Author: "Malcolm, C" / Topic: medicine - Searchworks@Jio Institute Digital Library Search Results

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1. Induced seismicity and geothermal energy production in the Salton Sea Geothermal Field, California

Author: Malcolm C. A. White and Nori Nakata
Subjects: Geothermal energy, Induced seismicity, Seismic hazards forecasting, Medicine, Science
Abstract: Abstract We analyze the relationship between geothermal energy production and seismic hazards in the Salton Sea Geothermal Field (SSGF) between 1972 and 2022. A clear increase in seismic activity accompanies geothermal energy production and is greatest to the east of the Brawley fault, where the amount of injection exceeds the amount of production. We estimate that, whereas there was a 2% chance of a M6.07 earthquake nucleating inside the SSGF within a fifty-year period prior to energy production (pre-production), there is an equal probability that a M6.70 earthquake nucleates there in a fifty-year period during which historically average energy production conditions persist (syn-production). Similarly, we estimate a 2% chance of a M7.15 and M6.92 occurring in the broader Brawley Seismic Zone (excluding the SSGF) within a fifty-year period during the pre- and syn-production eras, respectively. We find that linear regression models fail to reliably forecast the background seismicity rate as a function of fluid production and injection.
Published: 2025
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2. Obesity and diabetes are major risk factors for epicardial adipose tissue inflammation

Author: Vishal Vyas, Hazel Blythe, Elizabeth G. Wood, Balraj Sandhar, Shah-Jalal Sarker, Damian Balmforth, Shirish G. Ambekar, John Yap, Stephen J. Edmondson, Carmelo Di Salvo, Kit Wong, Neil Roberts, Rakesh Uppal, Ben Adams, Alex Shipolini, Aung Y. Oo, David Lawrence, Shyam Kolvekar, Kulvinder S. Lall, Malcolm C. Finlay, and M. Paula Longhi
Subjects: Cardiology, Inflammation, Medicine
Abstract: BACKGROUND Epicardial adipose tissue (EAT) directly overlies the myocardium, with changes in its morphology and volume associated with myriad cardiovascular and metabolic diseases. However, EAT’s immune structure and cellular characterization remain incompletely described. We aimed to define the immune phenotype of EAT in humans and compare such profiles across lean, obese, and diabetic patients.METHODS We recruited 152 patients undergoing open-chest coronary artery bypass grafting (CABG), valve repair/replacement (VR) surgery, or combined CABG/VR. Patients’ clinical and biochemical data and EAT, subcutaneous adipose tissue (SAT), and preoperative blood samples were collected. Immune cell profiling was evaluated by flow cytometry and complemented by gene expression studies of immune mediators. Bulk RNA-Seq was performed in EAT across metabolic profiles to assess whole-transcriptome changes observed in lean, obese, and diabetic groups.RESULTS Flow cytometry analysis demonstrated EAT was highly enriched in adaptive immune (T and B) cells. Although overweight/obese and diabetic patients had similar EAT cellular profiles to lean control patients, the EAT exhibited significantly (P ≤ 0.01) raised expression of immune mediators, including IL-1, IL-6, TNF-α, and IFN-γ. These changes were not observed in SAT or blood. Neither underlying coronary artery disease nor the presence of hypertension significantly altered the immune profiles observed. Bulk RNA-Seq demonstrated significant alterations in metabolic and inflammatory pathways in the EAT of overweight/obese patients compared with lean controls.CONCLUSION Adaptive immune cells are the predominant immune cell constituent in human EAT and SAT. The presence of underlying cardiometabolic conditions, specifically obesity and diabetes, rather than cardiac disease phenotype appears to alter the inflammatory profile of EAT. Obese states markedly alter EAT metabolic and inflammatory signaling genes, underlining the impact of obesity on the EAT transcriptome profile.FUNDING Barts Charity MGU0413, Abbott, Medical Research Council MR/T008059/1, and British Heart Foundation FS/13/49/30421 and PG/16/79/32419.
Published: 2021
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3. Looking beyond the imaging plane: 3D needle tracking with a linear array ultrasound probe

Author: Wenfeng Xia, Simeon J. West, Malcolm C. Finlay, Jean-Martial Mari, Sebastien Ourselin, Anna L. David, and Adrien E. Desjardins
Subjects: Medicine, Science
Abstract: Abstract Ultrasound is well suited for guiding many minimally invasive procedures, but its use is often precluded by the poor visibility of medical devices. When devices are not visible, they can damage critical structures, with life-threatening complications. Here, we developed the first ultrasound probe that comprises both focused and unfocused transducer elements to provide both 2D B-mode ultrasound imaging and 3D ultrasonic needle tracking. A fibre-optic hydrophone was integrated into a needle to receive Golay-coded transmissions from the probe and these data were processed to obtain tracking images of the needle tip. The measured tracking accuracy in water was better than 0.4 mm in all dimensions. To demonstrate the clinical potential of this system, insertions were performed into the spine and the uterine cavity, in swine and pregnant ovine models in vivo. In both models, the SNR ranged from 13 to 38 at depths of 22 to 38 mm, at out-of-plane distances of 1 to 15 mm, and at insertion angles of 33 to 42 degrees relative to the probe surface normal. This novel ultrasound imaging/tracking probe has strong potential to improve procedural outcomes by providing 3D needle tip locations that are co-registered to ultrasound images, while maintaining compatibility with current clinical workflow.
Published: 2017
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4. High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival

Author: Kunle Odunsi, Usha Menon, Holly R. Harris, Bo Qin, Minh Tung Phung, Sian Fereday, Hoda Anton-Culver, Aleksandra Gentry-Maharaj, Kathryn L. Terry, Celeste Leigh Pearce, Mary Anne Rossing, Elisa V. Bandera, Anna H. Wu, Andrew Berchuck, Harvey A. Risch, Kelly M. Bakulski, Jennifer A. Doherty, Ellen L. Goode, Robert A. Vierkant, Anna deFazio, Keitaro Matsuo, Anne Chase, Brad H. Nelson, Gillian E. Hanley, Renée T. Fortner, Susan J. Ramus, Katharine Brieger, Joellen M. Schildkraut, Kathleen R. Cho, Jean L. Richardson, Paul D. Pharaoh, Karen McLean, Cindy McKinnon Deurloo, Francesmary Modugno, Daniel W. Cramer, Britton Trabert, Bhramar Mukherjee, Malcolm C. Pike, Bronwyn Grout, Kirsten B. Moysich, Nicolas Wentzensen, David D.L. Bowtell, James D. Brenton, Stacey J. Winham, Lilah Khoja, Argyrios Ziogas, Penelope M. Webb, and Marc T. Goodman
Subjects: Oncology, medicine.medical_specialty, Epidemiology, Health Behavior, Endometriosis, Carcinoma, Ovarian Epithelial, Risk Assessment, Article, Internal medicine, Pelvic inflammatory disease, Humans, Medicine, Aged, Proportional Hazards Models, Inflammation, Ovarian Neoplasms, Framingham Risk Score, business.industry, Proportional hazards model, Mortality rate, Middle Aged, medicine.disease, Quartile, Female, business, Ovarian cancer, Body mass index
Abstract: Background: There is suggestive evidence that inflammation is related to ovarian cancer survival. However, more research is needed to identify inflammation-related factors that are associated with ovarian cancer survival and to determine their combined effects. Methods: This analysis used pooled data on 8,147 women with invasive epithelial ovarian cancer from the Ovarian Cancer Association Consortium. The prediagnosis inflammation-related exposures of interest included alcohol use; aspirin use; other nonsteroidal anti-inflammatory drug use; body mass index; environmental tobacco smoke exposure; history of pelvic inflammatory disease, polycystic ovarian syndrome, and endometriosis; menopausal hormone therapy use; physical inactivity; smoking status; and talc use. Using Cox proportional hazards models, the relationship between each exposure and survival was assessed in 50% of the data. A weighted inflammation-related risk score (IRRS) was developed, and its association with survival was assessed using Cox proportional hazards models in the remaining 50% of the data. Results: There was a statistically significant trend of increasing risk of death per quartile of the IRRS [HR = 1.09; 95% confidence interval (CI), 1.03–1.14]. Women in the upper quartile of the IRRS had a 31% higher death rate compared with the lowest quartile (95% CI, 1.11–1.54). Conclusions: A higher prediagnosis IRRS was associated with an increased mortality risk after an ovarian cancer diagnosis. Further investigation is warranted to evaluate whether postdiagnosis exposures are also associated with survival. Impact: Given that pre- and postdiagnosis exposures are often correlated and many are modifiable, our study results can ultimately motivate the development of behavioral recommendations to enhance survival among patients with ovarian cancer.
Published: 2022
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5. Endometriosis and menopausal hormone therapy impact the hysterectomy-ovarian cancer association

Author: Marc T. Goodman, Argyrios Ziogas, Jenny Chang-Claude, Anna H. Wu, Susan J. Jordan, Joellen M. Schildkraut, Minh Tung Phung, Francesmary Modugno, Penelope M. Webb, Daniel W. Cramer, Rachel Palmieri Weber, Andrew Berchuck, Bhramar Mukherjee, Holly R. Harris, Kathleen R. Cho, Hoda Anton-Culver, Harvey A. Risch, Kirsten B. Moysich, Renée T. Fortner, Celeste Leigh Pearce, Gillian E. Hanley, Kathryn L. Terry, Susanne K. Kjaer, Lilah Khoja, Alice W. Lee, Malcolm C. Pike, Allan Jensen, Karen McLean, Aruna Muthukumar, and Jennifer A. Doherty
Subjects: medicine.medical_specialty, Inverse Association, medicine.drug_class, medicine.medical_treatment, Endometriosis, Hysterectomy, Article, medicine, Humans, Ovarian Neoplasms, Gynecology, business.industry, Estrogen Replacement Therapy, Obstetrics and Gynecology, Cancer, Odds ratio, medicine.disease, Oncology, Estrogen, Case-Control Studies, Female, Hormone therapy, Menopause, business, Ovarian cancer
Abstract: Objective To evaluate the association between hysterectomy and ovarian cancer, and to understand how hormone therapy (HT) use and endometriosis affect this association. Methods We conducted a pooled analysis of self-reported data from 11 case-control studies in the Ovarian Cancer Association Consortium (OCAC). Women with (n = 5350) and without ovarian cancer (n = 7544) who never used HT or exclusively used either estrogen-only therapy (ET) or estrogen+progestin therapy (EPT) were included. Risk of invasive epithelial ovarian cancer adjusted for duration of ET and EPT use and stratified on history of endometriosis was determined using odds ratios (ORs) with 95% confidence intervals (CIs). Results Overall and among women without endometriosis, there was a positive association between ovarian cancer risk and hysterectomy (OR = 1.19, 95% CI 1.09-1.31 and OR = 1.20, 95% CI 1.09-1.32, respectively), but no association upon adjusting for duration of ET and EPT use (OR = 1.04, 95% CI 0.94-1.16 and OR = 1.06, 95% CI 0.95-1.18, respectively). Among women with a history of endometriosis, there was a slight inverse association between hysterectomy and ovarian cancer risk (OR = 0.93, 95% CI 0.69-1.26), but this association became stronger and statistically significant after adjusting for duration of ET and EPT use (OR = 0.69, 95% CI 0.48-0.99). Conclusions The hysterectomy-ovarian cancer association is complex and cannot be understood without considering duration of ET and EPT use and history of endometriosis. Failure to take these exposures into account in prior studies casts doubt on their conclusions. Overall, hysterectomy is not risk-reducing for ovarian cancer, however the inverse association among women with endometriosis warrants further investigation.
Published: 2022
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6. Mammographic texture features associated with contralateral breast cancer in the WECARE Study

Author: Tuong L. Nguyen, Gordon P. Watt, John L. Hopper, Charles F. Lynch, Anne S. Reiner, Jennifer D. Brooks, Meghan Woods, Leslie Bernstein, Julia A. Knight, Jonine L. Bernstein, Esther M. John, Christine Lin, Malcolm C. Pike, Xiaolin Liang, and Kathleen E. Malone
Subjects: medicine.medical_specialty, Texture (music), Brief Communication, Predictive markers, Odds, Contralateral breast cancer, Breast cancer, Cancer epidemiology, parasitic diseases, medicine, Pharmacology (medical), Radiology, Nuclear Medicine and imaging, RC254-282, Framingham Risk Score, business.industry, Confounding, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Second primary cancer, medicine.disease, Oncology, Risk factors, Cancer imaging, Radiology, business, Risk assessment
Abstract: To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a “texture risk score” using pre-treatment mammograms in a case–control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01–1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.
Published: 2021

7. Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE)

Author: Sven Mahner, Robertson Mackenzie, Aline Talhouk, Linda E. Kelemen, Gottfried E. Konecny, Jennifer Alsop, Rosalind Glasspool, Chiu-Chen Tseng, Joy Hendley, Dennis J. Slamon, Jennifer A. Doherty, Andrew Berchuck, Anna H. Wu, Anna M. Piskorz, Chen Wang, Cristina Rodríguez-Antona, D.G.H. de Silva, Valerie Rhenius, Peter A. Fasching, Stacey J. Winham, Gary L. Keeney, Teodora Goranova, Joshy George, Jan Lubinski, Michelle J. Henderson, Rex C. Bentley, Jenny Lester, Sabine Behrens, Joellen M. Schildkraut, Michael E. Carney, Timothy Budden, David G. Huntsman, Oleg Oszurek, Michael S. Anglesio, Jacek Gronwald, Ruby Yun-Ju Huang, Martin Köbel, Javier Benitez, Martin Widschwendter, Melissa C. Larson, Raghwa Sharma, Clara Bodelon, Usha Menon, Janusz Menkiszak, Blake Gilks, María Josefa Mosteiro García, Jesús García-Donas, Wafaa Elatre, Scott H. Kaufmann, Paul Haluska, Pamela J. Thompson, Boris Winterhoff, Susan J. Ramus, Louise A. Brinton, Simon A. Gayther, Mary Anne Rossing, Georgia Chenevix-Trench, Hugh Luk, Jolanta Lissowska, Marc T. Goodman, Billy Chen, Beth Y. Karlan, Naveena Singh, Sian Fereday, Mark E. Sherman, Ana Osorio, Lynne R. Wilkens, Maria P. Intermaggio, Brenda Y. Hernandez, Britton Trabert, Esther Herpel, Mercedes Jimenez-Linan, Janine Senz, Geyi Liu, Celeste Leigh Pearce, Samuel C Y Leong, Iain A. McNeish, Isabelle Ray-Coquard, Susana Banerjee, Malcolm C. Pike, Liz-Anne Lewsley, Helen Steed, Honglin Song, Samantha Hinsley, David D.L. Bowtell, James D. Brenton, Holly R. Harris, Tuan Zea Tan, Cezary Cybulski, Alicia Beeghly-Fadiel, A. Toloczko, Nikilyn Nevins, Robert S. Brown, Darren Ennis, Stephanie Chen, Euan A. Stronach, José Palacios, Sandra Orsulic, Anna deFazio, Geoff Macintyre, Kara L. Cushing-Haugen, Mila Volchek, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Ellen L. Goode, Paul D.P. Pharoah, Hanwei Sudderuddin, Stefan Kommoss, Derek S. Chiu, Huei San Leong, Peter Sinn, Catherine J. Kennedy, Chloe Karpinskyj, Alison Brand, Amy Lum, Veronica Chow, Nicolas Wentzensen, Tayyebeh M. Nazeran, Nadia Traficante, Dustin Johnson, Yoke-Eng Chiew, Casey S. Greene, Jennifer M Koziak, Renée T. Fortner, Imperial College Healthcare NHS Trust- BRC Funding, Cancer Research UK, Ovarian Cancer Action, Talhouk, Aline [0000-0001-7760-410X], George, Joshy [0000-0001-8510-8229], Wang, Chen [0000-0003-2638-3081], Tan, Tuan Zea [0000-0001-6624-1593], Behrens, Sabine [0000-0002-9714-104X], Bodelon, Clara [0000-0002-6578-2678], Brinton, Louise [0000-0003-3853-8562], Fortner, Renée T [0000-0002-1426-8505], García-Donas, Jesús [0000-0001-7731-3601], Gentry-Maharaj, Aleksandra [0000-0001-7270-9762], Glasspool, Rosalind [0000-0002-5000-1680], Greene, Casey S [0000-0001-8713-9213], Harris, Holly R [0000-0002-2572-6727], Kaufmann, Scott H [0000-0002-4900-7145], Kennedy, Catherine J [0000-0002-4465-5784], Köbel, Martin [0000-0002-6615-2037], Koziak, Jennifer M [0000-0001-5830-0397], Lissowska, Jolanta [0000-0003-2695-5799], McNeish, Iain A [0000-0002-9387-7586], Menkiszak, Janusz [0000-0001-8279-7196], Hinsley, Samantha [0000-0001-6903-4688], Pike, Malcolm C [0000-0003-4891-1199], Rodriguez-Antona, Cristina [0000-0001-8750-7338], Sinn, Peter [0000-0003-2836-6699], Trabert, Britton [0000-0002-1539-6090], Widschwendter, Martin [0000-0002-7778-8380], Winham, Stacey J [0000-0002-8492-9102], Brenton, James D [0000-0002-5738-6683], Brown, Robert [0000-0001-7960-5755], Chang-Claude, Jenny [0000-0001-8919-1971], deFazio, Anna [0000-0003-0057-4744], Fasching, Peter A [0000-0003-4885-8471], Kelemen, Linda E [0000-0003-4362-9784], Menon, Usha [0000-0003-3708-1732], Pharoah, Paul DP [0000-0001-8494-732X], Ramus, Susan J [0000-0003-0005-7798], Doherty, Jennifer A [0000-0002-1454-8187], Anglesio, Michael S [0000-0003-1639-5003], and Apollo - University of Cambridge Repository
Subjects: 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Neoplasm, Residual, Bevacizumab, 03 medical and health sciences, Ovarian tumor, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Ovarian carcinoma, Internal medicine, medicine, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Stage (cooking), Aged, Ovarian Neoplasms, business.industry, Cystadenoma, Serous, Cancer, Middle Aged, Precision medicine, Omics, medicine.disease, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Neoplasm Grading, Transcriptome, business, Algorithms, medicine.drug
Abstract: Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271
Published: 2020
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8. Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility.

