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1. The Impact of Childhood Trauma on Developing Bipolar Disorder: Current Understanding and Ensuring Continued Progress

Author

Quidé Y, Tozzi L, Corcoran M, Cannon DM, and Dauvermann MR

Subjects
bipolar disorder, childhood trauma, vulnerability, early onset, peripheral blood marker, brain, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Yann Quidé,1,2 Leonardo Tozzi,3 Mark Corcoran,4 Dara M Cannon,5 Maria R Dauvermann6,7 1School of Psychiatry, University of New South Wales (UNSW), Sydney, NSW, Australia; 2Neuroscience Research Australia, Randwick, NSW, Australia; 3Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; 4School of Psychology, National University of Ireland Galway, Galway, Ireland; 5Centre for Neuroimaging & Cognitive Genomics (NICOG), Clinical Neuroimaging Laboratory, NCBES Galway Neuroscience Centre, School of Medicine, National University of Ireland Galway, Galway, Ireland; 6Department of Psychiatry, University of Cambridge, Cambridge, UK; 7McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, USACorrespondence: Maria R DauvermannDepartment of Psychiatry, University of Cambridge, Clifford Allbutt Building, Cambridge Biomedical Campus Box 58, Cambridge CB2 0XY, UKTel +441223 465246Email md874@medschl.cam.ac.ukAbstract: Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it summarizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood.Keywords: bipolar disorder, childhood trauma, vulnerability, early onset, peripheral blood marker, brain

Published
2020

2. Myopic Traction Maculopathy: Diagnostic and Management Strategies

Author

Frisina R, Gius I, Palmieri M, Finzi A, Tozzi L, and Parolini B

Subjects
pathological myopia posterior staphyloma retinal detachment full thickness macular hole macular buckle pars plana vitrectomy myopic traction maculopathy, Ophthalmology, RE1-994
Abstract

Rino Frisina,1 Irene Gius,1 Michele Palmieri,2 Alessandro Finzi,3 Luigi Tozzi,1 Barbara Parolini2 1Department of Ophthalmology of University of Padova, Padova, Italy; 2Eyecare Clinic, Brescia, Italy; 3Villa Erbosa Di Bologna, Bologna, Emilia-Romagna, ItalyCorrespondence: Rino FrisinaDepartment of Ophthalmology of University of Padova, Via Giustiniani n. 2, Padova 35128, ItalyTel +39 0498212110Fax +39 049 8755169Email frisinarino@gmail.comAbstract: Pathologic myopia (PM) is an ocular disorder characterized by a spherical equivalent (SE) of more than – 6.0 diopters (D) or by an axial length (AL) of more than 26.5 millimeters (mm). PM is associated with myopic maculopathy (MM). The ATN classification describes all the aspects of MM which regroups atrophic, tractional and neovascular consequences to the sclera, choroid and retina of highly myopic eyes. The advent of OCT allowed to define the ultrastructural characteristics of the tractional changes in MM, described by the term myopic traction maculopathy (MTM). They include foveoschisis/maculoschisis/retinoschisis (FS/MS/RS), retinal/foveal detachment (RD/FD), lamellar macular holes (LMH) and full-thickness macular holes (FTMH) with or without RD (MHRD). The MTM staging system (MSS) describes all foveal and retinal changes related to MTM and their natural history interpreting them as different stages of a single progressive disorder. The management of MTM can be just observation for the earliest cases with good vision or surgery for the severe stages with vision loss. There are two possible surgical approaches: ab externo, that acts on the alteration of the scleral shape and includes posterior scleral reinforcement and macular buckle. Ab interno, that targets the alteration of the foveal profile and consists in pars plana vitrectomy with removal of all the epiretinal tractions, maneuvers on the internal limiting membrane, and the use of intravitreal tamponade and laser. As they target two different sides of the same pathology, the two techniques have to be selected on the base of the MTM stage, single or combined.Keywords: pathological myopia, posterior staphyloma, retinal detachment, full thickness macular hole, macular buckle, pars plana vitrectomy, myopic traction maculopathy

Published
2020

3. Treatment efficacy and effectiveness in adults with major depressive disorder and childhood trauma history: a comprehensive meta-analysis

Author

Kuzminskaite, E., Gathier, A.W., Cuijpers, P., Penninx, B.W.J.H., Ammerman, R.T., Brakemeier, E.L., Bruijniks, S., Carletto, S., Chakrabarty, T., Douglas, K., Dunlop, B.W., Elsaesser, M., Euteneuer, F., Guhn, A., Handley, E.D., Heinonen, E., Huibers, M.J.H., Jobst, A., Johnson, G.R., Klein, D.N., Kopf-Beck, J., Lemmens, L., Lu, X., Mohamed, S., Nakagawa, A., Okada, S., Rief, W., Tozzi, L., Trivedi, M.H., van Bronswijk, S., van Oppen, P., Zisook, S., Zobel, I., and Vinkers, C.H.

Published
2022
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4. Painting on polyurethane foam: 'Composizione-Superficie Lunare' by Giulio Turcato

Author

Sabatini, F, Manariti, A, di Girolamo, F, Bonaduce, I, Tozzi, L, Rava, A, Colombini, M, Lluveras-Tenorio, A, Sabatini F, Manariti A, di Girolamo F, Bonaduce I, Tozzi L, Rava A, Colombini MP, Lluveras-Tenorio A, Sabatini, F, Manariti, A, di Girolamo, F, Bonaduce, I, Tozzi, L, Rava, A, Colombini, M, Lluveras-Tenorio, A, Sabatini F, Manariti A, di Girolamo F, Bonaduce I, Tozzi L, Rava A, Colombini MP, and Lluveras-Tenorio A

Abstract

“Composizione-Superficie Lunare” (1965) is an artwork of the Italian artist Giulio Turcato (Mantua, 1912- Rome, 1995). This painting, inspired by moon travels, was created on a polyurethane foam support, material experimentalized by some other contemporary artists in the late 1960′s. In the present paper the organic and inorganic materials used as binders, fillers and pigments, as well as the support itself, have been investigated by means of a multi-analytical approach based on the application of Environmental Scanning Electron Microscopy Energy-Dispersive X-ray spectroscopy (ESEM–EDX), Micro-Attenuated Total Reflection Fourier Transform Infrared spectroscopy (µ-ATR–FTIR), High Performance Liquid Chromatography coupled with Diode Array Dectector and tandem Mass Spectrometry (HPLC–DAD, LC–MS/MS), Pyrolysis-Gas Chromatography and Evolved Gas Analysis coupled with Mass Spectrometry (Py-GC/MS, multi-shot Py-GC/MS and EGA–MS). The plethora of analytical techniques available allowed to provide for the first time a full characterization of the different materials used in “Composizione-Superficie Lunare” and of a Turcato's painting. The polyurethane foam artwork was painted using synthetic inorganic and organic pigments, such as methyl violet and manganese violet, dispersed in polyvinyl acetate as medium. The study was fundamental for establishing the original materials and aesthetics of the artwork as well as assessing the degradation state of the painting materials and of the polyurethane foam support. The results collected, crucial for planning an effective restoration campaign, highlight the importance of the contribution of analytical chemistry to cultural heritage.

Published
2020

8. LBA61 First analysis of RAIN-701: Study of tarloxotinib in patients with non-small cell lung cancer (NSCLC) EGFR Exon 20 insertion, HER2-activating mutations & other solid tumours with NRG1/ERBB gene fusions

Author

Liu, S.V., primary, Villaruz, L.C., additional, Lee, V.H.F., additional, Zhu, V.W., additional, Baik, C.S., additional, Sacher, A., additional, McCoach, C.E., additional, Nguyen, D., additional, Li, J.Y-C., additional, Pacheco, J.M., additional, Kim, C., additional, Burns, T.F., additional, Schenk, E.L., additional, Leighl, N., additional, Tozzi, L., additional, and Camidge, D.R., additional

Published
2020
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11. The impact of childhood trauma on developing bipolar disorder: Current understanding and ensuring continued progress

Author

Quidé, Y, Tozzi, L, Corcoran, M, Cannon, DM, Dauvermann, MR, Quidé, Y, Tozzi, L, Corcoran, M, Cannon, DM, and Dauvermann, MR

Abstract

Childhood trauma (CT) has been repeatedly linked to earlier onset and greater severity of bipolar disorder (BD) in adulthood. However, such knowledge is mostly based on retrospective and cross-sectional studies in adults with BD. The first objective of this selective review is to characterize the short-term effects of CT in the development of BD by focusing on studies in young people. The second objective is to describe the longer-term consequences of CT by considering studies with adult participants. This review first outlines the most prominent hypotheses linking CT exposure and the onset of BD. Then, it sum-marizes the psychological and biological risk factors implicated in the development of BD, followed by a discussion of original studies that investigated the role of CT in young people with early-onset BD, youths at increased risk of developing BD, or young people with BD with a focus on subclinical and clinical outcome measures. The review considers additional biological and psychological factors associated with a negative impact of CT on the long-term course of BD in later adulthood. Finally, we discuss how the integration of information of CT can improve ongoing early identification of BD and mitigate severe clinical expression in later adulthood.

