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1.  The TICOPA protocol (TIght COntrol of Psoriatic Arthritis): a randomised controlled trial to compare intensive management versus standard care in early psoriatic arthritis 
Background
Psoriatic Arthritis (PsA) is estimated to occur in 10-15% of people with psoriasis and accounts for 13% of people attending early arthritis clinics. With an increasing awareness of the poor outcomes associated with PsA and the availability of new effective, but costly, treatments, there is an urgent need to research the optimal treatment for patients with PsA. The aim of the TICOPA study is to establish whether, in treatment naive early PsA patients, “tight control” intensive management with protocol driven therapies and pre-defined objective targets for treatment can improve clinical outcome compared to standard care alone.
Methods/design
TICOPA is a UK multicentre, open-label, randomised controlled, parallel group trial of 206 patients with early PsA. Patients will be randomised on a 1:1 basis to receive either standard care (12 weekly review) or intensive management (4 weekly review) for a period of 48 weeks. Patients assigned to the intensive management group will follow a strict treatment protocol whereby dose continuation/escalation is determined through the objective assessment of the minimal disease activity (MDA) criteria. Patients assigned to the standard care group will have treatment prescribed as felt appropriate by the treating clinician, with no set protocol. The primary objective of the trial is to compare intensive management with standard care in terms of the proportion of patients achieving an ACR 20 response at 48 weeks post-randomisation, in order to determine whether intensive management has superior clinical efficacy. Key secondary outcomes include ACR 50 and 70, PASI 75 and X-ray Van der Heijde score at 48 weeks post-randomisation along with cost-effectiveness at 12, 24 and 28 weeks.
Discussion
The TICOPA trial will provide direct evidence as to whether the use of early and intensive treatment in PsA in routine clinical care leads to an improvement in patients’ disease activity and a reduction in radiological joint damage.
Trial registration
ISRCTN30147736, NCT01106079
doi:10.1186/1471-2474-14-101
PMCID: PMC3610193  PMID: 23517506
Psoriatic arthritis; Early psoriatic arthritis; Tight management; Tight control; Intensive management; Standard care
2.  Pain is Associated with Physical Activity and Health-Related Quality of Life in Overweight and Obese Children 
This study examined associations between pain, physical activity, physical fitness, and health-related quality of life (HRQOL) in overweight and obese children. Participants were 270 overweight and obese children 8–12 years of age and their parents. Children were separated into No Pain Frequency, Low Pain Frequency, and High Pain Frequency groups. Children in the Low Pain Frequency group spent less time in moderately intense physical activities compared to the No Pain Frequency group. Children in the High Pain Frequency group reported significantly lower HRQOL in most domains of functioning compared to children in the No Pain and Low Pain Frequency groups. Pain in overweight and obese children may negatively impact physical activity and HRQOL and should be assessed and treated in research and clinical work.
doi:10.1080/02739615.2013.837825
PMCID: PMC4254736  PMID: 25484483
3.  Major health-related behaviours and mental well-being in the general population: the Health Survey for England 
BMJ Open  2014;4(9):e005878.
Background
Major behavioural risk factors are known to adversely affect health outcomes and be strongly associated with mental illness. However, little is known about the association of these risk factors with mental well-being in the general population. We sought to examine behavioural correlates of high and low mental well-being in the Health Survey for England.
Methods
Participants were 13 983 adults, aged 16 years and older (56% females), with valid responses for the combined 2010 and 2011 surveys. Mental well-being was assessed using the Warwick-Edinburgh Mental Well-being Scale (WEMWBS). ORs of low and high mental well-being, compared to the middle-range category, were estimated for body mass index (BMI), smoking, drinking habits, and fruit and vegetable intake.
Results
ORs for low mental well-being were increased in obese individuals (up to 1.72, 95% CI 1.26 to 2.36 in BMI 40+ kg/m2). They increased in a linear fashion with increasing smoking (up to 1.98, 95% CI 1.55 to 2.53, >20 cigarettes/day) and with decreasing fruit and vegetable intake (up to 1.53, 95% CI 1.24 to 1.90, <1 portion/day); whereas ORs were reduced for sensible alcohol intake (0.78, 95% CI 0.66 to 0.91, ≤4 units/day in men, ≤3 units/day in women). ORs for high mental well-being were not correlated with categories of BMI or alcohol intake. ORs were reduced among ex-smokers (0.81, 95% CI 0.71 to 0.92), as well as with lower fruit and vegetable intake (up to 0.79, 95% CI 0.68 to 0.92, 1 to <3 portions/day).
Conclusions
Along with smoking, fruit and vegetable consumption was the health-related behaviour most consistently associated with mental well-being in both sexes. Alcohol intake and obesity were associated with low, but not high mental well-being.
doi:10.1136/bmjopen-2014-005878
PMCID: PMC4170205  PMID: 25239293
4.  Liposome encapsulated Disulfiram inhibits NFκB pathway and targets breast cancer stem cells in vitro and in vivo 
Oncotarget  2014;5(17):7471-7485.
Breast cancer stem cells (BCSCs) are pan-resistant to different anticancer agents and responsible for cancer relapse. Disulfiram (DS), an antialcoholism drug, targets CSCs and reverses pan-chemoresistance. The anticancer application of DS is limited by its very short half-life in the bloodstream. This prompted us to develop a liposome-encapsulated DS (Lipo-DS) and examine its anticancer effect and mechanisms in vitro and in vivo.
The relationship between hypoxia and CSCs was examined by in vitro comparison of BC cells cultured in spheroid and hypoxic conditions. To determine the importance of NFκB activation in bridging hypoxia and CSC-related pan-resistance, the CSC characters and drug sensitivity in BC cell lines were observed in NFκB p65 transfected cell lines. The effect of Lipo-DS on the NFκB pathway, CSCs and chemosensitivity was investigated in vitro and in vivo.
The spheroid cultured BC cells manifested CSC characteristics and pan-resistance to anticancer drugs. This was related to the hypoxic condition in the spheres. Hypoxia induced activation of NFκB and chemoresistance. Transfection of BC cells with NFκB p65 also induced CSC characters and pan-resistance. Lipo-DS blocked NFκB activation and specifically targeted CSCs in vitro. Lipo-DS also targeted the CSC population in vivo and showed very strong anticancer efficacy. Mice tolerated the treatment very well and no significant in vivo nonspecific toxicity was observed.
Hypoxia induced NFκB activation is responsible for stemness and chemoresistance in BCSCs. Lipo-DS targets NFκB pathway and CSCs. Further study may translate DS into cancer therapeutics.
PMCID: PMC4202137  PMID: 25277186
Breast cancer; cancer stem cells; Disulfiram; NFkappaB; chemoresistance
5.  A Pilot Study of Interpersonal Psychotherapy (IPT) for Alcohol Dependent Women with Co-occurring Major Depression 
Co-occurring major depression is prevalent among alcohol dependent women and is a risk factor for poor treatment outcomes. This uncontrolled pilot study tested the feasibility, acceptability, and initial effects of Interpersonal Psychotherapy (IPT) for women with co-occurring alcohol dependence and major depression (AD-MD) in an outpatient community addiction treatment program. Fourteen female patients with concurrent diagnoses of alcohol dependence and major depression participated. Assessments were conducted at baseline, mid-treatment (8- and 16-weeks), post-treatment (24-weeks), and follow-up (32-weeks). Participants attended a mode of 8 out of 8 possible sessions of IPT in addition to their routine addiction care, and reported high treatment satisfaction on the Client Satisfaction Questionnaire-8. Women’s drinking behavior, depressive symptoms, and interpersonal functioning improved significantly over the treatment period and were sustained at follow-up. These preliminary findings suggest that IPT is a feasible, highly acceptable adjunctive behavioral intervention for AD-MD women.
