underwent an MRI using a specified protocol near randomization. Images were interpreted centrally by those unaware of clinical characteristics. Results: Among the 918 substudy cohort participants, the mean age was 67 years and 60% were men with a median (interquartile range) of 64 (26–115) days between the qualifying ischemic stroke and MRI. On MRI, 855 (93%) had recent or chronic brain infarcts that were multiple in 646 (70%) and involved multiple arterial territories in 62% (401/646). Multiple brain infarcts were present in 68% (510/755) of those without a history of stroke or transient ischemic attack before the qualifying ESUS. Prior stroke/transient ischemic attack ( P 0 ( P P =0.01) were associated with multiple infarcts. Topographically, large and/or cortical infarcts were present in 89% (757/855) of patients with infarcts, while in 11% (98/855) infarcts were exclusively small and subcortical. Among those with multiple large and/or cortical infarcts, 57% (251/437) had one or more involving a different vascular territory from the qualifying ESUS. Conclusions: Most patients with ESUS, including those without prior clinical stroke or transient ischemic attack, had multiple large and/or cortical brain infarcts detected by MRI, reflecting a substantial burden of clinical stroke and covert brain infarction. Infarcts most frequently involved multiple vascular territories. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02313909.

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p = 0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11–1.98, p = 0.007). Nominal associations were also found between MDD-PRS and non-response (p = 0.013), as well as between SCZ-PRS and non-remission (p = 0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/., Smoking is the most well-established cause of chronic airflow obstruction (CAO) but particulate air pollution and poverty have also been implicated. We regressed sex-specific prevalence of CAO from 41 Burden of Obstructive Lung Disease study sites against smoking prevalence from the same study, the gross national income per capita and the local annual mean level of ambient particulate matter (PM2.5) using negative binomial regression. The prevalence of CAO was not independently associated with PM2.5 but was strongly associated with smoking and was also associated with poverty. Strengthening tobacco control and improved understanding of the link between CAO and poverty should be prioritised., Supported by Wellcome Trust grant 085790/Z/08/Z for the BOLD (Burden of Obstructive Lung Disease) Study. The initial BOLD programprogramme was funded in part by unrestricted educational grants to the Operations CenterCentre in Portland, Oregon from Altana, Aventis, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Merck, Novartis, Pfizer, Schering-Plough, Sepracor, and the University of Kentucky (Lexington, KY). A full list of local funders can be found at https://www.boldstudy.org.

Purpose: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. Methods: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. Results: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from − 2.41 ± 0.73 at baseline (n = 238) to − 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from − 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). Conclusions: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Pneumatosis cystoides intestinalis (PCI) is a rare condition characterized by the presence of gas-filled cysts in the subserosa or submucosa of the bowel wall. It is associated with various disorders including chronic obstructive pulmonary diseases, autoimmune disorders, and organ transplantation. PCI has also been observed following Hematopoietic Stem Cell Transplantation (HSCT), associated with chemotherapy, acute Graft versus Host Disease (GvHD), immunosuppression, and infections. Computed tomography (CT) provides an easy diagnosis because it highlights the presence of air bubbles in the intestinal wall and possible pneumoperitoneum. We report the case of a patient with severe acquired medullary aplasia undergoing allogeneic HSCT with subsequent development of cutaneous GvHD and an incidental finding of PCI during a CT scan of the chest in absence of gastrointestinal symptoms. Our work aims at clarifying a possible complication in pediatric patients undergoing HSCT to guide young or non-pediatric radiologists in the identification of this rare condition, helping the clinician in the correct conservative management of these patients and reserving the surgical treatment only to specific complications.

Thymoma is a rare neoplasm of the anterior mediastinum, which originates from the epithelium of the thymic gland; it occurs mainly in middle-aged adults and is much less common in children. The tumor has slow growth and is asymptomatic in most pediatric cases, thus resulting in an accidental discovery; one-third of the young patient presents symptoms related to the compression of the tumor mass on the surrounding anatomic structures and/or related to paraneoplastic syndromes. Surgery is the treatment of choice and complete resection of the thymoma achieves excellent long-term results in terms of disease-free survival. In this article, we report the clinical case of a 21-month-old girl who came to our observation for persistent cough for over a month investigated with a chest X-ray, performed in another hospital. The X-ray showed an extensive opacification of the left hemithorax with contralateral dislocation of the mediastinum. The instrumental investigations carried out in our hospital (ultrasound, computed tomography, and magnetic resonance of the chest) showed a voluminous expansive mass of the left antero-superior mediastinum, which occupied the entire ipsilateral hemithorax and not dissociable from the thymus. At the histologic examination, the mass resulted to be a B1 thymoma with a low degree of malignancy according to the histologic classification of thymic tumors of the World Health Organization.

Made available in DSpace on 2021-06-25T10:45:54Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-01-01 Purpose: To present the long-term follow-up outcomes of patients with intestinal neuronal dysplasia type B (IND-B) managed either conservatively or surgically. Methods: We conducted an ambispective, observational, longitudinal, and comparative study. Clinical data were reviewed at the start of treatment. After a minimum period of five years, the patients participated in semi-structured interviews in which the bowel function score (BFS) was applied to assess intestinal function, a proposed intestinal symptom index (ISI) to assess clinical symptoms, and a classification of clinical prognosis to assess treatment success. Comparisons between the two types of treatment were performed by evaluating pre- and post-treatment criteria. Results: Fifty patients diagnosed with IND-B were included in the study. Thirty-eight patients underwent surgical treatment (26 elective surgical treatment for primary colorectal resection and 12 emergency colostomies for intestinal obstruction or enterocolitis). Twelve patients were managed conservatively. With the exception of the patients who required an emergency operation (n = 12), the two groups were composed of patients with severe constipation who had similar clinical and functional characteristics at the time of IND-B diagnosis. A better clinical response was observed in patients submitted to conservative treatment, with a greater increase in the BFS (16.5 [-4/+18] versus 4 [-15/+17]; p = 0.001), indicating better bowel function and a more pronounced drop in ISI (-6 [-7/-4] versus -4 [-6/+1]; p = 0.015), suggesting fewer symptoms. The percentage of patients who had a successful treatment was higher in the group treated conservatively (72.7% versus 42.3%; p = 0.03). Conclusion: Conservative management showed better long-term outcomes than surgical management in children with IND-B. Department of Surgery Division of Pediatric Surgery Botucatu Medical School UNESP - São Paulo State University Botucatu Medical School UNESP - São Paulo State University Department of Pathology Botucatu Medical School UNESP - São Paulo State University Department of Surgery Division of Pediatric Surgery Botucatu Medical School UNESP - São Paulo State University Botucatu Medical School UNESP - São Paulo State University Department of Pathology Botucatu Medical School UNESP - São Paulo State University