Published
2020

12. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Author

Thompson, P.M. (Paul), Jahanshad, N. (Neda), Ching, C.R.K. (Christopher), Salminen, L.E. (Lauren E.), Thomopoulos, S.I. (Sophia I.), Bright, J. (Joanna), Baune, B.T., Bertolín, S. (Sara), Bralten, L.B.C. (Linda), Bruin, W.B. (Willem B.), Bülow, R. (Robin), Chen, J. (Jian), Chye, Y. (Yann), Dannlowski, U. (Udo), de Kovel, C.G.F. (Carolien G F), Donohoe, D.J. (Dennis), Eyler, L.T. (Lisa T.), Faraone, S.V. (Stephen), Favre, P. (Pauline), Filippi, C.A. (Courtney A.), Frodl, T. (Thomas), Garijo, D. (Daniel), Gil, Y. (Yolanda), Grabe, H.J. (Hans Jörgen), Grasby, K.L. (Katrina L.), Hajek, T. (Tomas), Han, L.K.M. (Laura K M), Hatton, W., Hilbert, K. (Kevin), Ho, T.C. (Tiffany C.), Holleran, L. (Laurena), Homuth, G. (Georg), Hosten, N. (Norbert), Houenou, J. (Josselin), Ivanov, I. (Iliyan), Jia, T. (Tianye), Kelly, S. (Sinead), Klein, M. (Marieke), Kwon, J.S. (Jun Soo), Laansma, M.A. (Max A.), Leerssen, J. (Jeanne), Lueken, U. (Ulrike), Nunes, A. (Abraham), Neill, J.O. (Joseph O'), Opel, N. (Nils), Piras, F. (Fabrizio), Piras, F. (Federica), Postema, M.C. (Merel C.), Pozzi, E. (Elena), Shatokhina, N. (Natalia), Soriano-Mas, C. (Carles), Spalletta, G. (Gianfranco), Sun, D. (Daqiang), Teumer, A. (Alexander), Tilot, A.K. (Amanda K.), Tozzi, L. (Leonardo), van der Merwe, C. (Celia), Someren, E.J.W. (Eus) van, van Wingen, G.A. (Guido A.), Völzke, H. (Henry), Walton, E. (Esther), Wang, L. (Lei), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Wright, M.J. (Margaret), Yun, J.-Y. (Je-Yeon), Zhang, G. (Guohao), Zhang-James, Y. (Yanli), Adhikari, B.M. (Bhim M.), Agartz, I. (Ingrid), Aghajani, M. (Moji), Aleman, A. (André), Althoff, R.R. (Robert R.), Altmann, A. (A.), Andreassen, O.A. (Ole), Baron, D.A. (David A.), Bartnik-Olson, B.L. (Brenda L.), Marie Bas-Hoogendam, J. (Janna), Baskin-Sommers, A.R. (Arielle R.), Bearden, C.E. (Carrie), Berner, L.A. (Laura A.), Boedhoe, P.S.W. (Premika S W), Brouwer, R.M. (Rachel), Buitelaar, J.K. (Jan), Caeyenberghs, K. (Karen), Cecil, C.A.M. (Charlotte), Cohen, R.A. (Ronald A.), Cole, J.H. (James H.), Conrod, P. (Patricia), De Brito, S.A. (Stephane A.), de Zwarte, S.M.C. (Sonja M C), Dennis, E.L. (Emily L.), Desrivieres, S. (Sylvane), Dima, D. (Danai), Ehrlich, S.M. (Stefan), Esopenko, C. (Carrie), Fairchild, G. (Graeme), Fisher, S.E. (Simon), Fouche, J.-P. (Jean-Paul), Francks, C. (Clyde), Frangou, S. (Sophia), Franke, B. (Barbara), Garavan, H.P. (Hugh P.), Glahn, D.C. (David), Groenewold, N.A. (Nynke A.), Gurholt, T.P. (Tiril P.), Gutman, B.A. (Boris A.), Hahn, T. (Tim), Harding, I.H. (Ian H.), Hernaus, D. (Dennis), Hibar, D.P. (Derrek P.), Hillary, F.G. (Frank G.), Hoogman, M. (Martine), Hulshoff Pol, H.E. (Hilleke E.), Jalbrzikowski, M. (Maria), Karkashadze, G.A. (George A.), Klapwijk, E.T. (Eduard T.), Knickmeyer, R.C. (Rebecca C.), Kochunov, P. (Peter), Koerte, I.K. (Inga K.), Kong, X.-Z. (Xiang-Zhen), Liew, S.-L. (Sook-Lei), Lin, A.P. (Alexander P.), Logue, M.W. (Mark W.), Luders, E. (Eileen), Macciardi, F. (Fabio), Mackey, S. (Scott), Mayer, A.R. (Andrew R.), McDonald, C.R. (Carrie R.), McMahon, A.B. (Agnes B.), Medland, S.E. (Sarah), Modinos, G. (Gemma), Morey, R.A. (Rajendra A.), Mueller, S.C. (Sven C.), Mukherjee, P. (Pratik), Namazova-Baranova, L. (L.), Nir, T.M. (Talia M.), Olsen, A. (Alexander), Paschou, P. (Peristera), Pine, D.S. (Daniel S.), Pizzagalli, F. (Fabrizio), Rentería, M.E. (Miguel), Rohrer, J.D. (Jonathan D.), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schumann, G. (Gunter), Shiroishi, M.S. (Mark S.), Sisodiya, S.M. (Sanjay), Smit, D.J.A. (Dirk J A), Sønderby, I.E. (Ida E.), Stein, D.J. (Dan J.), Stein, J.L., Tahmasian, M. (Masoud), Tate, D.F. (David F.), Turner, J. (Jessica), Heuvel, O.A. (Odile A.), Wee, N.J. (Nic) van der, van der Werf, Y.D. (Ysbrand), Erp, T.G.M. (Theo G.) van, van Haren, N.E.M. (Neeltje E M), van Rooij, D. (Daan), Van Velzen, L.S., Veer, I.M. (Ilya), Veltman, D.J. (Dick), Villalon-Reina, J.E. (Julio E.), Walter, H.J. (Henrik), Whelan, C.D. (Christopher), Wilde, E.A. (Elisabeth A.), Zarei, M. (Mojtaba), Zelman, V. (Vladimir), Thompson, P.M. (Paul), Jahanshad, N. (Neda), Ching, C.R.K. (Christopher), Salminen, L.E. (Lauren E.), Thomopoulos, S.I. (Sophia I.), Bright, J. (Joanna), Baune, B.T., Bertolín, S. (Sara), Bralten, L.B.C. (Linda), Bruin, W.B. (Willem B.), Bülow, R. (Robin), Chen, J. (Jian), Chye, Y. (Yann), Dannlowski, U. (Udo), de Kovel, C.G.F. (Carolien G F), Donohoe, D.J. (Dennis), Eyler, L.T. (Lisa T.), Faraone, S.V. (Stephen), Favre, P. (Pauline), Filippi, C.A. (Courtney A.), Frodl, T. (Thomas), Garijo, D. (Daniel), Gil, Y. (Yolanda), Grabe, H.J. (Hans Jörgen), Grasby, K.L. (Katrina L.), Hajek, T. (Tomas), Han, L.K.M. (Laura K M), Hatton, W., Hilbert, K. (Kevin), Ho, T.C. (Tiffany C.), Holleran, L. (Laurena), Homuth, G. (Georg), Hosten, N. (Norbert), Houenou, J. (Josselin), Ivanov, I. (Iliyan), Jia, T. (Tianye), Kelly, S. (Sinead), Klein, M. (Marieke), Kwon, J.S. (Jun Soo), Laansma, M.A. (Max A.), Leerssen, J. (Jeanne), Lueken, U. (Ulrike), Nunes, A. (Abraham), Neill, J.O. (Joseph O'), Opel, N. (Nils), Piras, F. (Fabrizio), Piras, F. (Federica), Postema, M.C. (Merel C.), Pozzi, E. (Elena), Shatokhina, N. (Natalia), Soriano-Mas, C. (Carles), Spalletta, G. (Gianfranco), Sun, D. (Daqiang), Teumer, A. (Alexander), Tilot, A.K. (Amanda K.), Tozzi, L. (Leonardo), van der Merwe, C. (Celia), Someren, E.J.W. (Eus) van, van Wingen, G.A. (Guido A.), Völzke, H. (Henry), Walton, E. (Esther), Wang, L. (Lei), Winkler, A.M. (Anderson), Wittfeld, K. (Katharina), Wright, M.J. (Margaret), Yun, J.-Y. (Je-Yeon), Zhang, G. (Guohao), Zhang-James, Y. (Yanli), Adhikari, B.M. (Bhim M.), Agartz, I. (Ingrid), Aghajani, M. (Moji), Aleman, A. (André), Althoff, R.R. (Robert R.), Altmann, A. (A.), Andreassen, O.A. (Ole), Baron, D.A. (David A.), Bartnik-Olson, B.L. (Brenda L.), Marie Bas-Hoogendam, J. (Janna), Baskin-Sommers, A.R. (Arielle R.), Bearden, C.E. (Carrie), Berner, L.A. (Laura A.), Boedhoe, P.S.W. (Premika S W), Brouwer, R.M. (Rachel), Buitelaar, J.K. (Jan), Caeyenberghs, K. (Karen), Cecil, C.A.M. (Charlotte), Cohen, R.A. (Ronald A.), Cole, J.H. (James H.), Conrod, P. (Patricia), De Brito, S.A. (Stephane A.), de Zwarte, S.M.C. (Sonja M C), Dennis, E.L. (Emily L.), Desrivieres, S. (Sylvane), Dima, D. (Danai), Ehrlich, S.M. (Stefan), Esopenko, C. (Carrie), Fairchild, G. (Graeme), Fisher, S.E. (Simon), Fouche, J.-P. (Jean-Paul), Francks, C. (Clyde), Frangou, S. (Sophia), Franke, B. (Barbara), Garavan, H.P. (Hugh P.), Glahn, D.C. (David), Groenewold, N.A. (Nynke A.), Gurholt, T.P. (Tiril P.), Gutman, B.A. (Boris A.), Hahn, T. (Tim), Harding, I.H. (Ian H.), Hernaus, D. (Dennis), Hibar, D.P. (Derrek P.), Hillary, F.G. (Frank G.), Hoogman, M. (Martine), Hulshoff Pol, H.E. (Hilleke E.), Jalbrzikowski, M. (Maria), Karkashadze, G.A. (George A.), Klapwijk, E.T. (Eduard T.), Knickmeyer, R.C. (Rebecca C.), Kochunov, P. (Peter), Koerte, I.K. (Inga K.), Kong, X.-Z. (Xiang-Zhen), Liew, S.-L. (Sook-Lei), Lin, A.P. (Alexander P.), Logue, M.W. (Mark W.), Luders, E. (Eileen), Macciardi, F. (Fabio), Mackey, S. (Scott), Mayer, A.R. (Andrew R.), McDonald, C.R. (Carrie R.), McMahon, A.B. (Agnes B.), Medland, S.E. (Sarah), Modinos, G. (Gemma), Morey, R.A. (Rajendra A.), Mueller, S.C. (Sven C.), Mukherjee, P. (Pratik), Namazova-Baranova, L. (L.), Nir, T.M. (Talia M.), Olsen, A. (Alexander), Paschou, P. (Peristera), Pine, D.S. (Daniel S.), Pizzagalli, F. (Fabrizio), Rentería, M.E. (Miguel), Rohrer, J.D. (Jonathan D.), Sämann, P.G. (Philipp), Schmaal, L. (Lianne), Schumann, G. (Gunter), Shiroishi, M.S. (Mark S.), Sisodiya, S.M. (Sanjay), Smit, D.J.A. (Dirk J A), Sønderby, I.E. (Ida E.), Stein, D.J. (Dan J.), Stein, J.L., Tahmasian, M. (Masoud), Tate, D.F. (David F.), Turner, J. (Jessica), Heuvel, O.A. (Odile A.), Wee, N.J. (Nic) van der, van der Werf, Y.D. (Ysbrand), Erp, T.G.M. (Theo G.) van, van Haren, N.E.M. (Neeltje E M), van Rooij, D. (Daan), Van Velzen, L.S., Veer, I.M. (Ilya), Veltman, D.J. (Dick), Villalon-Reina, J.E. (Julio E.), Walter, H.J. (Henrik), Whelan, C.D. (Christopher), Wilde, E.A. (Elisabeth A.), Zarei, M. (Mojtaba), and Zelman, V. (Vladimir)

