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Background: Individuals with Schizophrenia Spectrum Disorders (SSD) often suffer from obesity and do limited Physical Activity (PA). PA has many beneficial effects on a variety of somatic and mental variables and it should be strengthened among people with mental disorders. The relationship between Body Mass Index (BMI), Waist Circumference (WC), and PA in this population is poorly understood, with a lack of precise PA assessment. This study investigates the association between BMI, WC, weight, and PA in individuals with SSD and controls using accelerometers., Methods: One hundred twenty-six patients with SSD (residents and outpatients) and 110 sex- and age-matched controls were enrolled. Clinical, sociodemographic, and quality-of-life data were collected. PA was measured with a tri-axial ActiGraph GT9X and quantified by Vector Magnitude (VM). Relationships between PA and BMI, WC, and weight changes were analysed using linear regression models., Results: Patients were more likely to be unmarried, unemployed, and less educated compared to controls (p < 0.001). Residents had more medical comorbidities (p = 0.001), while outpatients had higher BMI, weight, and WC (p < 0.001). Residents reported more severe psychopathology, lower functioning, and greater use of psychopharmacological medications (p < 0.001). Higher PA levels were not significantly associated with lower BMI, WC, or weight. Although not statistically significant, increased PA showed a trend towards lower obesity risk., Conclusions: Sociodemographic, medical, and clinical characteristics of individuals with SSD define vulnerability factors that can inform tailored interventions to improve PA., 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 © 2024 Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs) appear to play an important role in intercellular communication in various physiological processes and pathological conditions such as cancer. Like enveloped viruses, EVs can transport their contents into the nucleus of recipient cells, and a new intracellular pathway has been described to explain the nuclear shuttling of EV cargoes. It involves a tripartite protein complex consisting of vesicle-associated membrane protein-associated protein A (VAP-A), oxysterol-binding protein (OSBP)-related protein-3 (ORP3) and late endosome-associated Rab7 allowing late endosome entry into the nucleoplasmic reticulum. Rab7 binding to ORP3-VAP-A complex can be blocked by the FDA-approved antifungal drug itraconazole. Here, we design a new series of smaller triazole derivatives, which lack the dioxolane moiety responsible for the antifungal function, acting on the hydrophobic sterol-binding pocket of ORP3 and evaluate their structure-activity relationship through inhibition of VOR interactions and nuclear transfer of EV and HIV-1 cargoes. Our investigation reveals that the most effective compounds that prevent nuclear transfer of EV cargo and productive infection by VSV-G-pseudotyped HIV-1 are those with a side chain between 1 and 4 carbons, linear or branched (methyl) on the triazolone region. These potent chemical drugs could find clinical applications either for nuclear transfer of cancer-derived EVs that impact metastasis or viral infection., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The United Kingdom patent application GB2598624A (applicants: M.F.S., G.R., P.D., G.C., A.L. and Technische Universität Dresden (TUD); inventors: M.F.S., G.R., P.D., G.C., D.C. and A.L.), European patent application EP3864409A1 (applicants: M.F.S., G.R., A.L. and TUD; inventors; M.F.S., G.R., D.C. and A.L.) and United States provisional patent number US20210353616A1 (applicants: M.F.S., G.R., A.L. and TUD; inventors: M.F.S., G.R., D.C. and A.L.) are pending. The authors declare no other competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Limited data are available on the long-term outcomes in recent years for late HIV diagnosis (LD)., Methods: All subjects with HIV enrolled in the ICONA cohort in 2009-2022 who started antiretroviral treatment (ART) within 4 months from diagnosis were included and divided into: (i) pre-ART CD4 count ≥350/mm 3 without AIDS (non-LD), (ii) pre-ART CD4 count <350/mm 3 without AIDS (LD asymptomatic), and (iii) with AIDS events pre-ART (LD-AIDS). The estimated probability and independent risk for mortality (all-cause and cause-specific) and treatment failure were evaluated., Results: Of 6813 participants (2448 non-LD, 3198 LD asymptomatic, and 1167 LD-AIDS), 161 (2.4%) died after ART initiation. At survival analysis, a higher probability of all-cause mortality has been identified for LD than non-LD (P <0.001) and within the former, for LD-AIDS over LD asymptomatic (P <0.001). After adjusting for confounders, LD showed a higher risk of all-cause mortality (vs non-LD adjusted hazard ratio (aHR) 5.51, P <0.001) and, in particular, being an AIDS presenter predicted a greater risk of all-cause (aHR = 4.42, P <0.001), AIDS-related (adjusted subhazard ratio [aSHR] = 16.86, P <0.001), and non-AIDS-related mortality (aSHR = 1.74, P = 0.022) than the rest of the late presenters. Among the short-term survivors in the LD-AIDS group, the long-term mortality was mediated by the lack of immune recovery at 2 years. Finally, LD compared with non-LD and, particularly, among the former, LD-AIDS over LD asymptomatic showed a greater risk of treatment failure., Conclusions: In recent years, LD subjects, particularly, AIDS presenters, remained at a higher risk of poorer outcomes. Public health strategies for early HIV diagnosis are urgently needed to constrain the mortality gap., Competing Interests: Declarations of competing interest A.M. received speaker honoraria from Gilead Sciences and ViiV Healthcare and travel fees and participated in advisory boards sponsored by ViiV Healthcare. A.C. received funding for scientific advisory boards, travel, or speaker honoraria from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, and MSD. A. Giacomelli reports speaker honoraria for ViiV Healthcare and Gilead Sciences and is an adviser for Janssen-Cilag and Mylan. C.P. received personal fees from Gilead Sciences for a case presentation and a travel grant and has served on an advisory board for Janssen-Cilag; A. Gori received speaker honoraria and fees for attending advisory boards from ViiV Healthcare, Gilead Sciences, Janssen-Cilag, MSD, BMS, Pfizer, and Novartis and received research grants from ViiV, BMS, and Gilead Sciences. A.S. received speaker honoraria or participated in advisory boards sponsored by Gilead Sciences, ViiV Healthcare, MSD, and Janssen-Cilag. A.B. received speaker honoraria and fees for attending advisory boards from Astra-Zeneca, BioMerieux, Janssen-Cilag, Nordic Pharma, Pfizer, Qiagen, SOBI, and ViiV and received research grants from Gilead; G.M. participated in the advisory boards of Gilead Sciences, ViiV Healthcare, Angelini, and Janssen-Cilag and received travel grants from ViiV Healthcare, MSD, and Janssen-Cilag; E.G. received grant support from Gilead Sciences and Mylan and speaker honoraria from Gilead Sciences. C.M. received speaker honoraria or participated in advisory boards sponsored by Gilead Sciences, ViiV Healthcare, MSD, and Janssen-Cilag and received research grants from Gilead Sciences; A.d.M. participated in advisory board of Gilead Sciences, ViiV Healthcare, MSD, Pfizer, and GSK and received research grant from Gilead Science, ViiV Healthcare, Merck Sharp and Dohme, GSK, and Janssen-Cilag; A.A. received research grants from Gilead Sciences, AstraZeneca, and ViiV Healthcare and honoraria from Gilead Science, AstraZeneca, GSK, Pfizer, MSD, Moderna, Mylan, Janssen-Cilag, and ViiV Healthcare; A.C-L., A.T., G.D.G., and