doi:10.1080/08897077.2012.746950
PMCID: PMC3711642  PMID: 23844953
Treatment; Alcohol; Depression; Co-occurring Disorders; Women
6.  Common non-synonymous SNPs associated with breast cancer susceptibility: findings from the Breast Cancer Association Consortium 
Milne, Roger L. | Burwinkel, Barbara | Michailidou, Kyriaki | Arias-Perez, Jose-Ignacio | Zamora, M. Pilar | Menéndez-Rodríguez, Primitiva | Hardisson, David | Mendiola, Marta | González-Neira, Anna | Pita, Guillermo | Alonso, M. Rosario | Dennis, Joe | Wang, Qin | Bolla, Manjeet K. | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Schoemaker, Minouk | Ko, Yon-Dschun | Brauch, Hiltrud | Hamann, Ute | Andrulis, Irene L. | Knight, Julia A. | Glendon, Gord | Tchatchou, Sandrine | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Li, Jingmei | Brand, Judith S. | Brenner, Hermann | Dieffenbach, Aida Karina | Arndt, Volker | Stegmaier, Christa | Lambrechts, Diether | Peuteman, Gilian | Christiaens, Marie-Rose | Smeets, Ann | Jakubowska, Anna | Lubinski, Jan | Jaworska-Bieniek, Katarzyna | Durda, Katazyna | Hartman, Mikael | Hui, Miao | Yen Lim, Wei | Wan Chan, Ching | Marme, Federick | Yang, Rongxi | Bugert, Peter | Lindblom, Annika | Margolin, Sara | García-Closas, Montserrat | Chanock, Stephen J. | Lissowska, Jolanta | Figueroa, Jonine D. | Bojesen, Stig E. | Nordestgaard, Børge G. | Flyger, Henrik | Hooning, Maartje J. | Kriege, Mieke | van den Ouweland, Ans M.W. | Koppert, Linetta B. | Fletcher, Olivia | Johnson, Nichola | dos-Santos-Silva, Isabel | Peto, Julian | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha J. | Long, Jirong | Chang-Claude, Jenny | Rudolph, Anja | Seibold, Petra | Flesch-Janys, Dieter | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Cox, Angela | Cross, Simon S. | Reed, Malcolm W.R. | Schmidt, Marjanka K. | Broeks, Annegien | Cornelissen, Sten | Braaf, Linde | Kang, Daehee | Choi, Ji-Yeob | Park, Sue K. | Noh, Dong-Young | Simard, Jacques | Dumont, Martine | Goldberg, Mark S. | Labrèche, France | Fasching, Peter A. | Hein, Alexander | Ekici, Arif B. | Beckmann, Matthias W. | Radice, Paolo | Peterlongo, Paolo | Azzollini, Jacopo | Barile, Monica | Sawyer, Elinor | Tomlinson, Ian | Kerin, Michael | Miller, Nicola | Hopper, John L. | Schmidt, Daniel F. | Makalic, Enes | Southey, Melissa C. | Hwang Teo, Soo | Har Yip, Cheng | Sivanandan, Kavitta | Tay, Wan-Ting | Shen, Chen-Yang | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Guénel, Pascal | Truong, Therese | Sanchez, Marie | Mulot, Claire | Blot, William | Cai, Qiuyin | Nevanlinna, Heli | Muranen, Taru A. | Aittomäki, Kristiina | Blomqvist, Carl | Wu, Anna H. | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O. | Bogdanova, Natalia | Dörk, Thilo | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M. | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Zhang, Ben | Couch, Fergus J. | Toland, Amanda E. | Yannoukakos, Drakoulis | Sangrajrang, Suleeporn | McKay, James | Wang, Xianshu | Olson, Janet E. | Vachon, Celine | Purrington, Kristen | Severi, Gianluca | Baglietto, Laura | Haiman, Christopher A. | Henderson, Brian E. | Schumacher, Fredrick | Le Marchand, Loic | Devilee, Peter | Tollenaar, Robert A.E.M. | Seynaeve, Caroline | Czene, Kamila | Eriksson, Mikael | Humphreys, Keith | Darabi, Hatef | Ahmed, Shahana | Shah, Mitul | Pharoah, Paul D.P. | Hall, Per | Giles, Graham G. | Benítez, Javier | Dunning, Alison M. | Chenevix-Trench, Georgia | Easton, Douglas F. | Berchuck, Andrew | Eeles, Rosalind A. | Olama, Ali Amin Al | Kote-Jarai, Zsofia | Benlloch, Sara | Antoniou, Antonis | McGuffog, Lesley | Offit, Ken | Lee, Andrew | Dicks, Ed | Luccarini, Craig | Tessier, Daniel C. | Bacot, Francois | Vincent, Daniel | LaBoissière, Sylvie | Robidoux, Frederic | Nielsen, Sune F. | Cunningham, Julie M. | Windebank, Sharon A. | Hilker, Christopher A. | Meyer, Jeffrey | Angelakos, Maggie | Maskiell, Judi | van der Schoot, Ellen | Rutgers, Emiel | Verhoef, Senno | Hogervorst, Frans | Boonyawongviroj, Prat | Siriwanarungsan, Pornthep | Schrauder, Michael | Rübner, Matthias | Oeser, Sonja | Landrith, Silke | Williams, Eileen | Ryder-Mills, Elaine | Sargus, Kara | McInerney, Niall | Colleran, Gabrielle | Rowan, Andrew | Jones, Angela | Sohn, Christof | Schneeweiß, Andeas | Bugert, Peter | Álvarez, Núria | Lacey, James | Wang, Sophia | Ma, Huiyan | Lu, Yani | Deapen, Dennis | Pinder, Rich | Lee, Eunjung | Schumacher, Fred | Horn-Ross, Pam | Reynolds, Peggy | Nelson, David | Ziegler, Hartwig | Wolf, Sonja | Hermann, Volker | Lo, Wing-Yee | Justenhoven, Christina | Baisch, Christian | Fischer, Hans-Peter | Brüning, Thomas | Pesch, Beate | Rabstein, Sylvia | Lotz, Anne | Harth, Volker | Heikkinen, Tuomas | Erkkilä, Irja | Aaltonen, Kirsimari | von Smitten, Karl | Antonenkova, Natalia | Hillemanns, Peter | Christiansen, Hans | Myöhänen, Eija | Kemiläinen, Helena | Thorne, Heather | Niedermayr, Eveline | Bowtell, D | Chenevix-Trench, G | deFazio, A | Gertig, D | Green, A | Webb, P | Green, A. | Parsons, P. | Hayward, N. | Webb, P. | Whiteman, D. | Fung, Annie | Yashiki, June | Peuteman, Gilian | Smeets, Dominiek | Brussel, Thomas Van | Corthouts, Kathleen | Obi, Nadia | Heinz, Judith | Behrens, Sabine | Eilber, Ursula | Celik, Muhabbet | Olchers, Til | Manoukian, Siranoush | Peissel, Bernard | Scuvera, Giulietta | Zaffaroni, Daniela | Bonanni, Bernardo | Feroce, Irene | Maniscalco, Angela | Rossi, Alessandra | Bernard, Loris | Tranchant, Martine | Valois, Marie-France | Turgeon, Annie | Heguy, Lea | Sze Yee, Phuah | Kang, Peter | Nee, Kang In | Mariapun, Shivaani | Sook-Yee, Yoon | Lee, Daphne | Ching, Teh Yew | Taib, Nur Aishah Mohd | Otsukka, Meeri | Mononen, Kari | Selander, Teresa | Weerasooriya, Nayana | staff, OFBCR | Krol-Warmerdam, E. | Molenaar, J. | Blom, J. | Brinton, Louise | Szeszenia-Dabrowska, Neonila | Peplonska, Beata | Zatonski, Witold | Chao, Pei | Stagner, Michael | Bos, Petra | Blom, Jannet | Crepin, Ellen | Nieuwlaat, Anja | Heemskerk, Annette | Higham, Sue | Cross, Simon | Cramp, Helen | Connley, Dan | Balasubramanian, Sabapathy | Brock, Ian | Luccarini, Craig | Conroy, Don | Baynes, Caroline | Chua, Kimberley
Human Molecular Genetics  2014;23(22):6096-6111.
