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1.  Improving access and continuity of care for homeless people: how could general practitioners effectively contribute? Results from a mixed study 
BMJ Open  2016;6(11):e013610.
Objectives
To analyse the views of general practitioners (GPs) about how they can provide care to homeless people (HP) and to explore which measures could influence their views.
Design
Mixed-methods design (qualitative –> quantitative (cross-sectional observational) → qualitative). Qualitative data were collected through semistructured interviews and through questionnaires with closed questions. Quantitative data were analysed with descriptive statistical analyses on SPPS; a content analysis was applied on qualitative data.
Setting
Primary care; views of urban GPs working in a deprived area in Marseille were explored by questionnaires and/or semistructured interview.
Participants
19 GPs involved in HP's healthcare were recruited for phase 1 (qualitative); for phase 2 (quantitative), 150 GPs who provide routine healthcare (‘standard’ GPs) were randomised, 144 met the inclusion criteria and 105 responded to the questionnaire; for phase 3 (qualitative), data were explored on 14 ‘standard’ GPs.
Results
In the quantitative phase, 79% of the 105 GPs already treated HP. Most of the difficulties they encountered while treating HP concerned social matters (mean level of perceived difficulties=3.95/5, IC 95 (3.74 to 4.17)), lack of medical information (mn=3.78/5, IC 95 (3.55 to 4.01)) patient's compliance (mn=3.67/5, IC 95 (3.45 to 3.89)), loneliness in practice (mn=3.45/5, IC 95 (3.18 to 3.72)) and time required for the doctor (mn=3.25, IC 95 (3 to 3.5)). From qualitative analysis we understood that maintaining a stable follow-up was a major condition for GPs to contribute effectively to the care of HP. Acting on health system organisation, developing a medical and psychosocial approach with closer relation with social workers and enhancing the collaboration between tailored and non-tailored programmes were also other key answers.
Conclusions
If we adapt the conditions of GPs practice, they could contribute to the improvement of HP's health. These results will enable the construction of a new model of primary care organisation aiming to improve access to healthcare for HP.
doi:10.1136/bmjopen-2016-013610
PMCID: PMC5168510  PMID: 27903566
PRIMARY CARE; general practitioners; homeless people; access to health care; mixed methods
2.  Rituximab for the treatment of patients with chronic lymphocytic leukemia 
Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5+/CD19+/CD20+/HLA-DR+/CD23+/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20) enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival. The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.
PMCID: PMC3004569  PMID: 21188098
rituximab; chronic lymphocytic leukemia; chemotherapy
3.  The chronic lymphocytic leukemia international prognostic index (CLL-IPI) predicts time to first treatment in early CLL: Independent Validation in a Prospective Cohort of Early Stage Patients 
American journal of hematology  2016;91(11):1090-1095.
The chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) combines 5 parameters (age, clinical stage, TP53 status [normal vs. del(17p) and/or TP53 mutation], IGHV mutational status, serum β2-microglobulin) to predict survival and time-to-first-treatment (TTFT) in CLL patients. We performed an observational study in 337 prospectively collected, Binet stage A patients to validate the ability of the CLL-IPI to predict TTFT in an independent cohort of early stage CLL patients. The CLL-IPI score stratified Binet stage A patients into three subgroups with different outcome. Since the CLL-IPI was originally developed to predict survival, we next investigated the optimal cut-off score to predict TTFT in Binet stage A patients. Recursive partitioning analysis identified three subsets with scores of 0 (n=139), 1 (n=90), and ≥ 2(n=108). The probability of remaining free from therapy 5 years after diagnosis was 85%, 67% and 46% in these three categories (P<0.0001.; C-statistic:c=0.72; 95% CI:0.58–0.81). This optimized CLL-IPI scoring for TTFT was subsequently validated in an independent cohort of Binet A patients from the Mayo Clinic (n=525). The ability of either original or optimized CLL-IPI to predict TTFT was equivalent to other prognostic models specifically designed for this endpoint (2011 MDACC score and O-CLL1 score). Although originally developed to predict suvival, the CLL-IPI is useful for predicting TTFT in early stage CLL patients.
doi:10.1002/ajh.24493
PMCID: PMC5072993  PMID: 27465919
CLL-IPI; early chronic lymphocytic leukemia; time to first treatment
4.  Current concepts and future strategies in the antimicrobial therapy of emerging Gram-positive spontaneous bacterial peritonitis 
World Journal of Hepatology  2017;9(30):1166-1175.
Spontaneous bacterial peritonitis (SBP) is the most common infection in end-stage liver disease patients. SBP is defined as an ascitic fluid infection with a polymorphonuclear leucocyte count ≥ 250/mm3 without an evident intra-abdominal surgically treatable source. Several mechanisms contribute to SBP occurrence, including translocation of gut bacteria and their products, reduced intestinal motility provoking bacterial overgrowth, alteration of the gut’s barrier function and local immune responses. Historically, Gram-negative enteric bacteria have been the main causative agents of SBP, thereby guiding the empirical therapeutic choice. However, over the last decade, a worryingly increasing prevalence of Gram-positive and multi-drug resistant (MDR) SBP has been seen. Recently, the microbiological spectrum of SBP seems to have changed in Europe due to a high prevalence of Gram-positive bacteria (48%-62%). The overall proportion of MDR bacteria is up to 22%-73% of cases. Consequently, empirical therapy based on third-generation cephalosporins or amoxicillin/clavulanic acid, can no longer be considered the standard of care, as these drugs are associated with poor outcomes. The aim of this review is to describe, with an epidemiological focus, the evidence behind this rise in Gram-positive and MDR SBP from 2000 to present, and illustrate potential targeted therapeutic strategies. An appropriate treatment protocol should include daptomycin plus ceftaroline and meropenem, with prompt stepdown to a narrower spectrum when cultures and sensitivity data are available in order to reduce both cost and potential antibiotic resistance development.
doi:10.4254/wjh.v9.i30.1166
PMCID: PMC5666303
Spontaneous bacterial peritonitis; Multi-drug resistant bacteria; End-stage liver disease; Cirrhosis; Critically ill patient
5.  Spontaneous peritonitis in critically ill cirrhotic patients: a diagnostic algorithm for clinicians and future perspectives 
Spontaneous peritonitis (SP) is the most common infection among decompensated end-stage liver disease patients. SP is the infection of ascitic fluid (neutrophil ascitic count ≥250/mL) without an alternative focus of abdominal infection. According to the causative agent, clinicians can make the diagnosis of spontaneous bacterial peritonitis or spontaneous fungal peritonitis. The mortality rate is very high, ranging from one-fifth of the patients with spontaneous bacterial peritonitis to four-fifths of the patients with spontaneous fungal peritonitis. An immediate and accurate diagnosis can improve the outcome in end-stage liver disease patients. The aim of this work is to provide physicians with a practical diagnostic guidance for SP diagnosis according to current evidence, in order to improve the management of cirrhotic patients with infected ascitic fluid.