G.O. have no competing interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A successful immunosensor is characterized by a proper antibody immobilization and orientation in order to enhance the antigen recognition. In this work, a thorough characterization of the antibody functionalized gold surface is performed to set up the best conditions to implement in an optical platform for the detection of Brucella sp. Two different strategies are evaluated, based on a random immobilization and on an oriented one: a direct antibody immobilization on carboxylic mixed polyethylene (PEG) self-assembled monolayer (SAM) or only carboxylic PEG SAM interface is compared to an oriented immobilization on a layer of protein G on the same PEG SAM interfaces. X-ray Photoelectron Spectroscopy (XPS), Time of Flight Secondary Ion Mass Spectrometry (ToF-SIMS) and contact angle (CA) are used to chemically characterize the gold functionalized surface and ToF-SIMS is also used to confirm the right antibody orientation. Optical characterization is applied to monitor the functionalization steps and fluorescence measurements are used to set up the proper experimental conditions and also to detect Brucella bacteria on the surface. Best results are obtained with a 10 ng/μl incubation solution of antibody immobilized, in an oriented way, on a mixed PEG SAM interface., 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 © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In the last decades a significant increase of the migratory phenomenon from South Asian countries to the Western World has occurred for social, economic and geopolitical reasons. The aim of this review is to describe cardiovascular risk factors, pathogenesis and treatments of coronary artery disease in South Asian patients. It is well established that South Asian populations have a higher prevalence of coronary artery disease and premature onset of myocardial infarction episodes than other populations. This higher predisposition might be caused by genetic factors, common in both South Asian patients residing in their birth country and in those residing abroad, but it may also be due to the new spatial environment in which they live. It will be important to examine the leading cardiovascular risk factors determining increasing incidence of coronary artery disease in the South Asian population. These include: insulin resistance, hypertension, dyslipidaemia and abdominal obesity caused by a diet rich in refined carbohydrates and saturated fats. Furthermore, it is important to examine emerging cardiovascular risk factors strictly related to this particular ethnic group. The evidence of higher levels of prothrombotic and proinflammatory factors, for example lipoprotein(a) and proinflammatory adipokines, as well as the influence of air pollution and psychosocial stress, may have consequences on the risk, treatment and outcomes of the coronary artery disease in this population. Migrants from South Asia deserve to be addressed and framed with particular care in terms of cardiovascular risk and especially in the management of acute coronary events., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Hyperbaric oxygen therapy (HBOT) has been proposed to address COVID-19- associated respiratory failure. However, its biochemical effects are poorly known., Method: 50 patients with hypoxemic COVID-19 pneumonia were divided into C group (standard care) and H group (standard care plus HBOT). Blood was obtained at t = 0 and t = 5 days. Oxygen saturation (O2 Sat) was followed up. White blood cell (WC) count, lymphocytes (L) and platelets (P) and serum analysis (glucose, urea, creatinine, sodium, potassium, ferritin, D dimer, LDH and CRP) were carried out. Plasma levels of sVCAM, sICAM, sPselectin, SAA and MPO, and of cytokines (IL-1β, IL-1RA, IL-6, TNFα, IFNα, IFNγ, IL-15, VEGF, MIP1α, IL-12p70, IL-2 and IP-10) were measured by multiplex assays. Angiotensin Converting Enzyme 2 (ACE-2) levels were determined by ELISA., Results: The average basal O2 Sat was 85 ± 3%. The days needed to reach O2 Sat >90% were: H: 3 ± 1 and C: 5 ± 1 (P < 0,01). At term, H increased WC, L and P counts (all, H vs C: P < 0,01). Also, H diminished D dimer levels (H vs C, P < 0,001) and LDH concentration (H vs C, P < 0.01]. At term, H showed lower levels of sVCAM, sPselectin and SAA than C with respect to basal values (H vs C: ΔsVCAM: P < 0,01; ΔsPselectin: P < 0,05; ΔSAA: P < 0,01). Similarly, H showed diminished levels of TNFα (ΔTNFα: P < 0,05) and increased levels of IL-1RA and VEGF than C respect to basal values (H vs C: ΔIL-1RA and ΔVEGF: P < 0,05)., Conclusion: Patients underwent HBOT improved O2 Sat with lower levels of severity markers (WC and platelets count, D dimer, LDH, SAA). Moreover, HBOT reduced proinflammatory agents (sVCAM, sPselectin, TNFα) and increased anti-inflammatory and pro-angiogenic ones (IL-1RA and VEGF)., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: This study aimed to (1) explore the changes in conspiracy mentality across the four waves of the COVID-19 pandemic; (2) assess the relationship between conspirative mentality and psychological/behavioural variables; (3) identify the predictors of conspirative mentality; and (4) explore the effect of conspirative mentality on COVID-19 protective behaviour., Study Design: This was a multiwave survey., Methods: A total of 10,013 Italian individuals, aged 18-70 years, were assessed across the four waves (from January to May 2021) through online survey. We collected information about the sociodemographic characteristics of participants, personal experiences of COVID-19 infection, trust, COVID-19 protective behaviours, COVID-19 risk perception, arousal, auto-efficacy, resilience and well-being. Conspiracy mentality was assessed with the Conspiracy Mentality Questionnaire. The statistical analyses included exploratory factorial analyses, Pearson correlations and multiple linear regressions., Results: The conspiracy mentality score during the COVID-19 pandemic was medium-high (mean 59.0 on a 0-100 scale) and slightly increased from 58.2 to 59.9 across months, in parallel with a slight decrease in trust in health institutions and scientific informational sources. Individuals aged >35 years, poorly educated and particularly scared about their financial situation were at risk of showing higher levels of conspirative mentality. Higher levels of conspirative mentality were risk factors for low levels of COVID-19 protective behaviours., Conclusions: Clear and effective communication may improve trust in health institutions and informational sources, decrease conspirative theories and increase compliance with protective behaviour., (Copyright © 2022 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: The configuration of having separate mental health services by age, namely child and adolescent mental health services (CAMHS) and adult mental health services (AMHS), might be a barrier to continuity of care that adversely affects young people's mental health. However, no studies have investigated whether discontinuity of care in the transition period affects mental health. We aimed to discern the type of care young people receive after reaching the upper age limit of their CAMHS and examine differences in outcomes at 24-month follow-up between young people receiving different types of care., Methods: To assess mental health in young people from 39 CAMHS in eight European countries (Belgium, Croatia, France, Germany, Italy, Ireland, the Netherlands, and the UK), we did a longitudinal cohort study. Eligible young people were CAMHS users up to 1 year younger than the upper age limit of their CAMHS or up to 3 months older, if they were still in CAMHS. Information on mental health service