Objectives People with schizophrenia (SCZ) present serious and generalised deficits in social cognition (SC), which affect negatively patients' functioning and treatment outcomes. The genetic background of SC has been investigated in disorders other than SCZ providing weak and sparse results. Thus, our aim was to explore possible genetic correlates of SC dysfunctions in SCZ patients with a genome-wide study (GWAS) approach. Methods We performed a GWAS meta-analysis of data coming from two cohorts made of 242 and 160 SCZ patients, respectively. SC was assessed with different tools in order to cover its different domains. Results We found GWAS significant association between the TMEM74 gene and the patients' ability in social inference as assessed by The Awareness of Social Inference Test; this association was confirmed by both SNP-based analysis (lead SNP rs3019332 p-value = 5.24 × 10-9) and gene-based analysis (p-value = 1.09 × 10-7). Moreover, suggestive associations of other genes with different dimensions of SC were also found. Conclusions Our study shows for the first time GWAS significant or suggestive associations of some gene variants with SC domains in people with SCZ. These findings should stimulate further studies to characterise the genetic underpinning of SC dysfunctions in SCZ.

Rationale On October 15th, 2020, the first Surgical National Consensus Conference on neoadjuvant chemotherapy (NACT) was promoted by the Italian Association of Breast Surgeons (ANISC). Method The Consensus Conference was entirely held online due to anti-Covid-19 restrictions and after an introductory four lectures held by national and international experts in the field, a total of nine questions were presented and a digital “real-time” voting system was obtained. A consensus was reached if 75% or more of all panelists agreed on a given question. Results A total of 202 physicians, from 76 different Italian Breast Centers homogeneously distributed throughout the Italian country, participated to the Conference. Most participants were surgeons (75%). Consensus was reached for seven out of the nine considered topics, including management of margins and lymph nodes at surgery, and there was good correspondence between the 32 “Expert Panelists” and the “Participants” to the Conference. Consensus was not achieved regarding the indications to NACT for high-grade luminal-like breast tumors, and the need to perform an axillary lymph node dissection in case of micrometastases in the sentinel lymph node after NACT. Conclusions NACT is a topic of major interest among surgeons, and there is need to develop shared guidelines. While a Consensus was obtained for most issues presented at this Conference, controversies still exist regarding indications to NACT in luminal B-like tumors and management of lymph node micrometastases. There is need for clinical studies and analysis of large databases to improve our knowledge on this subject.

Psychoneuroendocrineimmunology (PNEI) brings together knowledge acquired since the 1930s from endocrinology, immunology, neuroscience, and psychology. With PNEI, a model of research and interpretation of health and disease is emerging, which sees the human body as a structured and interconnected unit, where the psychological and biological systems are mutually coordinated. In the PNEI view, many factors could influence mental health, with the endocrine system involved in mediating the effects of environmental stress on mental health and inflammation in the onset and course of psychiatric disorders as a result of individual and collective conditions and behaviors. Among these, nutrition is one way by which the environment impacts physiology: indeed, many pieces of research showed that several elements (e.g., probiotics, fish oil, zinc) have a positive effect on mental disorders thus being potentially augmentation agents in treatment. Still, physical activity can moderate depressive symptoms, while prolonged stress increases the risk of psychopathology. Taken together, the PNEI-based approach may inform prevention and treatment strategies, also in the field of mental health care.

Contrary to what is commonly believed, music therapy is an old cure, the use of which is lost in the mists of time. Music always has been perceived to have particular healing powers, and the entire history of civilization contains aspects that link music to physical and mental healing. It seems that the adoption of music for therapeutic purposes harks back to a distant past, probably since the Paleolithic period: it was believed that listening to music could affect the behavior of human beings. In later centuries, the concept of "musical organ-tropism" was born and developed, because according to the type of music, one may affect the cardiovascular, respiratory, and neuroendocrine systems. Studies have shown that music can powerfully evoke and modulate emotions and moods, along with changes in heart activity, blood pressure, and breathing. Indeed, the following findings arise from the literature: heart and respiratory rates are higher in response to exciting music than in the case of tranquilizing music. In addition, music produces activity changes in brain structures (amygdala, hypothalamus, insular and orbitofrontal cortex) known to modulate heart function. This article provides a careful overview of music therapy history from prehistory to the present and a review of the latest applications of music therapy in cardiovascular diseases.

Purpose: The purpose of this study is to describe the safety and efficacy of 9G needle biopsy under tomosynthesis guidance with the patient in the prone position.Materials and methods: This is a retrospective observational study conducted on patients with non-palpable breast mass exclusively detectable through tomosynthesis, performed from the 1st January 2018 to the 1st August 2020. The procedures were performed by taking 12 tissue samples from each mass. The evaluated technical success was considered as a conclusive sample for histological diagnosis. We performed a comparison between the procedural data of interventions in patients who have a lesion 10mm and between high contrast and low contrast masses. The histological data of the samples were analyzed.Results: 500 biopsies of the total 1500 performed from the 1st January 2018 to the 1st August 2020 were included in the study; repetitions for inadequate withdrawal occurred 0.4% (3/500). No major complications have ever been observed. Two cases (0.2%) of minor bleeding were observed with self-limited bleeding from the skin breach at 90 minutes without clinical sequelae in an asymptomatic patient. The biopsy samples showed carcinoma in 55.2% (276/500). Conclusion: Our study suggests that the 9G needle sampling biopsy procedure through tomosynthesis guide with prone patient is a safe and effective procedure for the characterization of indeterminate breast mass.

Background Change is an ongoing process in any organizations. Over years, healthcare organizations have been exposed to multiple external stimuli to change (eg, ageing population, increasing incidence of chronic diseases, ongoing Sars-Cov-2 pandemic) that pointed out the need to convert the current healthcare organizational model. Nowadays, the topic is extremely relevant, rendering organizational change an urgency. The work is structured on a double level of analysis. In the beginning, the paper collects the overall literature on the topic of organisational change in order to identify, on the basis of the citation network, the main existing theoretical approaches. Secondly, the analysis attempts to isolate the scientific production related to the healthcare context, by analysing the body of literature outside the identified citation network, divided by clusters of related studies. Methodology This review adopted a quantitative-based method that employs jointly systematic literature review and bibliographic network analysis. Specifically, the study applied a citation network analysis (CNA) and a co-occurrence keywords analysis. The CNA allowed detecting the most relevant papers published over time, identifying the research streams in literature. Results The study showed four main findings. Firstly, consistent with past studies, works reviewed pointed out a convergence on the micro-level perspective for change's analysis. Secondly, an organic viewpoint whereby individual, organization and change's outcome contribute to any organizational change's action has been found in its early stage. Thirdly, works reported change combined with innovation's concept, although the structure of the relationship has not been outlined. Fourth, interestingly, contributions have been limited within the healthcare context. Conclusion Human dimension is the primary criticality to be managed to impede failure of the re-organizational path. Individuals are not passive recipients of change: individual change acceptance has been found a key input. Few papers discussed healthcare professionals' behaviour, and those available focused on technology-led changes perspective. In this view, individual acceptance of change within the healthcare context resulted being undeveloped and offers rooms for further analyses.

