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Gianenrico Senna,1,2 Maria Aliani,3 Elena Altieri,4 Pietro Bracciale,5 Luisa Brussino,6 Maria Filomena Caiaffa,7 Paolo Cameli,8 Giorgio Walter Canonica,9,10 Cristiano Caruso,11 Maria D’Amato,12 Fausto De Michele,13 Stefano Del Giacco,14 Fabiano Di Marco,15 Francesco Menzella,16 Girolamo Pelaia,17 Paola Rogliani,18,19 Micaela Romagnoli,20 Pietro Schino,21 Jan Walter Schroeder,22 Alessandra Vultaggio,23 Sara Rizzoli,24 Alessandro Zullo,24 Silvia Boarino,25 Marilena Palmisano,26 Alessandra Rossi,26 Gianfranco Vitiello,26 Stefano Centanni27 1Department of Medicine, University of Verona, Verona, Italy; 2Allergy Unit and Asthma Center, Verona University Hospital, Verona, Italy; 3UO Pneumologia e Pneumologia Riabilitativa, ICS Maugeri, IRCCS Bari, Bari, Italy; 4Reparto di Pneumologia, P.O., Garbagnate Milanese, Italy; 5Reparto di Pneumologia, Ospedale Ostuni, Ostuni, BR, Italy; 6Dipartimento di Scienze Mediche, SSDDU Allergologia e Immunologia Clinica, Università degli Studi di Torino, AO Ordine Mauriziano Umberto I, Torino, Italy; 7Cattedra e Scuola di Allergologia e Immunologia Clinica, Dipartimento di Scienze Mediche, Università di Foggia, Foggia, Italy; 8Respiratory Diseases and Lung Transplantation, Department of Medical and Surgical Sciences & Neurosciences, Siena University Hospital, Siena, Italy; 9Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, MI, Italy; 10Personalized Medicine Center: Asthma and Allergology, Humanitas Research Hospital, Rozzano, MI, Italy; 11Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico A. Gemelli, IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy; 12UOSD Malattie Respiratorie “Federico II”, Ospedale Monaldi, AO Dei Colli, Napoli, Italy; 13UOC Pneumologia e Fisiopatologia Respiratoria, AORN A. Cardarelli, Napoli, Italy; 14Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; 15Department of Health Sciences, Università Degli Studi Di Milano, Pneumologia, ASST Papa Giovanni XXIII, Bergamo, Italy; 16UOC Pneumologia, Ospedale “S. Valentino”, AULSS 2 Marca Trevigiana, Montebelluna, TV, Italy; 17Dipartimento di Scienze della Salute, Università Magna Graecia, Catanzaro, Italy; 18Division of Respiratory Medicine, University Hospital “Tor Vergata”, Roma, Italy; 19Unit of Respiratory Medicine, Department of Experimental Medicine, University of Rome “Tor Vergata”, Roma, Italy; 20UOC Pneumologia, ULSS 2 Marca Trevigiana, Treviso, Italy; 21Fisiopatologia Respiratoria, Ospedale Generale Regionale, Ente Ecclesiastico “F. Miulli”, Acquaviva delle Fonti, BA, Italy; 22Allergy and Clinical Immunology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy; 23Dipartimento di Medicina Sperimentale e Clinica, Università degli Studi di Firenze, Firenze, Italy; 24Medineos Observational Research - An IQVIA Company, Modena, Italy; 25Medical Evidence R&I, AstraZeneca, Milano, Italy; 26Medical Affairs R&I, AstraZeneca, Milano, Italy; 27Respiratory Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, Università degli Studi di Milano, Milano, ItalyCorrespondence: Marilena Palmisano, Medical Affairs R&I, AstraZeneca, Milano, Italy, Email marilena.palmisano@astrazeneca.comPurpose: Benralizumab effectively reduces severe eosinophilic asthma (SEA) exacerbations in patients with a wide range of baseline blood eosinophil count (BEC). Patients included in real-world studies are often characterized by high mean/median BEC, while patients with BEC close to 300 cells/mm3 are poorly represented. This post hoc analysis from the Italian study ANANKE aims to define the clinical features and corroborate the efficacy of benralizumab in real world in the BEC 300– 450 cells/mm3 subset of patients.Patients and Methods: Post hoc analysis of the Italian, multicenter, observational, retrospective real-life study ANANKE (NCT04272463). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment and presented for a BEC 300– 450 cells/mm3 subgroup of patients. Change over time of BEC, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use at 16, 24 and 48 weeks after benralizumab introduction were collected.Results: A total of 164 patients were analyzed, 34 of whom with a BEC of 300– 450 cells/mm3. This subgroup was more likely to be female (64.7%), with lower rates of severe exacerbations at baseline when compared to the total population (0.69 vs 1.01). After 48 weeks of benralizumab treatment, the BEC 300– 450 subset showed similar reductions in AER (− 94.8% vs − 92.2%) and OCS use (median dose reduction of 100% in both groups), as well as improvement in ACT score (median scores 22.5 vs 22) and lung function (pre-BD FEV1: +200 mL vs +300 mL) when compared to the total population. No discontinuations for safety reasons were registered.Conclusion: At baseline, apart from lower severe exacerbation rate, the BEC 300– 450 cells/mm3 subset of patients is comparable to the total population prescribed with benralizumab. In this real-life study, benralizumab is as effective in BEC 300– 450 patients as in the total population.Keywords: severe eosinophilic asthma, blood eosinophil count, benralizumab, observational, real-world evidence, real-life