use, mental health problems (ie, using the Health of the Nation Outcome Scale for Children and Adolescents, Youth Self-Report and Adult Self-Report, DSM-5, and ICD-10), and sociodemographic characteristics were collected using self-reported, parent-reported, and clinician-reported interviews and questionnaires. Mixed models were applied to assess relationships between baseline characteristics, mental health service use, and outcomes., Findings: The MILESTONE cohort included 763 young people. The participants were 60·0% female (n=458) and 40·0% male (n=305), 90·3% White (n=578), and had a mean age of 17·5 years (range 15·2-19·6 years). Over the 24-month follow-up period, 48 young people (6·3%) actively withdrew from the study. For young people, the higher their scores on the Health of the Nation Outcome Scale for Children and Adolescents (p=0·0009) and Youth Self-Report and Adult Self-Report (p=0·046), and who had a clinical classification of severe mental illness (p=0·0033), had suicidal thoughts or behaviours or self-harm (p=0·034), used psychotropic medication (p=0·0014), and had a self-reported or parent-reported need for continued treatment (p&lt;0·0001) at baseline, were more likely to transition to AMHS or stay in CAMHS than to have care end. Overall, over the 24-month follow-up period, the mental health of young people improved, but 24·4% of young people reported an increase in problems calculated using the reliable change index, of whom 5·3% had a clinically relevant increase in problems. At 24-month follow-up, no differences in change in mental health problems since baseline were found between young people who used different types of care (CAMHS, AMHS, or no care)., Interpretation: Although approximately half of young people reaching the upper age limit of their CAMHS stop using mental health services, this was not associated with a deterioration in their mental health. Young people with the most severe mental health problems are more likely to receive continued care. If replicated, our findings suggest investments in improving transitional care for all CAMHS users might not be cost-effective in times of rising health-care costs, but might be better targeted at a subgroup of young people with increasing mental health problems who do not receive continued treatment., Funding: European Commission's 7th Framework Programme., Competing Interests: Declaration of interests SPS was part funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care West Midlands, now recommissioned as the National Institute for Health Research Applied Research Collaboration West Midlands. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. PJS is the co-inventor of the HealthTracker, and is the Chief Executive Officer and shareholder in HealthTracker; and has received funding for clinical trials on Rett syndrome from Anavex Scientific, GW Pharma, and Newron Pharma, outside the submitted work. FCV publishes the Dutch translations of Achenbach System of Empirically Based Assessment, from which he receives remuneration. AM was a speaker and advisor for Infectopharm, Lilly, Neurim, and Shire, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Exposure to traumatic events (TEs) is associated with substance use disorders (SUDs). However, most studies focus on a single TE, and are limited to single countries, rather than across countries with variation in economic, social and cultural characteristics. We used cross-national data to examine associations of diverse TEs with SUD onset, and variation in associations over time., Methods: Data come from World Mental Health surveys across 22 countries. Adults (n = 65,165) retrospectively reported exposure to 29 TEs in six categories: "exposure to organised violence"; "participation in organised violence"; "interpersonal violence"; "sexual-relationship violence"; "other life-threatening events"; and those involving loved ones ("network traumas"). Discrete-time survival analyses were used to examine associations with subsequent first SUD onset., Results: Most (71.0%) reported experiencing at least one TE, with network traumas (38.8%) most common and exposure to organised violence (9.5%) least. One in five (20.3%) had been exposed to sexual-relationship violence and 26.6% to interpersonal violence. Among the TE exposed, lifetime SUD prevalence was 14.5% compared to 5.1% with no trauma exposure. Most TE categories (except organised violence) were associated with increased odds of SUD. Increased odds of SUD were also found following interpersonal violence exposure across all age ranges (ORs from 1.56 to 1.78), and sexual-relationship violence exposure during adulthood (ORs from 1.33 to 1.44), with associations persisting even after >11 years., Conclusion: Sexual and interpersonal violence have the most consistent associations with progression to SUD; increased risk remains for many years post-exposure. These need to be considered when working with people exposed to such traumas., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The right and left ventricle of heart are intimately connected by anatomical and functional links. Hence, acute changes in cardiac geometry and function can modify the performance and physiology of both sides of the heart, influencing each other. After a brief overview of the anatomy and related imaging techniques for the study of right ventricular function, we report a review-on the interesting correlation of acute anterior myocardial infarction and right ventricular function, very often underestimated., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms., Methods: We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment)., Results: 1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm., Conclusions: Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Patients with respiratory diseases suffer more from problems of severe psychiatric comorbidity than the general population. Asthma might cause psychiatric disorders and affect patients' quality of life negatively. Previous studies reported that mental disorders prevail in asthmatic patients, causing anxiety, depression, and suicidal risk. The aim of this study is to evaluate in real life the prevalence of psychological comorbidities in asthmatics with severe asthma treated by biologicals (Benralizumab, Mepolizumab, Omalizumab). This study starts with the hypothesis that psychological distress, anxiety, depression and suicidal risk in severe asthma patients decreases if treated by biologicals. This study involves a sample of 90 patients (32 males, 58 females and aged 53.92 ± 15.92) suffering from severe asthma and treated with the biological drugs of Benralizumab, Mepolizumab, Omalizumab during Covid-19 pandemic. At the beginning of the treatment (T0) and after 16 weeks (T1), there have been reported results from both clinical disease control, assessed using the ACT, and psychological disorders, assessed with the PSS, HADS and C-SSRS. In the sample of these patients treated with biologicals for severe asthma, the study reported a significant change in all observed parameters, including asthma control (ACT), stress (PSS), anxiety (HADS-A) and depressive symptoms (HADS-D, despite Covid-19 pandemic. In addition, there was a significant improvement in disease management, perceived stress, anxiety and depressive symptoms after a 16 week treatment for severe asthma, independent from the type of biologic drugs used during the pandemic., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Effective lymphaticovenular anastomosis (LVA) requires identification of functioning lymphatics, which are not always visible with contrast-based imaging in advanced-stage lymphedema patients. Ultrasound (US) allows to identify preoperatively functioning lymphatic vessels even