Candidate variant association studies have been largely unsuccessful in identifying common breast cancer susceptibility variants, although most studies have been underpowered to detect associations of a realistic magnitude. We assessed 41 common non-synonymous single-nucleotide polymorphisms (nsSNPs) for which evidence of association with breast cancer risk had been previously reported. Case-control data were combined from 38 studies of white European women (46 450 cases and 42 600 controls) and analyzed using unconditional logistic regression. Strong evidence of association was observed for three nsSNPs: ATXN7-K264R at 3p21 [rs1053338, per allele OR = 1.07, 95% confidence interval (CI) = 1.04–1.10, P = 2.9 × 10−6], AKAP9-M463I at 7q21 (rs6964587, OR = 1.05, 95% CI = 1.03–1.07, P = 1.7 × 10−6) and NEK10-L513S at 3p24 (rs10510592, OR = 1.10, 95% CI = 1.07–1.12, P = 5.1 × 10−17). The first two associations reached genome-wide statistical significance in a combined analysis of available data, including independent data from nine genome-wide association studies (GWASs): for ATXN7-K264R, OR = 1.07 (95% CI = 1.05–1.10, P = 1.0 × 10−8); for AKAP9-M463I, OR = 1.05 (95% CI = 1.04–1.07, P = 2.0 × 10−10). Further analysis of other common variants in these two regions suggested that intronic SNPs nearby are more strongly associated with disease risk. We have thus identified a novel susceptibility locus at 3p21, and confirmed previous suggestive evidence that rs6964587 at 7q21 is associated with risk. The third locus, rs10510592, is located in an established breast cancer susceptibility region; the association was substantially attenuated after adjustment for the known GWAS hit. Thus, each of the associated nsSNPs is likely to be a marker for another, non-coding, variant causally related to breast cancer risk. Further fine-mapping and functional studies are required to identify the underlying risk-modifying variants and the genes through which they act.
doi:10.1093/hmg/ddu311
PMCID: PMC4204770  PMID: 24943594
7.  Common genetic determinants of breast-cancer risk in East Asian women: a collaborative study of 23 637 breast cancer cases and 25 579 controls 
Human Molecular Genetics  2013;22(12):2539-2550.
In a consortium including 23 637 breast cancer patients and 25 579 controls of East Asian ancestry, we investigated 70 single-nucleotide polymorphisms (SNPs) in 67 independent breast cancer susceptibility loci recently identified by genome-wide association studies (GWASs) conducted primarily in European-ancestry populations. SNPs in 31 loci showed an association with breast cancer risk at P < 0.05 in a direction consistent with that reported previously. Twenty-one of them remained statistically significant after adjusting for multiple comparisons with the Bonferroni-corrected significance level of <0.0015. Eight of the 70 SNPs showed a significantly different association with breast cancer risk by estrogen receptor (ER) status at P < 0.05. With the exception of rs2046210 at 6q25.1, the seven other SNPs showed a stronger association with ER-positive than ER-negative cancer. This study replicated all five genetic risk variants initially identified in Asians and provided evidence for associations of breast cancer risk in the East Asian population with nearly half of the genetic risk variants initially reported in GWASs conducted in European descendants. Taken together, these common genetic risk variants explain ∼10% of excess familial risk of breast cancer in Asian populations.
doi:10.1093/hmg/ddt089
PMCID: PMC3658167  PMID: 23535825
8.  Large-scale genotyping identifies 41 new loci associated with breast cancer risk 
Michailidou, Kyriaki | Hall, Per | Gonzalez-Neira, Anna | Ghoussaini, Maya | Dennis, Joe | Milne, Roger L | Schmidt, Marjanka K | Chang-Claude, Jenny | Bojesen, Stig E | Bolla, Manjeet K | Wang, Qin | Dicks, Ed | Lee, Andrew | Turnbull, Clare | Rahman, Nazneen | Fletcher, Olivia | Peto, Julian | Gibson, Lorna | Silva, Isabel dos Santos | Nevanlinna, Heli | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Waisfisz, Quinten | Meijers-Heijboer, Hanne | Adank, Muriel | van der Luijt, Rob B | Hein, Rebecca | Dahmen, Norbert | Beckman, Lars | Meindl, Alfons | Schmutzler, Rita K | Müller-Myhsok, Bertram | Lichtner, Peter | Hopper, John L | Southey, Melissa C | Makalic, Enes | Schmidt, Daniel F | Uitterlinden, Andre G | Hofman, Albert | Hunter, David J | Chanock, Stephen J | Vincent, Daniel | Bacot, François | Tessier, Daniel C | Canisius, Sander | Wessels, Lodewyk F A | Haiman, Christopher A | Shah, Mitul | Luben, Robert | Brown, Judith | Luccarini, Craig | Schoof, Nils | Humphreys, Keith | Li, Jingmei | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Couch, Fergus J | Wang, Xianshu | Vachon, Celine | Stevens, Kristen N | Lambrechts, Diether | Moisse, Matthieu | Paridaens, Robert | Christiaens, Marie-Rose | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Johnson, Nichola | Aitken, Zoe | Aaltonen, Kirsimari | Heikkinen, Tuomas | Broeks, Annegien | Van’t Veer, Laura J | van der Schoot, C Ellen | Guénel, Pascal | Truong, Thérèse | Laurent-Puig, Pierre | Menegaux, Florence | Marme, Frederik | Schneeweiss, Andreas | Sohn, Christof | Burwinkel, Barbara | Zamora, M Pilar | Perez, Jose Ignacio Arias | Pita, Guillermo | Alonso, M Rosario | Cox, Angela | Brock, Ian W | Cross, Simon S | Reed, Malcolm W R | Sawyer, Elinor J | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Henderson, Brian E | Schumacher, Fredrick | Le Marchand, Loic | Andrulis, Irene L | Knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Lindblom, Annika | Margolin, Sara | Hooning, Maartje J | Hollestelle, Antoinette | van den Ouweland, Ans M W | Jager, Agnes | Bui, Quang M | Stone, Jennifer | Dite, Gillian S | Apicella, Carmel | Tsimiklis, Helen | Giles, Graham G | Severi, Gianluca | Baglietto, Laura | Fasching, Peter A | Haeberle, Lothar | Ekici, Arif B | Beckmann, Matthias W | Brenner, Hermann | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Swerdlow, Anthony | Ashworth, Alan | Orr, Nick | Jones, Michael | Figueroa, Jonine | Lissowska, Jolanta | Brinton, Louise | Goldberg, Mark S | Labrèche, France | Dumont, Martine | Winqvist, Robert | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Grip, Mervi | Brauch, Hiltrud | Hamann, Ute | Brüning, Thomas | Radice, Paolo | Peterlongo, Paolo | Manoukian, Siranoush | Bonanni, Bernardo | Devilee, Peter | Tollenaar, Rob A E M | Seynaeve, Caroline | van Asperen, Christi J | Jakubowska, Anna | Lubinski, Jan | Jaworska, Katarzyna | Durda, Katarzyna | Mannermaa, Arto | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Bogdanova, Natalia V | Antonenkova, Natalia N | Dörk, Thilo | Kristensen, Vessela N | Anton-Culver, Hoda | Slager, Susan | Toland, Amanda E | Edge, Stephen | Fostira, Florentia | Kang, Daehee | Yoo, Keun-Young | Noh, Dong-Young | Matsuo, Keitaro | Ito, Hidemi | Iwata, Hiroji | Sueta, Aiko | Wu, Anna H | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Shu, Xiao-Ou | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Teo, Soo Hwang | Yip, Cheng Har | Phuah, Sze Yee | Cornes, Belinda K | Hartman, Mikael | Miao, Hui | Lim, Wei Yen | Sng, Jen-Hwei | Muir, Kenneth | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Shen, Chen-Yang | Hsiung, Chia-Ni | Wu, Pei-Ei | Ding, Shian-Ling | Sangrajrang, Suleeporn | Gaborieau, Valerie | Brennan, Paul | McKay, James | Blot, William J | Signorello, Lisa B | Cai, Qiuyin | Zheng, Wei | Deming-Halverson, Sandra | Shrubsole, Martha | Long, Jirong | Simard, Jacques | Garcia-Closas, Montse | Pharoah, Paul D P | Chenevix-Trench, Georgia | Dunning, Alison M | Benitez, Javier | Easton, Douglas F
Nature genetics  2013;45(4):353-361e2.