Author: Madalene Earp, Jonathan P Tyrer, Stacey J Winham, Hui-Yi Lin, Ganna Chornokur, Joe Dennis, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Fiona Bruinsma, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Høgdall, Satoyo Hosono, Edwin S Iversen, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Audrey Y Jung, Beth Y Karlan, Melissa Kellar, Lambertus A Kiemeney, Boon Kiong Lim, Susanne K Kjaer, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Shashi Lele, Jenny Lester, Douglas A Levine, Zheng Li, Dong Liang, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, James Paul, Tanja Pejovic, Liisa M Pelttari, Jenny B Permuth, Malcolm C Pike, Elizabeth M Poole, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Ingo B Runnebaum, Iwona K Rzepecka, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston-Campbell, Ingvild L Tangen, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Shelley S Tworoger, Anne M van Altena, Ignace Vergote, Liv Cecilie Vestrheim Thomsen, Robert A Vierkant, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Yin-Ling Woo, Anna H Wu, Xifeng Wu, Yong-Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Alice W Lee, Celeste L Pearce, Andrew Berchuck, Joellen M Schildkraut, Susan J Ramus, Alvaro N A Monteiro, Steven A Narod, Thomas A Sellers, Simon A Gayther, Linda E Kelemen, Georgia Chenevix-Trench, Harvey A Risch, Paul D P Pharoah, Ellen L Goode, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR = 1.33, p = 4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR = 1.07, p = 0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR = 0.90, p = 0.00033; rs927062, OR = 0.94, p = 0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations.
Published: 2018
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9. Pregnancy outcomes and risk of endometrial cancer

Author: Lauren A. Wise, Jennifer A. Doherty, Harvey A. Risch, Sara H. Olson, Louise A. Brinton, Lynne R. Wilkens, Mengmeng Du, Piet A. van den Brandt, Herbert Yu, Diego Serraino, Carlotta Sacerdote, Malcolm C. Pike, Kirsten B. Moysich, Kristin E. Anderson, Fulvio Ricceri, Timothy R. Rebbeck, Stacey Petruzella, Leo J. Schouten, Elisabete Weiderpass, Amanda B. Spurdle, Renhua Na, Rachael Z. Stolzenberg-Solomon, Fabio Levi, Susan J. Jordan, Christine M. Friedenreich, Fabio Parazzini, Anna E. Prizment, Xiao-Ou Shu, Chu Chen, Lingeng Lu, Todd R. Sponholtz, Thomas E. Rohan, Veronica Wendy Setiawan, Anthony B. Miller, Peggy Reynolds, Penelope M. Webb, Britton Trabert, Vittorio Krogh, Julie R. Palmer, Eva Negri, Wanghong Xu, Gretchen L. Gierach, Marc T. Goodman, Susan E. McCann, Immaculata De Vivo, Hans-Olov Adami, Carlo La Vecchia, Anne Zeleniuch-Jacquotte, Nicolas Wentzensen, Linda S. Cook, J. S. Jordan, R. Na, E. Weiderpa, H. O. Adami, K. E. Anderson, P. A. van den Brandt, L. A. Brinton, C. Chen, L. S. Cook, J. A. Doherty, M. Du, C. M. Friedenreich, G. L. Gierach, M. T. Goodman, V. Krogh, F. Levi, L. Lu, A. B. Miller, S. E. McCann, B. K. Moysich, E. Negri, S. H. Olson, S. Petruzella, J. R. Palmer, F. Parazzini, M. C. Pike, A. E. Prizment, T. R. Rebbeck, P. Reynold, F. Ricceri, H. A. Risch, T. E. Rohan, C. Sacerdote, L. J. Schouten, D. Serraino, V. W. Setiawan, X. -O. Shu, T. R. Sponholtz, A. B. Spurdle, R. Z. Stolzenberg-Solomon, B. Trabert, N. Wentzensen, L. R. Wilken, L. A. Wise, H. Yu, C. La Vecchia, I. De Vivo, W. Xu, A. Zeleniuch-Jacquotte, P. M. Webb, Epidemiologie, and RS: GROW - R1 - Prevention
Subjects: Cancer Research, medicine.medical_specialty, miscarriage, induced abortion, Article, Miscarriage, 03 medical and health sciences, 0302 clinical medicine, AGE, Pregnancy, Risk Factors, Epidemiology, medicine, Humans, HORMONE-BINDING GLOBULIN, REPRODUCTIVE FACTORS, sex of offspring, business.industry, Obstetrics, Endometrial cancer, Pregnancy Outcome, endometrial cancer, parity, WOMEN, Odds ratio, PROGESTERONE, medicine.disease, Confidence interval, Endometrial Neoplasms, 3. Good health, ESTROGEN, Pooled analysis, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Cohort, Female, SEX, business
Abstract: A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.
Published: 2021

10. Contribution of thermogenic mechanisms by male and female mice lacking pituitary adenylate cyclase-activating polypeptide in response to cold acclimation

Author: Landon I. Short, Simon S Harris, Malcolm C Hughes, Erik N Schien, Sarah L. Gray, Maeghan A. M. Forster, Daemon L. Cline, Colin J Appleby, and Ekaterina Filatov
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Physiology, Acclimatization, Endocrinology, Diabetes and Metabolism, Adipose tissue, Adenylate kinase, Biology, Cyclase, Mice, 03 medical and health sciences, 0302 clinical medicine, Physiology (medical), Internal medicine, medicine, Cold acclimation, Animals, Endocrine system, Muscle, Skeletal, Mice, Knockout, Sex Characteristics, Thermogenesis, Adaptive Thermogenesis, Cold Temperature, Mice, Inbred C57BL, 030104 developmental biology, Endocrinology, Pituitary Adenylate Cyclase-Activating Polypeptide, Female, Energy Metabolism, 030217 neurology & neurosurgery
Abstract: This manuscript adds to the literature of endocrine regulation of adaptive thermogenesis and energy balance. It specifically describes the role of pituitary adenylate cyclase-activating polypeptide on the regulation of brown adipose tissue via the sympathetic nervous system with a focus on compensatory mechanisms of thermogenesis. We highlight sex-specific differences in energy metabolism.
Published: 2021
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11. Depot-Medroxyprogesterone Acetate Use Is Associated with Decreased Risk of Ovarian Cancer: The Mounting Evidence of a Protective Role of Progestins

Author: Marc T. Goodman, Susan J. Jordan, Kathryn L. Terry, Joellen M. Schildkraut, Kirsten B. Moysich, Jennifer A. Doherty, Penelope M. Webb, Karen McLean, Linda Titus, Anna H. Wu, Holly R. Harris, Alice W. Lee, Malcolm C. Pike, Celeste Leigh Pearce, Andrew Berchuck, Gillian E. Hanley, Minh Tung Phung, Francesmary Modugno, Bhramar Mukherjee, Kathleen R. Cho, and Daniel W. Cramer
Subjects: Adult, 0301 basic medicine, Oncology, Inverse Association, medicine.medical_specialty, Epidemiology, medicine.drug_class, Medroxyprogesterone Acetate, Carcinoma, Ovarian Epithelial, Risk Assessment, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Combined oral contraceptive - use, medicine, Humans, Medroxyprogesterone acetate, Epithelial ovarian cancer, Ovarian Neoplasms, business.industry, Middle Aged, medicine.disease, 030104 developmental biology, Increased risk, Contraceptive use, Contraceptive Agents, Hormonal, Case-Control Studies, 030220 oncology & carcinogenesis, Female, Progestins, Ovarian cancer, business, Progestin, medicine.drug
Abstract: Background: Combined oral contraceptive use is associated with a decreased risk of invasive epithelial ovarian cancer (ovarian cancer). There is suggestive evidence of an inverse association between progestin-only contraceptive use and ovarian cancer risk, but previous studies have been underpowered. Methods: The current study used primary data from 7,977 women with ovarian cancer and 11,820 control women in seven case–control studies from the Ovarian Cancer Association Consortium to evaluate the association between use of depot-medroxyprogesterone acetate (DMPA), an injectable progestin-only contraceptive, and ovarian cancer risk. Logistic models were fit to determine the association between ever use of DMPA and ovarian cancer risk overall and by histotype. A systematic review of the association between DMPA use and ovarian cancer risk was conducted. Results: Ever use of DMPA was associated with a 35% decreased risk of ovarian cancer overall (OR, 0.65; 95% confidence interval, 0.50–0.85). There was a statistically significant trend of decreasing risk with increasing duration of use (Ptrend < 0.001). The systematic review yielded six studies, four of which showed an inverse association and two showed increased risk. Conclusions: DMPA use appears to be associated with a decreased risk of ovarian cancer in a duration-dependent manner based on the preponderance of evidence. Further study of the mechanism through which DMPA use is associated with ovarian cancer is warranted. Impact: The results of this study are of particular interest given the rise in popularity of progestin-releasing intrauterine devices that have a substantially lower progestin dose than that in DMPA, but may have a stronger local effect.
Published: 2021
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12. Menopausal hormone therapy prior to the diagnosis of ovarian cancer is associated with improved survival

Author: Ellen L. Goode, Diether Lambrechts, Usha Menon, Sharon E. Johnatty, Kathryn L. Terry, Kelly M. Bakulski, Mary Anne Rossing, Simon A. Gayther, Gillian E. Hanley, Dale W. Garsed, Katharine Brieger, Harvey A. Risch, Celeste Leigh Pearce, Daniel W. Cramer, Susan J. Ramus, Kathleen R. Cho, Allan Jensen, Karen McLean, Anna deFazio, Holly R. Harris, Francesmary Modugno, Anna H. Wu, Paul D.P. Pharoah, Andrew Berchuck, Aleksandra Gentry-Maharaj, Susanne K. Kjaer, Britton Trabert, David D.L. Bowtell, Renée T. Fortner, Bhramar Mukherjee, Estrid Høgdall, Alice W. Lee, Aliya Alimujiang, Elisa V. Bandera, David G. Huntsman, Malcolm C. Pike, Michael S. Anglesio, Georgia Chenevix-Trench, Hoda Anton-Culver, Kirsten B. Moysich, Roberta B. Ness, Jolanta Kupryjanczyk, Nicolas Wentzensen, Susan J. Jordan, Jean L. Richardson, Hui Shen, Jennifer A. Doherty, Argyrios Ziogas, Penelope M. Webb, Marc T. Goodman, and Siri Peterson
Subjects: 0301 basic medicine, Oncology, PROGNOSIS, Neoplasm, Residual, IMPACT, medicine.medical_treatment, DISEASE, 0302 clinical medicine, Ovarian carcinoma, RISK, Ovarian Neoplasms, Estrogen Replacement Therapy, Hazard ratio, Obstetrics & Gynecology, WOMEN, Obstetrics and Gynecology, Hormone replacement therapy (menopause), Middle Aged, Debulking, Progression-Free Survival, Postmenopause, Survival Rate, 030220 oncology & carcinogenesis, Female, Life Sciences & Biomedicine, medicine.medical_specialty, CARCINOMA, Hormone Replacement Therapy, ESTROGENS, Article, REPLACEMENT THERAPY, 03 medical and health sciences, AGE, Internal medicine, medicine, Humans, Survival rate, Aged, Neoplasm Staging, Proportional Hazards Models, Science & Technology, Proportional hazards model, business.industry, medicine.disease, 030104 developmental biology, Hormone therapy, Progestins, Ovarian cancer, business
Abstract: PURPOSE: Prior studies of menopausal hormone therapy (MHT) and ovarian cancer survival have been limited by lack of hormone regimen detail and insufficient sample sizes. To address these limitations, a comprehensive analysis of 6419 post-menopausal women with pathologically confirmed ovarian carcinoma was conducted to examine the association between MHT use prior to diagnosis and survival. METHODS: Data from 15 studies in the Ovarian Cancer Association Consortium were included. MHT use was examined by type (estrogen-only (ET) or estrogen+progestin (EPT)), duration, and recency of use relative to diagnosis. Cox proportional hazards models were used to estimate the association between hormone therapy use and survival. Logistic regression and mediation analysis was used to explore the relationship between MHT use and residual disease following debulking surgery. RESULTS: Use of ET or EPT for at least five years prior to diagnosis was associated with better ovarian cancer survival (hazard ratio, 0.80; 95% CI, 0.74 to 0.87). Among women with advanced stage, high-grade serous carcinoma, those who used MHT were less likely to have any macroscopic residual disease at the time of primary debulking surgery (p for trend
Published: 2020
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13. Estrogen Plus Progestin Hormone Therapy and Ovarian Cancer