Delia Colombo,1 Emanuela Zagni,1 Mihaela Nica,1 Sara Rizzoli,2 Alessandra Ori,2 Gilberto Bellia1 1Patient Access, Novartis Farma S.p.A., Origgio, Varese, 2MediNeos Observational Research, Modena, Italy Background: MetaGeM is a wide gender-medicine project comprising post hoc and meta-analyses by gender of clinical outcomes, therapeutic approaches, and safety data from previously conducted observational studies to explore possible gender differences in real-life clinical settings. We report the results of the safety meta-analysis of seven MetaGeM studies, evaluating gender differences in adverse event (AE) incidence and severity. Methods: Data were collected between February 2002 and July 2013. Male and female patients were compared for the main safety variables, using Student’s t-test, χ² test, or Fisher’s exact test as appropriate. As supportive analysis, a logistic regression model was estimated to evaluate associations between gender and outcome. Results: In total, 4,870 patients (46% females, 54% males) were included in the analysis; age was higher for females (mean ± standard deviation 61.2±18.3 years) than males (56.3±16.6 years). Overall, 264 AEs were reported (59.1% in males). There were no significant gender differences in the percentage of patients with at least one AE: 3.0% for females versus 3.9% for males, χ² test P>0.05. According to the logistic regression model results, no association between gender and AEs occurrence seems to exist. A statistically significant gender difference in the percentage of drug-related AEs emerged (37.6% in females vs 20.8% in males, χ² P=0.0039). Slightly significantly more AEs in females were addressed with treatment compared with males (78.1% vs 66.7%, χ² P=0.0485). Total serious AEs (SAEs) were 47 (72% in males). The frequency of patients with ≥1 SAE was 0.6% in females versus 1.2% in males (χ² test P=0.0246). Conclusion: This safety analysis on a large sample of almost 5,000 patients with different diseases and treated with a wide range of different drugs provides a useful overview on possible gender differences in drug tolerability, which may be helpful in more accurately designing future clinical trials from a gender-specific perspective. Keywords: gender, drugs, safety, adverse events, meta-analysis

Delia Colombo,1 Gilberto Bellia,1 Donatella Vassellatti,1 Emanuela Zagni,1 Simona Sgarbi,2 Sara Rizzoli21Novartis Farma, Origgio, 2MediData, Modena, ltaly Abstract: Only recently has medical research begun to understand the importance of taking sex into account, recognizing that symptoms and responses to medical treatment may be very different between males and females. However, the analyses provided by the pharmaceutical industry to regulatory authorities often do not present safety and efficacy data by sex. Novartis has started a gender-medicine project called MetaGeM, which includes nine observational studies sponsored by Novartis Farma, Italy; conducted in Italy between 2002 and 2013 in a range of different clinical areas. The MetaGeM project aims to analyze and describe by means of post hoc analyses and meta-analyses, clinical outcomes, therapeutic approaches, and safety data of these studies, by sex: PSYCHAE; GENDER ATTENTION in psoriasis; Synergy in psoriatic arthritis; ICEBERG in HBsAg carriers; SURF and CETRA in liver- and renal transplanted patients, respectively; DEEP in Parkinson's disease; and EVOLUTION and AXEPT in Alzheimer's disease. The present paper describes the methodology of the MetaGeM project.Keywords: gender-medicine, MetaGeM project, methodology