Breast cancer is the most common cancer among women. Common variants at 27 loci have been identified as associated with susceptibility to breast cancer, and these account for ~9% of the familial risk of the disease. We report here a meta-analysis of 9 genome-wide association studies, including 10,052 breast cancer cases and 12,575 controls of European ancestry, from which we selected 29,807 SNPs for further genotyping. These SNPs were genotyped in 45,290 cases and 41,880 controls of European ancestry from 41 studies in the Breast Cancer Association Consortium (BCAC). The SNPs were genotyped as part of a collaborative genotyping experiment involving four consortia (Collaborative Oncological Gene-environment Study, COGS) and used a custom Illumina iSelect genotyping array, iCOGS, comprising more than 200,000 SNPs. We identified SNPs at 41 new breast cancer susceptibility loci at genome-wide significance (P < 5 × 10−8). Further analyses suggest that more than 1,000 additional loci are involved in breast cancer susceptibility.
doi:10.1038/ng.2563
PMCID: PMC3771688  PMID: 23535729
9.  Genome-wide association studies identify four ER negative–specific breast cancer risk loci 
Garcia-Closas, Montserrat | Couch, Fergus J | Lindstrom, Sara | Michailidou, Kyriaki | Schmidt, Marjanka K | Brook, Mark N | orr, Nick | Rhie, Suhn Kyong | Riboli, Elio | Feigelson, Heather s | Le Marchand, Loic | Buring, Julie E | Eccles, Diana | Miron, Penelope | Fasching, Peter A | Brauch, Hiltrud | Chang-Claude, Jenny | Carpenter, Jane | Godwin, Andrew K | Nevanlinna, Heli | Giles, Graham G | Cox, Angela | Hopper, John L | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | Dicks, Ed | Howat, Will J | Schoof, Nils | Bojesen, Stig E | Lambrechts, Diether | Broeks, Annegien | Andrulis, Irene L | Guénel, Pascal | Burwinkel, Barbara | Sawyer, Elinor J | Hollestelle, Antoinette | Fletcher, Olivia | Winqvist, Robert | Brenner, Hermann | Mannermaa, Arto | Hamann, Ute | Meindl, Alfons | Lindblom, Annika | Zheng, Wei | Devillee, Peter | Goldberg, Mark S | Lubinski, Jan | Kristensen, Vessela | Swerdlow, Anthony | Anton-Culver, Hoda | Dörk, Thilo | Muir, Kenneth | Matsuo, Keitaro | Wu, Anna H | Radice, Paolo | Teo, Soo Hwang | Shu, Xiao-Ou | Blot, William | Kang, Daehee | Hartman, Mikael | Sangrajrang, Suleeporn | Shen, Chen-Yang | Southey, Melissa C | Park, Daniel J | Hammet, Fleur | Stone, Jennifer | Veer, Laura J Van’t | Rutgers, Emiel J | Lophatananon, Artitaya | Stewart-Brown, Sarah | Siriwanarangsan, Pornthep | Peto, Julian | Schrauder, Michael G | Ekici, Arif B | Beckmann, Matthias W | Silva, Isabel dos Santos | Johnson, Nichola | Warren, Helen | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Marme, Federick | Schneeweiss, Andreas | Sohn, Christof | Truong, Therese | Laurent-Puig, Pierre | Kerbrat, Pierre | Nordestgaard, Børge G | Nielsen, Sune F | Flyger, Henrik | Milne, Roger L | Perez, Jose Ignacio Arias | Menéndez, Primitiva | Müller, Heiko | Arndt, Volker | Stegmaier, Christa | Lichtner, Peter | Lochmann, Magdalena | Justenhoven, Christina | Ko, Yon-Dschun | Muranen, Taru A | Aittomäki, Kristiina | Blomqvist, Carl | Greco, Dario | Heikkinen, Tuomas | Ito, Hidemi | Iwata, Hiroji | Yatabe, Yasushi | Antonenkova, Natalia N | Margolin, Sara | Kataja, Vesa | Kosma, Veli-Matti | Hartikainen, Jaana M | Balleine, Rosemary | Tseng, Chiu-Chen | Van Den Berg, David | Stram, Daniel O | Neven, Patrick | Dieudonné, Anne-Sophie | Leunen, Karin | Rudolph, Anja | Nickels, Stefan | Flesch-Janys, Dieter | Peterlongo, Paolo | Peissel, Bernard | Bernard, Loris | Olson, Janet E | Wang, Xianshu | Stevens, Kristen | Severi, Gianluca | Baglietto, Laura | Mclean, Catriona | Coetzee, Gerhard A | Feng, Ye | Henderson, Brian E | Schumacher, Fredrick | Bogdanova, Natalia V | Labrèche, France | Dumont, Martine | Yip, Cheng Har | Taib, Nur Aishah Mohd | Cheng, Ching-Yu | Shrubsole, Martha | Long, Jirong | Pylkäs, Katri | Jukkola-Vuorinen, Arja | Kauppila, Saila | knight, Julia A | Glendon, Gord | Mulligan, Anna Marie | Tollenaar, Robertus A E M | Seynaeve, Caroline M | Kriege, Mieke | Hooning, Maartje J | Van den Ouweland, Ans M W | Van Deurzen, Carolien H M | Lu, Wei | Gao, Yu-Tang | Cai, Hui | Balasubramanian, Sabapathy P | Cross, Simon S | Reed, Malcolm W R | Signorello, Lisa | Cai, Qiuyin | Shah, Mitul | Miao, Hui | Chan, Ching Wan | Chia, Kee Seng | Jakubowska, Anna | Jaworska, Katarzyna | Durda, Katarzyna | Hsiung, Chia-Ni | Wu, Pei-Ei | Yu, Jyh-Cherng | Ashworth, Alan | Jones, Michael | Tessier, Daniel C | González-Neira, Anna | Pita, Guillermo | Alonso, M Rosario | Vincent, Daniel | Bacot, Francois | Ambrosone, Christine B | Bandera, Elisa V | John, Esther M | Chen, Gary K | Hu, Jennifer J | Rodriguez-gil, Jorge L | Bernstein, Leslie | Press, Michael F | Ziegler, Regina G | Millikan, Robert M | Deming-Halverson, Sandra L | Nyante, Sarah | Ingles, Sue A | Waisfisz, Quinten | Tsimiklis, Helen | Makalic, Enes | Schmidt, Daniel | Bui, Minh | Gibson, Lorna | Müller-Myhsok, Bertram | Schmutzler, Rita K | Hein, Rebecca | Dahmen, Norbert | Beckmann, Lars | Aaltonen, Kirsimari | Czene, Kamila | Irwanto, Astrid | Liu, Jianjun | Turnbull, Clare | Rahman, Nazneen | Meijers-Heijboer, Hanne | Uitterlinden, Andre G | Rivadeneira, Fernando | Olswold, Curtis | Slager, Susan | Pilarski, Robert | Ademuyiwa, Foluso | Konstantopoulou, Irene | Martin, Nicholas G | Montgomery, Grant W | Slamon, Dennis J | Rauh, Claudia | Lux, Michael P | Jud, Sebastian M | Bruning, Thomas | Weaver, Joellen | Sharma, Priyanka | Pathak, Harsh | Tapper, Will | Gerty, Sue | Durcan, Lorraine | Trichopoulos, Dimitrios | Tumino, Rosario | Peeters, Petra H | Kaaks, Rudolf | Campa, Daniele | Canzian, Federico | Weiderpass, Elisabete | Johansson, Mattias | Khaw, Kay-Tee | Travis, Ruth | Clavel-Chapelon, Françoise | Kolonel, Laurence N | Chen, Constance | Beck, Andy | Hankinson, Susan E | Berg, Christine D | Hoover, Robert N | Lissowska, Jolanta | Figueroa, Jonine D | Chasman, Daniel I | Gaudet, Mia M | Diver, W Ryan | Willett, Walter C | Hunter, David J | Simard, Jacques | Benitez, Javier | Dunning, Alison M | Sherman, Mark E | Chenevix-Trench, Georgia | Chanock, Stephen J | Hall, Per | Pharoah, Paul D P | Vachon, Celine | Easton, Douglas F | Haiman, Christopher A | Kraft, Peter
Nature genetics  2013;45(4):392-398e2.
Estrogen receptor (ER)-negative tumors represent 20–30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry1. The etiology2 and clinical behavior3 of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition4. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10−12 and LGR6, P = 1.4 × 10−8), 2p24.1 (P = 4.6 × 10−8) and 16q12.2 (FTO, P = 4.0 × 10−8), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
doi:10.1038/ng.2561
PMCID: PMC3771695  PMID: 23535733
10.  Understanding Global Trends in Maternal Mortality 
CONTEXT
Despite the fact that most maternal deaths are preventable, maternal mortality remains high in many developing countries. Target A of Millennium Development Goal (MDG) 5 calls for a three-quarters reduction in the maternal mortality ratio (MMR) between 1990 and 2015.
METHODS
We derived estimates of maternal mortality for 172 countries over the period 1990–2008. Trends in maternal mortality were estimated either directly from vital registration data or from a hierarchical or multilevel model, depending on the data available for a particular country.
RESULTS
The annual number of maternal deaths worldwide declined by 34% between 1990 and 2008, from approximately 546,000 to 358,000 deaths. The estimated MMR for the world as a whole also declined by 34% over this period, falling from 400 to 260 maternal deaths per 100,000 live births. Between 1990 and 2008, the majority of the global burden of maternal deaths shifted from Asia to Sub-Saharan Africa. Differential trends in fertility, the HIV/ AIDS epidemic and access to reproductive health are associated with the shift in the burden of maternal deaths from Asia to Sub-Saharan Africa.