in limbs severely affected by lymphedema. Moreover, in our experience, we observed an interesting clinical sentry in advanced-stage lymphedema patients, the hand/foot sign that is analyzed in this paper., Patients and Methods: From January 2016 to January 2019, 76 consecutive advanced-stage secondary lymphedema patients underwent LVA. Preoperative planning included lymphoscintigraphy, indocyanine-green lymphography (ICG-L) and US. Patients' features, the hand/foot sign (preservation of more normal skin on the dorsum of the hand or foot), lymphatic degeneration, quantitative, qualitative, and composite outcomes at 1-year follow-up were evaluated., Results: An average number of 3±0.1 LVA was performed in upper limb lymphedema (ULL) (range 2-5, 47 patients) and of 4±1.08 LVAs in lower limb lymphedema (LLL) cases (range 4-7, 29 patients). The composite outcome was positive in 45 cases (59.7%). The "negative" hand /foot sign was significantly associated with presence of functioning lymphatic channels. The incidence of adverse outcomes was significantly higher in patients with positive hand/foot sign., Conclusion: Patients with no functioning lymphatic vessels detectable by lymphoscintigraphy and ICG-L may still have functioning lymphatic channels that can be identified preoperatively by ultra-high-frequency ultrasound and salvaged by LVA. The "hand/foot sign" is a simple clinical sentry that appears to be correlated with higher probability of being able to localize functional lymphatics for potential lymphovenous bypass surgery., Competing Interests: Declaration of Competing Interest Dr Akitatsu Hayashi and Dr Giuseppe Visconti are co-Editor of the book “Supermicrosurgical Lymphaticovenular Anastomosis: a Practical Textbook”. The other authors have no any interest to disclose., (Copyright © 2022. Published by Elsevier Ltd.)

Opioid receptors are divided into the three classical types: MOP(μ:mu), DOP(δ:delta) and KOP(κ:kappa) that are naloxone-sensitive and an additional naloxone-insensitive nociceptin/orphanin FQ(N/OFQ) peptide receptor(NOP). Studies to determine opioid receptor location and turnover variably rely on; (i) measuring receptor mRNA, (ii) genetically tagging receptors, (iii) labelling receptors with radioligands, (iv) use of antibodies in immunohistochemistry/Western Blotting or (v) measuring receptor function coupled with the use of selective antagonists. All have their drawbacks with significant issues relating to mRNA not necessarily predicting protein, poor antibody selectivity and utility of radiolabels in low expression systems. In this minireview we discuss use of fluorescently labelled opioid receptor ligands. To maintain the pharmacological properties of the corresponding parent ligand fluorescently labelled ligands must take into account fluorophore (brightness and propensity to bleach), linker length and chemistry, and site to which the linker (and hence probe) will be attached. Use of donor and acceptor fluorophores with spectral overlap facilitates use in FRET type assays to determine proximity of ligand or tagged receptor pairs. There is a wide range of probes of agonist and antagonist nature for all four opioid receptor types; caution is needed with agonist probes due to the possibility for internalization. We have produced two novel ATTO based probes; Dermorphin ATTO488 (MOP) and N/OFQ ATTO594 (NOP). These probes label MOP and NOP in a range of preparations and using N/OFQ ATTO594 we demonstrate internalization and ligand-receptor interaction by FRET. Fluorescent opioid probes offer potential methodological advantages over more traditional use of antibodies and radiolabels., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: We examined prevalence and factors associated with receiving perceived helpful alcohol use disorder (AUD) treatment, and persistence in help-seeking after earlier unhelpful treatment., Methods: Data came from 27 community epidemiologic surveys of adults in 24 countries using the World Health Organization World Mental Health surveys (n = 93,843). Participants with a lifetime history of treated AUD were asked if they ever received helpful AUD treatment, and how many professionals they had talked to up to and including the first time they received helpful treatment (or how many ever, if they had not received helpful treatment)., Results: 11.8% of respondents with lifetime AUD reported ever obtaining treatment (n = 9378); of these, 44% reported that treatment was helpful. The probability of obtaining helpful treatment from the first professional seen was 21.8%; the conditional probability of subsequent professionals being helpful after earlier unhelpful treatment tended to decrease as more professionals were seen. The cumulative probability of receiving helpful treatment at least once increased from 21.8% after the first professional to 79.7% after the seventh professional seen, following earlier unhelpful treatment. However, the cumulative probability of persisting with up to seven professionals in the face of prior treatments being unhelpful was only 13.2%., Conclusion: Fewer than half of people with AUDs who sought treatment found treatment helpful; the most important factor was persistence in seeking further treatment if a previous professional had not helped. Future research should examine how to increase the likelihood that AUD treatment is found to be helpful on any given contact., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The use of α-amino-γ lactam of Freidinger (Agl) may serve as an impressive method to increase the biological stability of peptides and an appropriate tool to elucidate their structure-activity relationships. The endomorphin-2 (EM-2) and [D-Ala 2 , des-Leu 5 ] enkephalin amide (DAPEA) are two linear opioid tetrapeptides agonists of MOR and MOR/DOR respectively. Herein, we investigated the influence of the incorporation of (R/S)-Agl in position 2 and 3 on the biological profile of the aforementioned products in vitro and in vivo. Receptor radiolabeled displacement and functional assays were used to measure in vitro the binding affinity and receptors activation of the novel analogues. The mouse tail flick and formalin tests allowed to observe their antinociceptive effect in vivo. Data revealed that peptide A2D was able to selectively bind and activate MOR with a potent antinociceptive effect after intracerebroventricular (i.c.v.) administration, performing better than the parent compounds EM-2 and DAPEA. Molecular docking calculations helped us to understand the key role exerted by the Freidinger Agl moiety in A2D for the interaction with the MOR binding pocket., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In recent years, the cancer survival of patients has improved thanks to advances in the pharmacological field. In many guidelines, cardiotoxicity induced by anticancer drugs was defined as a reduction from baseline in the left ventricular ejection fraction (LVEF) assessed by echocardiography. It is known that LVEF is not a sensible parameter in the detection of cardiotoxicity. Therefore, a decrease from baseline in the global longitudinal strain (GLS) or troponins elevation is used to detect subclinical cardiotoxicity. LVEF and GLS as well as the increase in some biomarkers are influenced by loading conditions that are frequent during chemotherapy. Other parameters not influenced by loading conditions should be used in the early diagnosis of cardiotoxicity. The aim of this review is to delineate the role of current strategies used in the early diagnosis of cardiotoxicity and to identify new strategies that could have greater application in the future in cardioncology., Competing Interests: Declaration of competing interest None declared., (Published by Elsevier Inc.)