The present manuscript aims to review the history, recent advances, evidence, and challenges of artificial intelligence (AI) in colonoscopy. Although it is mainly focused on polyp detection and characterization, it also considers other potential applications (i.e., inflammatory bowel disease) and future perspectives. Some of the most recent algorithms show promising results that are similar to human expert performance. The integration of AI in routine clinical practice will be challenging, with significant issues to overcome (i.e., regulatory, reimbursement). Medico-legal issues will also need to be addressed. With the exception of an AI system that is already available in selected countries (GI Genius; Medtronic, Minneapolis, MN, USA), the majority of the technology is still in its infancy and has not yet been proven to reach a sufficient diagnostic performance to be adopted in the clinical practice. However, larger players will enter the arena of AI in the next few months.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the most effective treatment in eradicating high-risk acute myeloid leukemia (AML). Here, we present data from a novel HLA-haploidentical HSCT protocol that addressed the 2 remaining major unmet medical needs: leukemia relapse and chronic graft-versus-host disease (cGVHD). Fifty AML patients were enrolled in the study. The conditioning regimen included total body irradiation for patients up to age 50 years and total marrow/lymphoid irradiation for patients age 51 to 65 years. Irradiation was followed by thiotepa, fludarabine, and cyclophosphamide. Patients received an infusion of 2 × 106/kg donor regulatory T cells on day −4 followed by 1 × 106/kg donor conventional T cells on day −1 and a mean of 10.7 × 106 ± 3.4 × 106/kgpurified CD34+ hematopoietic progenitor cells on day 0. No pharmacological GVHD prophylaxis was administered posttransplantation. Patients achieved full donor–type engraftment. Fifteen patients developed grade ≥2 acute GVHD (aGVHD). Twelve of the 15 patients with aGVHD were alive and no longer receiving immunosuppressive therapy. Moderate/severe cGVHD occurred in only 1 patient. Nonrelapse mortality occurred in 10 patients. Only 2 patients relapsed. Consequently, at a median follow-up of 29 months, the probability of moderate/severe cGVHD/relapse-free survival was 75% (95% confidence interval, 71%-78%). A novel HLA-haploidentical HSCT strategy that combines an age-adapted myeloablative conditioning regimen with regulatory and conventional T-cell adoptive immunotherapy resulted in an unprecedented cGVHD/relapse-free survival rate in 50 AML patients with a median age of 53 years. This trial was registered with the Umbria Region Institutional Review Board Public Registry as identification code 02/14 and public registry #2384/14 and at www.clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT03977103","term_id":"NCT03977103"}}NCT03977103.

Optic neuropathies, including glaucoma, are a group of neurodegenerative diseases, characterized by the progressive loss of retinal ganglion cells (RGCs), leading to irreversible vision loss. While previous studies demonstrated the potential to replace RGCs with primary neurons from developing mouse retinas, their use is limited clinically. We demonstrate successful transplantation of mouse induced pluripotent stem cell (miPSC)/mouse embryonic stem cell (mESC)-derived RGCs into healthy and glaucomatous mouse retinas, at a success rate exceeding 65% and a donor cell survival window of up to 12 months. Transplanted Thy1-GFP+ RGCs were able to polarize within the host retina and formed axonal processes that followed host axons along the retinal surface and entered the optic nerve head. RNA sequencing of donor RGCs re-isolated from host retinas at 24 h and 1 week post-transplantation showed upregulation of cellular pathways mediating axonal outgrowth, extension, and guidance. Additionally, we provide evidence of subtype-specific diversity within miPSC-derived RGCs prior to transplantation., Graphical abstract, The manuscript presents a first proof of concept for the use of diverse, miPSC/mESC-derived RGCs for cell replacement in the retina to treat glaucoma and other optic neuropathies.

Margaretha B Breebaart,1,2 Jordi Branders,2 Luc Sermeus,3 Sultan Termurziev,2 Helene Camerlynck,2 Lennert Van Putte,1 Marnik Van Putte Minelli,1 Stefan De Hert4 1Faculty of Medicine and Health Sciences, Antwerp University, Wilrijk, Belgium; 2Department of Anesthesia, Antwerp University Hospital, Edegem, Belgium; 3Department of Anesthesiology, St. Luc University Hospital, Brussels, Belgium; 4Department of Anesthesia and Perioperative Medicine, Ghent University Hospital, Ghent, BelgiumCorrespondence: Margaretha B BreebaartDepartment of Anesthesia, Antwerp University Hospital, Wilrijkstraat 10, Edegem, 2650, BelgiumTel +32 486911691Email Margaretha.breebaart@uza.bePurpose: Continuous sciatic nerve blocks have proven benefits for postoperative analgesia after foot surgery. However, the optimal mode of administration remains a point of debate. Ultrasound guided subparaneural injection accelerates onset time and increases duration after a single shot sciatic nerve block. This double blind prospective randomized trial compares the 48-hour local anesthetic (LA) dose consumption of an automated intermittent bolus technique to a continuous infusion regimen in a subparaneural sciatic nerve catheter after hallux valgus surgery.Patients and Methods: Patients scheduled for hallux valgus surgery were randomized to receive either a continuous infusion of levobupivacaine 0.125% at 5mL/h (group A) or an intermittent automated bolus of 9.8 mL every 2 hours with a background of 0.1 mL/h (group B), both with a PCA bolus of 6 mL and lockout of 30 minutes. The 48 hour LA consumption, PCA boluses, Numeric Rating Scale (NRS), satisfaction and return of normal sensation were recorded.Results: Sixteen patients were excluded because of protocol violation or technical problems and 42 patients remained for analysis. The 48 hour ropivacaine consumption was higher in group A (293 ± 60 mL) than group B (257± 33 mL). The median and highest NRS scores and patient satisfaction were not statistically different between groups. Normal sensation returned after 75 ± 22 hours (group A) and 70 ± 17 hours (group B).Conclusion: Programmed bolus administration in subparaneural sciatic nerve catheters reduces LA consumption 48 hours after surgery with equal analgesia and patient satisfaction. Return of sensation is variable and can last more than 75 hours.Keywords: locoregional anesthesia, sciatic nerve block, postoperative pain, local anesthetics, levobupivacaine, orthopedic surgery

Thoracic endovascular aortic repair (TEVAR) is a life-saving treatment for blunt thoracic aortic injury. We report long-term outcomes of two young patients who underwent TEVAR for blunt thoracic aortic injury with first-generation thoracic stent grafts. The off-label use of the endograft affected the outcomes: one case of open surgery conversion due to an aortoesophageal fistula and one case of endovascular relining for a voluminous pseudoaneurysm associated with a type III endoleak. Long-term follow-up is crucial in TEVAR, especially in case of a first-generation device used in an urgent setting.