CONCLUSIONS
Although the estimated annual rate of decline in the global MMR in 1990–2008 (2.3%) fell short of the level needed to meet the MDG 5 target, it was much faster than had been thought previously. Targeted efforts to improve access to quality maternal health care, as well as efforts to decrease unintended pregnancies through family planning, are necessary to further reduce the global burden of maternal mortality.
doi:10.1363/3903213
PMCID: PMC3886625  PMID: 23584466
11.  The TRACTISS Protocol: a randomised double blind placebo controlled clinical TRial of Anti-B-Cell Therapy In patients with primary Sjögren’s Syndrome 
Background
Primary Sjögren’s Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 – 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes.
Methods/design
TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition.
Discussion
The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity.
Trial registration
UKCRN Portfolio ID: 9809 ISRCTN65360827.
doi:10.1186/1471-2474-15-21
PMCID: PMC3937118  PMID: 24438039
Sjögren’s syndrome; Rituximab; Anti-B-cell; Double-blind; Placebo; Trial
12.  A New Method for Deriving Global Estimates of Maternal Mortality 
Statistics, politics, and policy  2012;3(2):2151-7509.1038.
Maternal mortality is widely regarded as a key indicator of population health and of social and economic development. Its levels and trends are monitored closely by the United Nations and others, inspired in part by the UN’s Millennium Development Goals (MDGs), which call for a three-fourths reduction in the maternal mortality ratio between 1990 and 2015. Unfortunately, the empirical basis for such monitoring remains quite weak, requiring the use of statistical models to obtain estimates for most countries.
In this paper we describe a new method for estimating global levels and trends in maternal mortality. For countries lacking adequate data for direct calculation of estimates, we employed a parametric model that separates maternal deaths related to HIV/AIDS from all others. For maternal deaths unrelated to HIV/AIDS, the model consists of a hierarchical linear regression with three predictors and variable intercepts for both countries and regions. The uncertainty of estimates was assessed by simulating the estimation process, accounting for variability both in the data and in other model inputs.
The method was used to obtain the most recent set of UN estimates, published in September 2010. Here, we provide a concise description and explanation of the approach, including a new analysis of the components of variability reflected in the uncertainty intervals.
Final estimates provide evidence of a more rapid decline in the global maternal mortality ratio than suggested by previous work, including another study published in April 2010. We compare findings from the two recent studies and discuss topics for further research to help resolve differences.
PMCID: PMC3886639  PMID: 24416714
maternal mortality; multilevel regression model; AIDS mortality; Millennium Development Goals
13.  Process evaluation of the Teamplay parenting intervention pilot: implications for recruitment, retention and course refinement 
BMC Public Health  2013;13:1102.
Background
Parenting programs could provide effective routes to increasing children’s physical activity and reducing screen-viewing. Many studies have reported difficulties in recruiting and retaining families in group parenting interventions. This paper uses qualitative data from the Teamplay feasibility trial to examine parents’ views on recruitment, attendance and course refinement.
Methods
Semi-structured interviews were conducted with 16 intervention and 10 control group parents of 6–8 year old children. Topics discussed with the intervention group included parents’ views on the recruitment, structure, content and delivery of the course. Topics discussed with the control group included recruitment and randomization. Interviews were digitally recorded, transcribed and thematically analyzed.
Results
Many parents in both the intervention and control group reported that they joined the study because they had been thinking about ways to improve their parenting skills, getting ideas on how to change behavior, or had been actively looking for a parenting course but with little success in enrolling on one. Both intervention and control group parents reported that the initial promotional materials and indicative course topics resonated with their experiences and represented a possible solution to parenting challenges. Participants reported that the course leaders played an important role in helping them to feel comfortable during the first session, engaging anxious parents and putting parents at ease. The most commonly reported reason for parents returning to the course after an absence was because they wanted to learn new information. The majority of parents reported that they formed good relationships with the other parents in the group. An empathetic interaction style in which leaders accommodated parent’s busy lives appeared to impact positively on course attendance.
Conclusions
The data presented indicate that a face-to-face recruitment campaign which built trust and emphasized how the program was relevant to families positively affected recruitment in Teamplay. Parents found the parenting component of the intervention attractive and, once recruited, attendance was facilitated by enjoyable sessions, empathetic leaders and support from fellow participants. Overall, data suggest that the Teamplay recruitment and retention approaches were successful and with small refinements could be effectively used in a larger trial.
doi:10.1186/1471-2458-13-1102
PMCID: PMC4219518  PMID: 24289111
Parenting; Recruitment; Retention; Intervention; Process evaluation
14.  Pressure relieving support surfaces: a randomised evaluation 2 (PRESSURE 2) 
Trials  2013;14(Suppl 1):P68.
doi:10.1186/1745-6215-14-S1-P68
PMCID: PMC3981508
15.  Time-Motion Analysis of Clinical Nursing Documentation During Implementation of an Electronic Operating Room Management System for Ophthalmic Surgery 
AMIA Annual Symposium Proceedings  2013;2013:1195-1204.
Efficiency and quality of documentation are critical in surgical settings because operating rooms are a major source of revenue, and because adverse events may have enormous consequences. Electronic health records (EHRs) have potential to impact surgical volume, quality, and documentation time. Ophthalmology is an ideal domain to examine these issues because procedures are high-throughput and demand efficient documentation. This time-motion study examines nursing documentation during implementation of an EHR operating room management system in an ophthalmology department. Key findings are: (1) EHR nursing documentation time was significantly worse during early implementation, but improved to a level near but slightly worse than paper baseline, (2) Mean documentation time varied significantly among nurses during early implementation, and (3) There was no decrease in operating room turnover time or surgical volume after implementation. These findings have important implications for ambulatory surgery departments planning EHR implementation, and for research in system design.
PMCID: PMC3900139  PMID: 24551402
16.  Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer 