Abstract

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Published
2020
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13. ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

Author

Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, Zelman, V, Thompson, PM, Jahanshad, N, Ching, CRK, Salminen, LE, Thomopoulos, SI, Bright, J, Baune, BT, Bertolin, S, Bralten, J, Bruin, WB, Buelow, R, Chen, J, Chye, Y, Dannlowski, U, de Kovel, CGF, Donohoe, G, Eyler, LT, Faraone, SV, Favre, P, Filippi, CA, Frodl, T, Garijo, D, Gil, Y, Grabe, HJ, Grasby, KL, Hajek, T, Han, LKM, Hatton, SN, Hilbert, K, Ho, TC, Holleran, L, Homuth, G, Hosten, N, Houenou, J, Ivanov, I, Jia, T, Kelly, S, Klein, M, Kwon, JS, Laansma, MA, Leerssen, J, Lueken, U, Nunes, A, Neill, JO, Opel, N, Piras, F, Postema, MC, Pozzi, E, Shatokhina, N, Soriano-Mas, C, Spalletta, G, Sun, D, Teumer, A, Tilot, AK, Tozzi, L, van der Merwe, C, Van Someren, EJW, van Wingen, GA, Voelzke, H, Walton, E, Wang, L, Winkler, AM, Wittfeld, K, Wright, MJ, Yun, J-Y, Zhang, G, Zhang-James, Y, Adhikari, BM, Agartz, I, Aghajani, M, Aleman, A, Althoff, RR, Altmann, A, Andreassen, OA, Baron, DA, Bartnik-Olson, BL, Bas-Hoogendam, J, Baskin-Sommers, AR, Bearden, CE, Berner, LA, Boedhoe, PSW, Brouwer, RM, Buitelaar, JK, Caeyenberghs, K, Cecil, CAM, Cohen, RA, Cole, JH, Conrod, PJ, De Brito, SA, de Zwarte, SMC, Dennis, EL, Desrivieres, S, Dima, D, Ehrlich, S, Esopenko, C, Fairchild, G, Fisher, SE, Fouche, J-P, Francks, C, Frangou, S, Franke, B, Garavan, HP, Glahn, DC, Groenewold, NA, Gurholt, TP, Gutman, BA, Hahn, T, Harding, IH, Hernaus, D, Hibar, DP, Hillary, FG, Hoogman, M, Pol, HE, Jalbrzikowski, M, Karkashadze, GA, Klapwijk, ET, Knickmeyer, RC, Kochunov, P, Koerte, IK, Kong, X-Z, Liew, S-L, Lin, AP, Logue, MW, Luders, E, Macciardi, F, Mackey, S, Mayer, AR, McDonald, CR, McMahon, AB, Medland, SE, Modinos, G, Morey, RA, Mueller, SC, Mukherjee, P, Namazova-Baranova, L, Nir, TM, Olsen, A, Paschou, P, Pine, DS, Pizzagalli, F, Renteria, ME, Rohrer, JD, Saemann, PG, Schmaal, L, Schumann, G, Shiroishi, MS, Sisodiya, SM, Smit, DJA, Sonderby, IE, Stein, DJ, Stein, JL, Tahmasian, M, Tate, DF, Turner, JA, van den Heuvel, OA, van der Wee, NJA, van der Werf, YD, van Erp, TGM, van Haren, NEM, van Rooij, D, van Velzen, LS, Veer, IM, Veltman, DJ, Villalon-Reina, JE, Walter, H, Whelan, CD, Wilde, EA, Zarei, M, and Zelman, V

Abstract

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors.

Published
2020

14. ENIGMA MDD: seven years of global neuroimaging studies of major depression through worldwide data sharing

Author

Schmaal, L, Pozzi, E, Ho, TC, van Velzen, LS, Veer, IM, Opel, N, Van Someren, EJW, Han, LKM, Aftanas, L, Aleman, A, Baune, BT, Berger, K, Blanken, TF, Capitao, L, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, C, Erwin-Grabner, T, Evans, J, Frodl, T, Fu, CHY, Godlewska, B, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Gutman, BA, Hall, GB, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Hilland, E, Irungu, B, Jonassen, R, Kelly, S, Kircher, T, Klimes-Dougan, B, Krug, A, Landro, NI, Lagopoulos, J, Leerssen, J, Li, M, Linden, DEJ, MacMaster, FP, McIntosh, AM, Mehler, DMA, Nenadic, I, Penninx, BWJH, Portella, MJ, Reneman, L, Renteria, ME, Sacchet, MD, Saemann, PG, Schrantee, A, Sim, K, Soares, JC, Stein, DJ, Tozzi, L, van Der Wee, NJA, van Tol, M-J, Vermeiren, R, Vives-Gilabert, Y, Walter, H, Walter, M, Whalley, HC, Wittfeld, K, Whittle, S, Wright, MJ, Yang, TT, Zarate, C, Thomopoulos, SI, Jahanshad, N, Thompson, PM, Veltman, DJ, Schmaal, L, Pozzi, E, Ho, TC, van Velzen, LS, Veer, IM, Opel, N, Van Someren, EJW, Han, LKM, Aftanas, L, Aleman, A, Baune, BT, Berger, K, Blanken, TF, Capitao, L, Couvy-Duchesne, B, Cullen, KR, Dannlowski, U, Davey, C, Erwin-Grabner, T, Evans, J, Frodl, T, Fu, CHY, Godlewska, B, Gotlib, IH, Goya-Maldonado, R, Grabe, HJ, Groenewold, NA, Grotegerd, D, Gruber, O, Gutman, BA, Hall, GB, Harrison, BJ, Hatton, SN, Hermesdorf, M, Hickie, IB, Hilland, E, Irungu, B, Jonassen, R, Kelly, S, Kircher, T, Klimes-Dougan, B, Krug, A, Landro, NI, Lagopoulos, J, Leerssen, J, Li, M, Linden, DEJ, MacMaster, FP, McIntosh, AM, Mehler, DMA, Nenadic, I, Penninx, BWJH, Portella, MJ, Reneman, L, Renteria, ME, Sacchet, MD, Saemann, PG, Schrantee, A, Sim, K, Soares, JC, Stein, DJ, Tozzi, L, van Der Wee, NJA, van Tol, M-J, Vermeiren, R, Vives-Gilabert, Y, Walter, H, Walter, M, Whalley, HC, Wittfeld, K, Whittle, S, Wright, MJ, Yang, TT, Zarate, C, Thomopoulos, SI, Jahanshad, N, Thompson, PM, and Veltman, DJ

Abstract

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

Published
2020

15. Interactive impact of childhood maltreatment, depression, and age on cortical brain structure: mega-analytic findings from a large multi-site cohort

Author

Tozzi, L, Garczarek, L, Janowitz, D, Stein, DJ, Wittfeld, K, Dobrowolny, H, Lagopoulos, J, Hatton, SN, Hickie, IB, Carballedo, A, Brooks, SJ, Vuletic, D, Uhlmann, A, Veer, IM, Walter, H, Buelow, R, Voelzke, H, Klinger-Koenig, J, Schnell, K, Schoepf, D, Grotegerd, D, Opel, N, Dannlowski, U, Kugel, H, Schramm, E, Konrad, C, Kircher, T, Jueksel, DI, Nenadic, I, Krug, A, Hahn, T, Steinstraeter, O, Redlich, R, Zaremba, D, Zurowski, B, Fu, CHY, Dima, D, Cole, J, Grabe, HJ, Connolly, CG, Yang, TT, Ho, TC, Lewinn, KZ, Li, M, Groenewold, NA, Salminen, LE, Walter, M, Simmons, AN, van Erp, TGM, Jahanshad, N, Baune, BT, van der Wee, NJA, van Tol, M-J, Penninx, BWJH, Hibar, DP, Thompson, PM, Veltman, DJ, Schmaal, L, Frodl, T, Tozzi, L, Garczarek, L, Janowitz, D, Stein, DJ, Wittfeld, K, Dobrowolny, H, Lagopoulos, J, Hatton, SN, Hickie, IB, Carballedo, A, Brooks, SJ, Vuletic, D, Uhlmann, A, Veer, IM, Walter, H, Buelow, R, Voelzke, H, Klinger-Koenig, J, Schnell, K, Schoepf, D, Grotegerd, D, Opel, N, Dannlowski, U, Kugel, H, Schramm, E, Konrad, C, Kircher, T, Jueksel, DI, Nenadic, I, Krug, A, Hahn, T, Steinstraeter, O, Redlich, R, Zaremba, D, Zurowski, B, Fu, CHY, Dima, D, Cole, J, Grabe, HJ, Connolly, CG, Yang, TT, Ho, TC, Lewinn, KZ, Li, M, Groenewold, NA, Salminen, LE, Walter, M, Simmons, AN, van Erp, TGM, Jahanshad, N, Baune, BT, van der Wee, NJA, van Tol, M-J, Penninx, BWJH, Hibar, DP, Thompson, PM, Veltman, DJ, Schmaal, L, and Frodl, T