Volume overload and fluid congestion are a fundamental issue in the assessment and management of patients with heart failure (HF). Recent studies have found that in acute decompensated heart failure (ADHF), right and left-sided pressures generally start to increase before any notable weight changes take place preceding an admission. ADHF may be a problem of volume redistribution among different vascular compartments instead of, or in addition to, fluid shift from the interstitial compartment. Thus, identifying heterogeneity of volume overload would allow guidance of tailored therapy. A comprehensive evaluation of congestive HF needs to take into account myriad parameters, including physical examination, echocardiographic values, and biomarker serum changes. Furthermore, potentially useful diagnostic tools include bioimpedance to measure intercompartmental fluid shifts, and evaluation of ultrasound lung comets to detect extravascular lung water., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) represents the arrhythmia of greatest clinical impact and catheter ablation of AF (CAAF) has become the most effective strategy for rhythm control in selected patients. Therefore, appropriate anticoagulation strategies are of paramount importance for patients undergoing CAAF, especially those at high risk, such those with high CHA2DS2VASc scores. Optimal management of anticoagulation before, during, and after CAAF is crucial. Several studies have evaluated the use of different anticoagulation strategies in the periprocedural period. Randomized controlled trial seem to suggest that in patients undergoing CAAF, uninterrupted (or minimally interrupted) direct oral anticoagulants (DOACs) provides an alternative to continuous vitamin K antagonists strategy, with low thromboembolic and bleeding risk., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A small library of 3-thia-7,9-diazabicyclo[3.3.1]nonanes was synthesized and their opioid receptors affinity and selectivity evaluated. Among these novel sulfur-bridged compounds, the (E) 9-[3'-(3-chlorophenyl)-but-2'-en-1'-yl]-7-propionyl-3-thia-7,9-diazabicyclo[3.3.1]nonane 2i emerged as the derivative with the highest μ receptor affinity (K i  = 85 nM) and selectivity (K i μ/δ = 58.8, K i μ/κ > 117.6). The antinociceptive activity of 2i was also evaluated in acute thermal pain. Docking studies disclosed the specific pattern of interactions of these derivatives., 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 Inc. All rights reserved.)

Bipolar disorder is a psychiatric pathology characterized by biphasic mood episodes of mania or hypomania and depression. The pharmacotherapy of bipolar disorder has significant adverse effects impairing treatment adherence and patient quality of life. The N/OFQ-NOP receptor system has been widely implicated with mood disorders. Clinical and preclinical findings suggest antidepressants actions for NOP antagonists. More recently, the administration of NOP agonists has shown to promote depressant states. The present study aimed to investigate the effects of non-peptide NOP ligands in methylphenidate-induced manic-like behavior in mice. The NOP agonist Ro 65-6570 (0.01-1 mg/kg, ip), at the higher dose, did not affect spontaneous locomotion per se, but prevented the methylphenidate (10 mg/kg, sc)-induced hyperlocomotion. The NOP partial agonist AT-090 (0.001-0.03 mg/kg, ip) and the NOP antagonist SB-612111 (1-10 mg/kg, ip) did not significantly affect the psychostimulant-induced hyperactivity. Experiments performed with mice lacking the NOP receptor (NOP(-/-)) demonstrated that the treatment with methylphenidate induced similar hyperlocomotion in NOP(-/-) and NOP(+/+) mice. In conclusion, these findings suggest a potential role for NOP agonists in the prevention of manic states, especially by counteracting the hyperactivity symptom of bipolar patients. However, more studies are necessary in order to evaluate these compounds in other features of bipolar disorder., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Aim: Elderly patients are at increased risk of hemorrhagic and thrombotic complications after an acute coronary syndrome (ACS). Frailty, comorbidities and low body weight have emerged as conditioning the prognostic impact of dual antiplatelet therapy (DAPT). The aim of the present study was to investigate the prognostic impact of body mass index (BMI) on clinical outcome among patients included in the Elderly-ACS 2 trial, a randomized, open-label, blinded endpoint study comparing low-dose (5 mg) prasugrel vs clopidogrel among elderly patients with ACS., Methods and Results: Our population is represented by 1408 patients enrolled in the Elderly-ACS 2 trial. BMI was calculated at admission. The primary endpoint of this analysis was cardiovascular (CV) mortality. Secondary endpoints were all-cause death, recurrent MI, Bleeding Academic Research Consortium (BARC) type 2 or 3 bleeding, and re-hospitalization for cardiovascular reasons or stent thrombosis within 12 months after index admission. Patients were grouped according to median values of BMI (

Prostaglandin D 2 (PGD 2 ) is a pleiotropic mediator, significantly involved in the pathogenesis of type 2 (T2) asthma because of its biologic actions exerted on both immune/inflammatory and airway structural cells. In particular, the pro-inflammatory and pro-remodelling effects of PGD 2 are mainly mediated by stimulation of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). This receptor is the target of the oral competitive antagonist fevipiprant, which on the basis of recent phase II studies is emerging as a potential very promising anti-asthma drug. Indeed, fevipiprant appears to be safe and effective, especially in consideration of its ability to inhibit eosinophilic bronchial inflammation and improve forced expiratory volume in one second (FEV 1 ). Further ongoing phase III trials will definitely clarify if fevipiprant can prospectively become a valid option for an efficacious add-on treatment of moderate-to-severe T2-high asthma., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Data on the epidemiology and risk factors for pouchitis following restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) in pediatric patients with ulcerative colitis (UC) are scarce., Aims: To determine incidence, risk factors and clinical outcome of pouchitis following IPAA in children., Methods: This multicenter, retrospective cohort study, included all pediatric UC patients who underwent colectomy and IPAA from January 2010 to December 2016., Results: Eighty-five patients were enrolled. During a median post-surgical period of 24.8 (range: 1.0-72.0) months following IPAA, 38 (44.7%) patients developed pouchitis, including 6 (15.8%) who developed chronic pouchitis. Kaplan-Meier survival estimates of the cumulative probability for pouchitis were 14.6% at 1 year and 27.3% and 51.5% at 2 and 5 years, respectively. Multiple Cox regression model showed that older age at colectomy (hazard ratio, HR: 0.89, p = 0.008) was a protective factor, whereas chronic active colitis as indication for surgery (HR: 4.45, p < 0.001), and a 3-stage IPAA (HR: 2.86, p = 0.028) increased the risk for pouchitis., Conclusions: Long-term risk for pouchitis is significantly high in pediatric-onset UC after IPAA. Younger age at colectomy, chronic active colitis as indication for surgery and 3-stage IPAA may increase the risk for pouchitis., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Introduction: The detection of a tooth with a sinus tract (ST) of endodontic origin and its pathway are conventionally assessed with a periapical radiograph and a gutta-percha cone introduced into its stoma. The aim of this study was to evaluate the possibility to detect STs and trace their route using ultrasound real-time examination., Methods: Two calibrated examiners performed echography on 10 patients who had a lesion of apical periodontitis (AP) and ST and 10 patients in the control group with AP without an ST recruited in 2 endodontic