Bojesen, Stig E | Pooley, Karen A | Johnatty, Sharon E | Beesley, Jonathan | Michailidou, Kyriaki | Tyrer, Jonathan P | Edwards, Stacey L | Pickett, Hilda A | Shen, Howard C | Smart, Chanel E | Hillman, Kristine M | Mai, Phuong L | Lawrenson, Kate | Stutz, Michael D | Lu, Yi | Karevan, Rod | Woods, Nicholas | Johnston, Rebecca L | French, Juliet D | Chen, Xiaoqing | Weischer, Maren | Nielsen, Sune F | Maranian, Melanie J | Ghoussaini, Maya | Ahmed, Shahana | Baynes, Caroline | Bolla, Manjeet K | Wang, Qin | Dennis, Joe | McGuffog, Lesley | Barrowdale, Daniel | Lee, Andrew | Healey, Sue | Lush, Michael | Tessier, Daniel C | Vincent, Daniel | Bacot, Françis | Vergote, Ignace | Lambrechts, Sandrina | Despierre, Evelyn | Risch, Harvey A | González-Neira, Anna | Rossing, Mary Anne | Pita, Guillermo | Doherty, Jennifer A | Álvarez, Nuria | Larson, Melissa C | Fridley, Brooke L | Schoof, Nils | Chang-Claude, Jenny | Cicek, Mine S | Peto, Julian | Kalli, Kimberly R | Broeks, Annegien | Armasu, Sebastian M | Schmidt, Marjanka K | Braaf, Linde M | Winterhoff, Boris | Nevanlinna, Heli | Konecny, Gottfried E | Lambrechts, Diether | Rogmann, Lisa | Guénel, Pascal | Teoman, Attila | Milne, Roger L | Garcia, Joaquin J | Cox, Angela | Shridhar, Vijayalakshmi | Burwinkel, Barbara | Marme, Frederik | Hein, Rebecca | Sawyer, Elinor J | Haiman, Christopher A | Wang-Gohrke, Shan | Andrulis, Irene L | Moysich, Kirsten B | Hopper, John L | Odunsi, Kunle | Lindblom, Annika | Giles, Graham G | Brenner, Hermann | Simard, Jacques | Lurie, Galina | Fasching, Peter A | Carney, Michael E | Radice, Paolo | Wilkens, Lynne R | Swerdlow, Anthony | Goodman, Marc T | Brauch, Hiltrud | García-Closas, Montserrat | Hillemanns, Peter | Winqvist, Robert | Dürst, Matthias | Devilee, Peter | Runnebaum, Ingo | Jakubowska, Anna | Lubinski, Jan | Mannermaa, Arto | Butzow, Ralf | Bogdanova, Natalia V | Dörk, Thilo | Pelttari, Liisa M | Zheng, Wei | Leminen, Arto | Anton-Culver, Hoda | Bunker, Clareann H | Kristensen, Vessela | Ness, Roberta B | Muir, Kenneth | Edwards, Robert | Meindl, Alfons | Heitz, Florian | Matsuo, Keitaro | du Bois, Andreas | Wu, Anna H | Harter, Philipp | Teo, Soo-Hwang | Schwaab, Ira | Shu, Xiao-Ou | Blot, William | Hosono, Satoyo | Kang, Daehee | Nakanishi, Toru | Hartman, Mikael | Yatabe, Yasushi | Hamann, Ute | Karlan, Beth Y | Sangrajrang, Suleeporn | Kjaer, Susanne Krüger | Gaborieau, Valerie | Jensen, Allan | Eccles, Diana | Høgdall, Estrid | Shen, Chen-Yang | Brown, Judith | Woo, Yin Ling | Shah, Mitul | Azmi, Mat Adenan Noor | Luben, Robert | Omar, Siti Zawiah | Czene, Kamila | Vierkant, Robert A | Nordestgaard, Børge G | Flyger, Henrik | Vachon, Celine | Olson, Janet E | Wang, Xianshu | Levine, Douglas A | Rudolph, Anja | Weber, Rachel Palmieri | Flesch-Janys, Dieter | Iversen, Edwin | Nickels, Stefan | Schildkraut, Joellen M | Silva, Isabel Dos Santos | Cramer, Daniel W | Gibson, Lorna | Terry, Kathryn L | Fletcher, Olivia | Vitonis, Allison F | van der Schoot, C Ellen | Poole, Elizabeth M | Hogervorst, Frans B L | Tworoger, Shelley S | Liu, Jianjun | Bandera, Elisa V | Li, Jingmei | Olson, Sara H | Humphreys, Keith | Orlow, Irene | Blomqvist, Carl | Rodriguez-Rodriguez, Lorna | Aittomäki, Kristiina | Salvesen, Helga B | Muranen, Taru A | Wik, Elisabeth | Brouwers, Barbara | Krakstad, Camilla | Wauters, Els | Halle, Mari K | Wildiers, Hans | Kiemeney, Lambertus A | Mulot, Claire | Aben, Katja K | Laurent-Puig, Pierre | van Altena, Anne M | Truong, Thérèse | Massuger, Leon F A G | Benitez, Javier | Pejovic, Tanja | Perez, Jose Ignacio Arias | Hoatlin, Maureen | Zamora, M Pilar | Cook, Linda S | Balasubramanian, Sabapathy P | Kelemen, Linda E | Schneeweiss, Andreas | Le, Nhu D | Sohn, Christof | Brooks-Wilson, Angela | Tomlinson, Ian | Kerin, Michael J | Miller, Nicola | Cybulski, Cezary | Henderson, Brian E | Menkiszak, Janusz | Schumacher, Fredrick | Wentzensen, Nicolas | Marchand, Loic Le | Yang, Hannah P | Mulligan, Anna Marie | Glendon, Gord | Engelholm, Svend Aage | Knight, Julia A | Høgdall, Claus K | Apicella, Carmel | Gore, Martin | Tsimiklis, Helen | Song, Honglin | Southey, Melissa C | Jager, Agnes | van den Ouweland, Ans M W | Brown, Robert | Martens, John W M | Flanagan, James M | Kriege, Mieke | Paul, James | Margolin, Sara | Siddiqui, Nadeem | Severi, Gianluca | Whittemore, Alice S | Baglietto, Laura | McGuire, Valerie | Stegmaier, Christa | Sieh, Weiva | Müller, Heiko | Arndt, Volker | Labrèche, France | Gao, Yu-Tang | Goldberg, Mark S | Yang, Gong | Dumont, Martine | McLaughlin, John R | Hartmann, Arndt | Ekici, Arif B | Beckmann, Matthias W | Phelan, Catherine M | Lux, Michael P | Permuth-Wey, Jenny | Peissel, Bernard | Sellers, Thomas A | Ficarazzi, Filomena | Barile, Monica | Ziogas, Argyrios | Ashworth, Alan | Gentry-Maharaj, Aleksandra | Jones, Michael | Ramus, Susan J | Orr, Nick | Menon, Usha | Pearce, Celeste L | Brüning, Thomas | Pike, Malcolm C | Ko, Yon-Dschun | Lissowska, Jolanta | Figueroa, Jonine | Kupryjanczyk, Jolanta | Chanock, Stephen J | Dansonka-Mieszkowska, Agnieszka | Jukkola-Vuorinen, Arja | Rzepecka, Iwona K | Pylkäs, Katri | Bidzinski, Mariusz | Kauppila, Saila | Hollestelle, Antoinette | Seynaeve, Caroline | Tollenaar, Rob A E M | Durda, Katarzyna | Jaworska, Katarzyna | Hartikainen, Jaana M | Kosma, Veli-Matti | Kataja, Vesa | Antonenkova, Natalia N | Long, Jirong | Shrubsole, Martha | Deming-Halverson, Sandra | Lophatananon, Artitaya | Siriwanarangsan, Pornthep | Stewart-Brown, Sarah | Ditsch, Nina | Lichtner, Peter | Schmutzler, Rita K | Ito, Hidemi | Iwata, Hiroji | Tajima, Kazuo | Tseng, Chiu-Chen | Stram, Daniel O | van den Berg, David | Yip, Cheng Har | Ikram, M Kamran | Teh, Yew-Ching | Cai, Hui | Lu, Wei | Signorello, Lisa B | Cai, Qiuyin | Noh, Dong-Young | Yoo, Keun-Young | Miao, Hui | Iau, Philip Tsau-Choong | Teo, Yik Ying | McKay, James | Shapiro, Charles | Ademuyiwa, Foluso | Fountzilas, George | Hsiung, Chia-Ni | Yu, Jyh-Cherng | Hou, Ming-Feng | Healey, Catherine S | Luccarini, Craig | Peock, Susan | Stoppa-Lyonnet, Dominique | Peterlongo, Paolo | Rebbeck, Timothy R | Piedmonte, Marion | Singer, Christian F | Friedman, Eitan | Thomassen, Mads | Offit, Kenneth | Hansen, Thomas V O | Neuhausen, Susan L | Szabo, Csilla I | Blanco, Ignacio | Garber, Judy | Narod, Steven A | Weitzel, Jeffrey N | Montagna, Marco | Olah, Edith | Godwin, Andrew K | Yannoukakos, Drakoulis | Goldgar, David E | Caldes, Trinidad | Imyanitov, Evgeny N | Tihomirova, Laima | Arun, Banu K | Campbell, Ian | Mensenkamp, Arjen R | van Asperen, Christi J | van Roozendaal, Kees E P | Meijers-Heijboer, Hanne | Collée, J Margriet | Oosterwijk, Jan C | Hooning, Maartje J | Rookus, Matti A | van der Luijt, Rob B | van Os, Theo A M | Evans, D Gareth | Frost, Debra | Fineberg, Elena | Barwell, Julian | Walker, Lisa | Kennedy, M John | Platte, Radka | Davidson, Rosemarie | Ellis, Steve D | Cole, Trevor | Paillerets, Brigitte Bressac-de | Buecher, Bruno | Damiola, Francesca | Faivre, Laurence | Frenay, Marc | Sinilnikova, Olga M | Caron, Olivier | Giraud, Sophie | Mazoyer, Sylvie | Bonadona, Valérie | Caux-Moncoutier, Virginie | Toloczko-Grabarek, Aleksandra | Gronwald, Jacek | Byrski, Tomasz | Spurdle, Amanda B | Bonanni, Bernardo | Zaffaroni, Daniela | Giannini, Giuseppe | Bernard, Loris | Dolcetti, Riccardo | Manoukian, Siranoush | Arnold, Norbert | Engel, Christoph | Deissler, Helmut | Rhiem, Kerstin | Niederacher, Dieter | Plendl, Hansjoerg | Sutter, Christian | Wappenschmidt, Barbara | Borg, Åke | Melin, Beatrice | Rantala, Johanna | Soller, Maria | Nathanson, Katherine L | Domchek, Susan M | Rodriguez, Gustavo C | Salani, Ritu | Kaulich, Daphne Gschwantler | Tea, Muy-Kheng | Paluch, Shani Shimon | Laitman, Yael | Skytte, Anne-Bine | Kruse, Torben A | Jensen, Uffe Birk | Robson, Mark | Gerdes, Anne-Marie | Ejlertsen, Bent | Foretova, Lenka | Savage, Sharon A | Lester, Jenny | Soucy, Penny | Kuchenbaecker, Karoline B | Olswold, Curtis | Cunningham, Julie M | Slager, Susan | Pankratz, Vernon S | Dicks, Ed | Lakhani, Sunil R | Couch, Fergus J | Hall, Per | Monteiro, Alvaro N A | Gayther, Simon A | Pharoah, Paul D P | Reddel, Roger R | Goode, Ellen L | Greene, Mark H | Easton, Douglas F | Berchuck, Andrew | Antoniou, Antonis C | Chenevix-Trench, Georgia | Dunning, Alison M
Nature genetics  2013;45(4):371-384e2.