doi:10.2147/TCRM.S144262
PMCID: PMC5652902
cirrhosis; spontaneous bacterial peritonitis; spontaneous fungal peritonitis; bacteriascites; fungal ascites
6.  Performance of the ATLAS track reconstruction algorithms in dense environments in LHC Run 2 
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S. | Bella, G. | Bellagamba, L. | Bellerive, A. | Bellomo, M. | Belotskiy, K. | Beltramello, O. | Belyaev, N. L. | Benary, O. | Benchekroun, D. | Bender, M. | Bendtz, K. | Benekos, N. | Benhammou, Y. | Benhar Noccioli, E. | Benitez, J. | Benjamin, D. P. | Benoit, M. | Bensinger, J. R. | Bentvelsen, S. | Beresford, L. | Beretta, M. | Berge, D. | Bergeaas Kuutmann, E. | Berger, N. | Beringer, J. | Berlendis, S. | Bernard, N. R. | Bernardi, G. | Bernius, C. | Bernlochner, F. U. | Berry, T. | Berta, P. | Bertella, C. | Bertoli, G. | Bertolucci, F. | Bertram, I. A. | Bertsche, C. | Bertsche, D. | Besjes, G. J. | Bessidskaia Bylund, O. | Bessner, M. | Besson, N. | Betancourt, C. | Bethani, A. | Bethke, S. | Bevan, A. J. | Beyer, J. | Bianchi, R. M. | Biebel, O. | Biedermann, D. | Bielski, R. | Biesuz, N. V. | Biglietti, M. | Billoud, T. R. V. | Bilokon, H. | Bindi, M. | Bingul, A. | Bini, C. | Biondi, S. | Bisanz, T. | Bittrich, C. | Bjergaard, D. M. | Black, C. W. | Black, J. E. | Black, K. M. | Blair, R. E. | Blazek, T. | Bloch, I. | Blocker, C. | Blue, A. | Blum, W. | Blumenschein, U. | Blunier, S. | Bobbink, G. J. | Bobrovnikov, V. S. | Bocchetta, S. S. | Bocci, A. | Bock, C. | Boehler, M. | Boerner, D. | Bogavac, D. | Bogdanchikov, A. G. | Bohm, C. | Boisvert, V. | Bokan, P. | Bold, T. | Boldyrev, A. S. | Bolz, A. E. | Bomben, M. | Bona, M. | Boonekamp, M. | Borisov, A. | Borissov, G. | Bortfeldt, J. | Bortoletto, D. | Bortolotto, V. | Boscherini, D. | Bosman, M. | Bossio Sola, J. D. | Boudreau, J. | Bouffard, J. | Bouhova-Thacker, E. V. | Boumediene, D. | Bourdarios, C. | Boutle, S. K. | Boveia, A. | Boyd, J. | Boyko, I. R. | Bracinik, J. | Brandt, A. | Brandt, G. | Brandt, O. | Bratzler, U. | Brau, B. | Brau, J. E. | Breaden Madden, W. D. | Brendlinger, K. | Brennan, A. J. | Brenner, L. | Brenner, R. | Bressler, S. | Briglin, D. L. | Bristow, T. M. | Britton, D. | Britzger, D. | Brochu, F. M. | Brock, I. | Brock, R. | Brooijmans, G. | Brooks, T. | Brooks, W. K. | Brosamer, J. | Brost, E. | Broughton, J. H | de Renstrom, P. A. Bruckman | Bruncko, D. | Bruni, A. | Bruni, G. | Bruni, L. S. | Brunt, BH | Bruschi, M. | Bruscino, N. | Bryant, P. | Bryngemark, L. | Buanes, T. | Buat, Q. | Buchholz, P. | Buckley, A. G. | Budagov, I. A. | Buehrer, F. | Bugge, M. K. | Bulekov, O. | Bullock, D. | Burch, T. J. | Burckhart, H. | Burdin, S. | Burgard, C. D. | Burger, A. M. | Burghgrave, B. | Burka, K. | Burke, S. | Burmeister, I. | Burr, J. T. P. | Busato, E. | Büscher, D. | Büscher, V. | Bussey, P. | Butler, J. M. | Buttar, C. M. | Butterworth, J. M. | Butti, P. | Buttinger, W. | Buzatu, A. | Buzykaev, A. R. | Cabrera Urbán, S. | Caforio, D. | Cairo, V. M. | Cakir, O. | Calace, N. | Calafiura, P. | Calandri, A. | Calderini, G. | Calfayan, P. | Callea, G. | Caloba, L. P. | Calvente Lopez, S. | Calvet, D. | Calvet, S. | Calvet, T. P. | Camacho Toro, R. | Camarda, S. | Camarri, P. | Cameron, D. | Caminal Armadans, R. | Camincher, C. | Campana, S. | Campanelli, M. | Camplani, A. | Campoverde, A. | Canale, V. | Cano Bret, M. | Cantero, J. | Cao, T. | Capeans Garrido, M. D. M. | Caprini, I. | Caprini, M. | Capua, M. | Carbone, R. M. | Cardarelli, R. | Cardillo, F. | Carli, I. | Carli, T. | Carlino, G. | Carlson, B. T. | Carminati, L. | Carney, R. M. D. | Caron, S. | Carquin, E. | Carrá, S. | Carrillo-Montoya, G. D. | Carvalho, J. | Casadei, D. | Casado, M. P. | Casolino, M. | Casper, D. W. | Castelijn, R. | Castillo Gimenez, V. | Castro, N. F. | Catinaccio, A. | Catmore, J. R. | Cattai, A. | Caudron, J. | Cavaliere, V. | Cavallaro, E. | Cavalli, D. | Cavalli-Sforza, M. | Cavasinni, V. | Celebi, E. | Ceradini, F. | Cerda Alberich, L. | Cerqueira, A. S. | Cerri, A. | Cerrito, L. | Cerutti, F. | Cervelli, A. | Cetin, S. A. | Chafaq, A. | Chakraborty, D. | Chan, S. K. | Chan, W. S. | Chan, Y. L. | Chang, P. | Chapman, J. D. | Charlton, D. G. | Chau, C. C. | Chavez Barajas, C. A. | Che, S. | Cheatham, S. | Chegwidden, A. | Chekanov, S. | Chekulaev, S. V. | Chelkov, G. A. | Chelstowska, M. A. | Chen, C. | Chen, H. | Chen, S. | Chen, S. | Chen, X. | Chen, Y. | Cheng, H. C. | Cheng, H. J. | Cheplakov, A. | Cheremushkina, E. | Cherkaoui El Moursli, R. | Chernyatin, V. | Cheu, E. | Chevalier, L. | Chiarella, V. | Chiarelli, G. | Chiodini, G. | Chisholm, A. S. | Chitan, A. | Chiu, Y. H. | Chizhov, M. V. | Choi, K. | Chomont, A. R. | Chouridou, S. | Christodoulou, V. | Chromek-Burckhart, D. | Chu, M. C. | Chudoba, J. | Chuinard, A. J. | Chwastowski, J. J. | Chytka, L. | Ciftci, A. K. | Cinca, D. | Cindro, V. | Cioara, I. A. | Ciocca, C. | Ciocio, A. | Cirotto, F. | Citron, Z. H. | Citterio, M. | Ciubancan, M. | Clark, A. | Clark, B. L. | Clark, M. R. | Clark, P. J. | Clarke, R. N. | Clement, C. | Coadou, Y. | Cobal, M. | Coccaro, A. | Cochran, J. | Colasurdo, L. | Cole, B. | Colijn, A. P. | Collot, J. | Colombo, T. | Conde Muiño, P. | Coniavitis, E. | Connell, S. H. | Connelly, I. A. | Constantinescu, S. | Conti, G. | Conventi, F. | Cooke, M. | Cooper-Sarkar, A. M. | Cormier, F. | Cormier, K. J. R. | Corradi, M. | Corriveau, F. | Cortes-Gonzalez, A. | Cortiana, G. | Costa, G. | Costa, M. J. | Costanzo, D. | Cottin, G. | Cowan, G. | Cox, B. E. | Cranmer, K. | Crawley, S. J. | Creager, R. A. | Cree, G. | Crépé-Renaudin, S. | Crescioli, F. | Cribbs, W. A. | Cristinziani, M. | Croft, V. | Crosetti, G. | Cueto, A. | Cuhadar Donszelmann, T. | Cukierman, A. R. | Cummings, J. | Curatolo, M. | Cúth, J. | Czirr, H. | Czodrowski, P. | D’amen, G. | D’Auria, S. | D’eramo, L. | D’Onofrio, M. | Da Cunha Sargedas De Sousa, M. J. | Via, C. Da | Dabrowski, W. | Dado, T. | Dai, T. | Dale, O. | Dallaire, F. | Dallapiccola, C. | Dam, M. | Dandoy, J. R. | Daneri, M. F. | Dang, N. P. | Daniells, A. C. | Dann, N. S. | Danninger, M. | Hoffmann, M. Dano | Dao, V. | Darbo, G. | Darmora, S. | Dassoulas, J. | Dattagupta, A. | Daubney, T. | Davey, W. | David, C. | Davidek, T. | Davies, M. | Davis, D. R. | Davison, P. | Dawe, E. | Dawson, I. | De, K. | de Asmundis, R. | De Benedetti, A. | De Castro, S. | De Cecco, S. | De Groot, N. | de Jong, P. | De la Torre, H. | De Lorenzi, F. | De Maria, A. | De Pedis, D. | De Salvo, A. | De Sanctis, U. | De Santo, A. | De Vasconcelos Corga, K. | De Vivie De Regie, J. B. | Dearnaley, W. J. | Debbe, R. | Debenedetti, C. | Dedovich, D. V. | Dehghanian, N. | Deigaard, I. | Del Gaudio, M. | Del Peso, J. | Prete, T. Del | Delgove, D. | Deliot, F. | Delitzsch, C. M. | Dell’Acqua, A. | Dell’Asta, L. | Dell’Orso, M. | Della Pietra, M. | della Volpe, D. | Delmastro, M. | Delporte, C. | Delsart, P. A. | DeMarco, D. A. | Demers, S. | Demichev, M. | Demilly, A. | Denisov, S. P. | Denysiuk, D. | Derendarz, D. | Derkaoui, J. 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With the increase in energy of the Large Hadron Collider to a centre-of-mass energy of 13 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {TeV}$$\end{document}TeV for Run 2, events with dense environments, such as in the cores of high-energy jets, became a focus for new physics searches as well as measurements of the Standard Model. These environments are characterized by charged-particle separations of the order of the tracking detectors sensor granularity. Basic track quantities are compared between 3.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of data collected by the ATLAS experiment and simulation of proton–proton collisions producing high-transverse-momentum jets at a centre-of-mass energy of 13 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {TeV}$$\end{document}TeV. The impact of charged-particle separations and multiplicities on the track reconstruction performance is discussed. The track reconstruction efficiency in the cores of jets with transverse momenta between 200 and 1600 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV is quantified using a novel, data-driven, method. The method uses the energy loss, \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$${\text { d}}{} \textit{E}/d\textit{x}$$\end{document}dE/dx, to identify pixel clusters originating from two charged particles. Of the charged particles creating these clusters, the measured fraction that fail to be reconstructed is \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$0.061 \pm 0.006\ {\text {(stat.)}} \pm 0.014\ {\text {(syst.)}}$$\end{document}0.061±0.006(stat.)±0.014(syst.) and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$0.093 \pm 0.017\ {\text {(stat.)}}\pm 0.021\ {\text {(syst.)}}$$\end{document}0.093±0.017(stat.)±0.021(syst.) for jet transverse momenta of 200–400 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV and 1400–1600 \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\text {GeV}$$\end{document}GeV, respectively.
doi:10.1140/epjc/s10052-017-5225-7
PMCID: PMC5638380
7.  Whole genome sequencing for the molecular characterization of carbapenem-resistant Klebsiella pneumoniae strains isolated at the Italian ASST Fatebenefratelli Sacco Hospital, 2012–2014 
BMC Infectious Diseases  2017;17:666.
Background
The emergence of carbapenem-resistant Klebsiella pneumoniae strains is threatening antimicrobial treatment.
Methods
Sixty-eight carbapenemase-producing K. pneumoniae strains isolated at Luigi Sacco University Hospital-ASST Fatebenefratelli Sacco (Milan, Italy) between 2012 and 2014 were characterised microbiologically and molecularly. They were tested for drug susceptibility and carbapenemase phenotypes, investigated by means of repetitive extra-genic palindromic polymerase chain reaction (REP-PCR), and fully sequenced by means of next-generation sequencing for the in silico analysis of multi-locus sequence typing (MLST), their resistome, virulome and plasmid content, and their core single nucleotide polymorphism (SNP) genotypes.
Results
All of the samples were resistant to carbapenems, other β-lactams and ciprofloxacin; many were resistant to aminoglycosides and tigecycline; and seven were resistant to colistin. Resistome analysis revealed the presence of blaKPC genes and, less frequently blaSHV, blaTEM, blaCTX-M and blaOXA, which are related to resistance to carbapenem and other β-lactams. Other genes conferring resistance to aminoglycoside, fluoroquinolone, phenicol, sulphonamide, tetracycline, trimethoprim and macrolide-lincosamide-streptogramin were also detected. Genes related to AcrAB-TolC efflux pump-dependent and pump-independent tigecycline resistance mechanisms were investigated, but it was not possible to clearly correlate the genomic features with tigecycline resistance because of the presence of a common mutation in susceptible, intermediate and resistant strains. Concerning colistin resistance, the mgrB gene was disrupted by an IS5-like element, and the mobile mcr-1 and mcr-2 genes were not detected in two cases. The virulome profile revealed type-3 fimbriae and iron uptake system genes, which are important during the colonisation stage in the mammalian host environment. The in silico detected plasmid replicons were classified as IncFIB(pQil), IncFIB(K), ColRNAI, IncX1, IncX3, IncFII(K), IncN, IncL/M(pMU407) and IncFIA(HI1). REP-PCR showed five major clusters, and MLST revealed six different sequence types: 512, 258, 307, 1519, 745 and 101. Core SNP genotyping, which led to four clusters, correlated with the MLST data. Isolates of the same sequencing type often had common genetic traits, but the SNP analysis allowed greater strain tracking and discrimination than either the REP-PCR or MLST analysis.