Author: Francesmary Modugno, Bhramar Mukherjee, Celeste Leigh Pearce, Mary Anne Rossing, Aliya Alimujiang, Susanne K. Kjaer, Marc T. Goodman, Penelope M. Webb, Kara L. Cushing-Haugen, Lynda D. Roman, Kathryn L. Terry, Anna H. Wu, Michael E. Carney, Andrew Berchuck, Kirstin B. Moysich, Holly R. Harris, Jennifer A. Doherty, David G. Huntsman, Estrid Høgdall, Alice W. Lee, Malcolm C. Pike, Pamela J. Thompson, Galina Lurie, Daniel O. Stram, Roberta B. Ness, Elisa V. Bandera, Allan Jensen, Daniel W. Cramer, and Ashley Wiensch
Subjects: Oncology, medicine.medical_specialty, endocrine system diseases, Epidemiology, medicine.drug_class, medicine.medical_treatment, Population, Risk Assessment, 01 natural sciences, Article, 010104 statistics & probability, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, 0101 mathematics, Risk factor, education, Ovarian Neoplasms, education.field_of_study, business.industry, Endometrial cancer, Estrogen Replacement Therapy, medicine.disease, Estrogen, Case-Control Studies, Hormonal therapy, Female, Hormone therapy, Ovarian cancer, business, Progestin, hormones, hormone substitutes, and hormone antagonists
Abstract: Background Menopausal estrogen-alone therapy is a risk factor for endometrial and ovarian cancers. When a progestin is included with the estrogen daily (continuous estrogen-progestin combined therapy), there is no increased risk of endometrial cancer. However, the effect of continuous estrogen-progestin combined therapy on risk of ovarian cancer is less clear. Methods We pooled primary data from five population-based case-control studies in the Ovarian Cancer Association Consortium, including 1509 postmenopausal ovarian cancer cases and 2295 postmenopausal controls. Information on previous menopausal hormonal therapy use, as well as ovarian cancer risk factors, was collected using in-person interviews. Logistic regression was used to assess the association between use of continuous estrogen-progestin combined therapy and risk of ovarian cancer by duration and recency of use and disease histotype. Results Ever postmenopausal use of continuous estrogen-progestin combined therapy was not associated with increased risk of ovarian cancer overall (OR = 0.85, 95% CI = 0.72, 1.0). A decreased risk was observed for mucinous ovarian cancer (OR = 0.40, 95% CI = 0.18, 0.91). The other main ovarian cancer histotypes did not show an association (endometrioid: OR = 0.86, 95% CI = 0.57, 1.3, clear cell: OR = 0.68, 95% CI = 0.40, 1.2; serous: OR = 0.98, 95% CI = 0.80, 1.2). Conclusions Given that estrogen-alone therapy has been shown to be associated with increased risk of ovarian cancer, these findings are consistent with the hypothesis that adding a progestin each day ameliorates the carcinogenic effects of estrogen on the cells of origin for all histotypes of ovarian cancer.
Published: 2020
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14. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author: Thomas P. Conrads, Gordana C. Popovic, Lilian van-Wagensveld, Ignace Vergote, Ellen L. Barlow, Annalyn Da-Anoy, Stacey J. Winham, Nicola S. Meagher, Catherine J. Kennedy, Michael Jones, Sabine Heublein, Linda E. Kelemen, Neil Lambie, Paul D.P. Pharoah, Peter Sinn, Claus Høgdall, Sanela Bilic, Alexander Hein, Yovanni Casablanca, Aline Talhouk, Christiani Bisinotto, Chiu-Chen Tseng, Matthias Ruebner, Nhu D Le, Estrid Høgdall, Arndt Hartmann, Malcolm C. Pike, Philipp Harter, Nina Neudeck, Sarah Taylor, Juergen Andress, Anna Fischer, Kunle Odunsi, Naoko Sasamoto, Janine M. Joseph, Marina Pavanello, Derek S. Chiu, Eun Young Kang, Ellen L. Goode, Susan L. Neuhausen, Rhonda Farrell, Stefan Kommoss, Esther Elishaev, Jenny Lester, Yu Yu, Carmel Quinn, Betty Leung, Susan J. Ramus, Jesus Garcia-Donas, Colin J.R. Stewart, Penny Coulson, Joshua Millstein, Adelyn Bolithon, Maria Lycke, Chen Wang, Andreas du Bois, Francesmary Modugno, Alexander B. Olawaiye, Celeste Leigh Pearce, Jessica Boros, G. Larry Maxwell, Constantina Mateoiu, Francisco José Candido dos Reis, Diether Lambrechts, Liselore Loverix, Katrina Tang, Siel Olbrecht, John Lewis Etter, Yee Leung, Kirsten B. Moysich, Katherine LaVigne-Mager, Matthias W. Beckmann, Kathryn L. Terry, Felix K. F. Kommoss, Arantzazu Barquin-Garcia, Monica Yagüe-Fernandez, Sergio Ruiz-Llorente, Helen Steed, M Grube, Michael S Anglesio, Nikilyn Nevins, Sebastian M. Armasu, Mona El-Bahrawy, Beyhan Ataseven, Minouk J. Schoemaker, Annette Staebler, Peter A. Fasching, Gottfried E. Konecny, Terry K. Morgan, Simon A. Gayther, Anna deFazio, Robert A. Vierkant, Martin Köbel, Ramona Erber, Cheng-Han Lee, Paul R. Harnett, Greg Robertson, Linda S Cook, Philip J. Crowe, Daniel W. Cramer, Alison Brand, Yajue Huang, Anusha Hettiaratchi, Florian Heitz, Beth Y. Karlan, Anthony J. Swerdlow, Adeline Tan, Anna H. Wu, Akira Hirasawa, Kate Lawrenson, Karin Sundfeldt, Paul A. Cohen, Robert P. Edwards, and Hugo M. Horlings
Subjects: Oncology, medicine.medical_specialty, medicine.medical_treatment, Proliferation, Article, Pathology and Forensic Medicine, MCM3, Internal medicine, Biomarkers, Tumor, Medicine, Humans, Proliferation Marker, RNA, Messenger, Molecular Biology, Cell Proliferation, Ovarian Neoplasms, Chemotherapy, Taxane, business.industry, Proportional hazards model, Surrogate endpoint, High-grade serous carcinoma, Minichromosome Maintenance Complex Component 3, Cell Biology, General Medicine, Cystadenocarcinoma, Serous, Gene expression profiling, Survival Rate, Serous fluid, Ki-67 Antigen, Immunohistochemistry, Female, business
Abstract: Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan–Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81–0.92, p < 0.0001, N = 1840) in multivariable analysis. MCM3 mRNA expression was highest in the HGSC C5.PRO molecular subtype, although no interaction was observed between MCM3, survival and molecular subtypes. MCM3 and Ki-67 protein levels were significantly lower after exposure to neoadjuvant chemotherapy compared to chemotherapy-naïve tumors: 37.0% versus 46.4% and 22.9% versus 34.2%, respectively. Among chemotherapy-naïve HGSC, high MCM3 protein levels were also associated with significantly longer disease-specific survival (HR = 0.52, 95% CI 0.36–0.74, p = 0.0003, N = 392) compared to cases with low MCM3 protein levels in multivariable analysis. MCM3 immunohistochemistry is a promising surrogate marker of proliferation in HGSC.
Published: 2021
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15. Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Author: Labeau, Sonia O, Afonso, Elsa, Benbenishty, Julie, Blackwood, Bronagh, Boulanger, Carole, Brett, Stephen J, Calvino-Gunther, Silvia, Chaboyer, Wendy, Coyer, Fiona, Deschepper, Mieke, François, Guy, Honore, Patrick M, Jankovic, Radmilo, Khanna, Ashish K, Llaurado-Serra, Mireia, Lin, Frances, Rose, Louise, Rubulotta, Francesca, Saager, Leif, Williams, Ged, Blot, Stijn I, Dritan, Muzha, Antoni Margarit Ribas, Fernando, Lipovesty, Cecilia, Loudet, Fiona, Coyer, Philipp, Eller, Nafseen, Mostafa, Patrick, M Honoré, Vanesa Mercado Telleria, Jasmina, Smajic, Paula Cristina Nogueira, Khalid Mahmood Khan Nafees, Romuald, Hentchoya, Louise, Rose, Javiera, Soledad, Frances, Lin, Yenny, Cardenas, Amylkar Garay Reyes, Alan, Sustic, Meropi, Mpouzika, Tamas, Vymazal, Hanne Irene Jensen, Hernan, Aguirre-Bermeo, Liivi, Maddison, Maija, Valta, Silvia, Calvino-Gunther, Frank, Bloos, Faustina Excel Adipa, Vasilios, Koulouras, Judy, Enamorado, Zsuzsann, Ágoston, Hrönn, Birgisdóttir, Amit, Gupta, Mohan, Gurjar, Bram, Kilapong, Seyed Mohammadreza Hashemian, Ignacio, Martin-Loeches, Julie, Benbenishty, Andrea, Cortegiani, Kelly, Fletcher, Yoshiro, Hayashi, Wangari, Waweru-Siika, Khalid, Abidi, Sang-Min, Lee, Burhan, Hadri, Mihails, Dolgusevs, Fayez François Abillama, Tomas, Jovaisa, Cyril, Thix, Muhammed, Elhadi, Basri Mat Nor, Shanti, Ratnam, Mohd Zulfakar Mazlan, Sundaresan, Maiyalagan, Luis, Sánchez-Hurtado, Adrian, Belii, Mendsaikhan, Naranpurev, Prabha, Gautam, Dylan De Lange, Rachael, Parke, Rose Ekama Ilesanmi, Mirjana, Shosholcheva, Antonija, Petosic, Ranveig, Lind, Madiha Hashmi Ffarcsi, Javier, Bogarin, Aaron Mark Hernandez, Malgorzata, Mikaszewska-Sokolewicz, Bruno, Sousa, Dana, Tomescu, Dorel, Sandesc, Theogene, Twagirumugabe, Vitaly, Gusarov, Maie, Ebaid, Radmilo, Jankovic, Gari, Slobodianiuk, Andrea, Martonova, Rihard, Knafelj, Mervyn, Mer, Emilio, Maseda, Bernardo, Panka, Joerg, C Schefold, Eva, Joelsson-Alm, Konlawij, Trongtrakul, Lorna, Merritt-Charles, Lamia Ouanes Besbes, Yalım, Dikmen, Lesia, Zgrzheblovska, Mark, Fielding, Francesca, Rubulotta, Ashish, K Khanna, Leif, Saager, Ingrid von der Osten, Alban, Greca, Alma, Cani, Nordian, Xhindi, Genci, Hyska, Antonio Margarit Ribas, Susana, Pinto, Paulo, Alves, Romina, Esposito, Emanuel, Valgolio, John Thomas Sanchez Minope, Antonio, Abdala, Maria, Ayala, Silvina, Bravo, Ana, Bantar, Patricia, Delgado, Gustavo, Badariotti, Fernando, Lipovestky, Ana, Diaz, Pablo, Saul, Mariano, Setten, Alejandra, Aucapina, Ysica, Acosta, Victor, Gonzalez, Luis, Camputaro, Fernando, Baccaro, Robert, Villa, Marcela, Mastantuono, Emiliano, Dean, Oscar Fernández Rostello, Patricia, Brizuela, Julio Ricardo Bartoli, Matias, Guereschi, Cristian, Quiroga, Sofia, Putruele, Paula, Villegas, Veronica, Curilen, Ruben, Fernandez, Mariangeles Gabriela Nocheretti, Rosana Gabriela Escalante, Cecilia Inés Loudet, Silvia, Fernandez, Ana Laura Gonzalez, Gustavo Andres Alvarez, Federico, Iglesias, Silvia, Chaparro, Graciela, Zakalik, Gonzalo, Pagella, Matías, Baini, Pierina Arias Campos, Ignacio, Sabbag, Armando, Schmukler, Imelda Perdomo Fonseca, Gonzalo Martín Alvarez, Mario, Ramirez, Fernando, Tapia, Carlos Alejandro Bascary, Graciela Del Valle Gimenez, Fernando Pablo Bertoletti, Esteban, Milioto, Pablo Julio Maldonaldo Bonsignore, Maria Alejandra Fernandez, Julie, Smith, Tim, Chimunda, Lorraine, Thompson, Teena, Maguire, Wendy, Chaboyer, Stacey, Watts, Marion, Mitchell, Madeleine, Powell, India, Lye, Leanne, Parsons, Nerilee, Baker, Claire, Reynolds, Amy, Thompson, Kristy, Masters, Kellie, Sosnowski, Lynette, Morrison, Gavin, D Leslie, Ramanathan, Lakshmanan, Alexis, Tabah, Wendy, Brown, Sharon, McDowell-Skaines, Andrea, Mclucas, Chris, Smith, Mandy, Tallot, Sarah, Jones, Michelle, Barakat-Johnson, Thomas, Leong, Rand, Butcher, Kerrie, Martin, Philipp, Douschan, Dirk von Lewinski, René, Schmutz, Uta, Kolussi, Fatema, Salman, Zainab, Ateya, Koen De Decker, Niels Van Regenmortel, Anita, Jans, Patricia, Wijnands, Stefano, Coremans, Patrick, M Honore, David De Bels, Tanja, Depuydt, Caroline, Paillet, Luc-Marie, Jacquet, Walter, Swinnen, Francis, Hannes, Matthia, Mergeay, Stijn Van de Velde, Silvie, Allaert, Pieter, Hoste, Christophe, Borin, Sandrine, Balon, Vincent, Fraipont, Patrick, Biston, Nicolas De Schryver, Thierry, Dugernier, Ilse Van Cotthem, Angelica Olivetto de Almeida, Silvia Angelica Jorge, Delmiro, Becker, Raysa Cristina Schmidt, Evellyn, Oliveira, Aline, Ramalho, Eliane, Mazocoli, Audrey, Fioretti, Elaine, Barros, Leticia, Serpa, Suzana, Bianchini, Ticiane, Campanili, Taís, Pantaleao, Paulo Carlos Garcia, Ana Lucia Vitti Ronchini, Rayanne, Santos, Nurulhuda Binti, A Manap, Sean, Bagshaw, Dominic, Carney, Jon, Davidow, Ella, Rokosh, Andréa Maria Laizner, Samantha, Smith, Megan, Mcquirter, Betty Star Kampayana, René, Favre, Martin, Sills, Julie, Dallaire, Cathy, Becker, Sherissa, Microys, Bonnie, Bowes, Jennifer, Lajeunesse, Rishi, Ghosh, Jacqueline, Baptiste-Savoie, Rose, Raizman, Gabriel, Suen, Noushin, Taghavi, Orla, Smith, Clare, Fielding, Julieta, Canales, Pia, Molina, Javiera, Chaparro, Maria Idalia Sepulveda, Matias Jesús Flamm Zamorano, Pamela, Rocha, Ximena, Villanueva, Paola, Araya, Meneses, Dayan, Fernando, Avalos, Xiaohan, Li, Liu, Yu, Xinxia, Li, Xiaoyan, Chen, Zhixia, Jiang, Jing, Yang, Jingfang, Chen, Lei, Yang, Kefang, Wang, Jie, Gao, Xiuhua, Fang, Ronghua, Zhao, Xinhua, Xia, Hongmei, Liu, Jing, Li, Haiyan, Wang, Gen, Meng, Yanhong, Di, Damei, Wang, Rong Hua Zhao, Li Ping Hu, Peipei, Xu, Qing Feng Jiao, Hai Yun Wang, Chun Jie Xia, Yan, Liu, Mei, Ye, Yan, Wan, Wenmei, Wang, Yajun, Ding, Aiua, Ren, Yan, Gao, Qi, Li, Guifang, Du, Yanling, Shen, Yanming, Ding, Ning, Li, Cui, Yuan, Lei, Tan, Qiang, Lin, Hailing, Guo, Howe, Yan, Xiao, Xu, Wei, Zhang, Jinxian, Liang, Libing, Zhang, Eryun, Tian, Qian, Zhao, Lin, Insu, Jingwen, Dong, Yanmei, Gu, Ying, Liu, Lina, Zhao, Wei, Wang, Hongmei, Qiao, Lili, Tuo, Mengmeng, Lv, Jin Yu Zhu, Jifen, Zhu, Ying, Wei, Man, Liu, Yin, He, Jiyin, Cheng, Jin, Liu, Jia, Na, Dongfang, Wei, Qing, Li, Xiaoying, Wu, Huan, Duan, Dongliang, Lin, Qiong, Liang, Xiaofang, Luo, Yunfeng, Xiong, Rong Fen Huang, Jing, Fu, Tao, Zan, Man, Ye, Zeya, Shi, Yanfei, Long, Yang, Lei, Xiaodi, Liu, Chen, Yumei, Lingling, Wang, Yali, Zhang, Yan, Xu, Cheng, Wang, Zhijuan, Chengxia, Sun, Jinhui, Song, Yingli, Wang, Xiumei, Liu, Yupeng, Liu, Yuxia, Yuan, Qingping, Huang, Fengling, Yang, Yun, Wu, Xianping, Luo, Xiaowu, Bai, Hong, Zheng, Min, Song, Yue, Sun, Zhangshuangzi, Li, Feifei, Luo, Miao, Liu, Li Chuntang Li, Xinjian, Li, Guiping, Zhang, Lina, Xiao, Tingting, Yu, Guangyuan, Gao, Wei, Wei, Fanglan, Wang, Ting, Han, Tingting, Li, Zeng, Qi, Jing Mei Zeng, Yan, Long, Fuqun, Pan, Jing, Wang, Guoxue, He, Haiyan, Chen, Feifei, Zhang, Chao, Yu, Gao, Chunhua, Xiuying, Yao, Dongmei, Bai, Liu, Lu, Xuelian, Xu, Yan, Wang, Xuejuan, Liang, Zhang, Na, Aizhi, Zhang, Xiaochun, Hu, Hui, Zhang, Ruixia, Wang, Poon Shing Tak, Sung Wai Ho, Qun Xia Jiang, Xinran, Ding, Liu, Hong, Limei, Miao, Zhaoxia, Feng, Liping, Huang, Juan, Wu, Yuping, Wang, Jiye, Guo, Baoke, Zhang, Chaoqun, Ma, Han, Yu, Congcong, Liu, Min, Ding, Linlin, Luan, Jing, Zheng, Shanshan, Lv, Shumin, Jiang, Wenzhen, Cao, Xiujuan, Xue, Guangyan, Liu, Xiyan, Wei, Youru, Jiang, Zhiru, Yao, Gao, Li, Jinhua, Li, Wenwen, Zhao, Mei, Jiang, Junping, Hao, Jing, Zhang, Caiju, Song, Feifei, Chen, Shuhui, Wang, Lili, Hu, Deyan, Cao, Jianhong, Wan, Xiaomin, Wang, Hongyan, Shao, Zhenxia, Zhang, Xia, Cui, Jingyu, Liu, Lijuan, Zhao, Xingguo, Li, Limei, Fan, Ling, Zhang, Min, Yu, Biyan, Li, Chunxia, Li, Ling, Liu, Xuelian, Liu, Wenmin, Chen, Yan, Li, Zhang, Zhigang, Yuchen, Wu, Chenghau, Mu, Guoyan, Zhu, Fan, Yang, Qi, Bo, Ling, Li, Meili, Chen, Jing Hua Jiang, Hai, Yin, Xuelian, Pang, Yue Ying Gong, Shunzhu, Yang, Xiaoli, Yan, Xianhong, Zheng, Dehong, Lei, Lei, Lei, Yinhua, Guo, Lihong, Liu, Jing, Yu, Wei, Sun, Aiping, Bi, Weiwei, Li, Yang, Wu, Ji, Li, Dongshu, Ni, Zijing, Wu, Bing, Song, Qin, Fei, Yang, Xiaoyan, Qiong, Ran, Xixi, Li, Xueping, Jiao, Hua, Ji, Sun, Zhiping, Hong, Ma, Jianhong, Mu, Yanhua, Hao, Yin, Li, Ying, Wang, Caihong, Hui, Wenjie, Ju, Yuxia, Huo, Yuxia, Wang, Lei, Chen, Yan, Yan, Qingli, Zhao, Hongjuan, Chen, Guijun, Bao, Ying, Cao, Hong, Li, Hong, Zhang, Ying, Zhang, Lina, Xu, Jia, Guixiang, Ying, Li, Hui Min Zhao, Xia, Huang, Zhaoxing, Dai, Yanman, Jian, Hongsu, Zhang, Zhixia, Tian, Zu Qing Cao, Miao, Li, Yang, Liu, Fei, Ouyang, Fuying, Ma, Wangyan, Jin, Liuyan, Ge, Shifen, Wu, Weilian, Yuan, Tianfei, Chen, Guanxiu, Shi, Zhihong, Chen, Kewei, Liu, Xue, Lin, Yuemen, Ly, Sun, Lijuan, Xiao Fang Tian, Shuo, Wang, Zhangxia, Feng, Xiaozhe, Liu, Yunchun, Dong, Jundi, Zhang, Nie, Bocui, Guoxian, Wang, Yingjuan, Zhao, Xiaojun, Wu, Qiao, Yang, Rongjun Ling Hu, Xue Qin Li, Zhu Jun Yu, Yanlan, Yao, Xiaoqiong, Deng, Yan, Xiao, Yan, Xie, Yanping, Yang, Huai, Yang, Yuming, Zhou, Zhuqing, Li, Min, Xiao, Yongxia, Yang, Yani, Tian, Luz Marina Silva Gama, Juan Sebastian Hernandez, Nestor, Caicedo, Jorge, Marin, Maria-Elena, Ochoa, Monica, Gomez, José, Rojas-Suarez, Jeniffer, Gonzalez, Amylkar José Garay Reyes, Edwin, Chapeta, Estefania, Orozco, Ina, Filipović-Grčić, Anita, Vuković, Suzana, Pečenković, Aleksandar, Šuput, Gordana, Zivanovic-Posilovic, Armanda, Bozena, Nikolina, Udiljak, Morena, Milic, Renata Curic Radivojevic, Slobodan, Mihaljevic, Marijana, Matas, Dinko, Tonkovic, Hemena, Čuljak, Ivana, Herceg, Gordana, Pavlisa, Milena, Dobric, Tatjana, Beker, Višnja Nesek Adam, Tanja, Goranovic, Chrysanthos, Markoulias, Mina, Mathaios, Maria, Mylordou, Eleni, Achilleos, Pavlina, Kleanthous, Veronika, Kotanidi, Maria, Foka, Iwy, Charalabous, Anna, Alexandrou, Marios, Georgiou, Artemis, Patsalos, Sofia, Zepoy, Constantina, Constantinou, Petr, Piza, Tomas, Vymazal, Elisabeth, Wiborg, Louise, Bruhn, Karin, Kaasby, Karin Rehnholt Pedersen, Sanne, Mikkelsen, Marie, Collet, Anne, Langvad, Hanne, Andresen, Susanne, Fischer, Inger Ebbesen Kjærgård, Britta, Jepsen, Birthe, Husted, Morten, Bestle, Anne Marie Kodal, Tina Charlotte Bitsch Hansen, Anne Sofie Bomholt Pedersen, Tina Damgaar Thomsen, Anisette, Hoegenhaven, Mette, From, Tine Melgaard Frandsen, Grit, Henning, Anja, Hansen, Inger Abildgaard Bliksted, Luis Mario Tamayo, Pedro, Mogrovejo, Carolina, Palaez, Diego Rolando Morocho Tutillo, Cintia Valencia Hurtado, Maria Fernanda García, Diana, Alvarez, Fausto, Guerrero, Alexandra, Vasquez, Martin, Kütimets, Kadri, Tamme, Eneli, Anvelt, Lomangisi, Dlamini-Sserumaga, Carita, Löfqvist, Virpi, Lusenius, Outi, Kauppi, Jenni-Katarina, Sakki, Tarja, Tervo-Heikkinen, Ulla, Kesti, Merja, Merilainen, Elina, Karjula, Minna, Peltomaa, Auli, Palmu, Maarit, Ahtiala, Maija Anniina Valta, Hervé, Mentec, Gaëtan, Plantefève, Guillaume, Besch, Sébastien, Pili-Floury, Stanislas, Ledochowski, Marc Danguy des Déserts, Christophe, Giacardi, Cédric, Daubin, Audrey, Massard, Yann Le Guen, Agnès, Blanc, Simon, Mandaroux, Silvia Calvino Günther, Prune, Avogadro, Anthony, Radavidson, Jean, Turc, Sébastien, Jochmans, Hervé, Quintard, Laetitia, Boyer, Cédric, Bruel, François, Philippart, Philippe, Montravers, Enora, Atchade, Nadine, Flessel, Benoît, Chinardet, Léa, Soulisse, Cindy, Pillard, Delphine, Ngo, Benjamin, Bongiorno, Nathalie, Heitzler, Virginie, Souppart, Nathalie, Gautheret, Jean-Francois, Timsit, Fatiha, Essardy, Muriel, Fartoukh, Daisy, Mehay, Fabienne, Etourneau, Jean-Christophe, Farkas, Pascal, Beuret, Gabriel, Preda, Etienne De Montmollin, Vincent, Castelain, Ulrich, Jaschinski, Monika, Rothenfusser, Detlef, Kindgen-Milles, Thomas, Dimski, Christine, Fiedler, Tobias, Heinicke, Patrick, Meybohm, Tobias, Schulze, Marc, Bota, Sabrina, Pelz, Tobias, Odenthal, Martin, Christ, Kathrin, Bösl, Achilleas, Chovas, Sebastian, Stehr, Philipp, Simon, Sarah, Grotheer, Sebastian, Schüppel, Stefan, Schaller, Lea, Albrecht, Andeas, Stübner, Stephan, Graeser, Nina, Kolbe, Martina, Lausch, Anja, Diers, Ulf, Guenther, Reimer, Riessen, Martin, Roller, Irene Pearl Osei, Anita-Chrysolyte, Kusi-Appiah, Yakubu, H Yakubu, Belinda, Guadi-Gosh, Christos, Dragoumanis, Christos, Christofis, Nikolaos, Kazakos, Styliani, Bastani, Charalampos, Martinos, Vasileios, Bekos, Metaxia, Papanikolaou, Theonymfi, Papavasilopoulou, Anna, Efthymiou, Vasiliki, Chantziara, Anna, Kyriakoudi, Nikolaos, Kakaras, Chrisi, Diakaki, Aikaterini, Flevari, Charikleia, Nikolaou, Kounougeri, Katerina, Lamprini, Avramopoulou, Kyriaki, Tsikritsaki, Georgios, Gkiokas, Eirini, Pantiora, Chrysostomos, Katsenos, Eirini-Chysovalanto, Patsiou, Paraskevi, Alexandropoulou, Ioannis, Koutsodimitropoulos, Epaminontas, Farmakis, Konstantina, Nestora, Marinos, Chatzis, Eumorfia, Kondili, Stella, Soundoulounaki, Ourania, Mousafiri, Dimitra, Lepida, Antonia, Liarmakopoulou, Georgios, Papathanakos, Mrina, Oikonomou, Panagiotis, Ioannides, Dimitrios, Papadopoulos, Ioannis, Staikos, Maria, Stafylaraki, Bogdan, Raitsiou, Konstantinos, Mandis, Ifigenia, Ravani, Styliani, Kourelea, Aikaterini, Efthimiou, Giannoula, Thoma, Apostolos, Bakas, Konstantinos, Psarulis, Souzana, Anisoglou, Eirini, Papageorgiou, Evangelia, Michailidou, Thomai, Tholioti, Athena, Lavrentieva, Evdokia, Sourla, Anastasia, Spyropoulou, Nikolaos, Pantelas, Kristina Mariana Matei Stalika, Ioannis, Georgakas, Antigoni, Karathanou, Syragoula, Tsikriki, Aikaterini, Dimoula, Sofia, Kanakaki, Aristeidis, Vakalos, Konstantinos, Pagioulas, Judy Enamorado Enamorado, Gabor, Nardai, Fatime, Hawchar, Asbjorn, Blondal, Brynja, Rygvadottir, Rannveig, J Jonasdottir, Hrönn, Birgisdottir, Bhagyesh, Shah, Shuchi, Kaushik, Swagata, Tripathy, Mukta, Singh, Sonika, Agarwal, Manish, Gupta, Meraj, Ahmad, Kishore, Mangal, Vaibhav, Bhargava, Vilas, Kushare, Simant, Jha, Lakshay, Bhakhtiani, Manoj, Kamal, Arvind, Baronia, Ade, Susanti, Mayang Indah Lestari, Zulkifli, Zulkifli, Windu, Baskoro, Farid, Zand, Fatemeh, Zarei, Ata, Mahmoodpoor, Farshad, Heidari, Fateme, Jafaraghaee, Aidan, O'Shea, Fiona, O'Shea, Caroline, O'Donnell, Geraldine, Craig, Gerry, Fitzpatrick, Lisa, Dunne, Jennifer, Hastings, Brian, Marsh, Caitriona, Cody, Elizabeth, Campbell, Deirdre, Doyle, Michelle, Pacturanan, Christine, Sheehan, Annette, Carey, Charlotte, Carter, Regina, Mulvey, Damien O'Connell Rosemary Finn, Catherine, Motherway, Amy, Walsh, Jennifer, Kehoe, Shella, Delossantos, Jennifer, Lalor, Siobhan, O'Nuallain, Helena, Behan, Sandra, Mcpherson, Ailesh, Corcoran, Patricia, Gordon, Glenda, Rooney, Dassy, Levy, Mazal, Azencot, Vladimir, Gurevich, Alinoy, Lavy, Valentina, Bendelari, Romina, Marconi, Antonio, Barone, Chiara, Gatti, Andrea, Giampaoletti, Cinzia, Borgognoni, Davide Massimo Ghioldi, Arena, Raimondo, Giacomo, Castiglione, Anna Vita Bruno, Giorgia, Rubulotta, Antonella, Mo, Amalia, Corso, Salvatore, Girianni, Andrea, Bruni, Eugenio, Garofalo, Salvatore Maurizio Maggiore, Alessandro Di Risio, Italo, Calamai, Rosario, Spina, Savino, Spadaro, Carlo Alberto Volta, Antonella, Cotoia, Lucia, Mirabella, Laura, Maulicino, Giancarlo, Abregal, Maria, Donvito, Paolo, D'Ambrosio, Filipo, Binda, Ileana, Adamina, Alessandro, Galazzi, Alessandra, Negro, Rosanna, Vaschetto, Fabio, Capuzzi, Margherita, Boschetto, Lucia, Stivanello, Luciano, Bonaccorso, Chiara, Megna, Pasquale, Iozzo, Antonino, Rizzo, Giovanni, Scire, Maria Rosa Taibi, Francesca Paola Tranello, Antonio, Manzo, Lidia, Traina, Beatrice, Pastore, Attilio, Quaini, Gian Domenico Giusti, Gloria, Montaldi, Federica, Piergentili, Federica, Mancini, Simona, Casaioli, Francesco, Uccelli, Fabio, Guarracino, Adriana, Onelli, Valentina Di Gravio, Maria, Cossu, Oliva, Matrona, Monica, Rocco, Daniela, Alampi, Federica, Dellafiore, Flavia, Ranalli, Matteo, Bossolasco, Elisabetta, Brizio, Pina, Migliorino, Paolo, Cortellazi, Moris, Rosati, Francesco, D'Ambrosio, Catia, Quagliotto, Erik, Roman-Pognuz, Alberto, Peratoner, De Rosa, Silvia, Marina Alessandra Martin, Francesca De Sanctis, Paolo, Ciorba, Patrick, Toppin, Hyacinth, Harding-Goldson, Shunsuke, Taito, Nobuaki, Shime, Ryohey, Yamamoto, Fumiya, Kanda, Akemi, Hirao, Moritoki, Egi, Ayako, Noguchi, Satoru, Hashimoto, Umeda, Aya, Hideaki, Sakuramoto, Akira, Ohuchi, Jun, Kataoka, Kumi, Maruyama, Izumi, Nakayama, Yoshimasa, Nishime, Koji, Fujimoto, Kenji, Takahashi, Mayumi, Tsujimoto, Masako, Shimizu, Eunice, Tole, Malcolm, C Correia, Je Hyeong Kim, Sunghoon, Park, Kyung Chan Kim, Jonghyun, Baek, Jung-Min, Bae, So Young Park, Tai Sun Park, Heung Bum Lee, Seung Yong Park, Jisoo, Park, Lee, Yeon-Joo, Cho, Young-Jae, Sang-Miin, Lee, Kyeongman, Jeon, Seok Chan Kim, Jongmin, Lee, Hyun Keun Chee, Jin Won Huh, Yun Su Sim, Junghyun, Kim, Youjin, Chang, Jong-Joon, Ahn, Byung Ju Kang, Won-Yeon, Lee, Seok Jeong Lee, Nehat, Baftiu, Ivasr, Krastins, Sonia, Stiban, Michel El Feghaly, Elie, Gharios, Marie, Merheb, Mohamed, Benlamin, Ala, Khaled, Wesal Ali Belkhair, Majd, Tabib, Firas, Ashour, Ahmed, Elhadi, Osama Wanees Emhemid Tababa, Taha, Khaled, Soad Imhmed, R Alkhumsi, Abdualhamid, I Alshrif, Ahmed Ali Aboufray, Aya, Alabuzidi, Ahmed Ramadan Triki, Mala, Elgammudi, Hajer Ben Zahra, Enas, Soula, Maram Milud Said Al-Alawi, Hazem, Ahmed, Mohamed Abdurazzag Ali Ghula, Saulius, Vosylius, Lucie, Mouton, Touraj, Rastegar, Claude, Sertznig, Gilles, Martin, Christian, Theisen, Christian, Ferretti, Fränk, Gils, Marc, Gallion, Asmah, Zainudin, Laila Kamaliah Kamalul Bahrin, Shanti Rudra Deva, Azmin Huda Abdul Rahim, Sherliza, Wahab, W Nazaruddin, W Hassan, Wan Nasrudin Wan Ismail, Mohd Nazri Ali, Tien Meng Khoo, Noryani Mohd Samat, Jenny May Geok Tong, Nik Azman Nik Adib, Mohd Basri Mat Nor, Shanthi, Ratnam, Nahla, Ismail, Siti Rohayah Sulaiman, Kit Weng Foong, Anita, Alias, Ngu Pei Hua, Jorge Macias Zermeno, Daniel, Blanco, Karely, Duran, Claudia Lizbeth Lopez Nava, San Juan Roman Nandyelly, Luis Alejandro Sanchez-Hurtado, Brigitte, Tejeda-Huezo, Mario Del Moral Armengol, Luis Pedro Ambriz Nava, Jorge Guerra Herrera, Gilberto Felipe Vazquez de Anda, Humberto, Gallegos-Perez, Nancy, Hernandez-Sanchez, Lucia, Hernandez-Ponce, Luis, Gorordo-Delsol, Marcos, Hernandez-Romero, Saira, Gomez, Fernando, Molinar, Silvio, A Ñamendys-Silva, Juan, P Romero-Gonzalez, Daira, Gonzalez, Antonio, Landaverde, Miguel Ángel Sosa, Berenice, Navarro, José Ivan Rodriguez de Molina Serrano, Sergio Reyes Iburrigarro, Alejandro, Ibarra, Joaquin, Aguirre, Mayra, Martinez-Gonzalez, Nayeli Rocio Cañas Padilla, Ana Alícia Velarde Pineda, Missael Vladimir Espinoza Villafuerte, María Ocotlan Gonzalez Herrera, Battsetseg, Baasanjav, Abdelhamid, Hachimi, Mina, Elkhayari, Tarek, Dendane, Nisha Bhandari Subedi, Sabina Dhakal Pathak, Meena, Manandhar, Laura Van Gulik, Mark Van Den Brink, Peter Van Vliet, Benjamin, Gerretsen, Lettie Van Den Berg, Marina De Haan, Binny, Tuinstra, Paul, Kuijpers, Jennifer, Reijntjens, Jan Wytze Vermeijden, Martin, Rinket, Margijske, Vanroest, Auke, Reidinga, Bert, Loef, Willem, Dieperink, Marisa, Onrust, Tom, Dormans, Laura, Bormans, 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Guillén, Josep Trenado Alvarez, Mercedes Del Cotillo, Jesus Emilio Barrueco-Francioni, Belen Burgos Conde, Maria Pilar Sogues Blanco, Maria