Background: The evolution of therapeutic landscape of human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC) has led to an unprecedented outcome improvement, even if the optimal sequence strategy is still debated. To address this issue and to provide a picture of the advancement of anti-HER2 treatments, we performed a large, multicenter, retrospective study of HER2-positive BC patients. Methods: The observational PANHER study included 1,328 HER2-positive advanced BC patients treated with HER2 blocking agents since June 2000 throughout July 2020. Endpoints of efficacy were progression-free survival (PFS) and overall survival (OS). Results: Patients who received a first-line pertuzumab-based regimen showed better PFS ( p < 0.0001) and OS ( p = 0.004) than those receiving other treatments. Median PFS and mOS from second-line starting were 8 and 28 months, without significant differences among various regimens. Pertuzumab-pretreated patients showed a mPFS and a mOS from second-line starting not significantly affected by type of second line, that is, T-DM1 or lapatinib/capecitabine ( p = 0.80 and p = 0.45, respectively). Conversely, pertuzumab-naïve patients receiving second-line T-DM1 showed a significantly higher mPFS compared with that of patients treated with lapatinib/capecitabine ( p = 0.004). Median OS from metastatic disease diagnosis was higher in patients treated with trastuzumab-based first line followed by second-line T-DM1 in comparison to pertuzumab-based first-line and second-line T-DM1 ( p = 0.003), although these data might be partially influenced by more favorable prognostic characteristics of patients in the pre-pertuzumab era. No significant differences emerged when comparing patients treated with ‘old’ or ‘new’ drugs ( p = 0.43), even though differences in the length of the follow-up between the two cohorts should be taken into account. Conclusion: Our results confirmed a relevant impact of first-line pertuzumab-based treatment and showed lower efficacy of second-line T-DM1 in trastuzumab/pertuzumab pretreated, as compared with pertuzumab-naïve patients. Our findings may help delineate a more appropriate therapeutic strategy in HER2-positive metastatic BC. Prospective randomized trials addressing this topic are awaited.

Background: To evaluate whether a model based on radiomic and clinical features may be associated with lymph node (LN) status and overall survival (OS) in lung cancer (LC) patients; to evaluate whether CT reconstruction algorithms may influence the model performance. Methods: patients operated on for LC with a pathological stage up to T3N1 were retrospectively selected and divided into training and validation sets. For the prediction of positive LNs and OS, the Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression model was used; univariable and multivariable logistic regression analysis assessed the association of clinical-radiomic variables and endpoints. All tests were repeated after dividing the groups according to the CT reconstruction algorithm. p-values < 0.05 were considered significant. Results: 270 patients were included and divided into training (n = 180) and validation sets (n = 90). Transfissural extension was significantly associated with positive LNs. For OS prediction, high- and low-risk groups were different according to the radiomics score, also after dividing the two groups according to reconstruction algorithms. Conclusions: a combined clinical–radiomics model was not superior to a single clinical or single radiomics model to predict positive LNs. A radiomics model was able to separate high-risk and low-risk patients for OS; CTs reconstructed with Iterative Reconstructions (IR) algorithm showed the best model performance.

Summary Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Funding Eli Lilly and Company. Translations For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Epidemiological studies on primary biliary cholangitis (PBC) have been based primarily on tertiary referral case series. We aimed to estimate the incidence and prevalence and describe comorbidities in hospitalized patients with PBC in Italy using a national hospital‐based data source. Data were extracted from the National Hospital Discharge Database, which includes all Italian individuals discharged from any hospital in the country. All adults diagnosed with biliary cirrhosis (International Classification of Diseases, Ninth Revision, Clinical Modification, 571.6) as the primary or secondary diagnosis from 2011 to 2015 were included. To determine whether a comorbidity was either more or less frequent in PBC patients compared with the general hospitalized Italian population, the standardized hospitalization ratio (SHR) was calculated. A total of 5,533 incident cases were identified from 2011 to 2015, 3,790 of whom were females (68.5%; female to male [F:M] ratio, 2.2:1). Prevalent cases were 9,664, of whom 7,209 were females (74.6%; F:M ratio, 2.9:1). The incident rate was 1.03 × 100,000 in males and 1.92 × 100,000 in females; prevalence was 1.89 × 100,000 in males and 4.75 × 100,000 in females. Extrahepatic autoimmune diseases, malignant neoplasms of liver and intrahepatic biliary ducts, and malignant neoplasms of gallbladder and extrahepatic bile ducts were found more frequently in PBC patients than in the general hospitalized population (SHR > 100), whereas cerebrovascular diseases and ischemic heart diseases were less frequent in PBC individuals (SHR < 100). Conclusion: This national study provides a survey of comorbidities associated with PBC. Hospitalized patients with PBC are more likely to have extrahepatic autoimmune diseases, hepatocellular carcinoma, and biliary tract cancers and a low risk of cardiovascular events

Background COVID-19 is now a worldwide pandemic. Among the many extra-pulmonary manifestations of COVID-19, recent evidence suggested a possible occurrence of thyroid dysfunction. Purpose The Aim of the present review is to summarize available studies regarding thyroid function alterations in patients with COVID-19 and to overview the possible physio-pathological explanations. Conclusions The repercussions of the thyroid of COVID-19 seem to be related, in part, with the occurrence of a “cytokine storm” that would, in turn, induce a “non-thyroidal illness”. Some specific cytokines and chemokines appear to have a direct role on the hypothalamus–pituitary–thyroid axis. On the other hand, some authors have observed an increased incidence of a destructive thyroiditis, either subacute or painless, in patients with COVID-19. The hypothesis of a direct infection of the thyroid by SARS-Cov-2 stems from the observation that its receptor, ACE2, is strongly expressed in thyroid tissue. Lastly, it is highly probable that some pharmaceutical agents largely used for the treatment of COVID-19 can act as confounding factors in the laboratory evaluation of thyroid function parameters.

Objectives This study sought to determine whether the breast gland adipose tissue is associated with different rates of major adverse cardiac events (MACEs) in pre-menopausal women. Backgr...