TERT-locus single nucleotide polymorphisms (SNPs) and leucocyte telomere measures are reportedly associated with risks of multiple cancers. Using the iCOGs chip, we analysed ~480 TERT-locus SNPs in breast (n=103,991), ovarian (n=39,774) and BRCA1 mutation carrier (11,705) cancer cases and controls. 53,724 participants have leucocyte telomere measures. Most associations cluster into three independent peaks. Peak 1 SNP rs2736108 minor allele associates with longer telomeres (P=5.8×10−7), reduced estrogen receptor negative (ER-negative) (P=1.0×10−8) and BRCA1 mutation carrier (P=1.1×10−5) breast cancer risks, and altered promoter-assay signal. Peak 2 SNP rs7705526 minor allele associates with longer telomeres (P=2.3×10−14), increased low malignant potential ovarian cancer risk (P=1.3×10−15) and increased promoter activity. Peak 3 SNPs rs10069690 and rs2242652 minor alleles increase ER-negative (P=1.2×10−12) and BRCA1 mutation carrier (P=1.6×10−14) breast and invasive ovarian (P=1.3×10−11) cancer risks, but not via altered telomere length. The cancer-risk alleles of rs2242652 and rs10069690 respectively increase silencing and generate a truncated TERT splice-variant.
doi:10.1038/ng.2566
PMCID: PMC3670748  PMID: 23535731
17.  Evaluation of Electronic Health Record Implementation in Ophthalmology at an Academic Medical Center (An American Ophthalmological Society Thesis) 
Purpose:
To evaluate three measures related to electronic health record (EHR) implementation: clinical volume, time requirements, and nature of clinical documentation. Comparison is made to baseline paper documentation.
Methods:
An academic ophthalmology department implemented an EHR in 2006. A study population was defined of faculty providers who worked the 5 months before and after implementation. Clinical volumes, as well as time length for each patient encounter, were collected from the EHR reporting system. To directly compare time requirements, two faculty providers who utilized both paper and EHR systems completed time-motion logs to record the number of patients, clinic time, and nonclinic time to complete documentation. Faculty providers and databases were queried to identify patient records containing both paper and EHR notes, from which three cases were identified to illustrate representative documentation differences.
Results:
Twenty-three faculty providers completed 120,490 clinical encounters during a 3-year study period. Compared to baseline clinical volume from 3 months pre-implementation, the post-implementation volume was 88% in quarter 1, 93% in year 1, 97% in year 2, and 97% in year 3. Among all encounters, 75% were completed within 1.7 days after beginning documentation. The mean total time per patient was 6.8 minutes longer with EHR than paper (P<.01). EHR documentation involved greater reliance on textual interpretation of clinical findings, whereas paper notes used more graphical representations, and EHR notes were longer and included automatically generated text.
Conclusion:
This EHR implementation was associated with increased documentation time, little or no increase in clinical volume, and changes in the nature of ophthalmic documentation.
PMCID: PMC3797873  PMID: 24167326
18.  Multiple strains of non-tuberculous mycobacteria in a patient with cystic fibrosis 
Journal of the Royal Society of Medicine  2010;103(Suppl 1):S34-S43.
doi:10.1258/jrsm.2010.s11009
PMCID: PMC2905029  PMID: 20573669
19.  Self-Reported Childhood Physical Abuse and Perpetration of Intimate Partner Violence: The Moderating Role of Psychopathic Traits 
Criminal justice and behavior  2012;39(7):910-922.
Whereas considerable evidence links childhood physical abuse with later perpetration of intimate partner violence (IPV), research to identify moderators of this relationship will increase our understanding of which victims of childhood abuse are at risk for later IPV. The present study examined dimensions of psychopathy as moderators of the relationship between physical abuse in childhood and perpetration of IPV in a sample of criminal offenders. Results indicated that, among individuals with higher levels of impulsive-irresponsible (i.e., Lifestyle) traits of psychopathy, childhood physical abuse was associated with later perpetration of IPV. Findings have implications for the propensity toward IPV perpetration among individuals who have experienced childhood physical abuse.
doi:10.1177/0093854812438160
PMCID: PMC3439214  PMID: 22984318
child abuse; psychopathy; intimate partner violence; aggression; antisocial behavior
20.  Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial 
The Lancet Oncology  2013;14(8):749-759.
Summary
Background
Therapeutic antibodies targeting EGFR have activity in advanced colorectal cancer, but results from clinical trials are inconsistent and the population in which most benefit is derived is uncertain. Our aim was to assess the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer.
Methods
In this open-label, randomised trial, we enrolled patients who had advanced colorectal cancer progressing after fluoropyrimidine treatment with or without oxaliplatin from 60 centres in the UK. From December, 2006 until June, 2008, molecularly unselected patients were recruited to a three-arm design including irinotecan (control), irinotecan plus ciclosporin, and irinotecan plus panitumumab (IrPan) groups. From June 10, 2008, in response to new data, the trial was amended to a prospectively stratified design, restricting panitumumab randomisation to patients with KRAS wild-type tumours; the results of the comparison between the irinotcan and IrPan groups are reported here. We used a computer-generated randomisation sequence (stratified by previous EGFR targeted therapy and then minimised by centre, WHO performance status, previous oxaliplatin, previous bevacizumab, previous dose modifications, and best previous response) to randomly allocate patients to either irinotecan or IrPan. Patients in both groups received 350 mg/m2 intravenous irinotecan every 3 weeks (300 mg/m2 if aged ≥70 years or a performance status of 2); patients in the IrPan group also received intravenous panitumumab 9 mg/kg every 3 weeks. The primary endpoint was overall survival in KRAS wild-type patients who had not received previous EGFR targeted therapy, analysed by intention to treat. Tumour DNA was pyrosequenced for KRASc.146, BRAF, NRAS, and PIK3CA mutations, and predefined molecular subgroups were analysed for interaction with the effect of panitumumab. This study is registered, number ISRCTN93248876.
Results
Between Dec 4, 2006, and Aug 31, 2010, 1198 patients were enrolled, of whom 460 were included in the primary population of patients with KRASc.12–13,61 wild-type tumours and no previous EGFR targeted therapy. 230 patients were randomly allocated to irinotecan and 230 to IrPan. There was no difference in overall survival between groups (HR 1·01, 95% CI 0·83–1·23; p=0·91), but individuals in the IrPan group had longer progression-free survival (0·78, 0·64–0·95; p=0·015) and a greater number of responses (79 [34%] patients vs 27 [12%]; p<0·0001) than did individuals in the irinotecan group. Grade 3 or worse diarrhoea (64 [29%] of 219 patients vs 39 [18%] of 218 patients), skin toxicity (41 [19%] vs none), lethargy (45 [21]% vs 24 [11%]), infection (42 [19%] vs 22 [10%]) and haematological toxicity (48 [22%] vs 27 [12%]) were reported more commonly in the IrPan group than in the irinotecan group. We recorded five treatment-related deaths, two in the IrPan group and three in the irinotecan group.
Interpretation
Adding panitumumab to irinotecan did not improve the overall survival of patients with wild-type KRAS tumours. Further refinement of molecular selection is needed for substantial benefits to be derived from EGFR targeting agents.
Funding
Cancer Research UK, Amgen Inc.
doi:10.1016/S1470-2045(13)70163-3
PMCID: PMC3699713  PMID: 23725851
21.  Limited Population Structure, Genetic Drift and Bottlenecks Characterise an Endangered Bird Species in a Dynamic, Fire-Prone Ecosystem 
PLoS ONE  2013;8(4):e59732.