Abstract

BACKGROUND: Childhood maltreatment (CM) plays an important role in the development of major depressive disorder (MDD). The aim of this study was to examine whether CM severity and type are associated with MDD-related brain alterations, and how they interact with sex and age. METHODS: Within the ENIGMA-MDD network, severity and subtypes of CM using the Childhood Trauma Questionnaire were assessed and structural magnetic resonance imaging data from patients with MDD and healthy controls were analyzed in a mega-analysis comprising a total of 3872 participants aged between 13 and 89 years. Cortical thickness and surface area were extracted at each site using FreeSurfer. RESULTS: CM severity was associated with reduced cortical thickness in the banks of the superior temporal sulcus and supramarginal gyrus as well as with reduced surface area of the middle temporal lobe. Participants reporting both childhood neglect and abuse had a lower cortical thickness in the inferior parietal lobe, middle temporal lobe, and precuneus compared to participants not exposed to CM. In males only, regardless of diagnosis, CM severity was associated with higher cortical thickness of the rostral anterior cingulate cortex. Finally, a significant interaction between CM and age in predicting thickness was seen across several prefrontal, temporal, and temporo-parietal regions. CONCLUSIONS: Severity and type of CM may impact cortical thickness and surface area. Importantly, CM may influence age-dependent brain maturation, particularly in regions related to the default mode network, perception, and theory of mind.

Published
2020

16. White matter disturbances in major depressive disorder: a coordinated analysis across 20 international cohorts in the ENIGMA MDD working group

Author

van Velzen, LS, Kelly, S, Isaev, D, Aleman, A, Aftanas, L, Bauer, J, Baune, BT, Brak, I, Carballedo, A, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Danilenko, K, Dannlowski, U, Enneking, V, Filimonova, E, Foerster, K, Frodl, T, Gotlib, IH, Groenewold, NA, Grotegerd, D, Harris, MA, Hatton, SN, Hawkins, EL, Hickie, IB, Ho, TC, Jansen, A, Kircher, T, Klimes-Dougan, B, Kochunov, P, Krug, A, Lagopoulos, J, Lee, R, Lett, TA, Li, M, MacMaster, FP, Martin, NG, McIntosh, AM, McLellan, Q, Meinert, S, Nenadic, I, Osipov, E, Penninx, BWJH, Portella, MJ, Repple, J, Roos, A, Sacchet, MD, Saemann, PG, Schnell, K, Shen, X, Sim, K, Stein, DJ, van Tol, M-J, Tomyshev, AS, Tozzi, L, Veer, IM, Vermeiren, R, Vives-Gilabert, Y, Walter, H, Walter, M, van der Wee, NJA, van der Werff, SJA, Schreiner, MW, Whalley, HC, Wright, MJ, Yang, TT, Zhu, A, Veltman, DJ, Thompson, PM, Jahanshad, N, Schmaal, L, van Velzen, LS, Kelly, S, Isaev, D, Aleman, A, Aftanas, L, Bauer, J, Baune, BT, Brak, I, Carballedo, A, Connolly, CG, Couvy-Duchesne, B, Cullen, KR, Danilenko, K, Dannlowski, U, Enneking, V, Filimonova, E, Foerster, K, Frodl, T, Gotlib, IH, Groenewold, NA, Grotegerd, D, Harris, MA, Hatton, SN, Hawkins, EL, Hickie, IB, Ho, TC, Jansen, A, Kircher, T, Klimes-Dougan, B, Kochunov, P, Krug, A, Lagopoulos, J, Lee, R, Lett, TA, Li, M, MacMaster, FP, Martin, NG, McIntosh, AM, McLellan, Q, Meinert, S, Nenadic, I, Osipov, E, Penninx, BWJH, Portella, MJ, Repple, J, Roos, A, Sacchet, MD, Saemann, PG, Schnell, K, Shen, X, Sim, K, Stein, DJ, van Tol, M-J, Tomyshev, AS, Tozzi, L, Veer, IM, Vermeiren, R, Vives-Gilabert, Y, Walter, H, Walter, M, van der Wee, NJA, van der Werff, SJA, Schreiner, MW, Whalley, HC, Wright, MJ, Yang, TT, Zhu, A, Veltman, DJ, Thompson, PM, Jahanshad, N, and Schmaal, L

Abstract

Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Published
2020

18. Letter: The response to somatostatin analogues in neuroendocrine tumours is influenced by the Ki67 score

Author

Faggiano, A, Carratù, A, Guadagno, E, Tafuto, S, Tatangelo, F, Riccardi, F, Mocerino, C, Palmieri, G, Damiano, V, Siciliano, R, Leo, S, Mauro, A, Tozzi, L, Battista, C, GUADAGNO, ELIA, DE ROSA, GAETANO, COLAO, ANNAMARIA, Faggiano, A, Carratù, A, Guadagno, E, Tafuto, S, Tatangelo, F, Riccardi, F, Mocerino, C, Palmieri, G, Damiano, V, Siciliano, R, Leo, S, Mauro, A, Tozzi, L, Battista, C, DE ROSA, Gaetano, Colao, Annamaria, and Guadagno, Elia

Subjects
Gastritis, Atrophic, medicine.medical_specialty, Hepatology, business.industry, Medicine (all), Gastroenterology, Neuroendocrine tumors, Bioinformatics, medicine.disease, Somatostatin, Text mining, Endocrinology, Stomach Neoplasm, Internal medicine, medicine, Pharmacology (medical), business, Neuroendocrine Tumor, Human
Published
2015

19. Childhood adversity impacts on brain subcortical structures relevant to depression

Author

Frodl, T, Janowitz, D, Schmaal, L, Tozzi, L, Dobrowolny, H, Stein, DJ, Veltman, DJ, Wittfeld, K, van Erp, TGM, Jahanshad, N, Block, A, Hegenscheid, K, Voelzke, H, Lagopoulos, J, Hatton, SN, Hickie, IB, Frey, EM, Carballedo, A, Brooks, SJ, Vuletic, D, Uhlmann, A, Veer, IM, Walter, H, Schnell, K, Grotegerd, D, Arolt, V, Kugel, H, Schramm, E, Konrad, C, Zurowski, B, Baune, BT, van der Wee, NJA, van Tol, M-J, Penninx, BWJH, Thompson, PM, Hibar, DP, Dannlowski, U, Grabe, HJ, Frodl, T, Janowitz, D, Schmaal, L, Tozzi, L, Dobrowolny, H, Stein, DJ, Veltman, DJ, Wittfeld, K, van Erp, TGM, Jahanshad, N, Block, A, Hegenscheid, K, Voelzke, H, Lagopoulos, J, Hatton, SN, Hickie, IB, Frey, EM, Carballedo, A, Brooks, SJ, Vuletic, D, Uhlmann, A, Veer, IM, Walter, H, Schnell, K, Grotegerd, D, Arolt, V, Kugel, H, Schramm, E, Konrad, C, Zurowski, B, Baune, BT, van der Wee, NJA, van Tol, M-J, Penninx, BWJH, Thompson, PM, Hibar, DP, Dannlowski, U, and Grabe, HJ

Abstract

Childhood adversity plays an important role for development of major depressive disorder (MDD). There are differences in subcortical brain structures between patients with MDD and healthy controls, but the specific impact of childhood adversity on such structures in MDD remains unclear. Thus, aim of the present study was to investigate whether childhood adversity is associated with subcortical volumes and how it interacts with a diagnosis of MDD and sex. Within the ENIGMA-MDD network, nine university partner sites, which assessed childhood adversity and magnetic resonance imaging in patients with MDD and controls, took part in the current joint mega-analysis. In this largest effort world-wide to identify subcortical brain structure differences related to childhood adversity, 3036 participants were analyzed for subcortical brain volumes using FreeSurfer. A significant interaction was evident between childhood adversity, MDD diagnosis, sex, and region. Increased exposure to childhood adversity was associated with smaller caudate volumes in females independent of MDD. All subcategories of childhood adversity were negatively associated with caudate volumes in females - in particular emotional neglect and physical neglect (independently from age, ICV, imaging site and MDD diagnosis). There was no interaction effect between childhood adversity and MDD diagnosis on subcortical brain volumes. Childhood adversity is one of the contributors to brain structural abnormalities. It is associated with subcortical brain abnormalities that are relevant to psychiatric disorders such as depression.

Published
2017

20. Improvement of well-being measures after regular physical exercise correlates with resting state connectivity in attentional and default mode networks

Author

Tozzi, L, Doolin, K, Carballedo, A, Lavelle, G, Doyle, M, McCarthy, H, O'Keane, V, and Frodl, T

Abstract

Our study aimed to assess resting state modifications across known brain networks after an extensive period of physical exercise and to investigate their correlations with behavioural measures of mood state and perceived health.