Luisa Blasco, Ana Isabel Clement, Clara, Hurtado, Luz Coronado Sanz, David, Perez-Torres, Estefanía, Prol-Silva, Jorge, Pereira, Iván Areán González, Anastasio Espejo Cano, Cesar Rodriguez Nuñez, Inmaculada Lorenzo Fernadez, Alejandra Azahara Marguello Fernandez, Rosa Del Bosque Diez, Badiola, Hilario, Begoña, Zalba-Etayo, Ana, Pascual-Bielsa, Preveen, Banwarie, Dick, Nahar, Alisha van Axel, Naraindath, N Boedjawan, Erika Backlund Jansson, Ann-Sofie, Malvemyr, Lotta, Johansson, Ulla, Sandberg, Catarina, Tingsvik, Gunilla, Mattsson, Gun, Löf, Martin, Spångfors, Mona, Ringdal, Sebastian, Geijer, Lotti, Orvelius, Mia, Hylen, Caroline, Lagerhäll, Eva, Åkerman, Viveca Hamback Hellkvist, Ulrica, Mickelsson, Ewa, Wahlbom, Ing-Marie, Larsson, Ewa, Wallin, Filippo, Boroli, Solenne, Ory, Margaret Lynn Jong, Alexander, Dullenkopf, Martin, Lang, Yvan, Fleury, 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Polgarova, Shaly, George, Ritoo, Kapoor, Ceri, Lynch, Nathalie, Fox, Karen, Cranmer, Natalie, Fox, Thomas, Llewellym, Kelly, Matthews, Louise, Maltby, Jowena, Ibao, Karen, Boulton, Rachel, Jarman, Karen, Baxter, Ashok Sundai Raj, Arif, Moghal, Joanne, White, Suzanne, Barrowcliffe, Mark, Pulletz, Vaarisan, Ganeshalingam, Rosaleen, Baruah, Carole, Boulanger, Helen, Baker, Justin, Woods, Poe Poe Ei, Vongayi, Ogbeide, Paul, Hayden, Jennifer, Hughes, Madhu, Balasubramanian, Armorel, Salberg, Rajnish, Saha, Dagmar, Holmquist, Claire, Derbyshire, Neil, Smith, Elizabeth, Stones, Jane, Ademokun, Monica, Popescu, Maria Schofield Legorburo, Samantha, North, Carole, Brett, Helen, Jaundoo, Jayne, Craig, Simon, Whiteley, Clare, Howcroft, Liz, Wilby, Peter, Delve, David, Shaw, Karen, Williams, Ingeborg, D Welters, Jane, Mcmullen, Stephen, Brett, Leah, Flores, Treiza, Trueman-Dawkins, Mae, Templeton, John, Adams, Catherine, Smith, John, Prowle, Heather, Byers, Andrea, Mcdonnell, Bernd Oliver Rose, Rosie, Reece-Anthony, Luis, Mendes, Marcela, Vizcaychipi, Rhian, Bull, Grace, Lacaden, Eleanor, Santiago, Carlos Castro Delgado, Sarah, Farnell-Ward, Elaine, Thorpe, Justine, Somerville, Anne, Williams, Donna, Cummings, Helen, Derrick, Sarah, Brumwell, Claire, Randell, Nicola, Mccann, Emma, Aves, Gillian, Berry, Tamas, Szakmany, Una, Gunter, Paul, Pulak, Nikki, Sarkar, Kerry, Wright, Vitor, Gomes, Jones, Jo, Ruth, Palfrey, Julie, Camsooksai, Abby, Lewis, Antony, Eneas, Ascanio, Tridente, Louise, Barr, Beverley, Thomas, Emma, Parkin, Daniel, Horner, Christian, Frey, Suzanne, Bench, Rachel, Baumber, Phil, Broadhurst, Matthew, Jackson, Lynne, Williams, Michele, Clark, Jonathan, Paddle, Sarah, Bean, Sarah, Buckley, Christopher, Palfreeman, Sophie, Liu, Nicola, Allison, Ben, Attwood, Penny, Parsons, Victoria, Houghton, Sarah Jane Turner, David, Higgins, Egidija, Bielskute, Nicola, Horrigan, Reni, Jacob, Karen, Habgood, Ahmed, Zaki, Amy, Collins, Jenny, Lord, Charalice, Ramiro, Agnieszka, 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European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators, Muzha, D., Ribas, A.M., Lipovesty, F., Loudet, C., Coyer, F., Eller, P., Mostafa, N., Honoré, P.M., Telleria, V.M., Smajic, J., Nogueira, P.C., Nafees, KMK, Hentchoya, R., Rose, L., Soledad, J., Lin, F., Cardenas, Y., Reyes, A.G., Sustic, A., Mpouzika, M., Vymazal, T., Jensen, H.I., Aguirre-Bermeo, H., Maddison, L., Valta, M., Calvino-Gunther, S., Bloos, F., Adipa, F.E., Koulouras, V., Enamorado, J., Ágoston, Z., Birgisdóttir, H., Gupta, A., Gurjar, M., Kilapong, B., Hashemian, S.M., Martin-Loeches, I., Benbenishty, J., Cortegiani, A., Fletcher, K., Hayashi, Y., Waweru-Siika, W., Abidi, K., Lee, S.M., Hadri, B., Dolgusevs, M., Abillama, F.F., Jovaisa, T., Thix, C., Elhadi, M., Nor, B.M., Ratnam, S., Mazlan, M.Z., Maiyalagan, S., Sánchez-Hurtado, L., Belii, A., Naranpurev, M., Gautam, P., De Lange, D., Parke, R., Ilesanmi, R.E., Shosholcheva, M., Petosic, A., Lind, R., Ffarcsi, M.H., Bogarin, J., Hernandez, A.M., Mikaszewska-Sokolewicz, M., Sousa, B., Tomescu, D., Sandesc, D., Twagirumugabe, T., Gusarov, V., Ebaid, M., Jankovic, R., Slobodianiuk, G., Martonova, A., Knafelj, R., Mer, M., Maseda, E., Panka, B., Schefold, J.C., Joelsson-Alm, E., Trongtrakul, K., Merritt-Charles, L., Besbes, L.O., Dikmen, Y., Zgrzheblovska, L., Fielding, M., Rubulotta, F., Khanna, A.K., Saager, L., von der Osten, I., Greca, A., Cani, A., Xhindi, N., Hyska, G., Pinto, S., Alves, P., Esposito, R., Valgolio, E., Minope, JTS, Abdala, A., Ayala, M., Bravo, S., Bantar, A., Delgado, P., Badariotti, G., Lipovestky, F., Diaz, A., Saul, P., Setten, M., Aucapina, A., Acosta, Y., Gonzalez, V., Camputaro, L., Baccaro, F., Villa, R., Mastantuono, M., Dean, E., Rostello, O.F., Brizuela, P., Bartoli, J.R., Guereschi, M., Quiroga, C., Putruele, S., Villegas, P., Curilen, V., Fernandez, R., Nocheretti, M.G., Escalante, R.G., Loudet, C.I., Fernandez, S., Gonzalez, A.L., Alvarez, G.A., Iglesias, F., Chaparro, S., Zakalik, G., Pagella, G., Baini, M., Campos, P.A., Sabbag, I., Schmukler, A., Fonseca, I.P., Alvarez, G.M., Ramirez, M., Tapia, F., Bascary, C.A., Del Valle Gimenez, G., Bertoletti, F.P., Milioto, E., Bonsignore, PJM, Fernandez, M.A., Smith, J., Chimunda, T., Thompson, L., Maguire, T., Chaboyer, W., Watts, S., Mitchell, M., Powell, M., Lye, I., Parsons, L., Baker, N., Reynolds, C., Thompson, A., Masters, K., Sosnowski, K., Morrison, L., Leslie, G.D., Lakshmanan, R., Tabah, A., Brown, W., McDowell-Skaines, S., McLucas, A., Smith, C., Tallot, M., Jones, S., Barakat-Johnson, M., Leong, T., Butcher, R., Martin, K., Douschan, P., von Lewinski, D., Schmutz, R., Kolussi, U., Salman, F., Ateya, Z., De Decker, K., Van Regenmortel, N., Jans, A., Wijnands, P., Coremans, S., Honore, P.M., De Bels, D., Depuydt, T., Paillet, C., Jacquet, L.M., Swinnen, W., Hannes, F., Mergeay, M., Van de Velde, S., Allaert, S., Hoste, P., Borin, C., Balon, S., Fraipont, V., Biston, P., De Schryver, N., Dugernier, T., Van 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Yuan, C., Tan, L., Lin, Q., Guo, H., Yan, H., Xu, X., Zhang, W., Liang, J., Zhang, L., Tian, E., Zhao, Q., InSu, L., Dong, J., Gu, Y., Zhao, L., Qiao, H., Tuo, L., Lv, M., Zhu, J.Y., Zhu, J., Wei, Y., Liu, M., He, Y., Cheng, J., Liu, J., Jia, N., Wei, D., Wu, X., Duan, H., Lin, D., Liang, Q., Luo, X., Xiong, Y., Huang, R.F., Fu, J., Zan, T., Shi, Z., Long, Y., Lei, Y., Liu, X., Yumei, C., Wang, L., Zhang, Y., Xu, Y., Cheng, X., Zhijuan, W., Sun, C., Song, J., Wang, Y., Yuan, Y., Huang, Q., Yang, F., Wu, Y., Bai, X., Zheng, H., Song, M., Sun, Y., Li, Z., Luo, F., Li, L.C., Zhang, G., Xiao, L., Yu, T., Gao, G., Wei, W., Wang, F., Han, T., Li, T., Zeng, Q., Zeng, J.M., Pan, F., Wang, J., He, G., Chen, H., Zhang, F., Chao, Y., Chunhua, G., Yao, X., Bai, D., Liu, L., Liang, X., Zhang, N., Zhang, A., Hu, X., Zhang, H., Wang, R., Tak, P.S., Ho, S.W., Jiang, Q.X., Ding, X., Hong, L., Miao, L., Feng, Z., Huang, L., Wu, J., Guo, J., Zhang, B., Ma, C., Han, Y., Liu, C., Ding, M., Luan, L., Zheng, J., Lv, S., Jiang, S., Cao, W., Xue, X., Liu, G., Wei, X., Jiang, Y., Yao, Z., Gao, L., Zhao, W., Jiang, M., Hao, J., Zhang, J., Song, C., Chen, F., Wang, S., Hu, L., Cao, D., Wan, J., Wang, X., Shao, H., Zhang, Z., Cui, X., Fan, L., Yu, M., Li, B., Li, C., Chen, W., Li, Y., Zhigang, Z., Yuchen, W., Mu, C., Zhu, G., Bo, Q., Li, L., Chen, M., Jiang, J.H., Yin, H., Pang, X., Gong, Y.Y., Yang, S., Yan, X., Zheng, X., Lei, D., Lei, L., Guo, Y., Yu, J., Sun, W., Bi, A., Li, W., Ni, D., Wu, Z., Song, B., Fei, Q., Xiaoyan, Y., Ran, Q., Xixi, L., Jiao, X., Ji, H., Zhiping, S., Hong, M., Jianhong, M., Hao, Y., Yin, L., Hui, C., Ju, W., Huo, Y., Chen, L., Yan, Y., Bao, G., Cao, Y., Xu, L., Guixiang, J., Zhao, H.M., Huang, X., Dai, Z., Jian, Y., Tian, Z., Cao, Z.Q., Li, M., Ouyang, F., Ma, F., Jin, W., Ge, L., Wu, S., Yuan, W., Chen, T., Shi, G., Chen, Z., Liu, K., Lin, X., Yuemen, L., Lijuan, S., Tian, X.F., Dong, Y., Bocui, N., Wang, G., Zhao, Y., Yang, Q., Hu, R.L., Li, X.Q., Yu, Z.J., Yao, 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D'Ambrosio, F., Quagliotto, C., Roman-Pognuz, E., Peratoner, A., De Rosa, S., Martin, M.A., De Sanctis, F., Ciorba, P., Toppin, P., Harding-Goldson, H., Taito, S., Shime, N., Yamamoto, R., Kanda, F., Hirao, A., Egi, M., Noguchi, A., Hashimoto, S., Aya, U., Sakuramoto, H., Ohuchi, A., Kataoka, J., Maruyama, K., Nakayama, I., Nishime, Y., Fujimoto, K., Takahashi, K., Tsujimoto, M., Shimizu, M., Tole, E., Correia, M.C., Kim, J.H., Park, S., Kim, K.C., Baek, J., Bae, J.M., Park, S.Y., Park, T.S., Lee, H.B., Park, J., Yeon-Joo, L., Young-Jae, C., Jeon, K., Kim, S.C., Lee, J., Chee, H.K., Huh, J.W., Sim, Y.S., Kim, J., Chang, Y., Ahn, J.J., Kang, B.J., Lee, W.Y., Lee, S.J., Baftiu, N., Krastins, I., Stiban, S., Feghaly, M.E., Gharios, E., Merheb, M., Benlamin, M., Khaled, A., Belkhair, W.A., Tabib, M., Ashour, F., Elhadi, A., Tababa, OWE, Khaled, T., Alkhumsi, SIR, Alshrif, A.I., Aboufray, A.A., Alabuzidi, A., Triki, A.R., Elgammudi, M., Zahra, H.B., Soula, E., Al-Alawi, MMS, Ahmed, H., Ghula, MAA, Vosylius, S., Mouton, L., Rastegar, T., Sertznig, C., Martin, G., Theisen, C., Ferretti, C., Gils, F., Gallion, M., Zainudin, A., Bahrin, LKK, Deva, S.R., Rahim, AHA, Wahab, S., Hassan, WNW, Ismail, WNW, Ali, M.N., Khoo, T.M., Samat, N.M., Tong, JMG, Adib, NAN, Nor, MBM, Ismail, N., Sulaiman, S.R., Foong, K.W., Alias, A., Hua, N.P., Zermeno, J.M., Blanco, D., Duran, K., Nava, CLL, Nandyelly, SJR, Sanchez-Hurtado, L.A., Tejeda-Huezo, B., Del Moral Armengol, M., Nava, LPA, Herrera, J.G., de Anda, GFV, Gallegos-Perez, H., Hernandez-Sanchez, N., Hernandez-Ponce, L., Gorordo-Delsol, L., Hernandez-Romero, M., Gomez, S., Molinar, F., Ñamendys-Silva, S.A., Romero-Gonzalez, J.P., Gonzalez, D., Landaverde, A., Sosa, M.Á., Navarro, B., de Molina Serrano, JIR, Iburrigarro, S.R., Ibarra, A., Aguirre, J., Martinez-Gonzalez, M., Padilla, NRC, Pineda, AAV, Villafuerte, MVE, Herrera, MOG, Baasanjav, B., Hachimi, A., Elkhayari, M., Dendane, T., Subedi, N.B., Pathak, S.D., Manandhar, M., Van 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A.S., Goller, S., Afonso, E., Larina, E., Labeau, Sonia O. 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Lee S.J., Baftiu N., Krastins I., Stiban S., Feghaly M.E., Gharios E., Merheb M., Benlamin M., Khaled A., Belkhair W.A., Tabib M., Ashour F., Elhadi A., Tababa O.W.E., Khaled T., Alkhumsi S.I.R., Alshrif A.I., Aboufray A.A., Alabuzidi A., Triki A.R., Elgammudi M., Zahra H.B., Soula E., Al-Alawi M.M.S., Ahmed H., Ghula M.A.A., Vosylius S., Mouton L., Rastegar T., Sertznig C., Martin G., Theisen C., Ferretti C., Gils F., Gallion M., Zainudin A., Bahrin L.K.K., Deva S.R., Rahim A.H.A., Wahab S., Hassan W.N.W., Ismail W.N.W., Ali M.N., Khoo T.M., Samat N.M., Tong J.M.G., Adib N.A.N., Nor M.B.M., Ismail N., Sulaiman S.R., Foong K.W., Alias A., Hua N.P., Zermeno J.M., Blanco D., Duran K., Nava C.L.L., Nandyelly S.J.R., Sanchez-Hurtado L.A., Tejeda-Huezo B., Del Moral Armengol M., Nava L.P.A., Herrera J.G., de Anda G.F.V., Gallegos-Perez H., Hernandez-Sanchez N., Hernandez-Ponce L., Gorordo-Delsol L., Hernandez-Romero M., Gomez S., Molinar F., Namendys-Silva S.A., Romero-Gonzalez J.P., Gonzalez D., Landaverde A., Sosa M.A., Navarro B., de Molina Serrano J.I.R., Iburrigarro S.R., Ibarra A., Aguirre J., Martinez-Gonzalez M., Padilla N.R.C., Pineda A.A.V., Villafuerte M.V.E., Herrera M.O.G., Baasanjav B., Hachimi A., Elkhayari M., Dendane T., Subedi N.B., Pathak S.D., Manandhar M., Van Gulik L., Van Den Brink M., Van Vliet P., Gerretsen B., Van Den Berg L., De Haan M., Tuinstra B., Kuijpers P., Reijntjens J., Vermeijden J.W., Rinket M., Vanroest M., Reidinga A., Loef B., Dieperink W., Onrust M., Dormans T., Bormans L., Koopmans M., Gerritsen R.T., Van Den Elst A., Evers M., Oiting O., Wilting R., Ramaker B., van der Kuil M., Fijen J.-W., Haas L., De Lange D., Haringman J., Newby L., Gilder E., Hacking D., Dagooc R., Song R., Waibel H., Dawn F., Rapley J., Chadwick L., Chapman C., Crone P., Albrett J., Marko P., Goodson J., Browne T., Whitticase R., Davidson C., Judd H., Owens D., Onyeka T., Ugwu I., Ilesanmi R., Adejumo P.O., Owojuyigbe A., Adenekan A., Uba S., Chime C., Jibrin D., Sankey B.J., Adekola O., Olanipekun S., Shosolcheva M., Gievski V., Kartalov A., Naumovski F., Kuzmanovska B., Trposak A., Bogoevska-Miteva Z., Rosalia R., Olsen B.F., Sjobo B., Jensen K.D., Sykehus D., Johansen B.F., Straede E., Johansen E., Finnstrom I.J., Toellefsen A., Ostenjo H., Bjorgen H., Bratsberg B., Kristoffersen E., Skorstad E.M., Hansen S., Vullum S., Lunde G.A., Arntsen W., Lund M., Akselsen G.R., Monstad K.R., Stenset A., Haugom H., Monsen B., Hogvall L., Trudvang S., Galaaen B., Malmin S.K., Andersen M.H., Hargott R.F., Andersen Y., Steffenak E., Nyhus M., Meland B., Hashmi M., Rivas N., Maidana E., de Jesus Ortiz A., Cabral D.M.B., Simi M., Aponte C., Rivas J.C., Gill S., Garcia A., Alvarenga G., Cespedes L., Perez H., Moreira M.L., Canete F., Gonzalez R., Monges N., Coman M., Pederzani M., Franco N., Aganon F., Martinez R., Noblezada-Uy D., Ellazar C.G., Cerezo F.D., Palo J.E., Aperocho C.A.J., Isanan M., Tubacka M., Jasiewicz P., Czuczwar M., Borys M., Gutysz-Wojnicka A., Glinka L., Gawda R., Bilawicz J., Cabrita P., Vieira J., Figueiredo M.F., Pinheiro C.M., Antunes N., Pedro L., Ferreira F., Parente I., Varela M., Fernandes F., Martins C., Viveiros A., Cavaco R., Rita C.S., Dias S., Feranandes A.M., Silva P., Nunes C., Cabral J., Pires F., Ferreira H., Santos J., Pinto V.M.V., Bispo B.M., Ferreira A., Molinos E., Lafuente E., Gregorio R., Costa H., Lima A., Ferreira S., Seromenho V., Luis E., Valerio I., Cesar H., Tavares A., Alsheikhly A.S., Mahmood S., Guran C.T., Moise A., Filipescu D.C., Luchian M., Popescu M., Scutariu M.A., Petrisor C., Hagau N., Grigoras I., Patrichi T., Gusarev V., Pivkina A., Kulakov V., Ignatenko O., Kovaleva J., Zhivotneva T., Zhedaeva M., Matiushkov N., Ershova O., Egorova N., Khoronenko V., Baskakov D., Sergeev D., Piradov M., Grishina L., Magomedov M., Zuev E., Gorokhovatsky U., Leonova A., Fadeeva L., Belskiy V., Galishevskiy D., Zubareva N., Tribulev M., Zueva O., Kiselev A., Kamenshchikov N., Tokareva E., Petrushin M., Starchenko I., Nshimyumuremyi I., Muhizi J., Buregeya E., Nzarora J., Assiri A., Ebaid M.S., Almekhlafi G., Mandourah Y., Velickovic J., Velickovic D., Jovanovic B., Hadzibegovic A., Stefanovic B., Misic V., Bumbasirevic V., Rajkovic M., Stojanovic M., Gavrilovic S., Stanojevic M., Yaghi A., Turcan A., Firment P., Rabarova D., Lancaricova D., Vlaovic J., Groznik M., Lukic M., Perme J., Sostaric M., Umek N., Mirkovic T., Dolenc S., Fister M., Zorko N., Markota A., Yeni N.P., Jali P., Schmollgruber S., Syed M.R., Parag N., Wise R., Galiana M., Navarro J.A., De Pablo A.M., Albert P., Martinez P., Mendiara Y., Garcia B., Llinas A.A., Riveiro M., Gallart E., Riera A., Sanz M., Salo S., Lajara M.A.G., Nieto M.V., Garcia R., Pena J.M.G., Gorgolas M.C., Isasi M.A., Sierra R., Gordo F., Conejo I., Salva-Costa V., Garzon-Tovar C., Lospitao S., Gutierrez P., Girona M., Adamuz J., Olivares P.G., de Ceballos J.P.G., Tirado C., De Wit I., Polo A.B.C., del Mar Diaz Salcedo M., Ripolles-Melchor J., Martinez-Hurtado E., Alvarez J.D., Arcas M.L.B., Gonzalez J.I.T., de la Ventana A.B.S., Calleja P.L.-A., Alvarez R.G., Zamora P.S., Guerrero A.O., Cosano R., Perez-Vacas J., Campos-Perez M., Barreiro E.M., Sanchez L.C., Diaz M.G., Jimenez R., Del Rio Cabajo L., Muriel D.S., Alonso H.F., Fernandez A.W., Pinan I.S., Albaiceta G.M., Fernandez M.C.I., Abos F.J.S., Monedero P., Chueca R.M., Aguirre L.G., Manosa S.C., Luque C.P., Calpe N., Losilla M.R., Fores M.T., Farre O., Fernandez O., del Rosario Villar Redondo M., Arteta Arteta D.S., Sanchez M.A.H., Espinosa C.P., Reyes L.M., Domenech L.C., Guillen C.V., Alvarez J.T., del Cotillo M., Barrueco-Francioni J.E., Conde B.B., Blanco M.P.S., Blasco M.L., Clement A.I., Hurtado C., Sanz L.C., Perez-Torres D., Prol-Silva E., Pereira J., Gonzalez I.A., Cano A.E., Nunez C.R., Fernadez I.L., Fernandez A.A.M., Del Bosque Diez R., Hilario B., Zalba-Etayo B., Pascual-Bielsa A., Banwarie P., Nahar D., van Axel A., Boedjawan N.N., Jansson E.B., Malvemyr A.-S., Johansson L., Sandberg U., Tingsvik C., Mattsson G., Lof G., Spangfors M., Ringdal M., Geijer S., Orvelius L., Hylen M., Lagerhall C., Akerman E., Hellkvist V.H., Mickelsson U., Wahlbom E., Larsson I.-M., Wallin E., Boroli F., Ory S., Jong M.L., Dullenkopf A., Lang M., Fleury Y., Maus M., Ben-Hamouda N., Fishman A., Hsu M.Y., Chang S.C., Trongtratul K., Sawawiboon C., Morakul S., Khwannimit B., Singh K., Ventour D., Figaro-Barclay D., Sankar-Maharaj S., Mebazaa M.S., Kamoun S., Elatrous S., Besbes L., Abroug F., Naija W., Elhechmi Y.Z., Sellami W., Hajjej Z., Merhabene T., Talik I., Kuscu O.O., Dilek O., Zerman A., Dal H.C., Turan S., Aydemir S., Yilmaz H., Calili D.K., Izdes S., Cengiz M., Gumus A., Tasdemir B., Kagnici A., Ay M., Ay S.A., Caliskan G., Akbas T., Balbay A.O., Efe S., Inal V., Elay G., Karabacak P., Ozserezli B., Senturk E., Demirkiran O., Bozbay S., Erdogan E., Akker M., Peker N., Ozgultekin A., Serin S.O., Turan C., Karaoren G., Goksu S., Karakurt S., Arikan H., Gul F., Cinel I., Kara I., Undar H.N., Bayraktar Y.S., Celik J.B., Tokur M.E., Aydin D.T., Yildiz I., Ozcan B., Erdivanli B., Eroglu A., Akdag D., Unlu N., Dungca A., Ali A., Thankamma B., Reyes P.E., John S., Rajendran A., Ahmad F.K.E., Smiley K.A., Hojden S., Miller M.T., Das Sasidharan Nair V., Antonio M.G.S., Qawasmeh K.A., Shawish S.A., Twiggs H., Rosado I., Babych V., Morren F., Young C., Vaughan-Jones N., Harris S., Burns K., Georgiev C., Shayamano R., Kerslake I., Creber P., Vochin A., O'Brien C., Caddell P., Hagan S., Hughes M., Torlinski T., Sherwin J., Kannan S., Markham A., Lebon R., Cupitt J., Cranshaw J., White N., Marriott V., Milner W., Groba C.B., Azoia J., Polgarova P., George S., Kapoor R., Lynch C., Fox N., Cranmer K., Llewellym T., Matthews K., Maltby L., Ibao J., Boulton K., Jarman R., Baxter K., Raj A.S., Moghal A., White J., Barrowcliffe S., Pulletz M., Ganeshalingam V., Baruah R., Baker H., Woods J., Ei P.P., Ogbeide V., Hayden P., Hughes J., Balasubramanian M., Salberg A., Saha R., Holmquist D., Derbyshire C., Smith N., Stones E., Ademokun J., Legorburo M.S., North S., Brett C., Jaundoo H., Craig J., Whiteley S., Howcroft C., Wilby L., Delve P., Shaw D., Williams K., Welters I.D., McMullen J., Brett S., Flores L., Trueman-Dawkins T., Templeton M., Adams J., Prowle J., Byers H., McDonnell A., Rose B.O., Reece-Anthony R., Mendes L., Vizcaychipi M., Bull R., Lacaden G., Santiago E., Delgado C.C., Farnell-Ward S., Thorpe E., Somerville J., Williams A., Cummings D., Derrick H., Brumwell S., Randell C., McCann N., Aves E., Berry G., Szakmany T., Gunter U., Pulak P., Sarkar N., Wright K., Gomes V., Jones J., Palfrey R., Camsooksai J., Lewis A., Eneas A., Tridente A., Barr L., Thomas B., Parkin E., Horner D., Frey C., Bench S., Baumber R., Broadhurst P., Jackson M., Williams L., Clark M., Paddle J., Bean S., Buckley S., Palfreeman C., Liu S., Allison N., Attwood B., Parsons P., Houghton V., Turner S.J., Higgins D., Bielskute E., Horrigan N., Jacob R., Habgood K., Zaki A., Collins A., Lord J., Ramiro C., Kubisz-Pudelko A., Kotze M., Williams H., Iovenko I., Tsarev A., Briva A., Mendez G., Napolitano L., Teig M., Rodriguez G.E., Ben-Jacob T., Potestio C., Eng T., Mahanes D., Khanna A., Duggal A., Nananmori M., Lois M., Karamchandani K., Bealer C., Barefield C., Terry D., Fivecoat P., Idowu O., Cata J., Clesi T., Peterson J., Hatton K., Dhaliwal J., Mueller D., Tao J., Eltorai A.S., Pastores S.M., Remor N., Salazar J., Barkas D., Joffe A., Barnes C., Sona C., Schallom M., Short J., Lorenzo J., Von Der Osten I., Borkowska M., Demarre L., Pleitinckx V., Xing C., Debue A.-S., Goller S., Larina E., Labeau, S. O., Blackwood, B., Brett, S. J., Deschepper, M., Francois, G., Honore, P. M., Khanna, A. K., Williams, G., Blot, S. I., Ribas, A. M., Telleria, V. M., Nogueira, P. C., Nafees, K. M. K., Reyes, A. G., Jensen, H. I., Adipa, F. E., Agoston, Z., Hashemian, S. M., Lee, S. -M., Abillama, F. F., Nor, B. M., Mazlan, M. Z., Sanchez-Hurtado, L., De lange, D., Ilesanmi, R. E., Ffarcsi, M. H., Hernandez, A. M., Schefold, J. C., Besbes, L. O., Minope, J. T. S., Rostello, O. F., Bartoli, J. R., Nocheretti, M. G., Escalante, R. G., Loudet, C. I., Gonzalez, A. L., Alvarez, G. A., Campos, P. A., Fonseca, I. P., Alvarez, G. M., Bascary, C. A., del Valle Gimenez, G., Bertoletti, F. P., Bonsignore, P. J. M., Fernandez, M. A., Leslie, G. D., Mclucas, A., Jacquet, L. -M., de Almeida, A. O., Jorge, S. A., Schmidt, R. C., Garcia, P. C., Ronchini, A. L. V., Manap, N. B. A., Laizner, A. M., Mcquirter, M., Kampayana, B. S., Sepulveda, M. I., Zamorano, M. J. F., Zhao, R. H., Hu, L. P., Jiao, Q. F., Wang, H. 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V., Namendys-Silva, S. A., Romero-Gonzalez, J. P., Sosa, M. A., de Molina Serrano, J. I. R., Iburrigarro, S. R., Padilla, N. R. C., Pineda, A. A. V., Villafuerte, M. V. E., Herrera, M. O. G., Subedi, N. B., Pathak, S. D., Vermeijden, J. W., Gerritsen, R. T., Fijen, J. -W., Adejumo, P. O., Sankey, B. J., Olsen, B. F., Jensen, K. D., Johansen, B. F., Finnstrom, I. J., Skorstad, E. M., Lunde, G. A., Akselsen, G. R., Monstad, K. R., Hogvall, L., Malmin, S. K., Andersen, M. H., Hargott, R. F., de Jesus Ortiz, A., Cabral, D. M. B., Rivas, J. C., Moreira, M. L., Ellazar, C. G., Cerezo, F. D., Palo, J. E., Aperocho, C. A. J., Figueiredo, M. F., Pinheiro, C. M., Rita, C. S., Feranandes, A. M., Pinto, V. M. V., Bispo, B. M., Lima, A., Alsheikhly, A. S., Guran, C. T., Filipescu, D. C., Scutariu, M. A., Ebaid, M. S., Velickovic, D., Rajkovic, M., Stanojevic, M., Turcan, A., Lancaricova, D., Yeni, N. P., Syed, M. R., Navarro, J. A., De Pablo, A. M., Llinas, A. A., Lajara, M. A. G., Nieto, M. V., Pena, J. M. G., Gorgolas, M. C., Isasi, M. A., Salva-Costa, V., Garzon-Tovar, C., Olivares, P. G., de Ceballos, J. P. G., Polo, A. B. C., del Mar Diaz Salcedo, M., Alvarez, J. D., Arcas, M. L. B., Gonzalez, J. I. T., de la Ventana, A. B. S., Calleja, P. L. -A., Alvarez, R. G., Zamora, P. S., Guerrero, A. O., Barreiro, E. M., Sanchez, L. C., Diaz, M. G., Muriel, D. S., Alonso, H. F., Fernandez, A. W., Pinan, I. S., Albaiceta, G. M., Fernandez, M. C. I., Abos, F. J. S., Chueca, R. M., Aguirre, L. G., Manosa, S. C., Luque, C. P., Losilla, M. R., Fores, M. T., del Rosario Villar Redondo, M., Arteta Arteta, D. S., Sanchez, M. A. H., Espinosa, C. P., Reyes, L. M., Domenech, L. C., Guillen, C. V., Alvarez, J. T., del Cotillo, M., Barrueco-Francioni, J. E., Conde, B. B., Blanco, M. P. S., Blasco, M. L., Clement, A. I., Sanz, L. C., Gonzalez, I. A., Cano, A. E., Nunez, C. R., Fernadez, I. L., Fernandez, A. A. M., Boedjawan, N. N., Jansson, E. B., Malvemyr, A. -S., Lof, G., Spangfors, M., Lagerhall, C., Akerman, E., Hellkvist, V. H., Larsson, I. -M., Jong, M. L., Hsu, M. Y., Chang, S. C., Mebazaa, M. S., Elhechmi, Y. Z., Kuscu, O. O., Dal, H. C., Calili, D. K., Izdes, S., Gumus, A., Tasdemir, B., Kagnici, A., Ay, S. A., Balbay, A. O., Ozserezli, B., Senturk, E., Serin, S. O., Gul, F., Cinel, I., Undar, H. N., Bayraktar, Y. S., Celik, J. B., Tokur, M. E., Aydin, D. T., Yildiz, I., Ozcan, B., Akdag, D., Unlu, N., Reyes, P. E., Ahmad, F. K. E., Smiley, K. A., Miller, M. T., Antonio, M. G. S., Qawasmeh, K. A., Shawish, S. A., Groba, C. B., Raj, A. S., Ei, P. P., Legorburo, M. S., Welters, I. D., Mcmullen, J., Mcdonnell, A., Rose, B. O., Delgado, C. C., Mccann, N., Turner, S. J., Rodriguez, G. E., Eltorai, A. S., Pastores, S. M., Demarre, L., and Debue, A. -S.
Subjects: Male, Original, medicine.medical_treatment, artificial, Critical Care and Intensive Care Medicine, Medical and Health Sciences, Pressure ulcer, law.invention, Decubitus epidemiology, ICU, Morbidity, Mortality, Outcome, Pressure injury, Risk factors, Adult, Aged, Hospital Mortality, Humans, Patient Discharge, Prevalence, Risk Factors, Intensive Care Units, Respiration, Artificial, 0302 clinical medicine, decubitus epidemiology, pressure injury, pressure ulcer, outcome, risk factors, morbidity, mortality, law, Medicine and Health Sciences, adults, Medicine, Simplified Acute Physiology Score, icu, ziekenhuissterfte, Immunodeficiency, intensive care, European Society of Intensive Care Medicine (ESICM) Trials Group Collaborators, mannen, volwassenen, COST, Intensive care unit, STATE, ULCERS, Underweight, medicine.symptom, Life Sciences & Biomedicine, Human, medicine.medical_specialty, risicofactoren, Decubitus epidemiology, ICU, Pressure injury, Pressure ulcer, Outcome, Risk factors, Morbidity, Mortality, pressure injuries, Intensive Care Unit, prevalentie, NO, 1117 Public Health and Health Services, DecubICUs Study Team, 03 medical and health sciences, Critical Care Medicine, Anesthesiology, General & Internal Medicine, Health Sciences, ouderen, Mechanical ventilation, Science & Technology, business.industry, decubitus, Risk Factor, 030208 emergency & critical care medicine, 1103 Clinical Sciences, Odds ratio, medicine.disease, Emergency & Critical Care Medicine, Confidence interval, 030228 respiratory system, Emergency medicine, kunstmatige ademhaling, RISK-FACTORS, business, respiration
Abstract: Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, Funder: Flemish Society for Critical Care Nurses, Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score < 19, ICU stay > 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat.
Published: 2021
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16. Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk.