Conclusion
Our findings support the importance of implementing bacterial genomics in clinical medicine in order to complement traditional methods and overcome their limited resolution.
Electronic supplementary material
The online version of this article (10.1186/s12879-017-2760-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12879-017-2760-7
PMCID: PMC5634883  PMID: 29017452
Carbapenem-resistant Klebsiella pneumoniae; Whole-genome sequencing; Bacteria epidemiology
8.  Study protocol of the internet user Cohort for Unbiased Recognition of gaming disorder in Early adolescence (iCURE), Korea, 2015–2019 
BMJ Open  2017;7(10):e018350.
Introduction
In 2013, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) proposed nine internet gaming disorder (IGD) diagnostic criteria as a condition warranting further empirical and clinical research. The aim of this study is to clarify the natural and clinical courses of IGD proposed DSM-5 in adolescents and to evaluate its risk and protective factors.
Methods and analysis
The Internet user Cohort for Unbiased Recognition of gaming disorder in Early Adolescence (iCURE) study is an ongoing multidisciplinary, prospective, longitudinal cohort study conducted in 21 schools in Korea. Participant recruitment commenced in March 2015 with the goal of registering 3000 adolescents. The baseline assessment included surveys on emotional, social and environmental characteristics. A parent or guardian completed questionnaires and a structured psychiatric comorbidity diagnostic interview regarding their children. Adolescents with the Internet Game Use-Elicited Symptom Screen total scores of 6 or higher were asked to participate in the clinical diagnostic interview. Two subcohorts of adolescents were constructed: a representative subcohort and a clinical evaluation subcohort. The representative subcohort comprises a randomly selected 10% of the iCURE to investigate the clinical course of IGD based on clinical diagnosis and to estimate the false negative rate. The clinical evaluation subcohort comprised participants meeting three or more of the nine IGD criteria, determined by clinical diagnostic interview, to show the clinical course of IGD. Follow-up data will be collected annually for the 3 years following the baseline assessments. The primary endpoint is 2-year incidence, remission and recurrence rates of IGD. Cross-sectional and longitudinal associations between exposures and outcomes as well as mediation factors will be evaluated.
Ethics and dissemination
This study is approved by the Institutional Review Board of the Catholic University of Korea. Results will be published in peer-reviewed journals.
Trial registration number
ClinicalTrials.gov (identifier: NCT02415322).
doi:10.1136/bmjopen-2017-018350
PMCID: PMC5640066  PMID: 28982839
internet gaming disorder; adolescents; cohort; protocol
9.  Streptococcus pneumoniae(Spn) Nasopharyngeal Carriage in Children Under 3 Years Old, Attending Day Care Centers in Argentina 
Open Forum Infectious Diseases  2017;4(Suppl 1):S462.
Abstract
Background
In 2012 the 13-valent conjugated pneumococcal vaccine (PCV-13) was introduced in the National Immunization Program. We performed an epidemiological study to describe SPN nasopharyngeal carriage prevalence.
Methods
Between June to September 2015 it was performed a cross-sectional study among children <3 years old, attending day care centers. Nasopharyngeal samples were collected from children at public and private centers from 5 cities of Argentina (Salta (North West), Trelew (South), Rosario (Centre), Buenos Aires (Capital city) and Posadas (North East)). Samples were analyzed at references hospitals of each city and isolates were submitted to the INEI “Dr. Carlos G. Malbrán “, for confirming and serotyping. We considered completed schedule 3 doses of PCV13, administrated14 days prior to enrollment.
Results
We included 359 toddlers, 61,6% (IC95% 56,3–66,6) were SPN carriers. Median age was 24 months, without significative difference in carriage status. Multivariate analysis showed that independently of age, sex and socioeconomic level, variables associated with carriage were:
· City: Taking Salta as reference (less carriage prevalence), Rosario and Posadas were statistically associated with higher prevalence rates: OR: 3,1 (IC95% 1,3–7,1) y OR: 2,8 (IC96% 1,2–6,3) respectively
· Children attending to public day care centers had higher carriage rates than those attending private ones: OR: 1,9 (IC95% 1,06–3,4)
· Children sharing bedroom with 3 or more persons, were associated to mayor risk or carriage: OR: 1,7 (IC95% 1,03–2,7)
We found 46 serotypes in the 221 isolates. (2 couldn’t be serotyped), 90,9% (IC95% 86,3–94,3) were non PCV 13 serotypes (most frequent were 15B, 23B and 11A). Only 7 of 46 were PCV13 serotypes. (Graphic 1)
Of the 20 toddlers with PCV13 serotypes, 16 were completely vaccinated
Graphic 1: S pneumoniae serotype distribution. N = 221
Conclusion
Nasopharyngeal carriage of SPN was high in children < 3 years old attending day care centers. Most isolates were Non PCV13 serotypes. The independent predictors for higher prevalence rates were: 1- Children living in the north east and Centre of the country. 2- Those attending public day care centers and 3- Those with 3 or more persons per room.
Disclosures
All authors: No reported disclosures.
doi:10.1093/ofid/ofx163.1180
PMCID: PMC5630784
10.  Community Acquired Pneumonia Incidence Among Children Under 5 Years of Age in Concordia Argentina. Universal Vaccination Impact 
Open Forum Infectious Diseases  2017;4(Suppl 1):S462-S463.
Abstract
Background
In January 2012, Argentine introduced PCV-13 to the National Immunization Program. We performed an epidemiological study in order to describe consolidated pneumonia and pneumococcal disease incidence following PCV-13 routine vaccination.
Methods
Between April2014-March2016, a population-based surveillance study was carried out in Concordia. Clinical data, vaccination status and digital chest X-rays were recorded from children < 5 years old with pneumonia and pleural effusion. A pediatrician and a radiologist interpreted the images independently. A second reference radiologist arbitrated when discordances occurred. Bacterial etiology was investigated in blood and/or in pleural fluid. Probably bacterial pneumonia (PBP) was determined following WHO protocol. Results were compared with previous data (2002–2005) from the pre-PCV-13 vaccination era. Variables associated to consolidated pneumonia were evaluated by multivariate analysis using logistic regression
Results
330 patients under 5 years old with pneumonia were assisted during the study period. Of these, 92 (27.9%-IC95% 23.2–33.1) were classified as PBP. Annual incidence rate, in pre and post vaccination period and impact of vaccination are described in table 1. Incidence of pneumococcal disease could not be estimated as pneumococcal isolation was negative in all cases.
Multivariate analysis of post-PCV-13 vaccination era showed that incidence of consolidated pneumonia was significantly higher in hospitalized toddlers than outpatients OR: 2,97 (1,65–5,38). Table 1: PBP incidence (*100.000) by study period. Vaccination impact
Conclusion
A significant decline in consolidated pneumonia and pleural effusion incidence in <5 year old children was evidenced in Concordia after the introduction of PCV13 into national immunization program.