Published
2015

21. Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis

Author

Rumi, E, Pietra, D, Pascutto, C, Guglielmelli, P, Martínez Trillos, A, Casetti, I, Colomer, D, Pieri, L, Pratcorona, M, Rotunno, G, Sant'Antonio, E, Bellini, M, Cavalloni, C, Mannarelli, C, Milanesi, C, Boveri, E, Ferretti, V, Astori, C, Rosti, V, Cervantes, F, Barosi, G, Vannucchi, Am, Cazzola, M, Associazione Italiana per la Ricerca sul Cancro Gruppo Italiano Malattie Mieloproliferative Investigators Collaborators Vannucchi AM, Balliu, M, Bartalucci, N, Biamonte, F, Bisognin, A, Bogani, C, Bortoluzzi, S, Bosi, A, Coppe, A, Fanelli, T, Fjerza, R, Loiacono, I, Marchioli, R, Martinelli, S, Masciulli, A, Pancrazzi, A, Paoli, C, Saccoman, C, Spolverini, A, Susini, Mc, Tozzi, L, Azzan, C, Badalucco, S, Balduini, A, Bonetti, E, Campanelli, R, Catarsi, P, Isgrò, Am, Lupo, Ml, Magrini, U, Massa, M, Poletto, V, Villani, L, Ambaglio, I, Bernasconi, P, Casetti, Ic, Catricalà, S, Elena, C, Fugazza, E, Gall, A, Malcovati, L, Ripamonti, F, Rossi, M, Dejana, E, Breviario, F, Corada, M, Erba, Bg, Rambaldi, A, Amaru, A, Barbui, T, Belotti, C, Boroni, C, Ferrari, Ml, Finazzi, G, Finazzi, Mc, Golay, J, Gritti, G, Salmoiraghi, S, Cilloni, Daniela, Campia, V, Carturan, S, Guerrasio, Angelo, Manfredini, R, Bianchi, E, Salati, S, Tagliafico, E, Tenedini, E, and Zini, R.

Subjects
Oncology, Male, Clinical Trials and Observations, Leukocytosis, DNA Mutational Analysis, Kaplan-Meier Estimate, Biochemistry, Risk Factors, hemic and lymphatic diseases, Aged, 80 and over, Leukemia, biology, Incidence (epidemiology), food and beverages, Anemia, Hematology, Middle Aged, Prognosis, Cell Transformation, Neoplastic, Female, medicine.symptom, Receptors, Thrombopoietin, Adult, medicine.medical_specialty, Adolescent, Immunology, Lower risk, Risk Assessment, Young Adult, Internal medicine, medicine, Humans, Myelofibrosis, Aged, Proportional Hazards Models, business.industry, Proportional hazards model, Cell Biology, Janus Kinase 2, medicine.disease, Thrombocytopenia, Primary Myelofibrosis, Mutation, biology.protein, business, Calreticulin
Abstract

We studied the impact of driver mutations of JAK2, CALR, (calreticulin gene) or MPL on clinical course, leukemic transformation, and survival of patients with primary myelofibrosis (PMF). Of the 617 subjects studied, 399 (64.7%) carried JAK2 (V617F), 140 (22.7%) had a CALR exon 9 indel, 25 (4.0%) carried an MPL (W515) mutation, and 53 (8.6%) had nonmutated JAK2, CALR, and MPL (so-called triple-negative PMF). Patients with CALR mutation had a lower risk of developing anemia, thrombocytopenia, and marked leukocytosis compared with other subtypes. They also had a lower risk of thrombosis compared with patients carrying JAK2 (V617F). At the opposite, triple-negative patients had higher incidence of leukemic transformation compared with either CALR-mutant or JAK2-mutant patients. Median overall survival was 17.7 years in CALR-mutant, 9.2 years in JAK2-mutant, 9.1 years in MPL-mutant, and 3.2 years in triple-negative patients. In multivariate analysis corrected for age, CALR-mutant patients had better overall survival than either JAK2-mutant or triple-negative patients. The impact of genetic lesions on survival was independent of current prognostic scoring systems. These observations indicate that driver mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Published
2014

23. High frequency of endothelial colony forming cells marks a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis

Author

Rosti, V, Bonetti, E, Bergamaschi, G, Campanelli, R, Guglielmelli, P, Maestri, M, Magrini, U, Massa, M, Tinelli, C, Viarengo, G, Villani, L, Primignani, M, Vannucchi, Am, Frassoni, F, Barosi, G, Agimm, Investigators, INCLUDING VANNUCCHI AM, Antonioli, E, Bartalucci, N, Biamonte, F, Bogani, C, Bosi, A, Fjerza, R, Malevolti, E, Pancrazzi, A, Pieri, L, Spolverini, A, Susini, Mc, Tozzi, L, Bortoluzzi, Stefania, Bisognin, A, Coppe, A, Marchioli, R, Azzan, C, Badalucco, S, Balduini, A, Carolei, A, Currao, M, Isgrã’, Ma, Lupo, Ml, Magni, V, Cazzola, M, Bernasconi, P, Boggi, S, Elena, C, Gallãœ, A, Malcovati, L, Pascutto, C, Passamonti, F, Pietra, D, Rumi, E, Dejana, E, Corada, M, Giannotta, M, Rambaldi, A, Ferrari, Ml, Finazzi, G, Finazzi, Mc, Magri, M, Quaresmini, G, Montalvo, Ml, Ricci, C, Salmoiraghi, S, Spinelli, O, Amaru, A, Golay, J, Cilloni, D, Arruga, F, Bracco, E, Carturan, S, Gaidano, V, Guerrasio, A, Pradotto, M, Manfredini, R, Bianchi, E, Montanari, M, Salati, S, Tagliafico, E, Tenedini, E, and Zini, R.

Subjects
Male, Pathology, myeloproliferative neoplasm, Gastroenterology, Cohort Studies, Hematologic Cancers and Related Disorders, splanchnic vein thrombosis, Hemoglobins, Polycythemia vera, Molecular Cell Biology, Odds Ratio, Splanchnic Circulation, Polycythemia Vera, Aged, 80 and over, Venous Thrombosis, Thrombocytosis, Likelihood Functions, Multidisciplinary, Hematology, Middle Aged, Venous thrombosis, Oncology, Medicine, Female, Cellular Types, Research Article, Adult, medicine.medical_specialty, Clinical Pathology, Science, Sensitivity and Specificity, Myeloproliferative Disorders, Diagnostic Medicine, Internal medicine, medicine, Humans, Myelofibrosis, Biology, Myeloproliferative neoplasm, Aged, Essential thrombocythemia, business.industry, Endothelial Cells, Cancers and Neoplasms, Odds ratio, medicine.disease, Thrombocytopenia, Cross-Sectional Studies, Splanchnic vein thrombosis, business, Biomarkers, General Pathology
Abstract

Increased mobilization of circulating endothelial progenitor cells may represent a new biological hallmark of myeloproliferative neoplasms. We measured circulating endothelial colony forming cells (ECFCs) in 106 patients with primary myelofibrosis, fibrotic stage, 49 with prefibrotic myelofibrosis, 59 with essential thrombocythemia or polycythemia vera, and 43 normal controls. Levels of ECFC frequency for patient's characteristics were estimated by using logistic regression in univariate and multivariate setting. The sensitivity, specificity, likelihood ratios, and positive predictive value of increased ECFC frequency were calculated for the significantly associated characteristics. Increased frequency of ECFCs resulted independently associated with history of splanchnic vein thrombosis (adjusted odds ratio = 6.61, 95% CI = 2.54-17.16), and a summary measure of non-active disease, i.e. hemoglobin of 13.8 g/dL or lower, white blood cells count of 7.8×10(9)/L or lower, and platelet count of 400×10(9)/L or lower (adjusted odds ratio = 4.43, 95% CI = 1.45-13.49) Thirteen patients with splanchnic vein thrombosis non associated with myeloproliferative neoplasms were recruited as controls. We excluded a causal role of splanchnic vein thrombosis in ECFCs increase, since no control had elevated ECFCs. We concluded that increased frequency of ECFCs represents the biological hallmark of a non-active myeloproliferative neoplasm with high risk of splanchnic vein thrombosis. The recognition of this disease category copes with the phenotypic mimicry of myeloproliferative neoplasms. Due to inherent performance limitations of ECFCs assay, there is an urgent need to arrive to an acceptable standardization of ECFC assessment.

Published
2010

28. Hydroxyurea does not appreciably reduce JAK2 V617F allele burden in patients with polycythemia vera or essential thrombocythemia

Author

Antonioli, E., primary, Carobbio, A., additional, Pieri, L., additional, Pancrazzi, A., additional, Guglielmelli, P., additional, Delaini, F., additional, Ponziani, V., additional, Bartalucci, N., additional, Tozzi, L., additional, Bosi, A., additional, Rambaldi, A., additional, Barbui, T., additional, and Vannucchi, A. M., additional

Published
2010
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29. Advanced automotive diesel assessment program

Author

Sekar, R and Tozzi, L

Subjects
Mechanical Engineering
Abstract

Cummins Engine Company completed an analytical study to identify an advanced automotive (light duty) diesel (AAD) power plant for a 3,000-pound passenger car. The study resulted in the definition of a revolutionary diesel engine with several novel features. A 3,000-pound car with this engine is predicted to give 96.3, 72.2, and 78.8 MPG in highway, city, and combined highway-city driving, respectively. This compares with current diesel powered cars yielding 41.7, 35.0, and 37.7 MPG. The time for 0-60 MPH acceleration is 13.9 sec. compared to the baseline of 15.2 sec. Four technology areas were identified as crucial in bringing this concept to fruition. They are: (1) part-load preheating, (2) positive displacement compounding, (3) spark assisted diesel combustion system, and (4) piston development for adiabatic, oilless diesel engine. Marketing and planning studies indicate that an aggressive program with significant commitment could result in a production car in 10 years from the date of commencement.

Published
1983

30. Detailed performance analysis of the A.A.D. - concept B

Author

Sekar, R and Tozzi, L

Subjects
Mechanical Engineering
Abstract

New concepts for engine performance improvement are seen through the adoption of heat regeneration techniques; advanced methods to enhance the combustion; and higher efficiency air handling machinery, such as the positive displacement helical screw expander and compressor. Each of these concepts plays a particular role in engine performance improvement. First regeneration has a great potential for achieving higher engine thermal efficiency through the recovery of waste energy. Although the concept itself is not new (this technique is used in the gas turbine), the application to reciprocating internal combustion engines is quite unusual and presents conceptual difficulties. The second important area is better control of the combustion process in terms of heat transfer characteristics, combustion products, and heat release rate. The third area for performance improvement is in the adoption of high efficiency air handling machinery. In particular, positive displacement helical expander and compressor exhibit an extremely high efficiency over a wide range of operating conditions.