Author: Ganna Chornokur, Hui-Yi Lin, Jonathan P Tyrer, Kate Lawrenson, Joe Dennis, Ernest K Amankwah, Xiaotao Qu, Ya-Yu Tsai, Heather S L Jim, Zhihua Chen, Ann Y Chen, Jennifer Permuth-Wey, Katja K H Aben, Hoda Anton-Culver, Natalia Antonenkova, Fiona Bruinsma, Elisa V Bandera, Yukie T Bean, Matthias W Beckmann, Maria Bisogna, Line Bjorge, Natalia Bogdanova, Louise A Brinton, Angela Brooks-Wilson, Clareann H Bunker, Ralf Butzow, Ian G Campbell, Karen Carty, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Julie M Cunningham, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Andreas du Bois, Evelyn Despierre, Ed Dicks, Jennifer A Doherty, Thilo Dörk, Matthias Dürst, Douglas F Easton, Diana M Eccles, Robert P Edwards, Arif B Ekici, Peter A Fasching, Brooke L Fridley, Yu-Tang Gao, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T Goodman, Jacek Gronwald, Patricia Harrington, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A T Hildebrandt, Peter Hillemanns, Claus K Hogdall, Estrid Hogdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Bu-Tian Ji, Beth Y Karlan, Linda E Kelemen, Mellissa Kellar, Lambertus A Kiemeney, Camilla Krakstad, Susanne K Kjaer, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D Le, Alice W Lee, Shashi Lele, Arto Leminen, Jenny Lester, Douglas A Levine, Dong Liang, Boon Kiong Lim, Jolanta Lissowska, Karen Lu, Jan Lubinski, Lene Lundvall, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R McLaughlin, Iain McNeish, Usha Menon, Roger L Milne, Francesmary Modugno, Kirsten B Moysich, Roberta B Ness, Heli Nevanlinna, Ursula Eilber, Kunle Odunsi, Sara H Olson, Irene Orlow, Sandra Orsulic, Rachel Palmieri Weber, James Paul, Celeste L Pearce, Tanja Pejovic, Liisa M Pelttari, Malcolm C Pike, Elizabeth M Poole, Harvey A Risch, Barry Rosen, Mary Anne Rossing, Joseph H Rothstein, Anja Rudolph, Ingo B Runnebaum, Iwona K Rzepecka, Helga B Salvesen, Eva Schernhammer, Ira Schwaab, Xiao-Ou Shu, Yurii B Shvetsov, Nadeem Siddiqui, Weiva Sieh, Honglin Song, Melissa C Southey, Beata Spiewankiewicz, Lara Sucheston, Soo-Hwang Teo, Kathryn L Terry, Pamela J Thompson, Lotte Thomsen, Ingvild L Tangen, Shelley S Tworoger, Anne M van Altena, Robert A Vierkant, Ignace Vergote, Christine S Walsh, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S Whittemore, Kristine G Wicklund, Lynne R Wilkens, Anna H Wu, Xifeng Wu, Yin-Ling Woo, Hannah Yang, Wei Zheng, Argyrios Ziogas, Hanis N Hasmad, Andrew Berchuck, Georgia Chenevix-Trench, AOCS management group, Edwin S Iversen, Joellen M Schildkraut, Susan J Ramus, Ellen L Goode, Alvaro N A Monteiro, Simon A Gayther, Steven A Narod, Paul D P Pharoah, Thomas A Sellers, and Catherine M Phelan
Subjects: Medicine, Science
Abstract: BACKGROUND:Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. METHODS:In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q
Published: 2015
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17. Brca1 Mutations Enhance Mouse Reproductive Functions by Increasing Responsiveness to Male-Derived Scent.