practices. They also traced the pattern of the STs with a computer program. The images were then submitted to 2 calibrated and blinded observers who were asked to describe the presence of AP and ST and to trace it with the same program. The data obtained were compared with the clinical and radiographic diagnosis of ST. For sensitivity, specificity, accuracy, and positive and negative predictive values, the receiver operating characteristic curve and Fisher exact test were used (P < .05)., Results: Interobserver agreement was high as was the diagnostic accuracy of the ultrasound examination of STs (mean value = 97.5%), and the Fisher exact test showed statistical significance (P < .05). High sensitivity and a negative predictive value and 100% specificity and a positive predictive value were also obtained. The application of the 3-dimensional mode further enabled the reconstructions of the more complex paths, and the implementation with color power Doppler disclosed the vascularity surrounding the STs., Conclusions: The ultrasound examination is a technique feasible to describe and trace the STs of endodontic origin., (Copyright © 2019 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Background: Illicit drug use and associated disease burden are estimated to have increased over the past few decades, but large gaps remain in our knowledge of the extent of use of these drugs, and especially the extent of problem or dependent use, hampering confident cross-national comparisons. The World Mental Health (WMH) Surveys Initiative involves a standardised method for assessing mental and substance use disorders via structured diagnostic interviews in representative community samples of adults. We conducted cross-national comparisons of the prevalence and correlates of drug use disorders (DUDs) in countries of varied economic, social and cultural nature., Methods and Findings: DSM-IV DUDs were assessed in 27 WMH surveys in 25 countries. Across surveys, the prevalence of lifetime DUD was 3.5%, 0.7% in the past year. Lifetime DUD prevalence increased with country income: 0.9% in low/lower-middle income countries, 2.5% in upper-middle income countries, 4.8% in high-income countries. Significant differences in 12-month prevalence of DUDs were found across country in income groups in the entire cohort, but not when limited to users. DUDs were more common among men than women and younger than older respondents. Among those with a DUD and at least one other mental disorder, onset of the DUD was usually preceded by the 'other' mental disorder., Conclusions: Substantial cross-national differences in DUD prevalence were found, reflecting myriad social, environmental, legal and other influences. Nonetheless, patterns of course and correlates of DUDs were strikingly consistent. These findings provide foundational data on country-level comparisons of DUDs., (Copyright © 2019. Published by Elsevier B.V.)

Background: We report our clinical experience of a supraclavicular lymph node flap (LNF) using a novel method of harvesting based on the compartimental lymphatic and vascular anatomy of the right posterior neck triangle, which allows to harvest two independent LNFs from the same donor site., Patients and Methods: We report a case series of 10 consecutive patients affected by cancer-related lower extremity lymphedema, who underwent compartimental dual LNF transfer from the right supraclavicular area to the affected lower limb, from August 2015 to March 2017. The superficial compartment flap (venous flap along the external jugular vein) was anastomosed in a flow-through fashion along the course of the great saphenous vein in the knee region, whereas the deep compartment flap (transverse cervical artery/vein flap) was anastomosed in an end-to-end fashion to the medial sural artery and comitantes vein. Flap viability was checked by color Doppler ultrasound postoperatively. Patients were assessed preoperatively and underwent follow-up at 6 and 12 months after surgery. Data were prospectively collected., Results: All the flaps resulted to be viable. No major postoperative complications were observed neither at the donor nor at the recipient sites. Patients did not report dysesthesia of the homoteral chest. An overall reduction in the lower extremity lymphedema (LEL) index (mean ± SD: 33.7 ± 22.5) and an improvement in the lymph flow and tracer appearance time at postoperative lymphoscintigraphy were observed. All the patients reported an improved quality of life after surgery., Conclusions: Compartimental supraclavicular dual LNF harvest seems promising in the treatment of peripheral lymphedema. Sparing of supraclavicular nerves might reduce the morbidity associated with the conventional surgical approach. Larger studies are needed to confirm our findings., Level of Evidence: IV, therapeutic study., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Reported findings on reactivity to stress of the sympathetic-adreno-medullar (SAM) and hypothalamic-pituitary-adrenal (HPA) systems in panic disorder (PD) are very variable. This inconsistency may be explained by differences in treatment exposure, illness duration and emotion regulation strategies. The present study examined the reactivity to mental stress of the SAM and HPA axes in a sample of first episode, drug naïve patients with PD which avoids confounds of medications exposure and illness chronicity. Activation of the SAM axis was evaluated by dosage of salivary alpha-amylase (sAA) and heart rate. Activation of the HPA axis was tested by dosage of salivary cortisol. Psychological assessments were done by the Self-Rating Depression Scale, the Self-Rating Anxiety Scale, the State-Trait Anxiety Inventory, the Cope Orientation to Problems Experienced (COPE) Inventory and the 16 Personality Factor Questionnaire (16PF). Patients showed reduced sAA stress reactivity, higher baseline cortisol levels and a more rapid decrease in stress cortisol levels as compared with controls. A significant correlation was found between active coping strategies and cortisol levels (response to stress). The findings suggest that blunted SAM stress reactivity and a rapid decrease in stress cortisol levels reflect traits that may enhance vulnerability to psychopathology in patients with PD., (Copyright © 2018 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

We have compared the anti-proliferative activity in vitro, of R 2 SnGala (1-3) [R = Me, n-Bu, Ph] and novel R 3 SnGala (4, 5) [R = Me, n-Bu] with D-(+)-Galacturonic acid [HGala; Gala q- , q = (2) and (1) for R 2 SnGala and R 3 SnGala, respectively] compounds, towards human tumor cell lines of intestinal carcinoma (HCT-116) and breast adenocarcinoma (MCF-7). The new synthesized 4 and 5 compounds were characterized, in solution, by 1 H, 13 C and 119 Sn NMR, that showed that HGala acts as monoanionic moiety and evidenced the dynamic behavior of the compounds, due to inter-conversions involving the anomeric carbon atom of the ligand. Cell viability, apoptosis induction and cell cycle distribution were analyzed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay and flow cytometry, respectively. The cytotoxicity of the compounds, in the micro-submicromolar range, changed in the order of the organotin(IV) moieties, according to 5 > 3 > 2, while 1 and 4, containing Me n Sn(IV) (n = 2,3) moieties, were ineffective. Compound 5 showed peculiar cytotoxic effects. It did not cause time dependent inhibition of cell growth nor accumulated into the cells. Cell death induced by the active 2, 3, and 5, was shown to be apoptotic by measuring the exposure of phosphatidylserine to the outer membrane and the loss of mitochondrial potential. All the cytotoxic compounds induced an accumulation of cells in the subG0/G1phase, while only 2 and 3 perturbed the cell cycle confining viable cells in G0/G1phase. Finally, none of the compounds investigated affected the viability of normal intestinal or liver cells, indicating selectivity towards tumor cells., (Copyright © 2018. Published by Elsevier Inc.)