Published
1983

31. Long term technology development program

Author

Sekar, R and Tozzi, L

Subjects
Mechanical Engineering
Abstract

In the Advanced Adiabatic Development program, the following technology were identified as critical: piston development for oil-less, adiabatic engine; positive displacement compounding and charge system; experimental evaluation of the preheat concept; combustion system with positive ignition assist; and ceramic manufacturing technology. Of these five areas, ceramic manufacturing technology is the pacing item, and is already being addressed by several organizations. Therefore the four remaining areas need immediate attention. Since the lead time involved in engine development and production is long, this technology development should be done concurrently with the AAD engine development. A four year program is outlined which will simultaneously study these first four areas. This program requires two test rigs; one single cylinder adiabatic engine; and one multicylinder adiabatic turbocompound engine.

Published
1983

32. New perspectives for advanced automobile diesel engines

Author

Tozzi, L, Sekar, R, Kamo, R, and Wood, J. C

Subjects
Mechanical Engineering
Abstract

Computer simulation results are presented for advanced automobile diesel engine performance. Four critical factors for performance enhancement were identified: (1) part load preheating and exhaust gas energy recovery, (2) fast heat release combustion process, (3) reduction in friction, and (4) air handling system efficiency. Four different technology levels were considered in the analysis. Simulation results are compared in terms of brake specific fuel consumption and vehicle fuel economy in km/liter (miles per gallon). Major critical performance sensitivity areas are: (1) combustion process, (2) expander and compressor efficiency, and (3) part load preheating and compound system. When compared to the state of the art direct injection, cooled, automobile diesel engine, the advanced adiabatic compound engine concept showed the unique potential of doubling the fuel economy. Other important performance criteria such as acceleration, emissions, reliability, durability and multifuel capability are comparable to or better than current passenger car diesel engines.

Published
1983

36. Selected food intake and risk of multiple pregnancies.

Author

Parazzini, Fabio, Chatenoud, Liliane, Bettoni, Gaia, Tozzi, Luca, Turco, Simonetta, Surace, Matteo, Di Cintio, Elisabetta, Benzi, Guido, Parazzini, F, Chatenoud, L, Bettoni, G, Tozzi, L, Turco, S, Surace, M, Di Cintio, E, and Benzi, G

Abstract

In order to explore the association between multiple birth risk and diet, data were analysed from a case-control study on risk factors for multiple births conducted in Italy between 1988 and 1998. A total of 185 cases (median age 30 years) were interviewed: 36 women delivered monozygotic and 149 delivered spontaneous dizygotic multiple births. The control group comprised 498 women who gave birth at term (>37 weeks gestation) to healthy infants on randomly selected days at the same clinic. Women were specifically excluded if they reported a history of multiple pregnancy or they had received treatment for infertility for the index pregnancy. No marked differences emerged in daily intake between cases and controls and a total of 35 foods items, including the major sources of beta-carotene, retinol, ascorbic acid, vitamin D, E, methionine folate and calcium in the Italian diet. Likewise intake of selected micronutrients was largely similar in dizygotic cases, monozygotic cases and controls, with the only exception of a slightly lower intake of folates in dizygotic pregnancies in comparison with controls: this difference was statistically significant (P < 0.05), but limited in quantitative terms (mean daily intake of folate 192.4, 183.2 and 191.4 μg respectively in monozygotic, dizygotic cases and controls). In conclusion, the results of this study do not support the role of diet in the development of multiple births. [ABSTRACT FROM PUBLISHER]

Published
2001
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38. Coffee and alcohol intake, smoking and risk of multiple pregnancy.

Author

Parazzini, F, Chatenoud, L, Benzi, G, Di Cintio, E, Dal Pino, D, Tozzi, L, and Fedele, L

Abstract

We analysed the relationship between coffee and alcohol intake, smoking and risk of multiple pregnancies using data from a case-control study on risk factors for multiple births conducted in Italy. Cases were 133 women who delivered multiple births not related to treatment for infertility (33 monozygotic and 100 dizygotic twins). Controls were 395 women admitted for normal delivery at the same clinic where cases had been identified. The odds ratios (OR) of multiple pregnancy were 1.5[95% confidence interval (CI) 0.8-2.8] and 2.0 (95% CI 1.0-3.7) for women drinking respectively one to two or three or more cups of coffee per day in comparison with non-coffee drinkers. Considering separately dizygotic and monozygotic pregnancies, the estimated OR were respectively for women drinking three or more cups of coffee, 1.7 and 3.1 for dizygotic and monozygotic pregnancies. The risk of multiple pregnancy tended to be higher in women drinking >or= 15 alcohol drinks per week: in comparison with tea-totallers the estimated OR for drink > or = 15 glasses per week were 2.3 and 2.6 respectively for dizygotic and monozygotic pregnancies. Heavy smokers (> or = 10 cigarettes per day) were at increased risk of multiple pregnancy: in comparison with never smokers, the estimated OR for multiple pregnancy was 1.6 (95% CI 0.9-2.7). Considering separately the two groups of multiple pregnancy, the OR of dizygotic and monozygotic pregnancy were 1.4 (95% CI 0.8-2.5) and 2.4 (95% CI 0.9-6.1) for women smoking > or = 10 cigarettes/day, but the trend in risk with number of cigarettes smoked per day and duration of the habit was not significant.

Published
1996
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40. Therapeutic sequences in patients with grade 1−2 neuroendocrine tumors (NET): an observational multicenter study from the ELIOS group

Author

Ferdinando Riccardi, Carmela Mocerino, Ivana Puliafito, Elios, Antonella Di Sarno, Roberta Modica, Giuseppe Badalamenti, A. Bianco, Chiara De Divitiis, Antongiulio Faggiano, Valentina Guarnotta, Silvana Di Maio, Lucia Tozzi, Margaret Ottaviano, Salvatore Tafuto, Giovannella Palmieri, Silvana Leo, Pasquale Dolce, Annamaria Colao, Faggiano A., Di Maio S., Mocerino C., Ottaviano M., De Divitiis C., Guarnotta V., Dolce P., Modica R., Puliafito I., Tozzi L., Di Sarno A., Leo S., Riccardi F., Palmieri G., Tafuto S., Bianco A., Badalamenti G., Colao A., Faggiano, A., Di Maio, S., Mocerino, C., Ottaviano, M., De Divitiis, C., Guarnotta, V., Dolce, P., Modica, R., Puliafito, I., Tozzi, L., Di Sarno, A., Leo, S., Riccardi, F., Palmieri, G., Tafuto, S., Bianco, A., Badalamenti, G., and Colao, A.

Subjects
Male, Oncology, medicine.medical_specialty, High-dose somatostatin analogs, neuroendocrine tumors, PRRT, sequence of treatments, somatostatin analogues, targeted therapy, Lung Neoplasms, Databases, Factual, Settore MED/06 - Oncologia Medica, Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Antineoplastic Agents, High-dose somatostatin analog, Neuroendocrine tumors, Octreotide, Somatostatin analogue, Targeted therapy, Settore MED/13 - Endocrinologia, Endocrinology, Neuroendocrine tumor, Stomach Neoplasms, Internal medicine, Diabetes mellitus, Intestinal Neoplasms, Sequence of treatment, medicine, Humans, Everolimus, Retrospective Studies, Chemotherapy, business.industry, Disease Management, Middle Aged, medicine.disease, Discontinuation, Pancreatic Neoplasms, Neuroendocrine Tumors, Radionuclide therapy, Female, Observational study, Somatostatin, business, medicine.drug
Abstract

Purpose: Many different treatments are suggested by guidelines to treat grade 1−2 (G1−G2) neuroendocrine tumors (NET). However, a precise therapeutic algorithm has not yet been established. This study aims at identifying and comparing the main therapeutic sequences in G1−G2 NET. Methods: A retrospective observational Italian multicenter study was designed to collect data on therapeutic sequences in NET. Median progression-free survival (PFS) was compared between therapeutic sequences, as well as the number and grade of side effects and the rate of dose reduction/treatment discontinuation. Results: Among 1182 patients with neuroendocrine neoplasia included in the ELIOS database, 131 G1–G2 gastroenteropancreatic, lung and unknown primary NET, unresectable or persistent/relapsing after surgery, treated with ≥2 systemic treatments, were included. Four main therapeutic sequences were identified in 99 patients: (A) somatostatin analogs (SSA) standard dose to SSA high dose (n = 36), (B) SSA to everolimus (n = 31), (C) SSA to chemotherapy (n = 17), (D) SSA to peptide receptor radionuclide therapy (PRRT) (n = 15). Median PFS of the second-line treatment was not reached in sequence A, 33 months in sequence B, 20 months in sequence C, 30 months in sequence D (p = 0.16). Both total number and severity of side effects were significantly higher in sequences B and C than A and D (p = 0.04), as well as the rate of dose reduction/discontinuation (p = 0.03). Conclusions: SSA followed by SSA high dose, everolimus, chemotherapy or PRRT represent the main therapeutic sequences in G1−G2 NET. Median PFS was not significantly different between sequences. However, the sequences with SSA high dose or PRRT seem to be better tolerated than sequences with everolimus or chemotherapy.

Published
2019

41. Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the xelbevoct study

Author

Elisabetta Nobili, Lucia Tozzi, Antonio D'Avolio, Nadia Birocco, Alfredo Berruti, Guido Biasco, Luigi Dogliotti, Adriano Massimiliano Priola, Marco Volante, Nicola Fazio, Lisa Bodei, Anna Maria Ferrero, Mauro Papotti, Mirella Torta, Maria Pia Brizzi, Vito Amoroso, Berruti A, Fazio N, Ferrero A, Brizzi MP, Volante M, Nobili E, Tozzi L, Bodei L, Torta M, D Avolio A, Priola AM, Birocco N, Amoroso V, Biasco G, Papotti M, and Dogliotti L

Subjects
Oncology, Adult, Male, medicine.medical_specialty, Cancer Research, Bevacizumab, Phases of clinical research, Octreotide, Neuroendocrine tumors, Antibodies, Monoclonal, Humanized, Pancreatic endocrine tumor, Gastroenterology, Deoxycytidine, Disease-Free Survival, Capecitabine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Vitamin D and neurology, Genetics, Medicine, Humans, Neoplasm Metastasis, Aged, Neoplasm Staging, Proteinuria, business.industry, Middle Aged, medicine.disease, Regimen, Neuroendocrine Tumors, Treatment Outcome, Administration, Metronomic, Female, Fluorouracil, medicine.symptom, business, medicine.drug, Research Article
Abstract

We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset. This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression. Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome. The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy. Trial registration number NCT01203306 .