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum–etoposide) showed a significant improvement in overall survival versus platinum–etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide alone. Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum–etoposide, durvalumab plus platinum–etoposide, or platinum–etoposide alone. In all groups, patients received etoposide 80–100 mg/m2 on days 1–3 of each cycle with investigator's choice of either carboplatin area under the curve 5–6 mg/mL/min or cisplatin 75–80 mg/m2 on day 1 of each cycle. Patients in the platinum–etoposide group received up to six cycles of platinum–etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum–etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum–etoposide versus platinum–etoposide and for durvalumab plus tremelimumab plus platinum–etoposide versus platinum–etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum–etoposide, 268 to durvalumab plus platinum–etoposide, and 269 to platinum–etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3–27·9). Durvalumab plus tremelimumab plus platinum–etoposide was not associated with a significant improvement in overall survival versus platinum–etoposide (hazard ratio [HR] 0·82 [95% CI 0·68–1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6–12·0) versus 10·5 months (9·3–11·2). Durvalumab plus platinum–etoposide showed sustained improvement in overall survival versus platinum–etoposide (HR 0·75 [95% CI 0·62–0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3–14·7) versus 10·5 months (9·3–11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum–etoposide group, and 88 [33%] of 266 patients in the platinum–etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group, 85 (32%) in the durvalumab plus platinum–etoposide group, and 97 (36%) in the platinum–etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum–etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum–etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum–etoposide group (pancytopenia and thrombocytopenia [n=1 each]). Interpretation: First-line durvalumab plus platinum–etoposide showed sustained overall survival improvement versus platinum–etoposide but the addition of tremelimumab to durvalumab plus platinum–etoposide did not significantly improve outcomes versus platinum–etoposide. These results support the use of durvalumab plus platinum–etoposide as a new standard of care for the first-line treatment of ES-SCLC. Funding: AstraZeneca.

In pediatric age, duodenal hematoma is rare and generally occurs following a closed abdominal trauma due to the crushing of the duodenum against the rigid plane of the spine; it rarely follows anticoagulant therapy, pancreatitis, bleeding disorders, vasculitis, tumors or upper digestive endoscopy. Duodenal hematoma is a rare cause of obstruction of the upper gastrointestinal tract and acute pancreatitis, and the diagnosis is sometimes difficult and late. On the other hand, the identification of the pathology in its initial stages allows the young patients to be subjected to a conservative treatment that resolves the issue most of the time, thus avoiding surgery. In this article we describe an unusual case of duodenal hematoma, following esophagus-gastro-duodenoscopy, in a 12-year-old boy with Di George syndrome.

Hepatic haemangiomas are the most common benign hepatic tumour; they are usually solitary, less than 5 cm in size, and clinically silent. Giant cavernous haemangiomas are a minor subset of hepatic haemangiomas, often symptomatic due to a mass lesion, complications or compression of adjacent structures. Few of these are pedunculated—often difficult to diagnose because of their exophytic development and greater tendency towards complications through the twisting of their peduncle. We report the case of a 55-year-old woman with a giant pedunculated hepatic cavernous haemangioma causing abdominal pain, with epigastralgia mimicking a gastric stromal tumour. We discuss the diagnostic workup, focusing on the useful of computed tomography and magnetic resonance imaging findings and giving a brief report of the therapeutic management and literature review.

Background Parkinson’s disease (PD) is a systemic disease clinically defined by the degeneration of dopaminergic neurons in the brain. While alterations in the gut microbiome composition have been reported in PD, their functional consequences remain unclear. Herein, we addressed this question by an analysis of stool samples from the Luxembourg Parkinson’s Study (n = 147 typical PD cases, n = 162 controls). Results All individuals underwent detailed clinical assessment, including neurological examinations and neuropsychological tests followed by self-reporting questionnaires. Stool samples from these individuals were first analysed by 16S rRNA gene sequencing. Second, we predicted the potential secretion for 129 microbial metabolites through personalised metabolic modelling using the microbiome data and genome-scale metabolic reconstructions of human gut microbes. Our key results include the following. Eight genera and seven species changed significantly in their relative abundances between PD patients and healthy controls. PD-associated microbial patterns statistically depended on sex, age, BMI, and constipation. Particularly, the relative abundances of Bilophila and Paraprevotella were significantly associated with the Hoehn and Yahr staging after controlling for the disease duration. Furthermore, personalised metabolic modelling of the gut microbiomes revealed PD-associated metabolic patterns in the predicted secretion potential of nine microbial metabolites in PD, including increased methionine and cysteinylglycine. The predicted microbial pantothenic acid production potential was linked to the presence of specific non-motor symptoms. Conclusion Our results suggest that PD-associated alterations of the gut microbiome can translate into substantial functional differences affecting host metabolism and disease phenotype.

In previous years, the role of gastroesophageal (GE) ultrasound as a diagnostic tool in gastroesophageal reflux disease (GERD) has been disputed. Most authors believe that it is difficult to diagnose GERD without correlation studies between esophageal pathology and ultrasonographic signs. Indeed, there are many anatomic descriptions of the normal GE junction. The fact that GERD diagnosis was made by morphological studies was believed to be an incorrect deduction. We revisit the pathophysiologic data concerning the gastroesophageal junction and gastric function and review the data in the literature of the past 30 years.

Adventitial cystic disease of the venous system is an extremely rare condition. Forty-five cases have been described in the literature during the last 70 years, but they may not be representative of the real incidence of this pathologic process. We report a case of an adventitial cyst compressing the right external iliac vein and presenting with edema of the ipsilateral leg. Ultrasound imaging and computed tomography angiography showed the typical features of cystic disease and venous stenosis. Cyst excision was performed with a double surgical access. No perioperative complications were reported. There was no recurrence at 4-year follow-up.

Alterations in peripheral vascular endothelial growth factor (VEGF) levels were observed in major depressive disorder and relative treatments and were shown to be influenced by genetic variants. The study objective was to explore, at a genome-wide level, possible interplaying effects between the genetic background and major depressive disorder in regulating VEGF levels. Moreover, we aimed to investigate the association between these variants and response to electroconvulsive therapy. A genome-wide association study was carried out both on controls and patients with major depressive disorder (n = 145; n = 121) in correlation with serum VEGF levels determined by ELISA. Five SNPs not included in SNP arrays were additionally genotyped. Seventy-one patients with treatment-resistant depression underwent electroconvulsive therapy and were evaluated as responders/nonresponders. An association between VEGF levels and a locus in 6p21.1, downstream the VEGF gene, was evidenced both in controls (best SNP: FDR-corrected p = 2.4 × 10-5 ) and in patients with major depressive disorder (best SNP: FDR-corrected p = 2.6 × 10-3 ). The alleles associated with lower VEGF concentrations in patients were also associated with nonresponse to electroconvulsive therapy (p = .01). These results confirm a role of SNPs in 6p21.1 locus as major influencers of circulating VEGF levels also in patients affected by major depressive disorder and indicate a possible implication in response to electroconvulsive therapy.