Author: Ying Liu, Malcolm C Pike, Nancy Wu, Yvonne G Lin, Sara Mucowski, Vasu Punj, Yuan Tang, Hai-Yun Yen, Frank Z Stanczyk, Elena Enbom, Theresa Austria, Martin Widschwendter, Robert Maxson, and Louis Dubeau
Subjects: Medicine, Science
Abstract: We compared the gene expression profiles of ovarian granulosa cells harboring either mutant or wild type Brca1 to follow up on our earlier observation that absence of a functional Brca1 in these important regulators of menstrual/estrous cycle progression leads to prolongation of the pre-ovulatory phase of the estrous cycle and to increased basal levels of circulating estradiol. Here we show that ovarian granulosa cells from mice carrying a conditional Brca1 gene knockout express substantially higher levels of olfactory receptor mRNA than granulosa cells from wild type littermates. This led us to hypothesize that reproductive functions in mutant female mice might be more sensitive to male-derived scent than in wild type female mice. Indeed, it is well established that isolation from males leads to complete cessation of mouse estrous cycle activity while exposure to olfactory receptor ligands present in male urine leads to resumption of such activity. We found that Brca1-/- female mice rendered anovulatory by unisexual isolation resumed ovulatory activity more rapidly than their wild type littermates when exposed to bedding from cages where males had been housed. The prime mediator of this increased responsiveness appears to be the ovary and not olfactory neurons. This conclusion is supported by the fact that wild type mice in which endogenous ovaries had been replaced by Brca1-deficient ovarian transplants responded to male-derived scent more robustly than mutant mice in which ovaries had been replaced by wild type ovarian transplants. Our findings not only have important implications for our understanding of the influence of olfactory signals on reproductive functions, but also provide insights into mechanisms whereby genetic risk factors for breast and extra uterine Müllerian carcinomas may influence menstrual activity in human, which is itself an independent risk factor for these cancers.
Published: 2015
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18. 'I am not a statistic' ovarian cancer survivors’ views of factors that influenced their long-term survival