Background: FIBRONET was an observational, multicentre, prospective cohort study investigating the baseline characteristics, clinical course of disease and use of antifibrotic treatment in Italian patients with idiopathic pulmonary fibrosis (IPF).Methods: Patients aged ≥ 40 years diagnosed with IPF within the previous 3 months at 20 Italian centres were consecutively enrolled and followed up for 12 months, with evaluations at 3, 6, 9 and 12 months. The primary objective was to describe the clinical course of IPF over 12 months of follow-up, including changes in lung function measured by % predicted forced vital capacity (FVC% predicted).Results: 209 patients (82.3% male, mean age 69.54 ± 7.43 years) were enrolled. Mean FVC% predicted was relatively preserved at baseline (80.01%). The mean time between IPF diagnosis and initiation of antifibrotic therapy was 6.38 weeks; 72.3% of patients received antifibrotic therapy within the first 3 months of follow-up, and 83.9% within 12 months of follow-up. Mean FVC% predicted was 80.0% at baseline and 82.2% at 12 months, and 47.4% of patients remained stable (i.e. had no disease progression) in terms of FVC% predicted during the study.Conclusions: FIBRONET is the first prospective, real-life, observational study of patients with IPF in Italy. The short time between diagnosis and initiation of antifibrotic therapy, and the stable lung function between baseline and 12 months, suggest that early diagnosis and prompt initiation of antifibrotic therapy may preserve lung function in patients with IPF.Trial Registration: NCT02803580. [ABSTRACT FROM AUTHOR]

Severe psychiatric illnesses, for instance schizophrenia, and affective diseases or autism spectrum disorders, have been associated with cognitive impairment and perturbed excitatory-inhibitory balance in the brain. Effects in juvenile mice can elucidate how erythropoietin (EPO) might aid in rectifying hippocampal transcriptional networks and synaptic structures of pyramidal lineages, conceivably explaining mitigation of neuropsychiatric diseases. An imminent conundrum is how EPO restores synapses by involving interneurons. By analyzing ~12,000 single-nuclei transcriptomic data, we generated a comprehensive molecular atlas of hippocampal interneurons, resolved into 15 interneuron subtypes. Next, we studied molecular alterations upon recombinant human (rh)EPO and saw that gene expression changes relate to synaptic structure, trans-synaptic signaling and intracellular catabolic pathways. Putative ligand-receptor interactions between pyramidal and inhibitory neurons, regulating synaptogenesis, are altered upon rhEPO. An array of in/ex vivo experiments confirms that specific interneuronal populations exhibit reduced dendritic complexity, synaptic connectivity, and changes in plasticity-related molecules. Metabolism and inhibitory potential of interneuron subgroups are compromised, leading to greater excitability of pyramidal neurons. To conclude, improvement by rhEPO of neuropsychiatric phenotypes may partly owe to restrictive control over interneurons, facilitating re-connectivity and synapse development., (© 2024. The Author(s).)

Purpose: Benralizumab effectively reduces severe eosinophilic asthma (SEA) exacerbations in patients with a wide range of baseline blood eosinophil count (BEC). Patients included in real-world studies are often characterized by high mean/median BEC, while patients with BEC close to 300 cells/mm 3 are poorly represented. This post hoc analysis from the Italian study ANANKE aims to define the clinical features and corroborate the efficacy of benralizumab in real world in the BEC 300-450 cells/mm 3 subset of patients., Patients and Methods: Post hoc analysis of the Italian, multicenter, observational, retrospective real-life study ANANKE (NCT04272463). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment and presented for a BEC 300-450 cells/mm 3 subgroup of patients. Change over time of BEC, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use at 16, 24 and 48 weeks after benralizumab introduction were collected., Results: A total of 164 patients were analyzed, 34 of whom with a BEC of 300-450 cells/mm 3 . This subgroup was more likely to be female (64.7%), with lower rates of severe exacerbations at baseline when compared to the total population (0.69 vs 1.01). After 48 weeks of benralizumab treatment, the BEC 300-450 subset showed similar reductions in AER (-94.8% vs -92.2%) and OCS use (median dose reduction of 100% in both groups), as well as improvement in ACT score (median scores 22.5 vs 22) and lung function (pre-BD FEV 1 : +200 mL vs +300 mL) when compared to the total population. No discontinuations for safety reasons were registered., Conclusion: At baseline, apart from lower severe exacerbation rate, the BEC 300-450 cells/mm 3 subset of patients is comparable to the