Disclosures
All authors: No reported disclosures.
doi:10.1093/ofid/ofx163.1181
PMCID: PMC5631075
11.  Establishment of primary mixed cell cultures from spontaneous canine mammary tumors: Characterization of classic and new cancer-associated molecules 
PLoS ONE  2017;12(9):e0184228.
There are many factors which make canine cancer like cancer in humans. The occurrence of spontaneous mammary tumors in pet dogs, tumor genetics, molecular targets and exposure to the same environmental risk factors are among these factors. Therefore, the study of canine cancer can provide useful information to the oncology field. This study aimed to establish and characterize a panel of primary mixed cell cultures obtained from spontaneous canine mammary tumors. Eight established cell cultures obtained from one normal mammary gland, one complex adenoma, one mixed adenoma, two complex carcinomas and two mixed carcinomas were analyzed. The gene expression levels of classic molecular cancer players such as fibroblast growth factor receptor (FGFR) 2, breast cancer (BRCA) 1, BRCA2 and estrogen receptor (ESR) 1 were evaluated. For the first time, three orphan nuclear receptors, estrogen-related receptors (ERRs) α, β and γ were studied in canine mammary cancer. The highest expression level of ERRα was observed in complex carcinoma-derived cell culture, while the highest levels of ERRβ and γ were observed in cells derived from a mixed carcinoma. Meanwhile, complex carcinomas presented the highest levels of expression of ESR1, BRCA1 and FGFR2 among all samples. BRCA2 was found exclusively in complex adenoma. The transcription factor GATA3 had its highest levels in mixed carcinoma samples and its lowest levels in complex adenoma. Proliferation assays were also performed to evaluate the mixed cell cultures response to ER ligands, genistein and DES, both in normoxia and hypoxic conditions. Our results demonstrate that morphological and functional studies of primary mixed cell cultures derived from spontaneous canine mammary tumors are possible and provide valuable tool for the study of various stages of mammary cancer development.
doi:10.1371/journal.pone.0184228
PMCID: PMC5612463  PMID: 28945747
12.  Antihyperglycemic treatment in patients with type 2 diabetes in Italy: the impact of age and kidney function 
Oncotarget  2017;8(37):62039-62048.
We describe AHA utilization pattern according to age and renal function in type 2 diabetes mellitus (T2DM), in real-life conditions.
The analysis was performed using the data set of electronic medical records collected between 1 January and 31 December, 2011 in 207 Italian diabetes centers. The study population consisted of 157,595 individuals with T2DM. The AHA treatment regimens was evaluated. Kidney function was assessed by eGFR, estimated using the CKD-EPI formula. Other determinations: HbA1c, blood pressure (BP), low- density lipoprotein (LDL-c), total and high density lipoprotein cholesterol (TC and HDL-c), triglycerides (TG) and serum uric acid (SUA). Quality of care was assessed through Q score.
The proportion of subjects taking metformin declined progressively across age quartiles along with eGFR values, but remained high in oldest subjects (i.e. 54.5 %). On the other hand, the proportion of patients on secretagogues or insulin increased with aging (i.e. 54.7% and 37% in the fourth age quartile, respectively). The percentage of patients with low eGFR (i.e. <30 ml/min/1.73m2) taking either metformin or sulphonilureas/repaglinide was particularly high (i.e. 15.3% and 34.3% respectively).
In a large real-life cohort of T2DM, metformin or sulphonylureas/repaglinide, although not recommended, are frequently prescribed to elderly subjects with severe kidney disease.
doi:10.18632/oncotarget.18816
PMCID: PMC5617484
type 2 diabetes mellitus; nephropathy; age; antihyperglycemic treatment; eGFR
13.  MET Activation and Physical Dynamics of the Metastatic Process: The Paradigm of Cancers of Unknown Primary Origin 
EBioMedicine  2017;24:34-42.
The molecular and cellular mechanisms which drive metastatic spread are the topic of constant debate and scientific research due to the potential implications for cancer patients' prognosis. In addition to genetics and environmental factors, mechanics of single cells and physical interaction with the surrounding environment play relevant role in defining invasive phenotype. Reconstructing the physical properties of metastatic clones may help to clarify still open issues in disease progression as well as to lead to new diagnostic and therapeutic approaches. In this perspective cancer of unknown primary origin (CUP) identify the ideal model to study physical interactions and forces involved in the metastatic process. We have previously demonstrated that MET oncogene is mutated with unexpected high frequency in CUPs. We here analyze and discuss how the MET activation by somatic mutation may affect physical properties in giving rise to such a highly malignant syndrome, as that defined by CUP.
Graphical Abstract
Image 1
Highlights
•CUPs define a highly malignant syndrome still lacking effective therapy•The genetic program of invasive growth is activated in CUPs by MET somatic mutations•The non-catalytic MET SEMA domain is involved in neoplastic invasiveness•Changes affecting the SEMA domain of MET might affect the physical interaction of CUP cells and surrounding microenvironment
doi:10.1016/j.ebiom.2017.09.025
PMCID: PMC5652293  PMID: 29037604
Cancer; Metastasis; MET oncogene; Invasive growth; Mechanical forces; Rheology
15.  Histological assessment of granulomas in natural and experimental Schistosoma mansoni infections using whole slide imaging 
PLoS ONE  2017;12(9):e0184696.
The pathology of schistosomiasis mansoni, a neglected tropical disease of great clinical and socioeconomic importance, results from the parasite eggs that become trapped in host tissues, particularly in the liver and intestines. Continuous antigenic stimulation from these eggs leads to recruitment of inflammatory cells to the sites of infection with formation of periovular granulomas. These complex structures have variable size and composition and are the most striking histopathological feature of schistosomiasis mansoni. However, evaluation of granulomas by conventional microscopy methods is time-consuming and limited, especially in large-scale studies. Here, we used high resolution Whole Slide Imaging (WSI), which allows fast scanning of entire histological slides, and multiple morphometric evaluations, to assess the granulomatous response elicited in target organs (liver, small and large intestines) of two models of schistosomiasis mansoni. One of the advantages of WSI, also termed virtual microscopy, is that it generates images that simultaneously offer high resolution and a wide field of observation. By using a model of natural (Nectomys squamipes, a wild reservoir captured from endemic areas in Brazil) and experimental (Swiss mouse) infection with Schistosoma mansoni, we provided the first detailed WSI characterization of granulomas and other pathological aspects. WSI and quantitative analyses enabled a fast and reliable assessment of the number, evolutional types, frequency and areas of granulomas and inflammatory infiltrates and revealed that target organs are differentially impacted by inflammatory responses in the natural and experimental infections. Remarkably, high-resolution analysis of individual eosinophils, key cells elicited by this helminthic infection, showed a great difference in eosinophil numbers between the two infections. Moreover, features such as the intestinal egg path and confluent granulomas were uncovered. Thus, WSI may be a suitable tool for detailed and precise histological analysis of granulomas and other pathological aspects for clinical and research studies of schistosomiasis.
doi:10.1371/journal.pone.0184696
PMCID: PMC5597217  PMID: 28902908
16.  Searching Novel Therapeutic Targets for Scleroderma: P2X7-Receptor Is Up-regulated and Promotes a Fibrogenic Phenotype in Systemic Sclerosis Fibroblasts 
Objectives: Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways.