BackgroundThere is emerging evidence suggesting a link between ambient heat exposure and chronic obstructive pulmonary disease (COPD) hospitalisations. Individual and contextual characteristics can affect population vulnerabilities to COPD hospitalisation due to heat exposure. This study quantifies the effect of ambient heat on COPD hospitalisations and examines population vulnerabilities by age, sex, and contextual characteristics.MethodsIndividual data on COPD hospitalisation at high geographical resolution (postcodes) during 2007-2018 in England was retrieved from the small area health statistics unit. Maximum temperature at 1 km×1km resolution was available from the UK Met Office. We employed a case-cross over study design and fitted Bayesian conditional Poisson regression models. We adjusted for relative humidity and national holidays, and examined effect modification by age, sex, green space, average temperature, deprivation and urbanicity.ResultsAfter accounting for confounding, we found a 1.47% (95% Credible Interval 1.19% to 1.73%), increase in the hospitalisation risk for every 1°C increase in temperatures above 23.2°C (lags 0-2 days). We reported weak evidence of an effect modification by sex and age. We found a strong spatial determinant of the COPD hospitalisation risk due to heat exposure, that was alleviated when we accounted for contextual characteristics. 1 851 (95% CrI 1 576 to 2 079) COPD hospitalisations were associated with temperatures above 23.2°C annually.ConclusionOur study suggests that resources should be allocated to support the public health systems, for instance through developing or expanding heat-health alerts, to challenge the increasing future heat-related COPD hospitalisation burden.Key MessagesWhat is the key question?What is the short-term effect of heat exposure on COPD hospitalisation and which contextual/societal factors affect population vulnerability?What is the bottom line?For every 1°C increase in summer temperatures higher than 23.2°C, the risk of COPD hospitalisation increases by 1.47%, and populations in the North and in the South East are more vulnerable.Why read on?This large nationwide study in England using individual data quantifies the effect of heat exposure on COPD hospitalisations; these findings inform future policies regarding preparedness and resilience of public health systems against the increasing COPD burden due to the increasing temperatures.

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P-8) interactions with sex on lung function, and 21 showed suggestive interactions (P-6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein (HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10-6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Behavioral Inhibition (BI) is a temperamental trait characterized by fear and wariness in reaction to new and unfamiliar stimuli, both social and non-social. BI has been recognized as possible forerunner of anxiety disorders, especially social anxiety and phobia, therefore, its assessment is clinically relevant. The present study aimed to examine the psychometric properties of the Italian adaptation of the Behavioral Inhibition Questionnaire (BIQ), which measures BI in preschool children. The BIQ was completed by 417 Italian parents (230 mothers, 187 fathers) of 270 preschoolers aged 3–5. Confirmatory factor analysis showed a good internal validity: the factorial structure was corresponding to the original six-factor version. Results showed excellent internal consistency, significant item-total correlations, good inter-rater reliability, convergent validity (by correlating the BIQ with the Italian Questionnaires of Temperament-QUIT, the Anxiety-Shy Conner’s Scale and the Laboratory Temperament Assessment Battery) and discriminant validity (i.e., no correlation with Conners’ ADHD scale). Significant correlations emerged between BI indexes and total BIQ scores of parents and maternal (but not paternal) versions of the questionnaire. Altogether, the results are promising and consistent with previous validation studies, suggesting the BIQ as a reliable and valid measure for evaluating parents’ perception of BI in Italian preschoolers.

A review on the reference values of the acoustical parameters that have the greatest influence on students' performance at different ages has been completed in this study. Published studies from 2002 to 2020 were summarized, which focus on testing learning attainments and cognitive skills, speech intelligibility, and subjective perceptions under different classroom acoustic conditions. Only 38 papers out of the 56 containing empirical findings on the influence of acoustical parameters on students’ performance were considered, as the remaining 18 lacked ecological validity or did not respond to the selection criteria. Studies were only included if they considered normal hearing subjects and typical lesson settings provided in classrooms without an amplification system. Thus, the studies selected involved subjects between 5 and 40 years old. The values of the acoustical parameters that led to better or worse learning performance were tabulated and the distribution of occurrences was created. The median and interquartile range for the distribution of occurrences were used to describe the central tendency and dispersion and analyzed considering two different age groups. The results obtained were used to develop classroom acoustic guidelines for better learning performance for students under or over 12 years of age, and identified the thresholds that lead to worse performances.

A variety of neuropsychiatric complications has been described in association with Covid-19 infection. Large scale studies presenting a wider picture of these complications and their relative frequency are lacking. The objective of our study was to describe the spectrum of neurological and psychiatric complications in patients with Covid-19 seen in a multidisciplinary hospital center over six months. We conducted a retrospective, observational study on all patients showing neurological or psychiatric symptoms in the context of Covid-19 seen in the medical and university neuroscience department of Assistance Publique Hopitaux de Paris -Sorbonne University. We collected demographic data, comorbidities, symptoms and severity of Covid-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from CSF analysis, MRI, EEG and EMG. A total of 249 Covid-19 patients with a de novo neurological or psychiatric manifestation were included in the database and 245 were included in the final analyses. One-hundred fourteen patients (47%) were admitted to the intensive care unit and 10 (4%) died. The most frequent neuropsychiatric complications diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%), and cerebrovascular disorders (16%). No patients showed CSF evidence of SARS-CoV-2. Encephalopathy was associated with older age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the intensive care unit. The majority of these neuropsychiatric complications could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders., Graphical Abstract Graphical Abstract