Published
2014

42. Overexpression of microRNA-16-2 contributes to the abnormal erythropoiesis in polycythemia vera

Author

Paola Guglielmelli, Lorenzo Tozzi, Alberto Bosi, Ilaria Iacobucci, Alessandro M. Vannucchi, Giovanni Martinelli, Costanza Bogani, Vanessa Ponziani, Guglielmelli P, Tozzi L, Bogani C, Iacobucci I, Ponziani V, Martinelli G, Bosi A, and Vannucchi AM

Subjects
Small interfering RNA, Myeloid, Immunology, Antigens, CD34, Biology, Biochemistry, Mice, Polycythemia vera, Erythroid Cells, hemic and lymphatic diseases, POLYCYTHEMIA, microRNA, medicine, Animals, Humans, Erythropoiesis, Progenitor cell, Polycythemia Vera, Cell Biology, Hematology, medicine.disease, Up-Regulation, Mice, Inbred C57BL, Haematopoiesis, MicroRNAs, medicine.anatomical_structure, Erythropoietin, Cancer research, medicine.drug
Abstract

Deregulated expression of microRNAs is associated with neoplasia. Here, we show that mature miR-16 levels are abnormally increased in CD34+ cells of patients with polycythemia vera as a consequence of preferential expression of miR-16-2 on chromosome 3 rather than of miR-16-1 on chromosome 13. Forced expression of miRNA-16 in normal CD34+ cells stimulated erythroid cell proliferation and maturation. Conversely, exposure of polycythemia vera CD34+ cells to small interfering RNA against pre-miR-16-2 reduced erythroid colonies and largely prevented formation of erythropoietin-independent colonies; myeloid progenitors remained unaffected. Experiments with knock down of JAK2 indicated that overexpression of miR-16 was independent of JAK/STAT pathway activation. Mice injected with an miR-16 antagomir showed a blunted erythroid response to exogenous erythropoietin, which indicates a role of miR-16 in normal erythropoiesis. These data suggest that deregulation of miR-16-2 contributes to abnormal expansion of erythroid lineage in polycythemia vera. However, the mechanisms for miR-16-2 overexpression remain to be elucidated, because no genetic abnormalities at the miR-16-2 locus were discovered.

Published
2011

43. Coffee drinking and risk of preterm birth

Author

C. Maffioletti, Liliane Chatenoud, Luca Tozzi, Vito Chiantera, Luigi Fedele, Francesca Chiaffarino, Elena Ricci, Fabio Parazzini, Chiaffarino, F., Parazzini, F., Chatenoud, L., Ricci, E., Tozzi, L., Chiantera, V., Maffioletti, C., and Fedele, L.

Subjects
Adult, medicine.medical_specialty, Pediatrics, Adolescent, Epidemiology, Pregnancy Trimester, Third, Medicine (miscellaneous), Coffee, Normal for gestational age, Pregnancy, Caffeine, medicine, Odds Ratio, Birth Weight, Humans, Risk factor, Preterm birth, Risk factors, Nutrition and Dietetics, Obstetrics, business.industry, Risk Factor, Case-control study, Infant, Newborn, Pregnancy Outcome, Gestational age, Small for gestational age, Odds ratio, Middle Aged, medicine.disease, Case-Control Studies, Infant, Small for Gestational Age, Gestation, Premature Birth, Female, Case-Control Studie, business, Infant, Premature, Human, Food Science
Abstract

Objectives: We analysed the association between coffee drinking before and during the three trimesters of pregnancy and the risk of preterm birth of babies normal for gestational age (NGA) or small for gestational age (SGA). Methods: Case-control study conducted in University clinics of North Italy. Cases were 502 women who delivered at < weeks of gestation. The controls included 1966 women who gave birth at term (≥37 weeks of gestation) to healthy infants on randomly selected days at the hospitals where cases had been identified. Results: There was inverse association for coffee consumption in the third trimester of pregnancy in SGA cases compared to NGA (heterogeneity test between OR: χ12 P≤0.05). In comparison with not drinkers, all the ORs of overall intake of caffeine were closed near the unity for both SGA and NGA preterm birth. Conclusion: Compared with no consumption, a low consumption of coffee during pregnancy may not have significant effects on preterm birth. © 2006 Nature Publishing Group. All rights reserved.

Published
2006

44. Maternal coffee drinking in pregnancy and risk of small for gestational age birth

Author

Francesca Chiaffarino, Fabio Parazzini, Sonia Cipriani, Liliane Chatenoud, Vito Chiantera, Luca Tozzi, Luigi Fedele, Parazzini, F., Chiaffarino, F., Chatenoud, L., Tozzi, L., Cipriani, S., Chiantera, V., and Fedele, L.

Subjects
Adult, medicine.medical_specialty, Adolescent, Epidemiology, Pregnancy Trimester, Third, Medicine (miscellaneous), Coffee, Risk Factors, Pregnancy, Odds Ratio, Humans, Medicine, Risk factor, Nutrition and Dietetics, Dose-Response Relationship, Drug, business.industry, Obstetrics, Risk Factor, Confounding, Infant, Newborn, Pregnancy Outcome, medicine.disease, Confidence interval, Diet, Small for gestational age birth, Pregnancy Trimester, First, Case-Control Studies, Pregnancy Trimester, Second, Infant, Small for Gestational Age, Gestation, Small for gestational age, Term Birth, Female, Case-Control Studie, business, Human, Food Science
Abstract

Objective: We have analysed the association between coffee drinking before and during the three trimesters of pregnancy and risk of small for gestational age (SGA) birth. Methods: Cases were 555 women who delivered SGA births (ie

Published
2005

45. Family history of breast, ovarian and endometrial cancer and risk of breast cancer

Author

Silvia Franceschi, Luca Tozzi, Eva Negri, Fabio Parazzini, C. La Vecchia, PARAZZINI F, LAVECCHIA C, NEGRI E, FRANCESCHI S, and TOZZI L

Subjects
Adult, medicine.medical_specialty, Urban Population, Epidemiology, Mammary gland, Breast Neoplasms, Breast cancer, Risk Factors, medicine, Confidence Intervals, Odds Ratio, Humans, First-degree relatives, Family history, Risk factor, skin and connective tissue diseases, Medical History Taking, Aged, Gynecology, Ovarian Neoplasms, Obstetrics, business.industry, Endometrial cancer, Age Factors, General Medicine, Odds ratio, Middle Aged, medicine.disease, Endometrial Neoplasms, medicine.anatomical_structure, Logistic Models, Italy, Case-Control Studies, Multivariate Analysis, Female, Ovarian cancer, business
Abstract

The relationship between family history of breast, ovarian and endometrial cancer and risk of breast cancer was analysed using data from a case-control study of breast cancer conducted in the greater Milan area, Northern Italy. The cases studied were 3415 women (median age 52 years, range 23-74) who had histologically confirmed breast cancer diagnosed within the year preceding the interview. The controls were 2916 women (median age 54 years; range 21-74) in hospital for a spectrum of acute illnesses excluding gynaecological, hormonal or neoplastic conditions. A total of 375 cases (11.0%) and 128 controls (4.4%) reported a history of breast cancer in first degree relatives. Compared with women with no family history of breast cancer, the RR was 2.7 (95% confidence interval [Cl] : 2.2-3.3) in those with one first degree relative affected and 2.8 (95% Cl : 1.3-5.7) in those with two or more affected relatives. In comparison with women without family history of ovarian cancer the RR of breast cancer was 1.4 195% Cl : 0.9-2.3) for those reporting one or more first degree relatives with ovarian cancer. However, the multivariate estimate for family history of ovarian cancer, including a term for familial breast cancer, decreased to 0.8 (95% Cl : 0.5-1.4). The risk of breast cancer was similar in women reporting a family history of breast cancer (RR = 2.2) and in those reporting a family history of both breast and ovarian cancer (RR = 2.5), in comparison with women reporting no family history of breast and/or ovarian cancer. When the relation with family history of breast cancer was analysed in strata of women with and without family history of ovarian cancer, no difference was found in the RR estimates: the RR for family history of breast cancer was 2.8 in women with family history of ovarian cancer and 2.7 in those without history of ovarian cancer. No relation was found between history of endometrial cancer in first degree relatives and risk of breast cancer.

Published
1993

46. Neural circuit basis of pathological anxiety.

Author

Akiki TJ, Jubeir J, Bertrand C, Tozzi L, and Williams LM

Subjects
Humans, Animals, Neural Pathways physiopathology, Anxiety physiopathology, Nerve Net physiopathology, Nerve Net diagnostic imaging, Nerve Net pathology, Anxiety Disorders physiopathology, Anxiety Disorders pathology, Brain physiopathology, Brain pathology
Abstract

Anxiety disorders are the most prevalent mental health conditions worldwide. Unfortunately, the understanding of the precise neurobiological mechanisms that underlie these disorders remains limited. Current diagnostic classifications, based on observable symptoms rather than underlying pathophysiology, do not capture the heterogeneity within and across anxiety disorders. Recent advances in functional neuroimaging have provided new insights into the neural circuits implicated in pathological anxiety, revealing dysfunctions that cut across traditional diagnostic boundaries. In this Review, we synthesize evidence that highlights abnormalities in neurobehavioural systems related to negative valence, positive valence, cognitive systems and social processes. We emphasize that pathological anxiety arises not only from heightened reactivity in acute threat ('fear') circuits but also from alterations in circuits that mediate distant (potential) and sustained threat, reward processing, cognitive control and social processing. We discuss how circuit vulnerabilities can lead to the emergence and maintenance of pathological anxiety. Once established, these neural abnormalities can be exacerbated by maladaptive behaviours that prevent extinction learning and perpetuate anxiety disorders. By delineating the specific neural mechanisms in each neurobiological system, we aim to contribute to a more comprehensive understanding of the neurobiology of anxiety disorders, potentially informing future research directions in this field., Competing Interests: Competing interests: L.M.W. declares US Patent Applications 10/034,645 and 15/820,338: ‘Systems and methods for detecting complex networks in MRI image data’. T.J.A. serves on the scientific advisory board of and has stock options with Mindbloom, and receives payment for editorial work from Elsevier. L.T. is employed by Ceribell Inc. The remaining authors declare no competing interests., (© 2024. Springer Nature Limited.)