Methods: Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca2+ fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated.
Results: P2X7R expression and Ca2+ permeability induced by the selective P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)ATP (BzATP) were markedly higher in SSc than control fibroblasts. Moreover, increased αSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway.
Conclusion: In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca2+-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc.
doi:10.3389/fphar.2017.00638
PMCID: PMC5602350
systemic sclerosis; P2X7 receptor; dermal fibroblasts; collagen; fibrosis; ERK
17.  Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series 
The Lancet. Global Health  2017;5(10):e984-e991.
Summary
Background
Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data.
Methods
In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms “RSV”, “respiratory syncytial virus”, or “respiratory syncytial viral” combined with “mortality”, “fatality”, “death”, “died”, “deaths”, or “CFR” for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables.
Findings
We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3–11·0) in low-income or lower middle-income countries, 4·0 years (2·0–10·0) in upper middle-income countries, and 7·0 years (3·6–16·8) in high-income countries.
Interpretation
This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S2214-109X(17)30344-3
PMCID: PMC5599304  PMID: 28911764
18.  Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study 
Shi, Ting | McAllister, David A | O'Brien, Katherine L | Simoes, Eric A F | Madhi, Shabir A | Gessner, Bradford D | Polack, Fernando P | Balsells, Evelyn | Acacio, Sozinho | Aguayo, Claudia | Alassani, Issifou | Ali, Asad | Antonio, Martin | Awasthi, Shally | Awori, Juliet O | Azziz-Baumgartner, Eduardo | Baggett, Henry C | Baillie, Vicky L | Balmaseda, Angel | Barahona, Alfredo | Basnet, Sudha | Bassat, Quique | Basualdo, Wilma | Bigogo, Godfrey | Bont, Louis | Breiman, Robert F | Brooks, W Abdullah | Broor, Shobha | Bruce, Nigel | Bruden, Dana | Buchy, Philippe | Campbell, Stuart | Carosone-Link, Phyllis | Chadha, Mandeep | Chipeta, James | Chou, Monidarin | Clara, Wilfrido | Cohen, Cheryl | de Cuellar, Elizabeth | Dang, Duc-Anh | Dash-yandag, Budragchaagiin | Deloria-Knoll, Maria | Dherani, Mukesh | Eap, Tekchheng | Ebruke, Bernard E | Echavarria, Marcela | de Freitas Lázaro Emediato, Carla Cecília | Fasce, Rodrigo A | Feikin, Daniel R | Feng, Luzhao | Gentile, Angela | Gordon, Aubree | Goswami, Doli | Goyet, Sophie | Groome, Michelle | Halasa, Natasha | Hirve, Siddhivinayak | Homaira, Nusrat | Howie, Stephen R C | Jara, Jorge | Jroundi, Imane | Kartasasmita, Cissy B | Khuri-Bulos, Najwa | Kotloff, Karen L | Krishnan, Anand | Libster, Romina | Lopez, Olga | Lucero, Marilla G | Lucion, Florencia | Lupisan, Socorro P | Marcone, Debora N | McCracken, John P | Mejia, Mario | Moisi, Jennifer C | Montgomery, Joel M | Moore, David P | Moraleda, Cinta | Moyes, Jocelyn | Munywoki, Patrick | Mutyara, Kuswandewi | Nicol, Mark P | Nokes, D James | Nymadawa, Pagbajabyn | da Costa Oliveira, Maria Tereza | Oshitani, Histoshi | Pandey, Nitin | Paranhos-Baccalà, Gláucia | Phillips, Lia N | Picot, Valentina Sanchez | Rahman, Mustafizur | Rakoto-Andrianarivelo, Mala | Rasmussen, Zeba A | Rath, Barbara A | Robinson, Annick | Romero, Candice | Russomando, Graciela | Salimi, Vahid | Sawatwong, Pongpun | Scheltema, Nienke | Schweiger, Brunhilde | Scott, J Anthony G | Seidenberg, Phil | Shen, Kunling | Singleton, Rosalyn | Sotomayor, Viviana | Strand, Tor A | Sutanto, Agustinus | Sylla, Mariam | Tapia, Milagritos D | Thamthitiwat, Somsak | Thomas, Elizabeth D | Tokarz, Rafal | Turner, Claudia | Venter, Marietjie | Waicharoen, Sunthareeya | Wang, Jianwei | Watthanaworawit, Wanitda | Yoshida, Lay-Myint | Yu, Hongjie | Zar, Heather J | Campbell, Harry | Nair, Harish
Lancet (London, England)  2017;390(10098):946-958.
Summary
Background
We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015.
Methods
We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity.
Findings
We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6–50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7–3·8) hospital admissions, and 59 600 (48 000–74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2–1·7) hospital admissions, and 27 300 (UR 20 700–36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600–149 400). Incidence and mortality varied substantially from year to year in any given population.
Interpretation
Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group.
Funding
The Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(17)30938-8
PMCID: PMC5592248  PMID: 28689664
19.  Endoplasmic Reticulum Stress in Obesity and Obesity-Related Disorders: An Expanded View 
The Endoplasmic Reticulum (ER) is most notable for its central roles in calcium ion storage, lipid biosynthesis, and protein sorting and processing. By virtue of its extensive membrane contact sites that connect the ER to most other organelles and to the plasma membrane, the ER can also regulate diverse cellular processes including inflammatory and insulin signaling, nutrient metabolism, and cell proliferation and death via a signaling pathway called the unfolded protein response (UPR). Chronic UPR activation has been observed in liver and/or adipose tissue of dietary and genetic murine models of obesity, and in human obesity and non-alcoholic fatty liver disease (NAFLD). Activation of the UPR in obesity and obesity-related disorders likely has two origins. One linked to classic ER stress involving the ER lumen and one linked to alterations to the ER membrane environment. This review discusses both of these origins and also considers the role of post-translational protein modifications, such as acetylation and palmitoylation, and ER-mitochondrial interactions to obesity-mediated impairments in the ER and activation of the UPR.
doi:10.1016/j.metabol.2016.05.002
PMCID: PMC4980576  PMID: 27506731
Unfolded Protein Response; Non-alcoholic fatty liver disease; Adipose Tissue; Liver; Lipid Composition; Calcium
20.  Association between body shape index and small dense LDL particles in a cohort of mediterranean women: findings from Progetto ATENA 
Small dense LDL particles (sd-LDL) and body shape index (ABSI), were evaluated in 228 women, living in Naples, Italy (Progetto ATENA). Serum cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, insulin, HOMA, Apo B, hs-CPR and sd-LDL were measured. LDL particle separation was performed by Lipoprint System: seven LDL subfractions were obtained and LDL score (% of sd-LDL particles) calculated. ABSI was calculated according to Krakauer’s formula: ABSI (m11/6 kg−2/3). The association between sd-LDL and ABSI was evaluated taking into account different adjustment models. Women with elevated levels of ABSI show the following OR of having high LDL score: 2.39, p = 0.002; unadjusted; 2.47, p = 0.002; adjusted for age; 2.13, p = 0.011; adjusted for age and Apo B; 1.93, p = 0.026; adjusted for age and Apo B and triglycerides. ABSI was associated with elevated LDL score independently of age, Systolic pressure, Apo B and triglycerides. Median of LDL diameter decreased among ABSI quartiles: quartile I: 271.5 nm, quartile II: 270.7 nm, quartile III 270.5 nm, quartile IV 269.4 nm; Kruskall Wallis Test: p = 0.016. These results are in line with the hypothesis that ABSI could be a marker of visceral abdominal associated to adverse metabolic changes including presence of elevated sd-LDL, a risk factor for premature cardiovascular disease.
doi:10.3164/jcbn.17-13
PMCID: PMC5612817
body shape index; women; small dense LDL
21.  Nano-topography Enhances Communication in Neural Cells Networks 
Scientific Reports  2017;7:9841.