BackgroundClassifying individuals at high chronic obstructive pulmonary disease (COPD)-risk creates opportunities for early COPD detection and active intervention.ObjectiveTo develop and validate a statistical model to predict 10-year probabilities of COPD defined by post-bronchodilator airflow obstruction (post-BD-AO; forced expiratory volume in 1 s/forced vital capacitySettingGeneral Caucasian populations from Australia and Europe, 10 and 27 centres, respectively.ParticipantsFor the development cohort, questionnaire data on respiratory symptoms, smoking, asthma, occupation and participant sex were from the Tasmanian Longitudinal Health Study (TAHS) participants at age 41–45 years (n=5729) who did not have self-reported COPD/emphysema at baseline but had post-BD spirometry and smoking status at age 51–55 years (n=2407). The validation cohort comprised participants from the European Community Respiratory Health Survey (ECRHS) II and III (n=5970), restricted to those of age 40–49 and 50–59 with complete questionnaire and spirometry/smoking data, respectively (n=1407).Statistical methodRisk-prediction models were developed using randomForest then externally validated.ResultsArea under the receiver operating characteristic curve (AUCROC) of the final model was 80.8% (95% CI 80.0% to 81.6%), sensitivity 80.3% (77.7% to 82.9%), specificity 69.1% (68.7% to 69.5%), positive predictive value (PPV) 11.1% (10.3% to 11.9%) and negative predictive value (NPV) 98.7% (98.5% to 98.9%). The external validation was fair (AUCROC 75.6%), with the PPV increasing to 17.9% and NPV still 97.5% for adults aged 40–49 years with ≥1 respiratory symptom. To illustrate the model output using hypothetical case scenarios, a 43-year-old female unskilled worker who smoked 20 cigarettes/day for 30 years had a 27% predicted probability for post-BD-AO at age 53 if she continued to smoke. The predicted risk was 42% if she had coexistent active asthma, but only 4.5% if she had quit after age 43.ConclusionThis novel and validated risk-prediction model could identify adults aged in their 40s at high 10-year COPD-risk in the general population with potential to facilitate active monitoring/intervention in predicted ‘COPD cases’ at a much earlier age.

Background and aims: Adequate bowel cleansing is critical to ensure quality and safety of a colonoscopy. A novel 1-L polyethylene glycol plus ascorbate (1L-PEG+ASC) regimen was previously validated against low-volume regimens but was never compared with high-volume regimens. Methods: In a phase IV study, patients undergoing colonoscopy were randomized 1:1 to receive split-dose 1L PEG+ASC or a split-dose 4-L PEG-based regimen (4L-PEG) in 5 Italian centers. Preparation was assessed with the Boston Bowel Preparation Scale (BBPS) by local endoscopists and centralized reading, both blinded to the randomization arm. The primary endpoint was noninferiority of 1L-PEG+ASC in colon cleansing. Secondary endpoints were superiority of 1L-PEG+ASC, patient compliance, segmental colon cleansing, adenoma detection rate, tolerability, and safety. Results: Three hundred eighty-eight patients (median age, 59.8 years) were randomized between January 2019 and October 2019: 195 to 1L-PEG+ASC and 193 to 4L-PEG. Noninferiority of 1L-PEG+ASC was demonstrated for cleansing in both the entire colon (BBPS≥ 6: 97.9% vs 93%; relative risk [RR], 1.03; 95% confidence interval [CI], 1.001-1.04; P superiority= .027) and in the right-sided colon segment (98.4% vs 96.0%; RR, 1.02; 95% CI, .99-1.02; P noninferiority= .013). Compliance was higher with 1L-PEG+ASC than with 4L-PEG (178/192 [92.7%] vs 154/190 patients [81.1%]; RR, 1.10; 95% CI, 1.05-1.12), whereas no difference was found regarding safety (moderate/severe side effects: 20.8% vs 25.8%; P= .253). No difference in adenoma detection rate (38.8% vs 43.0%) was found. Conclusions: One-liter PEG+ASC showed noninferiority compared with 4L-PEG in achieving adequate colon cleansing and provided a higher patient compliance. No differences in tolerability and safety were detected. (Clinical trial registration number: NCT03742232.).

The COVID-19 outbreak disproportionately affected the elderly and areas with higher population density. Among the multiple factors possibly involved, a role for air pollution has also been hypothesized. This nationwide observational study demonstrated the significant positive relationship between COVID-19 incidence rates and PM2.5 and NO2 levels in Italy, both considering the period 2016&ndash, 2020 and the months of the epidemic, through univariate regression models, after logarithmic transformation of the variables, as the data were not normally distributed. That relationship was confirmed by a multivariate analysis showing the combined effect of the two pollutants, adjusted for the old-age index and population density. An increase in PM2.5 and NO2 concentrations by one unit (1 &micro, g/m3) corresponded to an increase in incidence rates of 1.56 and 1.24 &times, 104 people, respectively, taking into account the average levels of air pollutants in the period 2016&ndash, 2020, and 2.79 and 1.24 &times, 104 people during March&ndash, May 2020. Considering the entire epidemic period (March&ndash, October 2020), these increases were 1.05 and 1.01 &times, 104 people, respectively, and could explain 59% of the variance in COVID-19 incidence rates (R2 = 0.59). This evidence could support the implementation of targeted responses by focusing on areas with low air quality to mitigate the spread of the disease.

Novel and complementary experimental models are required for investigating the molecular mechanisms underlying the resistance to the available therapies of patients with major depression (Treatment-Resistant Depression, TRD) that occurs in at least one third of patients and need to be deeply investigated. Here, we have established a patient-specific disease model for TRD by reprogramming peripheral blood mononuclear cells (PBMCs) from two TRD patients into induced pluripotent stem cells (iPSCs), using non-integrating Sendai virus. These lines show the typical morphology of pluripotent cells, express pluripotency markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers.

Background: Although most of the analyses included transverse colon cancers (TCC) among right colon cancer (RCC), it is not completely clear if they present total similarities with RCC or if they have their specific features. Therefore, we present an observational study to evaluate clinicopathological characteristics and survival data of patients with TCC. Methods: We retrospectively reviewed 450 RCC, of whom 97 stages I&ndash, IV TCC were included in this multicenter study, clinicopathological and molecular parameters were analyzed to identify prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: Most of TCC cases were male (61%), with &le, 70 years old (62%), and good performance status (ECOG PS 0, 68%). According to WHO classification, 41 (49%) and 40 (48%) tumors were classified as well to moderate and poorly/undifferentiated respectively, regardless of mucinous component (30%). About molecular data, 8 (26%), 45 (63%), and 14 (24%) were MSI-H, KRAS wild-type, and BRAF V600E mutant, respectively. With a median follow-up of 34 months, there were 29 and 50 disease recurrences and deaths respectively. Charlson comorbidity index &ge, 5 was a significant prognostic factor for DFS (HR = 7.67, 95% CI 2.27&ndash, 25.92). Colon obstruction/perforation (HR = 2.65, 95% CI 1.01&ndash, 7.01), and BRAF mutant (HR = 3.03, 95% CI 0.97&ndash, 9.50) cases showed a worst, despite not statistically significant, DFS. Whereas for OS, at the multivariate model, only tumor grade differentiation (HR = 5.26, 95% CI 1.98&ndash, 14.01) and BRAF mutation status (3.71, 95% CI 1.07&ndash, 12.89) were independent prognostic factors. Conclusions: Poorly/undifferentiated tumor grade and BRAF V600E mutation are independent prognostic factors for OS in TCC. Further prospective clinical trials are needed to better define TCC treatment in order to improve patient outcome.