total population prescribed with benralizumab. In this real-life study, benralizumab is as effective in BEC 300-450 patients as in the total population., Competing Interests: GS has nothing to declare; MA has nothing to declare; EA has nothing to declare; PB has nothing to declare; LB has nothing to declare; MFC has nothing to declare; PC reports having received in the last 3 years research grants and fees as speaker from AstraZeneca-MedImmune, Guidotti-Malesci and GlaxoSmithKline; GWC reports having received in the last 3 years research grants as well as lecture or advisory board fees from A. Menarini, Allergy – Therapeutics, AstraZeneca-MedImmune, Boehringer Ingelheim, Chiesi, Faes, Genentech, Guidotti-Malesci, GlaxoSmithKline, HAL Allergy, Novartis, Sanofi-Aventis, Sanofi-Genzyme/Regeneron, Stallergenes-Greer, Thermo Fisher, Valeas, Vifor Pharma; CC has nothing to declare; MDA has nothing to declare; FDMa has received lectures fees at national and international meetings and consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompé, Guidotti/Malesci, GlaxoSmithKline, Menarini, Novartis, and Zambon; SDG received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini, Novartis, Sanofi; FDMi has nothing to declare; FM declares research funding as Principal investigator by AstraZeneca, Chiesi Farmaceutici, Novartis, Sanofi; fees as speaker/lecturer by AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Sanofi; GP has received lecture fees and consultancy fees from AlfaSigma, AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti-Malesci, Menarini, Mundipharma, Novartis, Sanofi, Zambon; PR has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis, her department has received funding from Almirall, Boehringer Ingelheim, Chiesi, Novartis, and Zambon; MR declares grants and personal fees from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, Chiesi, GSK, Menarini, Guidotti, AlfaSigma, Zambon; PS has nothing to declare; JWS has nothing to declare; AV participated as a lecturer/speaker in scientific meetings under the sponsorship of AstraZeneca, Chiesi, GlaxoSmithKline, Novartis; SR and AZ are employees of Medineos Observational Research – an IQVIA company, Modena Italy contracted by AstraZeneca, Italy; SB, MP and AR are AstraZeneca employees; GV was an AstraZeneca employee at the time of manuscript preparation; SC declares grants and/or personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas., (© 2022 Senna et al.)

Background: Severe asthma is a heterogeneous inflammatory disease driven by eosinophilic inflammation in the majority of cases. Despite biologic therapy patients may still be sub-optimally controlled, and the choice of the best biologic is a matter of debate. Indeed, switching between biologics is common, but no official guidelines are available and real-world data are limited., Materials and Methods: In this post hoc analysis of the Italian, multi-center, observational, retrospective study, ANANKE. Patients with severe eosinophilic asthma treated with benralizumab were divided in two groups based on history of previous biologic therapy (biologic-experienced [suboptimal response] vs naïve). Baseline clinical and laboratory characteristics were collected in the 12 months prior to benralizumab treatment. Change over time in blood eosinophils, annualized exacerbation rate (AER), asthma control (ACT), lung function and oral corticosteroid (OCS) use following benralizumab initiation were collected in the two groups., Results: A total of 147 biologic-naïve and 58 biologic-experienced (34 omalizumab, 19 mepolizumab, and 5 omalizumab-mepolizumab) patients were enrolled. Biologic-experienced patients were more likely to be atopic and have a higher AER despite more frequent OCS use. Similar reductions in AER (>90% in both groups), OCS use (≥49% reduction in dosage and ≥41% able to eliminate OCS), ACT improvement (≥7 points gained in 48 weeks) and lung function (≥300 mL of FEV 1 improvement in 48 weeks) were observed after benralizumab introduction within the two groups. There were no registered discontinuations of benralizumab for safety reasons., Conclusion: In this post hoc analysis, patients who were switched to benralizumab because of suboptimal control with a previous biologic therapy were more likely to be atopic and more often treated with omalizumab. Benralizumab is effective in both naïve patients and those previously treated with a biologic., Competing Interests: FM declares research fundings as Principal Investigator by AstraZeneca, Chiesi