Neural cells are the smallest building blocks of the central and peripheral nervous systems. Information in neural networks and cell-substrate interactions have been heretofore studied separately. Understanding whether surface nano-topography can direct nerve cells assembly into computational efficient networks may provide new tools and criteria for tissue engineering and regenerative medicine. In this work, we used information theory approaches and functional multi calcium imaging (fMCI) techniques to examine how information flows in neural networks cultured on surfaces with controlled topography. We found that substrate roughness S a affects networks topology. In the low nano-meter range, S a = 0–30 nm, information increases with S a. Moreover, we found that energy density of a network of cells correlates to the topology of that network. This reinforces the view that information, energy and surface nano-topography are tightly inter-connected and should not be neglected when studying cell-cell interaction in neural tissue repair and regeneration.
doi:10.1038/s41598-017-09741-w
PMCID: PMC5575309  PMID: 28851984
22.  Trends in the number and the quality of trial protocols involving children submitted to a French Institutional Review Board 
Background
There is a great need for high quality clinical research for children. The European Pediatric Regulation aimed to improve the quality of clinical trials in order to increase the availability of treatments for children. The main purpose of this study was to assess the evolution of both the number and the quality of pediatric trial protocols that were submitted to a French Institutional Review Board (IRB00009118) before and after the initiation of the EU Pediatric Regulation.
Methods
All protocols submitted to the IRB00009118 between 2003 and 2014 and conducting research on subjects under eighteen years of age were eligible. The quality of randomized clinical trials was assessed according to the guidelines developed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network and ranked using the Jadad score.
Results
Out of 622 protocols submitted to the Institutional Review Board (IRB), 21% (133/622) included children. Among these 133 pediatric protocols, the number of submitted pediatric protocols doubled between the two studied periods. From 2003 to 2008, 47 protocols including 21 institutionally sponsored were submitted to the IRB and from 2009 until 2014, 86 protocols including 48 institutionally sponsored were submitted. No significant trend was observed on the quality of RCTs. The overall median score of RCTs on the Jadad scale was high (3.5), 70.0% of protocols had a Jadad score ≥ 3, and 30.0% had a score < 3.
Conclusion
Following the EU Pediatric Regulation, the number of pediatric protocols submitted to the IRB00009118 tends to increase, but no change was noticed regarding their quality.
doi:10.1186/s12874-017-0395-4
PMCID: PMC5569539  PMID: 28835231
European Pediatric Regulation; Institutional Review board; Randomized Clinical Trials
23.  Fiducial, total and differential cross-section measurements of t-channel single top-quark production in pp collisions at 8 TeV using data collected by the ATLAS detector 
Aaboud, M. | Aad, G. | Abbott, B. | Abdallah, J. | Abdinov, O. | Abeloos, B. | AbouZeid, O. S. | Abraham, N. L. | Abramowicz, H. | Abreu, H. | Abreu, R. | Abulaiti, Y. | Acharya, B. S. | Adachi, S. | Adamczyk, L. | Adams, D. L. | Adelman, J. | Adomeit, S. | Adye, T. | Affolder, A. A. | Agatonovic-Jovin, T. | Aguilar-Saavedra, J. A. | Ahlen, S. P. | Ahmadov, F. | Aielli, G. | Akerstedt, H. | Åkesson, T. P. A. | Akimov, A. V. | Alberghi, G. L. | Albert, J. | Albrand, S. | Verzini, M. J. Alconada | Aleksa, M. | Aleksandrov, I. N. | Alexa, C. | Alexander, G. | Alexopoulos, T. | Alhroob, M. | Ali, B. | Aliev, M. | Alimonti, G. | Alison, J. | Alkire, S. P. | Allbrooke, B. M. M. | Allen, B. W. | Allport, P. P. | Aloisio, A. | Alonso, A. | Alonso, F. | Alpigiani, C. | Alshehri, A. A. | Alstaty, M. | Gonzalez, B. Alvarez | Piqueras, D. Álvarez | Alviggi, M. G. | Amadio, B. T. | Coutinho, Y. Amaral | Amelung, C. | Amidei, D. | Santos, S. P. Amor Dos | Amorim, A. | Amoroso, S. | Amundsen, G. | Anastopoulos, C. | Ancu, L. S. | Andari, N. | Andeen, T. | Anders, C. F. | Anders, J. K. | Anderson, K. J. | Andreazza, A. | Andrei, V. | Angelidakis, S. | Angelozzi, I. | Angerami, A. | Anghinolfi, F. | Anisenkov, A. V. | Anjos, N. | Annovi, A. | Antel, C. | Antonelli, M. | Antonov, A. | Antrim, D. J. | Anulli, F. | Aoki, M. | Bella, L. Aperio | Arabidze, G. | Arai, Y. | Araque, J. P. | Arce, A. T. H. | Arduh, F. A. | Arguin, J-F. | Argyropoulos, S. | Arik, M. | Armbruster, A. J. | Armitage, L. J. | Arnaez, O. | Arnold, H. | Arratia, M. | Arslan, O. | Artamonov, A. | Artoni, G. | Artz, S. | Asai, S. | Asbah, N. | Ashkenazi, A. | Åsman, B. | Asquith, L. | Assamagan, K. | Astalos, R. | Atkinson, M. | Atlay, N. B. | Augsten, K. | Avolio, G. | Axen, B. | Ayoub, M. K. | Azuelos, G. | Baak, M. A. | Baas, A. E. | Baca, M. J. | Bachacou, H. | Bachas, K. | Backes, M. | Backhaus, M. | Bagiacchi, P. | Bagnaia, P. | Bai, Y. | Baines, J. T. | Bajic, M. | Baker, O. K. | Baldin, E. M. | Balek, P. | Balestri, T. | Balli, F. | Balunas, W. K. | Banas, E. | Banerjee, Sw. | Bannoura, A. A. E. | Barak, L. | Barberio, E. L. | Barberis, D. | Barbero, M. | Barillari, T. | Barisits, M-S. | Barklow, T. | Barlow, N. | Barnes, S. L. | Barnett, B. M. | Barnett, R. M. | Barnovska-Blenessy, Z. | Baroncelli, A. | Barone, G. | Barr, A. J. | Navarro, L. Barranco | Barreiro, F. | da Costa, J. Barreiro Guimarães | Bartoldus, R. | Barton, A. E. | Bartos, P. | Basalaev, A. | Bassalat, A. | Bates, R. L. | Batista, S. J. | Batley, J. R. | Battaglia, M. | Bauce, M. | Bauer, F. | Bawa, H. S. | Beacham, J. B. | Beattie, M. D. | Beau, T. | Beauchemin, P. H. | Bechtle, P. | Beck, H. P. | Becker, K. | Becker, M. | Beckingham, M. | Becot, C. | Beddall, A. J. | Beddall, A. | Bednyakov, V. A. | Bedognetti, M. | Bee, C. P. | Beemster, L. J. | Beermann, T. A. | Begel, M. | Behr, J. K. | Bell, A. S. | Bella, G. | Bellagamba, L. | Bellerive, A. | Bellomo, M. | Belotskiy, K. | Beltramello, O. | Belyaev, N. L. | Benary, O. | Benchekroun, D. | Bender, M. | Bendtz, K. | Benekos, N. | Benhammou, Y. | Noccioli, E. Benhar | Benitez, J. | Benjamin, D. P. | Bensinger, J. R. | Bentvelsen, S. | Beresford, L. | Beretta, M. | Berge, D. | Kuutmann, E. Bergeaas | Berger, N. | Beringer, J. | Berlendis, S. | Bernard, N. R. | Bernius, C. | Bernlochner, F. U. | Berry, T. | Berta, P. | Bertella, C. | Bertoli, G. | Bertolucci, F. | Bertram, I. A. | Bertsche, C. | Bertsche, D. | Besjes, G. J. | Bylund, O. Bessidskaia | Bessner, M. | Besson, N. | Betancourt, C. | Bethani, A. | Bethke, S. | Bevan, A. J. | Bianchi, R. M. | Bianco, M. | Biebel, O. | Biedermann, D. | Bielski, R. | Biesuz, N. V. | Biglietti, M. | De Mendizabal, J. Bilbao | Billoud, T. R. V. | Bilokon, H. | Bindi, M. | Bingul, A. | Bini, C. | Biondi, S. | Bisanz, T. | Bjergaard, D. M. | Black, C. W. | Black, J. E. | Black, K. M. | Blackburn, D. | Blair, R. E. | Blazek, T. | Bloch, I. | Blocker, C. | Blue, A. | Blum, W. | Blumenschein, U. | Blunier, S. | Bobbink, G. J. | Bobrovnikov, V. S. | Bocchetta, S. S. | Bocci, A. | Bock, C. | Boehler, M. | Boerner, D. | Bogaerts, J. A. | Bogavac, D. | Bogdanchikov, A. G. | Bohm, C. | Boisvert, V. | Bokan, P. | Bold, T. | Boldyrev, A. S. | Bomben, M. | Bona, M. | Boonekamp, M. | Borisov, A. | Borissov, G. | Bortfeldt, J. | Bortoletto, D. | Bortolotto, V. | Bos, K. | Boscherini, D. | Bosman, M. | Sola, J. D. Bossio | Boudreau, J. | Bouffard, J. | Bouhova-Thacker, E. V. | Boumediene, D. | Bourdarios, C. | Boutle, S. K. | Boveia, A. | Boyd, J. | Boyko, I. R. | Bracinik, J. | Brandt, A. | Brandt, G. | Brandt, O. | Bratzler, U. | Brau, B. | Brau, J. E. | Madden, W. D. Breaden | Brendlinger, K. | Brennan, A. J. | Brenner, L. | Brenner, R. | Bressler, S. | Bristow, T. M. | Britton, D. | Britzger, D. | Brochu, F. 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Detailed measurements of t-channel single top-quark production are presented. They use 20.2 fb\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$^{-1}$$\end{document}-1 of data collected by the ATLAS experiment in proton–proton collisions at a centre-of-mass energy of 8 TeV at the LHC. Total, fiducial and differential cross-sections are measured for both top-quark and top-antiquark production. The fiducial cross-section is measured with a precision of 5.8% (top quark) and 7.8% (top antiquark), respectively. The total cross-sections are measured to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (tq) = 56.7^{+4.3}_{-3.8}\;\mathrm{pb}$$\end{document}σtot(tq)=56.7-3.8+4.3pb for top-quark production and \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\sigma _{\text {tot}} (\bar{t} q) = 32.9^{+3.0}_{-2.7}\;\mathrm{pb}$$\end{document}σtot(t¯q)=32.9-2.7+3.0pb for top-antiquark production, in agreement with the Standard Model prediction. In addition, the ratio of top-quark to top-antiquark production cross-sections is determined to be \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$R_t=1.72 \pm 0.09$$\end{document}Rt=1.72±0.09. The differential cross-sections as a function of the transverse momentum and rapidity of both the top quark and the top antiquark are measured at both the parton and particle levels. The transverse momentum and rapidity differential cross-sections of the accompanying jet from the t-channel scattering are measured at particle level. All measurements are compared to various Monte Carlo predictions as well as to fixed-order QCD calculations where available.
doi:10.1140/epjc/s10052-017-5061-9
PMCID: PMC5589447
24.  A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum 
Scientific Reports  2017;7:7363.
The N-palmitoylethanolamine (PEA) is an endogenous member of the endocannabinoid system (ECS) with several biological functions, including a neuromodulatory activity in the central nervous system. To shed light on the neuronal function of PEA, we investigated its involvement in the control of both excitatory and inhibitory transmission in the murine striatum, a brain region strongly modulated by the ECS. By means of electrophysiological recordings, we showed that PEA modulates inhibitory synaptic transmission, through activation of GPR55 receptors, promoting a transient increase of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency. The subsequently rundown effect on sIPSC frequency was secondary to the delayed stimulation of presynaptic cannabinoid CB1 receptors (CB1Rs) by the endocannabinoid 2-AG, whose synthesis was stimulated by PEA on postsynaptic neurons. Our results indicate that PEA, acting on GPR55, enhances GABA transmission in the striatum, and triggers a parallel synthesis of 2-AG at the postsynaptic site, that in turn acts in a retrograde manner to inhibit GABA release through the stimulation of presynaptic CB1Rs. This electrophysiological study identifies a previously unrecognized function of PEA and of GPR55, demonstrating that GABAergic transmission is under the control of this compound and revealing that PEA modulates the release of the endocannabinoid 2-AG.
doi:10.1038/s41598-017-07519-8
PMCID: PMC5544685  PMID: 28779174
25.  The Continuous Motion Technique for a New Generation of Scanning Systems 
Scientific Reports  2017;7:7310.
In the present paper we report the development of the Continuous Motion scanning technique and its implementation for a new generation of scanning systems. The same hardware setup has demonstrated a significant boost in the scanning speed, reaching 190 cm2/h. The implementation of the Continuous Motion technique in the LASSO framework, as well as a number of new corrections introduced are described in details. The performance of the system, the results of an efficiency measurement and potential applications of the technique are discussed.
doi:10.1038/s41598-017-07869-3
PMCID: PMC5544715  PMID: 28779133

Results 1-25 (786)