Background: Intramedullary unlocked nailing is a safe and used treatment for stable pertrocantheric fractures. Due to the femoral anterior bow of the shaft or a wrong entry point, the distal tip of the nail can be impinging the anterior cortex. This type of situation can compromise the function of the nail, leading to nonunion of the fracture, and cut-out. The aim of this study was to assess the relationship between nail impingement of the anterior cortex of the femur and cut-out and nonunion incidence in patients with pertrochanteric stable fracture treated with an IM nail in an unlocked configuration., Material and Methods: A retrospective study based on medical records and imaging from the archives of our Level I academic medical center was conducted. The study included patients with proximal femoral fractures treated with short cephalomedullary nails between January 2012 and May 2015. The data collected were analyzed to a possible correlation with the healing time and occurrence of nonunion and cut-out., Results: The study population counted 429 cases. Applying the inclusion criteria the final series was composed of 169 patients: 112 females (66.73%) and 57 males (33.27%), with a mean age of 81.23 years (range: 67-93 years). Distal tip impingement was observed in 22 cases (13.02%). In total 16 (9.47%) postoperative complications were recorded: 8 non-union and 7 cut-outs. Consolidation was registered in 153 cases and the fracture healing time averaged 14.4 ± 3.8 weeks (range, 11-24 weeks). The cortical impingement was correlated with nonunion and cut-out (p < 0.001) Logistic regression analysis revealed jamming sign significantly affected the fracture healing time (p < 0.001)., Conclusion: The occurrence of cut-out and nonunion after cephalomedullary nailing of stable pertrochanteric fractures appear to be correlated to the presence of the cortical impingement. For this reason, the fake unlocked femoral nail with the cortical impingement is a configuration to avoid in stable pertrochanteric femur fractures., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: The treatment of intra-articular calcaneal fractures is still complex and controversial. Although open reduction and internal fixation (ORIF) is favored by many authors, several percutaneous techniques have been introduced to reduce complications and to obtain satisfactory clinical and radiological results. Among these percutaneous treatments, balloon reduction and bone graft augmentation is gaining an increasing popularity., Materials and Methods: We retrospectively examined a series of 42 patients treated operatively with a minimally invasive reduction technique using an inflatable bone tamp filled with tricalcium phosphate (calcaneoplasty) for Sander's type II, III and IV calcaneal fractures between 2010 and 2015. Conventional X-rays and CT scan were performed pre-operatively, at 3 and 12 months post-operatively and at the last-follow-up. The American Orthopaedic Foot and Ankle Society (AOFAS) score and the Maryland Foot Score (MFS) were used for clinical evaluation. Bohler's angle and the Score Analysis of Verona (SAVE) were calculated to assess bone reduction., Results: All 42 patients were available for clinical and radiographic follow-up at an average of 665 months (range 38-92). At the last follow-up the mean AOFAS score was 82.1 (good) and the mean MFS was 80.8 (good). The mean Bohler's angle improved from 1.29° pre-operatively to 27.8° at the last follow-up. The SAVE highlighted good and excellent results in 30 (72%) patients. There were only 3 (7.1%) cases of superficial skin infection with only 6 (14.2%) patients complaining of residual pain. No cases of adverse reaction or deep infection were observed., Conclusions: Calcaneoplasty appears to be a valid option of treatment for calcaneal fractures and a reliable alternative to ORIF. This technique allows stable fracture reduction and early weight-bearing combined with good clinical and radiological results and few complications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Stone extraction represents the most frequent indication for endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic papillary large balloon dilation (EPLBD) is a recent introduced approach consisting of an endoscopic papillary large balloon dilation following limited endoscopic sphyncterotomy (ES), which has been proven to be safe and effective for extraction of large common bile duct (CBD) stones. Peri-ampullary diverticula (PAD) are described in 10-20% of patients undergoing ERCP. Aim of our study is to evaluate efficacy and safety of EPLBD for the extraction of large biliary stones in patients with PAD., Methods: The prospectively collected endoscopy databases of 4 Italian ERCP high-volume centers were reviewed retrospectively, and all consecutive patients with an instrumental diagnosis of large biliary stones and PAD, between September 2014 and October 2016, were included in this study., Results: Eighty-one patients (36 males, median age 75 years) were treated between September 2014 and October 2016. Deep biliary cannulation was reached in 78/80 patients. Successful extraction was achieved in 74/78 patients at the first attempt. AEs occurred in 8 patients (1 severe). Younger age, stone size and incomplete stone extraction were significantly associated with AEs., Conclusions: EPLBD is an effective and safe technique in patients with PAD and large biliary stones, which avoids the need of other techniques, thereby reducing the risks of adverse events., (Copyright © 2018. Published by Elsevier Ltd.)