The desmoid tumor is a locally aggressive proliferative disease within the family of soft-tissue sarcomas. Despite its relatively good prognosis, the clinical management of desmoid tumors requires constant multidisciplinary evaluation due to its highly variable clinical behavior. Recently, active surveillance has being regarded as the appropriate strategy at diagnosis, as indolent persistence or spontaneous regressions are not uncommon. Here, we review the most recent advances in desmoid tumor therapy, including low-dose chemotherapy and treatment with tyrosine kinase inhibitors. We also explore the recent improvements in our knowledge of the molecular biology of this disease, which are leading to clinical trials with targeted agents.

Introduction: Studies on the epidemiology of primary sclerosing cholangitis (PSC) are mainly based on tertiary referral centers, and are retrospective case series susceptible to selection bias. The aim of this study was to estimate incidence, survival and cause of mortality of PSC in Italy, using population-based data. Methods: Data collected from the National Rare Diseases Registry (RNMR) and the National Mortality Database (NMD) were integrated and analyzed. Results: We identified 502 PSC incident cases. The crude incidence rate between 2012 and 2014 was 0.10 per 100,000 individuals. Sixty percent were male, mean age at disease onset and at diagnosis were 33 and 37 years, respectively, highlighting a mean diagnostic delay of 4 years. The rate of interregional mobility was 12%. Ten-year survival was 92%. In 32% of cases the cause of death was biliary-related, 12% died of biliary or gallbladder cancer. Conclusions: For rare diseases such as PSC, population-based cohort&rsquo, s studies are of paramount importance. Incidence rates of PSC in Italy are markedly lower and survival much longer than the ones reported from tertiary, single-centre series. Moreover, the diagnostic delay and the patient interregional mobility highlights the need for increasing awareness on the disease and for resource reallocation among Italian regions within the National Health Service

In clinical practice, an antidepressant prescription is a trial and error approach, which is time consuming and discomforting for patients. This study investigated an in silico approach for ranking antidepressants based on their hypothetical likelihood of efficacy. We predicted the transcriptomic profile of citalopram remitters by performing an in silico transcriptomic-wide association study on STAR*D GWAS data (N = 1163). The transcriptional profile of remitters was compared with 21 antidepressant-induced gene expression profiles in five human cell lines available in the connectivity-map database. Spearman correlation, Pearson correlation, and the Kolmogorov–Smirnov test were used to determine the similarity between antidepressant-induced profiles and remitter profiles, subsequently calculating the average rank of antidepressants across the three methods and a p value for each rank by using a permutation procedure. The drugs with the top ranks were those having a high positive correlation with the expression profiles of remitters and that may have higher chances of efficacy in the tested patients. In MCF7 (breast cancer cell line), escitalopram had the highest average rank, with an average rank higher than expected by chance (p = 0.0014). In A375 (human melanoma) and PC3 (prostate cancer) cell lines, escitalopram and citalopram emerged as the second-highest ranked antidepressants, respectively (p = 0.0310 and 0.0276, respectively). In HA1E (kidney) and HT29 (colon cancer) cell types, citalopram and escitalopram did not fall among top antidepressants. The correlation between citalopram remitters’ and (es)citalopram-induced expression profiles in three cell lines suggests that our approach may be useful and with future improvements, it can be applicable at the individual level to tailor treatment prescription.

Background: Nickel (Ni) oral consumption may elicit systemic reactions in patients affected by systemic nickel allergy syndrome (SNAS), including gastrointestinal symptoms, which in turn are associated with gut dysbiosis. We evaluated the effects of a low-Ni diet alone or in combination with the oral consumption of appropriate probiotics on Ni-sensitivity and urinary dysbiosis markers in SNAS patients. Methods: n = 51 patients with SNAS and concomitant intestinal dysbiosis were enrolled in the study. According to the urinary indican/skatole levels, quantified through a colorimetric and a high-performance liquid chromatographic method, respectively, patients were assigned to a dysbiosis type/grade and followed a low-Ni diet for three months. Along with the diet, 22 patients also consumed probiotics based on the dysbiosis type. In particular, a Lactobacilli- or Bifidobacteria-containing formulation was administered to patients with fermentative or putrefactive dysbiosis, respectively, while a broad-spectrum probiotic formulation containing both Lactobacilli and Bifidobacteria was administered to patients with mixed dysbiosis. After three months, patients were invited to repeat the Ni-stimulation and the dysbiosis tests. Results: The fermentative dysbiosis group represented the largest group followed by the mixed dysbiosis group, while only two patients had putrefactive dysbiosis. Overall, at three months of treatment in general (diet alone with or without probiotics), the Ni-sensitivity and dysbiosis levels were strongly ameliorated. The association of a low-Ni diet with a specific probiotic oral supplementation was significantly more effective in decreasing dysbiosis levels or reaching eubiosis than with diet alone. Conclusion: Our results, while confirming the benefits of a low-Ni diet in SNAS patients, strongly support that appropriate adjuvant treatment with probiotics significantly helps to improve intestinal dysbiosis or restore a healthy microbiota.

Background An isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q), are the most frequent anomalies in the bone marrow of patients with Shwachman-Diamond syndrome, which is caused in most cases by mutations of the SBDS gene. These clonal changes imply milder haematological symptoms and lower risk of myelodysplastic syndromes and acute myeloid leukaemia, thanks to already postulated rescue mechanisms. Results Bone marrow from fourteen patients exhibiting either the i(7)(q10) or the del(20)(q) and coming from two large cohorts of patients, were subjected to chromosome analyses, Fluorescent In Situ Hybridization with informative probes and array-Comparative Genomic Hybridization. One patient with the i(7)(q10) showed a subsequent clonal rearrangement of the normal chromosome 7 across years. Four patients carrying the del(20)(q) evolved further different del(20)(q) independent clones, within a single bone marrow sample, or across sequential samples. One patient with the del(20)(q), developed a parallel different clone with a duplication of chromosome 3 long arm. Eight patients bore the del(20)(q) as the sole chromosomal abnormality. An overall overview of patients with the del(20)(q), also including cases already reported, confirmed that all the deletions were interstitial. The loss of material varied from 1.7 to 26.9 Mb and resulted in the loss of the EIF6 gene in all patients. Conclusions Although the i(7)(q) and the del(20)(q) clones are frequent and clinically benign in Shwachman Diamond-syndrome, in the present work we show that they may rearrange, may be lost and then reconstructed de novo, or may evolve with independent clones across years. These findings unravel a striking selective pressure exerted by SBDS deficiency driving to karyotype instability and to specific clonal abnormalities.