Farmaceutici, Novartis, Sanofi; fees as speaker/lecturer by AstraZeneca, Chiesi Farmaceutici, GlaxoSmithKline, Novartis, Sanofi. SC declares grants and/or personal fees from AstraZeneca, Boheringer Ingelheim, Chiesi, Glaxo Smith Kline, Guidotti, Menarini, Novartis, Valeas. SD received grants and/or personal fees from AstraZeneca, Chiesi, Glaxo Smith Kline, Menarini, Novartis. FDi has received lectures fees at national and international meetings and consultancy fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi Farmaceutici, Dompe, Guidotti/Malesci, GlaxoSmithKline, Menarini, Novartis, and Zambon. GP has received lecture fees and consultancy fees from Alfasigma, AstraZeneca, Chiesi, GlaxoSmithKline, Guidotti-Malesci, Menarini, Mundipharma, Novartis, Sanofi, and Zambon. PR has participated as a lecturer, speaker, and advisor in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Biofutura, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Menarini Group, Mundipharma, and Novartis, her department has received funding from Almirall, Boehringer Ingelheim, Chiesi, Novartis, and Zambon. MR declares grants and personal fees from Boehringer Ingelheim, Roche, AstraZeneca, Novartis, Chiesi, GSK, Menarini, Guidotti, AlfaSigma, and Zambon. AV received payment for lectures and consultant arrangements from Novartis, GlaxoSmithKline, Teva, and AstraZeneca. GC has received grant/research support from Boehringer Ingelheim, ALK, and Stallergenes, and honoraria or consultation fees from Menarini, GSK, Sanofi, Teva, Hal, AstraZeneca, and Novartis. AZ and SR were employed by MediNeos Observational Research – an IQVIA company. SB and GV were employed by AstraZeneca SpA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Caruso, Cameli, Altieri, Aliani, Bracciale, Brussino, Caiaffa, Canonica, Centanni, D’Amato, Del Giacco, De Michele, Pastorello, Pelaia, Rogliani, Romagnoli, Schino, Caminati, Vultaggio, Zullo, Rizzoli, Boarino, Vitiello, Menzella and Di Marco.)

Background: Phenotypic features and outcome differences between sexes have been reported in psoriatic arthritis (PsA). However, little is known about sex differences in effectiveness of biologics in clinical practice. Methods: Post hoc gender analysis of the CHRONOS, a multicenter, noninterventional, retroprospective Italian real-world study assessing 6-month and 1-year effectiveness of biologics for PsA. Results: Eligible patients were 399, 43.1% men. Sociodemographic characteristics, type of arthritis, baseline Disease Activity Score 28 joints (DAS28), and duration of biologic treatment were rather homogeneous. More men were overweight/obese and naive to biologics. The most frequently used biologics were TNF-inhibitors and secukinumab in both sexes. DAS28 responders were 72.7% (women) and 70.5% (men) at 6 months, and 68.0% in both sexes at 1 year. American College of Rheumatology (ACR) response showed a trend for men versus women to achieve more frequently ACR50 (32.6% vs. 26.5% at 6 months; 34.9% vs. 20.0% at 1 year) and ACR70 (22.3% vs. 12.4% at 6 months and 25.0% vs. 13.0% at 1 year). Global satisfaction with treatment at enrollment and after 6 months was slightly higher among men [mean (standard deviation) Treatment Satisfaction Questionnaire for Medication-9 (TSQM-9) score: 68.6 (18.6) and 69.9 (18.2), respectively] than women [65.3 (18.2), 66.2 (18.5)]. Conclusions: Overall response to biologics for PsA was rather favorable. With similar baseline disease severity, men appear to have a somewhat earlier and better response with higher treatment satisfaction., Competing Interests: D.C. was a part-time employee of Novartis Farma Italy when the study was conducted. F.I. received speaker/consultation fees from AbVie, Roche, MSD, UCB, Lily, Jansen, Sanofi, Pfizer, and Novartis. F.C. received speaker fees from Abbvie, Lilly, BMS, Galapagos, and Pfizer. S.R. is an employee of MediNeos Observational Research (Modena, Italy), hired by Novartis Farma Italy, responsible for the design and conduction of the CHRONOS study, as well as scientific support, clinical operations, data management, and statistical analysis. B.R. is an employee of MediNeos Observational Research (Modena, Italy), hired by Novartis Farma Italy, responsible for the design and conduction of the CHRONOS study, as well as scientific support, clinical operations, data management, and statistical analysis. M.F., R.O., and E.Z. are employees of Novartis Farma Italy. No further CoI were declared., (© Delia Colombo et al., 2021; Published by Mary Ann Liebert, Inc.)