Municipal solid waste incinerators emissions contain pollutants that, despite their low concentration, might adversely affect reproductive health. In the present study, we examined rates of miscarriage and birth defects among women who resided or were employed in the vicinity of a municipal solid waste incinerator plant from 2003 to 2013. In 2009, a progressive shutdown of the old incineration lines and operation of a new line caused considerably higher atmospheric release of polycyclic aromatic hydrocarbons, particularly of dioxins, due to these irregular operating conditions, technological renovation, and increased capacity. We used dioxin emission levels, based on a dispersion model, to define exposure status of the residing population to air pollutants emitted by the waste incinerator. In women who resided in areas characterized by higher emission exposures compared with a referent area, the relative risk (RR) of miscarriage was 1.04 (95% confidence interval (CI) 0.80-1.32) based on 62 cases overall, with little evidence of a dose-response relation. RRs were similarly null for both 2003-2008 and 2010-2013 periods (RR 1.12 (95% CI 0.80-1.53) and 0.98 (95% CI 0.63-1.48), respectively). Concerning birth defects in the offspring of women residing in the exposed area, no evidence of increased risk emerged, since the prevalence ratio at birth was 0.64 (95% CI 0.29-1.26), with comparable results in the 2003-2008 and 2010-2013 period. Corresponding analyses carried out in municipal residents who worked in the exposed area confirmed these findings. We also did not detect abnormally high rates of miscarriage and birth defects in the exposed cohorts in the single year 2009. Overall, these results do not suggest an effect of exposure to the emissions of the municipal solid waste incinerator we investigated on two indicators of reproductive health. However, the limited statistical stability of the estimates and the absence of individual-based information on some potential confounders suggest caution in the interpretation of study findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Clinical and molecular factors are essential to define the prognosis in patients with glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status, age, Karnofsky Performance Status (KPS), and extent of surgical resection are the most relevant prognostic factors. Our investigation of the role of gender in predicting prognosis shows a slight survival advantage for female patients., Methods: We performed a prospective evaluation of the Project of Emilia Romagna on Neuro-Oncology (PERNO) registry to identify prognostic factors in patients with GBM who received standard treatment., Results: A total of 169 patients (99 males [58.6%] and 70 females [41.4%]) were evaluated prospectively. MGMT methylation was evaluable in 140 patients. Among the male patients, 36 were MGMT methylated (25.7%) and 47 were unmethylated (33.6%); among the female patients, 32 were methylated (22.9%) and 25 were unmethylated (17.9%). Survival was longer in the methylated females compared with the methylated males (P = 0.028) but was not significantly different between the unmethylated females and the unmethylated males (P = 0.395). In multivariate analysis, gender and MGMT methylation status considered together (methylated females vs. methylated males; hazard ratio [HR], 0.459; 95% confidence interval [CI], 0.242-0.827; P = 0.017), age (HR, 1.025; 95% CI, 1.002-1.049; P = 0.032), and KPS (HR, 0.965; 95% CI, 0.948-0.982; P < 0.001) were significantly correlated with survival., Conclusions: Survival was consistently longer among MGMT methylated females compared with males. Gender can be considered as a further prognostic factor., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The WHO Child and Adolescent Mental Health Atlas, published in 2005, reported that child and adolescent mental health services (CAMHS) in Europe differed substantially in their architecture and functioning. We assessed the characteristics of national CAMHS across the European Union (EU), including legal aspects of adolescent care. Using an online mapping survey aimed at expert(s) in each country, we obtained data for all 28 countries in the EU. The characteristics and activities of CAMHS (ie, availability of services, inpatient beds, and clinicians and organisations, and delivery of specific CAMHS services and treatments) varied considerably between countries, as did funding sources and user access. Neurodevelopmental disorders were the most frequent diagnostic group (up to 81%) for people seen at CAMHS (data available from only 13 [46%] countries). 20 (70%) countries reported having an official national child and adolescent mental health policy, covering young people until their official age of transition to adulthood. The heterogeneity in resource allocation did not seem to match epidemiological burden. Substantial improvements in the planning, monitoring, and delivery of mental health services for children and adolescents are needed., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The aim of this large retrospective study was to provide a logistic risk model along an additive score to predict early mortality after surgical treatment of patients with heart valve or prosthesis infective endocarditis (IE)., Methods: From 2000 to 2015, 2715 patients with native valve endocarditis (NVE) or prosthesis valve endocarditis (PVE) were operated on in 26 Italian Cardiac Surgery Centers. The relationship between early mortality and covariates was evaluated with logistic mixed effect models. Fixed effects are parameters associated with the entire population or with certain repeatable levels of experimental factors, while random effects are associated with individual experimental units (centers)., Results: Early mortality was 11.0% (298/2715); At mixed effect logistic regression the following variables were found associated with early mortality: age class, female gender, LVEF, preoperative shock, COPD, creatinine value above 2mg/dl, presence of abscess, number of treated valve/prosthesis (with respect to one treated valve/prosthesis) and the isolation of Staphylococcus aureus, Fungus spp., Pseudomonas Aeruginosa and other micro-organisms, while Streptococcus spp., Enterococcus spp. and other Staphylococci did not affect early mortality, as well as no micro-organisms isolation. LVEF was found linearly associated with outcomes while non-linear association between mortality and age was tested and the best model was found with a categorization into four classes (AUC=0.851)., Conclusions: The following study provides a logistic risk model to predict early mortality in patients with heart valve or prosthesis infective endocarditis undergoing surgical treatment, called "The EndoSCORE"., (Copyright © 2017. Published by Elsevier B.V.)

HSCR is a congenital disorder of the enteric nervous system, characterized by the absence of neurons along a variable length of the gut resulting from loss-of-function RET mutations. Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by impaired response to hypercapnia and hypoxemia caused by heterozygous mutations of the PHOX2B gene, mostly polyalanine (polyA) expansions but also missense, nonsense, and frameshift mutations, while polyA contractions are common in the population and believed neutral. HSCR associated CCHS can present in patients carrying PHOX2B mutations. Indeed, RET expression is orchestrated by different transcriptional factors among which PHOX2B, thus suggesting its possible role in HSCR pathogenesis. Following the observation of HSCR patients carrying in frame trinucleotide deletions within the polyalanine stretch in exon 3 (polyA contractions), we have verified the hypothesis that these PHOX2B variants do reduce its transcriptional activity, likely resulting in a down-regulation of RET expression and, consequently, favouring the development of the HSCR phenotype. Using proper reporter constructs, we show here that the in vitro transactivation of the RET promoter by different HSCR-associated PHOX2B polyA variants has resulted significantly lower compared to the effect of PHOX2B wild type protein. In particular, polyA contractions do induce a reduced transactivation of the RET promoter, milder compared to the severe polyA expansions associated with CCHS+HSCR, and correlated with the length of the deleted trait, with a more pronounced effect when contractions are larger., (Copyright © 2017 Elsevier B.V. All rights reserved.)