Published
2025
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47. Personalized brain circuit scores identify clinically distinct biotypes in depression and anxiety.

Author

Tozzi L, Zhang X, Pines A, Olmsted AM, Zhai ES, Anene ET, Chesnut M, Holt-Gosselin B, Chang S, Stetz PC, Ramirez CA, Hack LM, Korgaonkar MS, Wintermark M, Gotlib IH, Ma J, and Williams LM

Subjects
Humans, Male, Female, Adult, Middle Aged, Precision Medicine, Young Adult, Cognition physiology, Magnetic Resonance Imaging, Brain diagnostic imaging, Brain physiopathology, Depression physiopathology, Depression diagnostic imaging, Depression therapy, Anxiety physiopathology
Abstract

There is an urgent need to derive quantitative measures based on coherent neurobiological dysfunctions or 'biotypes' to enable stratification of patients with depression and anxiety. We used task-free and task-evoked data from a standardized functional magnetic resonance imaging protocol conducted across multiple studies in patients with depression and anxiety when treatment free (n = 801) and after randomization to pharmacotherapy or behavioral therapy (n = 250). From these patients, we derived personalized and interpretable scores of brain circuit dysfunction grounded in a theoretical taxonomy. Participants were subdivided into six biotypes defined by distinct profiles of intrinsic task-free functional connectivity within the default mode, salience and frontoparietal attention circuits, and of activation and connectivity within frontal and subcortical regions elicited by emotional and cognitive tasks. The six biotypes showed consistency with our theoretical taxonomy and were distinguished by symptoms, behavioral performance on general and emotional cognitive computerized tests, and response to pharmacotherapy as well as behavioral therapy. Our results provide a new, theory-driven, clinically validated and interpretable quantitative method to parse the biological heterogeneity of depression and anxiety. Thus, they represent a promising approach to advance precision clinical care in psychiatry., (© 2024. The Author(s).)

Published
2024
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48. A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial.

Author

Hack LM, Tozzi L, Zenteno S, Olmsted AM, Hilton R, Jubeir J, Korgaonkar MS, Schatzberg AF, Yesavage JA, O'Hara R, and Williams LM

Subjects
Humans, Female, Adult, Male, Depression drug therapy, Quality of Life, Antidepressive Agents therapeutic use, Cognition, Citalopram therapeutic use, Depressive Disorder, Major diagnosis
Abstract

Importance: Cognitive deficits in depression have been associated with poor functional capacity, frontal neural circuit dysfunction, and worse response to conventional antidepressants. However, it is not known whether these impairments combine together to identify a specific cognitive subgroup (or "biotype") of individuals with major depressive disorder (MDD), and the extent to which these impairments mediate antidepressant outcomes., Objective: To undertake a systematic test of the validity of a proposed cognitive biotype of MDD across neural circuit, symptom, social occupational function, and treatment outcome modalities., Design, Setting, and Participants: This secondary analysis of a randomized clinical trial implemented data-driven clustering in findings from the International Study to Predict Optimized Treatment in Depression, a pragmatic biomarker trial in which patients with MDD were randomized in a 1:1:1 ratio to antidepressant treatment with escitalopram, sertraline, or venlafaxine extended-release and assessed at baseline and 8 weeks on multimodal outcomes between December 1, 2008, and September 30, 2013. Eligible patients were medication-free outpatients with nonpsychotic MDD in at least the moderate range, and were recruited from 17 clinical and academic practices; a subset of these patients underwent functional magnetic resonance imaging. This prespecified secondary analysis was performed between June 10, 2022, and April 21, 2023., Main Outcomes and Measures: Pretreatment and posttreatment behavioral measures of cognitive performance across 9 domains, depression symptoms assessed using 2 standard depression scales, and psychosocial function assessed using the Social and Occupational Functioning Assessment Scale and World Health Organization Quality of Life scale were analyzed. Neural circuit function engaged during a cognitive control task was measured using functional magnetic resonance imaging., Results: A total of 1008 patients (571 [56.6%] female; mean [SD] age, 37.8 [12.6] years) participated in the overall trial and 96 patients participated in the imaging substudy (45 [46.7%] female; mean [SD] age, 34.5 [13.5] years). Cluster analysis identified what may be referred to as a cognitive biotype of 27% of depressed patients with prominent behavioral impairment in executive function and response inhibition domains of cognitive control. This biotype was characterized by a specific profile of pretreatment depressive symptoms, worse psychosocial functioning (d = -0.25; 95% CI, -0.39 to -0.11; P < .001), and reduced activation of the cognitive control circuit (right dorsolateral prefrontal cortex: d = -0.78; 95% CI, -1.28 to -0.27; P = .003). Remission was comparatively lower in the cognitive biotype positive subgroup (73 of 188 [38.8%] vs 250 of 524 [47.7%]; P = .04) and cognitive impairments persisted regardless of symptom change (executive function: ηp2 = 0.241; P < .001; response inhibition: ηp2 = 0.750; P < .001). The extent of symptom and functional change was specifically mediated by change in cognition but not the reverse., Conclusions and Relevance: Our findings suggest the presence of a cognitive biotype of depression with distinct neural correlates, and a functional clinical profile that responds poorly to standard antidepressants and instead may benefit from therapies specifically targeting cognitive dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT00693849.

Published
2023
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49. Machine Learning Prediction of Estimated Risk for Bipolar Disorders Using Hippocampal Subfield and Amygdala Nuclei Volumes.

Author

Huth F, Tozzi L, Marxen M, Riedel P, Bröckel K, Martini J, Berndt C, Sauer C, Vogelbacher C, Jansen A, Kircher T, Falkenberg I, Thomas-Odenthal F, Lambert M, Kraft V, Leicht G, Mulert C, Fallgatter AJ, Ethofer T, Rau A, Leopold K, Bechdolf A, Reif A, Matura S, Biere S, Bermpohl F, Fiebig J, Stamm T, Correll CU, Juckel G, Flasbeck V, Ritter P, Bauer M, Pfennig A, and Mikolas P

Abstract

The pathophysiology of bipolar disorder (BD) remains mostly unclear. Yet, a valid biomarker is necessary to improve upon the early detection of this serious disorder. Patients with manifest BD display reduced volumes of the hippocampal subfields and amygdala nuclei. In this pre-registered analysis, we used structural MRI ( n = 271, 7 sites) to compare volumes of hippocampus, amygdala and their subfields/nuclei between help-seeking subjects divided into risk groups for BD as estimated by BPSS-P, BARS and EPI bipolar . We performed between-group comparisons using linear mixed effects models for all three risk assessment tools. Additionally, we aimed to differentiate the risk groups using a linear support vector machine. We found no significant volume differences between the risk groups for all limbic structures during the main analysis. However, the SVM could still classify subjects at risk according to BPSS-P criteria with a balanced accuracy of 66.90% (95% CI 59.2-74.6) for 10-fold cross-validation and 61.9% (95% CI 52.0-71.9) for leave-one-site-out. Structural alterations of the hippocampus and amygdala may not be as pronounced in young people at risk; nonetheless, machine learning can predict the estimated risk for BD above chance. This suggests that neural changes may not merely be a consequence of BD and may have prognostic clinical value.

Published
2023
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50. Effects of physiological fluctuations on the estimation of vascular flow in eyes with idiopathic macular pucker.

Author

Frisina R, De Salvo G, Tozzi L, Gius I, Sahyoun JY, Parolini B, and Meduri A

Subjects
Humans, Fluorescein Angiography methods, Retinal Vessels diagnostic imaging, Visual Acuity, Tomography, Optical Coherence methods, Retrospective Studies, Epiretinal Membrane surgery, Macula Lutea blood supply
Abstract

Objectives: To evaluate the macular vascular flow in eyes with idiopathic macular pucker (Eye iMP ), pre and post pars plana vitrectomy with epiretinal and limiting membranes peeling, and to compare it with the vascular flow in the healthy fellow eyes (Eye fellow ), taken as physiological reference value., Methods: 40 eyes of 40 patients were recruited. Best-corrected visual acuity (BCVA) was evaluated. Spectral domain optical coherence tomography (SD-OCT) and OCT-angiography parameters were central foveal thickness (CFT), choroidal thickness (CT), foveal avascular zone (FAZ) area, vessel area density (VAD), vessel length fraction (VLF), vessel density index (VDI) of superficial capillary plexus (SCP) and deep vascular complex (DVC), choriocapillaris (CC) flow. Absolute and relative difference calculation was applied to evaluate macular vascular flow in Eye iMP adjusted for physiological changes detected in Eye fellow ., Follow-Up: 6 months., Results: BCVA improved (p = 0.003) in all cases following surgery. CFT reduced postoperatively (p = 0.0138). FAZ area was smaller in Eye iMP than Eye fellow (p = 0.0071) preoperatively and postoperatively it shrank further (p = 0.0027). After surgery, inverse correlation between FAZ area and BCVA was detected (r-0.683). VAD of SCP was pre- and post-operatively higher in Eye iMP than Eye fellow (baseline p = 0.0344, 6th month p = 0.0466). Relative difference of VDI of SCP (p = 0.0096) and CC flow (p = 0.0013) at 6 months reduced. DVC flow changed significantly only in Eye fellow . CT increased post-operatively in both Eyei MP (p = 0.0345) and Eye fellow (p = 0.00423), but relative difference did not change., Conclusions: Vascular flow indices monitoring demonstrated significant changes in both eyes: Eye iMP and Eye fellow . Relative difference of vascular flow provided objective estimate of changes due to iMP surgery taking into account physiological changes in Eye fellow ., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Published
2023
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