Author: Anne Chase, Jean L. Richardson, Malcolm C. Pike, Georgia Chenevix-Trench, Celeste Leigh Pearce, Ashley Wiensch, Lilah Khoja, Aliya Alimujiang, and Penelope M. Webb
Subjects: 0301 basic medicine, Gerontology, Michigan, media_common.quotation_subject, New York, Disease, California, Alberta, 03 medical and health sciences, 0302 clinical medicine, Cancer Survivors, Health care, medicine, Humans, Healthy Lifestyle, Meditation, Prospective cohort study, Neoplasm Staging, media_common, Ovarian Neoplasms, business.industry, Social Support, Obstetrics and Gynecology, Cancer, Focus Groups, Middle Aged, medicine.disease, Focus group, humanities, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Female, business, Ovarian cancer, Qualitative research
Abstract: Objective Although a high proportion of women with advanced stage ovarian cancer die within five years, approximately 30% will survive longer than this. The factors contributing to exceptional survival are currently poorly understood. The viewpoints of ovarian cancer survivors were qualitatively explored to determine the factors they felt have influenced their exceptional ovarian cancer survival. Methods Four focus groups, one each in Los Angeles (California), Ann Arbor (Michigan), New York (New York) and Edmonton (Alberta, Canada), were conducted with women who had survived at least five years. Physical activity, diet, meditation, prayer, treatment, complementary medicine, and side effects were explored in semi-structured discussions. The audiotaped sessions were transcribed and coded and then analyzed using Dedoose Version 8.0.35, a qualitative analysis software. Results Of the 26 women who participated, 23 had advanced stage disease. Three overarching themes emerged: (a) survivors had improved their ‘lifestyles’, including but not limited to fitness and diet; (b) survivors were able to draw on strong support systems, which included family, friends, support groups, faith communities, and healthcare workers; and (c) survivors had a strong life purpose, which manifested as positivity, taking charge of their lives, and advocating for themselves. Conclusions Long-term survivors have varying experiences with their cancer, but identified lifestyle modification, motivation and persistence, strong life purpose, and strong support systems as key elements in their better survival. These preliminary findings indicate the need for further prospective studies to determine whether meaningful differences exist between short term and long term survivors on these characteristics.
Published: 2019
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19. Predicting the difficult laparoscopic cholecystectomy: development and validation of a pre-operative risk score using an objective operative difficulty grading system