In adult cornu ammonis hippocampi, erythropoietin (EPO) expression drives the differentiation of new neurons, independent of DNA synthesis, and increases dendritic spine density. This substantial brain hardware upgrade is part of a regulatory circle: during motor-cognitive challenge, neurons experience "functional" hypoxia, triggering neuronal EPO production, which in turn promotes improved performance. Here, we show an unexpected involvement of resident microglia. During EPO upregulation and stimulated neurodifferentiation, either by functional or inspiratory hypoxia, microglia numbers decrease. Treating mice with recombinant human (rh)EPO or exposure to hypoxia recapitulates these changes and reveals the involvement of neuronally expressed IL-34 and microglial CSF1R. Surprisingly, EPO affects microglia in phases, initially by inducing apoptosis, later by reducing proliferation, and overall dampens microglia activity and metabolism, as verified by selective genetic targeting of either the microglial or pyramidal neuronal EPO receptor. We suggest that during accelerating neuronal differentiation, EPO acts as regulator of the CSF1R-dependent microglia., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Fingolimod is the first oral agent approved for treatment of relapsing-remitting multiple sclerosis (RRMS). We aimed to evaluate fingolimod effectiveness in a real-world sample of RRMS patients., Methods: A retrospective, multicentre study in patients treated with fingolimod, whom clinical and radiological data were collected in the 2 years preceding and following the initiation of fingolimod., Results: Out of 414 patients, 56.8% received prior first-line injectable disease-modifying therapies, 25.4% were previously treated with natalizumab, 1.2% with immunosuppressant agents, and 16.7% were treatment naive. The annualized relapse rate decreased by 65% in the first year and by 70% after two years of treatment. Age ≤ 40 years, ≥ 1 relapse in the 24 months before fingolimod initiation and previous treatment with natalizumab were risk factors for relapses. Overall, 67.9% patients had no evidence of disease activity (NEDA-3) after 1 year and 54.6% after 2 years of treatment. A higher proportion of naïve (81.2% in 1 year and 66.7% after 2 years) or first-line injected patients (70.2% and 56.6%) achieved NEDA-3 than those previously treated with natalizumab (54.3% and 42.9%)., Conclusions: Fingolimod appeared to be effective in naive patients and after first-line treatment failure in reducing risk of relapse and disease activity throughout the 2-year follow-up.

Background: This paper is aimed to (i) develop an innovative classification of COPD, multi-dimensional phenotype, based on a multidimensional assessment; (ii) describe the identified multi-dimensional phenotypes., Methods: An exploratory factor analysis to identify the main classificatory variables and, then, a cluster analysis based on these variables were run to classify the COPD-diagnosed 514 patients enrolled in the STORICO (trial registration number: NCT03105999) study into multi-dimensional phenotypes., Results: The circadian rhythm of symptoms and health-related quality of life, but neither comorbidity nor respiratory function, qualified as primary classificatory variables. Five multidimensional phenotypes were identified: the MILD COPD characterized by no night-time symptoms and the best health status in terms of quality of life, quality of sleep, level of depression and anxiety, the MILD EMPHYSEMATOUS with prevalent dyspnea in the early-morning and day-time, the SEVERE BRONCHITIC with nocturnal and diurnal cough and phlegm, the SEVERE EMPHYSEMATOUS with nocturnal and diurnal dyspnea and the SEVERE MIXED COPD distinguished by higher frequency of symptoms during 24h and worst quality of life, of sleep and highest levels of depression and anxiety., Conclusions: Our results showed that properly collected respiratory symptoms play a primary classificatory role of COPD patients. The longitudinal observation will disclose the discriminative and prognostic potential of the proposed multidimensional phenotype., Trial Registration: Trial registration number: NCT03105999, date of registration: 10th April 2017., Competing Interests: B.F. reports grants and personal fees from ASTRAZENECA (https://www.astrazeneca.com/), grants and personal fees from BAYER (https://www.bayer.com/), personal fees from CHIESI (https://www.chiesi.com/), personal fees from GSK (https://it.gsk.com/), personal fees from GUIDOTTI (https://www.labguidotti.it/), grants and personal fees from GRIFOLS (https://www.grifols.com/en/home), grants from INSMED (https://www.insmed.com/), 408 personal fees from MENARINI (https://www.menarini.it), personal fees from NOVARTIS (https://www.novartis.com/), grants and personal fees from PFIZER (https://www.pfizer.com/), personal fees from TEVA (https://www.tevapharm.com/), personal fees from ZAMBON (https://www.zambon.com/it), outside the submitted work. R.S. and S.L. are employees of Medineos Observational Research (http://www.medineos.com/) and received salary from this company. This does not alter authors adherence to PLOS ONE policies on sharing data and materials. The other authors declare that they have no competing interests.

Alpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The insulin-like growth factor-1 receptor (IGF-1R) signaling is a key regulator of lifespan, growth, and development. While reduced IGF-1R signaling delays aging and Alzheimer's disease progression, whether and how it regulates information processing at central synapses remains elusive. Here, we show that presynaptic IGF-1Rs are basally active, regulating synaptic vesicle release and short-term plasticity in excitatory hippocampal neurons. Acute IGF-1R blockade or transient knockdown suppresses spike-evoked synaptic transmission and presynaptic cytosolic Ca(2+) transients, while promoting spontaneous transmission and resting Ca(2+) level. This dual effect on transmitter release is mediated by mitochondria that attenuate Ca(2+) buffering in the absence of spikes and decrease ATP production during spiking activity. We conclude that the mitochondria, activated by IGF-1R signaling, constitute a critical regulator of information processing in hippocampal neurons by maintaining evoked-to-spontaneous transmission ratio, while constraining synaptic facilitation at high frequencies. Excessive IGF-1R tone may contribute to hippocampal hyperactivity associated with Alzheimer's disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Clinical practice guidelines represent a key tool to improve quality and reduce variability of cancer care. In 2004, Italian Association of Medical Oncology (AIOM) launched the RIGHT (research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) program. The third step, RIGHT-3, evaluated the concordance between AIOM lung cancer guidelines and Italian clinical practice., Materials and Methods: RIGHT-3 was a retrospective observational study, conducted in 53 Italian centers treating lung cancer. Sampling from AIOM database of 230 centers was stratified by presence of thoracic surgery and geographic distribution. To describe the adherence to AIOM guidelines (2009 edition), 11 indicators regarding diagnostic and treatment procedures were identified. Patients with non-small-cell lung cancer (NSCLC) diagnosis who had first visit in 2010 were divided into 3 groups, based on TNM stage: I-II-IIIA (5 indicators), IIIB (3 indicators) and IV (3 indicators)., Results: 708 patients were enrolled; 680 were eligible: 225 patients in stage I-II-IIIA; 156 patients in stage IIIB; 299 patients in stage IV. Cyto-histological diagnosis was available in 96%, 97%, 96% of stage I-II-IIIA, IIIB, IV respectively. Positron-emission tomography was performed in 64% of stage I-II-IIIA and 46% of stage IIIB. 88% of stage I-II patients eligible for surgery underwent lobectomy; after surgery, 61% of stage II and 57% of stage IIIA patients received adjuvant chemotherapy. Among stage IIIB patients who received combined chemo- radiotherapy, sequential approach was more common than concomitant treatment (86% vs. 14%). Among stage IV patients, 87% received platinum-based first-line treatment, and 70% received second-line., Conclusion: The RIGHT-3 study showed that, in 2010, adherence to Italian NSCLC guidelines was high for many indicators (including those related to treatment of stage IV patients), but lower for some diagnostic procedures. Guidelines adherence monitoring can be useful to reduce variability in cancer care., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Data on puberty development are available for several countries but not for Central Asia., Aim: Using data collected during the Kazakhstan Health and Nutrition Survey (KHA-ES), we evaluated the relationship between the living environment (rural vs. urban), ethnicity (Russians vs. Kazakhs) and pubertal status in children living in Kazakhstan., Subjects and Methods: Genital (G1-G5), breast (B1-B5) and pubic hair (PH1-PH5) development were evaluated in a sample of 2389 boys and 2416 girls using Tanner's criteria. Age at menarche was evaluated using the 'status quo' and 'recall' methods., Results: Rural children were older than urban children at stages > or =G2 for males and > or =B2 for females, and this difference was more evident for Russian males. Differences levelled out at later stages of development in Kazakh males and in the pooled girls. The living environment was slightly but significantly associated with median age at menarche (12.89 years for urban Kazakhs to 13.43 years for rural Kazakhs). Male and female Kazakhs were older than Russians at stages 4 and 5, especially in the urban area., Conclusion: A relationship between pubertal status and the living environment was present in a rapidly modernizing country such as Kazakhstan.