Fire is a major disturbance process in many ecosystems world-wide, resulting in spatially and temporally dynamic landscapes. For populations occupying such environments, fire-induced landscape change is likely to influence population processes, and genetic patterns and structure among populations. The Mallee Emu-wren Stipiturus mallee is an endangered passerine whose global distribution is confined to fire-prone, semi-arid mallee shrublands in south-eastern Australia. This species, with poor capacity for dispersal, has undergone a precipitous reduction in distribution and numbers in recent decades. We used genetic analyses of 11 length-variable, nuclear loci to examine population structure and processes within this species, across its global range. Populations of the Mallee Emu-wren exhibited a low to moderate level of genetic diversity, and evidence of bottlenecks and genetic drift. Bayesian clustering methods revealed weak genetic population structure across the species' range. The direct effects of large fires, together with associated changes in the spatial and temporal patterns of suitable habitat, have the potential to cause population bottlenecks, serial local extinctions and subsequent recolonisation, all of which may interact to erode and homogenise genetic diversity in this species. Movement among temporally and spatially shifting habitat, appears to maintain long-term genetic connectivity. A plausible explanation for the observed genetic patterns is that, following extensive fires, recolonisation exceeds in-situ survival as the primary driver of population recovery in this species. These findings suggest that dynamic, fire-dominated landscapes can drive genetic homogenisation of populations of species with low-mobility and specialised habitat that otherwise would be expected to show strongly structured populations. Such effects must be considered when formulating management actions to conserve species in fire-prone systems.
doi:10.1371/journal.pone.0059732
PMCID: PMC3634030  PMID: 23626668
22.  Glycan Binding Avidity Determines the Systemic Fate of Adeno-Associated Virus Type 9 
Journal of Virology  2012;86(19):10408-10417.
Glycans are key determinants of host range and transmissibility in several pathogens. In the case of adeno-associated viruses (AAV), different carbohydrates serve as cellular receptors in vitro; however, their contributions in vivo are less clear. A particularly interesting example is adeno-associated virus serotype 9 (AAV9), which displays systemic tropism in mice despite low endogenous levels of its primary receptor (galactose) in murine tissues. To understand this further, we studied the effect of modulating glycan binding avidity on the systemic fate of AAV9 in mice. Intravenous administration of recombinant sialidase increased tissue levels of terminally galactosylated glycans in several murine tissues. These conditions altered the systemic tropism of AAV9 into a hepatotropic phenotype, characterized by markedly increased sequestration within the liver sinusoidal endothelium and Kupffer cells. In contrast, an AAV9 mutant with decreased glycan binding avidity displayed a liver-detargeted phenotype. Altering glycan binding avidity also profoundly affected AAV9 persistence in blood circulation. Our results support the notion that high glycan receptor binding avidity appears to impart increased liver tropism, while decreased avidity favors systemic spread of AAV vectors. These findings may not only help predict species-specific differences in tropism for AAV9 on the basis of tissue glycosylation profiles, but also provide a general approach to tailor AAV vectors for systemic or hepatic gene transfer by reengineering capsid-glycan interactions.
doi:10.1128/JVI.01155-12
PMCID: PMC3457279  PMID: 22787229
23.  Validation of the mothers object relations scales in 2–4 year old children and comparison with the child–parent relationship scale 
Background
The quality of the parent–child relationship has an important effect on a wide range of child outcomes. The evaluation of interventions to promote healthy parenting and family relationships is dependent on outcome measures which can quantify the quality of parent–child relationships. Between the Mothers’ Object Relations – Short Form (MORS-SF) scale for babies and the Child–parent Relationship Scale (C-PRS) there is an age gap where no validated scales are available. We report the development and testing of an adaptation of the MORS-SF; the MORS (Child) scale and its use in children from the age of 2 years to 4 years. This scale aims to capture the nature of the parent–child relationship in a form which is short enough to be used in population surveys and intervention evaluations.
Methods
Construct and criterion validity, item salience and internal consistency were assessed in a sample of 166 parents of children aged 2–4 years old and compared with that of the C-PRS. The performance of the MORS (Child) as part of a composite measure with the HOME inventory was compared with that of the C-PRS using data collected in a randomised controlled trial and the national evaluation of Sure Start.
Results
MORS (Child) performed well in children aged 2–4 with high construct and criterion validity, item salience and internal consistency. One item in the C-PRS failed to load on either subscale and parents found this scale slightly more difficult to complete than the MORS (Child). The two measures performed very similarly in a factor analysis with the HOME inventory producing almost identical loadings.
Conclusions
Adapting the MORS-SF for children aged 2–4 years old produces a scale to assess parent–child relationships that is easy to use and outperforms the more commonly used C-PRS in several respects.
doi:10.1186/1477-7525-11-49
PMCID: PMC3620709  PMID: 23518176
Parent; Child; Relationship; Outcome measure; Psychometrics; Validity; Internal consistency
24.  Evaluation of the effectiveness and cost-effectiveness of Families for Health V2 for the treatment of childhood obesity: study protocol for a randomized controlled trial 
Trials  2013;14:81.
Background
Effective programs to help children manage their weight are required. Families for Health focuses on a parenting approach, designed to help parents develop their parenting skills to support lifestyle change within the family. Families for Health V1 showed sustained reductions in overweight after 2 years in a pilot evaluation, but lacks a randomized controlled trial (RCT) evidence base.
Methods/design
This is a multi-center, investigator-blind RCT, with parallel economic evaluation, with a 12-month follow-up. The trial will recruit 120 families with at least one child aged 6 to 11 years who is overweight (≥91st centile BMI) or obese (≥98th centile BMI) from three localities and assigned randomly to Families for Health V2 (60 families) or the usual care control (60 families) groups. Randomization will be stratified by locality (Coventry, Warwickshire, Wolverhampton).
Families for Health V2 is a family-based intervention run in a community venue. Parents/carers and children attend parallel groups for 2.5 hours weekly for 10 weeks. The usual care arm will be the usual support provided within each NHS locality.
A mixed-methods evaluation will be carried out. Child and parent participants will be assessed at home visits at baseline, 3-month (post-treatment) and 12-month follow-up. The primary outcome measure is the change in the children’s BMI z-scores at 12 months from the baseline. Secondary outcome measures include changes in the children’s waist circumference, percentage body fat, physical activity, fruit/vegetable consumption and quality of life. The parents’ BMI and mental well-being, family eating/activity, parent–child relationships and parenting style will also be assessed.
Economic components will encompass the measurement and valuation of service utilization, including the costs of running Families for Health and usual care, and the EuroQol EQ-5D health outcomes. Cost-effectiveness will be expressed in terms of incremental cost per quality-adjusted life year gained. A de novo decision-analytic model will estimate the lifetime cost-effectiveness of the Families for Health program.
Process evaluation will document recruitment, attendance and drop-out rates, and the fidelity of Families for Health delivery. Interviews with up to 24 parents and children from each arm will investigate perceptions and changes made.
Discussion
This paper describes our protocol to assess the effectiveness and cost-effectiveness of a parenting approach for managing childhood obesity and presents challenges to implementation.
Trial registration
Current Controlled Trials http://ISRCTN45032201
doi:10.1186/1745-6215-14-81
PMCID: PMC3610242  PMID: 23514100
Childhood obesity; Weight management; Parenting; Randomized controlled trial; Economic evaluation
25.  Feasibility trial evaluation of a physical activity and screen-viewing course for parents of 6 to 8 year-old children: Teamplay 
Background
Many children spend too much time screen-viewing (watching TV, surfing the internet and playing video games) and do not meet physical activity (PA) guidelines. Parents are important influences on children’s PA and screen-viewing (SV). There is a shortage of parent-focused interventions to change children’s PA and SV.
Methods
Teamplay was a two arm individualized randomized controlled feasibility trial. Participants were parents of 6–8 year old children. Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours. Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA (MVPA) were derived. Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV. Measures were assessed at baseline (time 0) at the end of the intervention (week 8) and 2 months after the intervention had ended (week 16).
Results
There were 75 participants who provided consent and were randomized but 27 participants withdrew post-randomization. Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA. At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA. The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention (time 0 = 76%, time 1 = 39%, time 2 = 50%), while the control group proportion increased slightly (79%, 86% and 87%). Parental weekday TV watching decreased in both groups. In post-study interviews many mothers reported problems associated with wearing the accelerometers. In terms of a future full-scale trial, a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA.
Conclusions
Teamplay is a promising parenting program in an under-researched area. The intervention was acceptable to parents, and all elements of the study protocol were successfully completed. Simple changes to the trial protocol could result in more complete data collection and study engagement.
doi:10.1186/1479-5868-10-31
PMCID: PMC3598924  PMID: 23510646
Parenting; Intervention; Feasibility trial; Physical activity; TV

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