Kazakhstan is undergoing a rapid modernization process, which carries the risk of an epidemic of obesity and cardiovascular disease. We enrolled a sample of about 50 children for every combination of gender, environment (urban vs. rural), ethnic group (Kazakh vs. Russian), and age group from 7 to 18 years, for a total of 4,808 children. Anthropometry and blood pressure were measured on all children while fasting blood cholesterol and glucose were measured only in 2,616 children aged > or =12 years. The prevalence of overweight and risk of overweight ranged from 2.8 (rural male Kazakhs) to 9.1% (urban male Russians). The prevalence of prehypertension and hypertension ranged from 8.3 (urban females) to 15.9% (rural females); that of hypercholesterolemia from 11.5 (male rural Russians) to 26.5% (female rural Kazakhs); and the overall prevalence of impaired fasting glucose was 0.1%. We conclude that overweight and cardiovascular risk factors are less prevalent in children living in Kazakhstan than in those living in Western countries. However, these figures are not negligible and suggest that preventive measures are needed to contain the epidemic of overweight and cardiovascular disease that will most likely accompany the modernization of Kazakhstan in the next years., (Copyright 2007 Wiley-Liss, Inc.)

Background: Spirometric parameters are influenced by several factors and many reference data are available in the literature. However, no spirometric data are available for children and adolescents from Central Asia., Aim: The study aimed to calculate spirometric reference curves on the basis of anthropometry, ethnicity (Kazakh vs. Russian) and living environment (urban vs. rural)., Subjects and Methods: Spirometry (FEV1, FVC and FEF25-75%) was performed and anthropometric measurements taken for 1926 male and 1967 female Kazakh children aged 7-18 years., Results: Height explained almost all the variance of forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1) for both sexes, while age and inspiratory circumference contributed slightly to the prediction. Moreover, FVC and FEV1 were greater in Russians than in Kazakhs and ethnicity did enter the prediction model for these parameters. The living environment had a marginal effect on spirometry. In fact, forced expiratory flow 25-75% (FEF25-75%) was slightly higher in urban than in rural females, FVC was slightly higher in rural than in urban males, while FEV1 was not affected. Finally, among several spirometric equations available in the literature, those performing better in our children were obtained in developed countries., Conclusion: Anthropometry was the most important predictor of spirometry. Age and ethnicity were also predictors, while the contribution of the living environment was more limited.

The effect of 19 venoms from solitary wasps, solitary bees, social wasps and ants were investigated for their effects on nicotinic acetylcholine receptors (nAChR) and ionotropic glutamate receptors (IGRs) of both the N-methyl-d-aspartate (NMDAR) and non-NMDAR type. Whole-cell patch clamp of human muscle TE671 cells was used to study nAChR, and of rat cortical and cerebellar granule cells for IGRs. Solitary wasp venoms caused significant voltage-dependent antagonism of nAChR responses to 10 microM ACh and NMDAR responses to 100 microM NMDA (+10 microM glycine) when co-applied at 1 microg/ml with the agonists. At positive holding potentials (V(H)) potentiation of these receptors was observed with some venoms. Solitary bee venoms only affected nAChR by causing either voltage-independent antagonism or potentiation of their responses to 10 microM ACh. Of four social wasp venoms, one acted on nAChR by potentiating responses to 10 ACh, while another generated an ACh-like response when applied alone. They had no effect on IGRs. Of the two ant venoms, one caused voltage-independent inhibition of nAChR. Neither affected IGRs. The data indicate the presence of nAChR agonists and antagonists and NMDAR antagonists in Hymenopteran venoms and warrant further investigation to separate and identify these venom components.

One prerequisite for understanding the physiological relevance of intercellular calcium waves in glia is the examination of mechanisms that trigger these waves. Here, we show that stimulation of cultured septal neurons to produce a large and sustained calcium rise in the soma can initiate calcium waves in surrounding glial cells. The initiation of calcium waves is dependent on calcium influx through voltage-gated calcium channels on the neuron. The waves are not due to direct stimulation of the glial cells or to loss of neuronal membrane integrity. Mechanism of wave initiation is distinct from that involved in wave propagation and does not involve glutamate or acetylcholine release. Communication via gap junctions, or nitric oxide production, is not involved in the initial signaling between a stimulated neuron and the surrounding astrocytes. Suramin, a blocker of P2 receptors blocked the waves but failed to abolish the responses in glial cells immediately surrounding the stimulated neuron. Our results suggest that patterns of calcium rises on neurons, like those seen in glutamate cytotoxicity, can cause calcium waves in surrounding glial cells.