Author: Nassar, A. H. M., Hodson, J., H. J., Ng, Vohra, R. S., Katbeh, T., Zino, S., Griffiths, E. A., Kirkham, A. J., Pasquali, S., Marriott, P., Johnstone, M., Spreadborough, P., Alderson, D., Fenwick, S., Elmasry, M., Nunes, Q. M., Kennedy, D., Khan, R. B., Khan, M. A. S., Magee, C. J., Jones, S. M., Mason, D., Parappally, C. P., Mathur, P., Saunders, M., Jamel, S., Haque, S. U., Zafar, S., Shiwani, M. H., Samuel, N., Dar, F., Jackson, A., Lovett, B., Dindyal, S., Winter, H., Fletcher, T., Rahman, S., Wheatley, K., Nieto, T., Ayaani, S., Youssef, H., Nijjar, R. S., Watkin, H., Naumann, D., Emesih, S., Sarmah, P. B., Lee, K., Joji, N., Lambert, J., Heath, J., Teasdale, R. L., Weerasinghe, C., Needham, P. J., Welbourn, H., Forster, L., Finch, D., Blazeby, J. M., Robb, W., Mcnair, A. G. K., Hrycaiczuk, A., Charalabopoulos, A., Kadirkamanathan, S., Tang, C. -B., Jayanthi, N. V. G., Noor, N., Dobbins, B., Cockbain, A. J., Nilsen-Nunn, A., de Siqueira, J., Pellen, M., Cowley, J. B., W. -M., Ho, Miu, V., White, T. J., Hodgkins, K. A., Kinghorn, A., Tutton, M. G., Al-Abed, Y. A., Menzies, D., Ahmad, A., Reed, J., Khan, S., Monk, D., Vitone, L. J., Murtaza, G., Joel, A., Brennan, S., Shier, D., Zhang, C., Yoganathan, T., Robinson, S. J., Mccallum, I. J. D., Jones, M. J., Elsayed, M., Tuck, L., Wayman, J., Carney, K., Aroori, S., Hosie, K. B., Kimble, A., Bunting, D. M., Fawole, A. S., Basheer, M., Dave, R. V., Sarveswaran, J., Jones, E., Kendal, C., Tilston, M. P., Gough, M., Wallace, T., Singh, S., Mockford, J. D. K. A., Issa, E., Shah, N., Chauhan, N., Wilson, T. R., Forouzanfar, A., Wild, J. R. L., Nofal, E., Bunnell, C., Madbak, K., Rao, S. T. V., Devoto, L., Siddiqi, N., Khawaja, Z., Hewes, J. C., Gould, L., Chambers, A., Rodriguez, D. U., Sen, G., Robinson, S., Bartlett, F., Rae, D. M., Stevenson, T. E. J., Sarvananthan, K., Dwerryhouse, S. J., Higgs, S. M., Old, O. J., Hardy, T. J., Shah, R., Hornby, S. T., Keogh, K., Frank, L., Al-Akash, M., Upchurch, E. A., Frame, R. J., Hughes, M., Jelley, C., Weaver, S., Roy, S., Sillo, T. O., Galanopoulos, G., Cuming, T., Cunha, P., Tayeh, S., Kaptanis, S., Heshaishi, M., Eisawi, A., Abayomi, M., Ngu, W. S., Fleming, K., Bajwa, D. S., Chitre, V., Aryal, K., Ferris, P., Silva, M., Lammy, S., Mohamed, S., Khawaja, A., Hussain, A., Ghazanfar, M. A., Bellini, M. I., Ebdewi, H., Elshaer, M., Gravante, G., Drake, B., Ogedegbe, A., Mukherjee, D., Arhi, C., Giwa, L., Iqbal, N., Watson, N. F., Aggarwal, S. K., Orchard, P., Villatoro, E., Willson, P. D., Mok, K. W. J., Woodman, T., Deguara, J., Garcea, G., Babu, B. I., Dennison, A. R., Malde, D., Lloyd, D., Satheesan, S., Al-Taan, O., Boddy, A., Slavin, J. P., Jones, R. P., Ballance, L., Gerakopoulos, S., Jambulingam, P., Mansour, S., Sakai, N., Acharya, V., Sadat, M. M., Karim, L., Larkin, D., Amin, K., Khan, A., Law, J., Jamdar, S., Smith, S. R., Sampat, K., O'Shea, K. M., Manu, M., Asprou, F. M., Malik, N. S., Chang, J., Lewis, M., Roberts, G. P., Karavadra, B., Photi, E., Hewes, J., Rodriguez, D., O'Reilly, D. A., Rate, A. J., Sekhar, H., Henderson, L. T., Starmer, B. Z., Coe, P. O., Tolofari, S., Barrie, J., Bashir, G., Sloane, J., Madanipour, S., Halkias, C., Trevatt, A. E. J., Borowski, D. W., Hornsby, J., Courtney, M. J., Virupaksha, S., Seymour, K., Hawkins, H., Bawa, S., Gallagher, P. V., Reid, A., Wood, P., Finch, J. G., Guy Finch, J., Parmar, J., Stirland, E., Gardner-Thorpe, J., Al-Muhktar, A., Peterson, M., Majeed, A., Bajwa, F. M., Martin, J., Choy, A., Tsang, A., Pore, N., Andrew, D. R., Al-Khyatt, W., Taylor, C., Bhandari, S., Subramanium, D., Toh, S. K. C., Carter, N. C., Tate, S., Pearce, B., Wainwright, D., Mercer, S. J., Knight, B., Vijay, V., Alagaratnam, S., Sinha, S., El-Hasani, S. S., Hussain, A. A., Bhattacharya, V., Kansal, N., Fasih, T., Jackson, C., Siddiqui, M. N., Chishti, I. A., Fordham, I. J., Siddiqui, Z., Bausbacher, H., Geogloma, I., Gurung, K., Tsavellas, G., Basynat, P., Shrestha, A. K., Basu, S., Chhabra, A., Harilingam, M., Rabie, M., Akhtar, M., Kumar, P., Jafferbhoy, S. F., Hussain, N., Raza, S., Haque, M., Alam, I., Aseem, R., Patel, S., Asad, M., Booth, M. I., Ball, W. R., Wood, C. P. J., Pinho-Gomes, A. C., Kausar, A., Obeidallah, M. R., Varghase, J., Lodhia, J., Bradley, D., Rengifo, C., Lindsay, D., Gopalswamy, S., Finlay, I., Wardle, S., Bullen, N., Iftikhar, S. Y., Awan, A., Ahmed, J., Leeder, P., Fusai, G., Bond-Smith, G., Psica, A., Puri, Y., Hou, D., Noble, F., Szentpali, K., Broadhurst, J., Date, R., Hossack, M. R., Goh, Y. L., Turner, P., Shetty, V., Riera, M., Macano, C. A. W., Sukha, A., Preston, S. R., Hoban, J. R., Puntis, D. J., Williams, S. V., Krysztopik, R., Kynaston, J., Batt, J., Doe, M., Goscimski, A., Jones, G. H., Hall, C., Carty, N., Panteleimonitis, S., Gunasekera, R. T., Sheel, A. R. G., Lennon, H., Hindley, C., Reddy, M., Kenny, R., Elkheir, N., Mcglone, E. R., Rajaganeshan, R., Hancorn, K., Hargreaves, A., Prasad, R., Longbotham, D. A., Vijayanand, D., Wijetunga, I., Ziprin, P., Nicolay, C. R., Yeldham, G., Read, E., Gossage, J. A., Rolph, R. C., Ebied, H., Phull, M., Khan, M. A., Popplewell, M., Kyriakidis, D., Henley, N., Packer, J. R., Derbyshire, L., Porter, J., Appleton, S., Farouk, M., Basra, M., Jennings, N. A., Ali, S., Kanakala, V., Ali, H., Lane, R., Dickson-Lowe, R., Zarsadias, P., Mirza, D., Puig, S., Al Amari, K., Vijayan, D., Sutcliffe, R., Marudanayagam, R., Hamady, Z., Prasad, A. R., Patel, A., Durkin, D., Kaur, P., Bowen, L., Byrne, J. P., Pearson, K. L., Delisle, T. G., Davies, J., Tomlinson, M. A., Johnpulle, M. A., Slawinski, C., Macdonald, A., Nicholson, J., Newton, K., Mbuvi, J., Farooq, A., Mothe, B. S., Zafrani, Z., Brett, D., Francombe, J., Barnes, J., Cheung, M., Al-Bahrani, A. Z., Preziosi, G., Urbonas, T., Alberts, J., Mallik, M., Patel, K., Segaran, A., Doulias, T., Sufi, P. A., Yao, C., Pollock, S., Manzelli, A., Wajed, S., Kourkulos, M., Pezzuto, R., Wadley, M., Hamilton, E., Jaunoo, S., Padwick, R., Sayegh, M., Newton, R. C., Hebbar, M., Farag, S. F., Spearman, J., Hamdan, M. F., D'Costa, C., Blane, C., Giles, M., Peter, M. B., Hirst, N. A., Hossain, T., Pannu, A., El-Dhuwaib, Y., Morrison, T. E. M., Taylor, G. W., Thompson, R. L. E., Mccune, K., Loughlin, P., Lawther, R., Byrnes, C. K., Simpson, D. J., Mawhinney, A., Warren, C., Mckay, D., Mcilmunn, C., Martin, S., Macartney, M., Diamond, T., Davey, P., Jones, C., Clements, J. M., Digney, R., Chan, W. M., Mccain, S., Gull, S., Janeczko, A., Dorrian, E., Harris, A., Dawson, S., Johnston, D., Mcaree, B., Ghareeb, E., Thomas, G., Connelly, M., Mckenzie, S., Cieplucha, K., Spence, G., Campbell, W., Hooks, G., Bradley, N., Hill, A. D. K., Cassidy, J. T., Boland, M., Burke, P., Nally, D. M., Khogali, E., Shabo, W., Iskandar, E., Mcentee, G. P., O'Neill, M. A., Peirce, C., Lyons, E. M., O'Sullivan, A. W., Thakkar, R., Carroll, P., Ivanovski, I., Balfe, P., Lee, M., Winter, D. C., Kelly, M. E., Hoti, E., Maguire, D., Karunakaran, P., Geoghegan, J. G., Mcdermott, F., Martin, S. T., Cross, K. S., Cooke, F., Zeeshan, S., Murphy, J. O., Mealy, K., Mohan, H. M., Nedujchelyn, Y., Ullah, M. F., Ahmed, I., Giovinazzo, F., Milburn, J., Prince, S., Brooke, E., Buchan, J., Khalil, A. M., Vaughan, E. M., Ramage, M. I., Aldridge, R. C., Gibson, S., Nicholson, G. A., Vass, D. G., Grant, A. J., Holroyd, D. J., Jones, M. A., Sutton, C. M. L. R., O'Dwyer, P., Nilsson, F., Weber, B., Williamson, T. K., Lalla, K., Bryant, A., Carter, C. R., Forrest, C. R., Hunter, D. I., Nassar, A. H., Orizu, M. N., Knight, K., Qandeel, H., Suttie, S., Belding, R., Mcclarey, A., Boyd, A. T., Guthrie, G. J. K., Lim, P. J., Luhmann, A., Watson, A. J. M., Richards, C. H., Nicol, L., Madurska, M., Harrison, E., Boyce, K. M., Roebuck, A., Ferguson, G., Pati, P., Wilson, M. S. J., Dalgaty, F., Fothergill, L., Driscoll, P. J., Mozolowski, K. L., Banwell, V., Bennett, S. P., Rogers, P. N., Skelly, B. L., Rutherford, C. L., Mirza, A. K., Lazim, T., Lim, H. C. C., Duke, D., Ahmed, T., Beasley, W. D., Wilkinson, M. D., Maharaj, G., Malcolm, C., Brown, T. H., Al-Sarireh, B., Shingler, G. M., Mowbray, N., Radwan, R., Morcous, P., Wood, S., Kadhim, A., Stewart, D. J., Baker, A. L., Tanner, N., Shenoy, H., Hafiz, S., De Marchi, J. A., Singh-Ranger, D., Hisham, E., Ainley, P., O'Neill, S., Terrace, J., Napetti, S., Hopwood, B., Rhys, T., Downing, J., Kanavati, O., Coats, M., Aleksandrov, D., Kallaway, C., Yahya, S., Templeton, A., Trotter, M., Lo, C., Dhillon, A., Heywood, N., Aawsaj, Y., Hamdan, A., Reece-Bolton, O., Mcguigan, A., Shahin, Y., Aymon, Luther, A. A., Nicholson, J. A., Rajendran, I., Boal, M., and Ritchie, J.
Subjects: Adult, Male, operative difficulty, medicine.medical_specialty, medicine.medical_treatment, Difficulty grading, difficult cholecystectomy, predictive score, surgery, laparoscopic, cholecystectomy, Surgical planning, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Preoperative Care, Humans, Medicine, Laparoscopic cholecystectomy, Framingham Risk Score, business.industry, General surgery, Reproducibility of Results, Middle Aged, medicine.disease, Pre operative, Single surgeon, Cholecystectomy, Laparoscopic, ROC Curve, 030220 oncology & carcinogenesis, Multivariate Analysis, Cholecystitis, Female, 030211 gastroenterology & hepatology, Surgery, Cholecystectomy, business, Abdominal surgery
Abstract: The prediction of a difficult cholecystectomy has traditionally been based on certain pre-operative clinical and imaging factors. Most of the previous literature reported small patient cohorts and have not used an objective measure of operative difficulty. The aim of this study was to develop a pre-operative score to predict difficult cholecystectomy, as defined by a validated intra-operative difficulty grading scale. Two cohorts from prospectively maintained databases of patients who underwent laparoscopic cholecystectomy were analysed: the CholeS Study (8755 patients) and a single surgeon series (4089 patients). Factors potentially predictive of difficulty were correlated to the Nassar intra-operative difficulty scale. A multivariable binary logistic regression analysis was then used to identify factors that were independently associated with difficult laparoscopic cholecystectomy, defined as operative difficulty grades 3 to 5. The resulting model was then converted to a risk score, and validated on both internal and external datasets. Increasing age and ASA classification, male gender, diagnosis of CBD stone or cholecystitis, thick-walled gallbladders, CBD dilation, use of pre-operative ERCP and non-elective operations were found to be significant independent predictors of difficult cases. A risk score based on these factors returned an area under the ROC curve of 0.789 (95% CI 0.773–0.806, p
Published: 2019
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20. Interval breast cancer risk associations with breast density, family history and breast tissue aging

Author: Mark A. Jenkins, Yun Mi Song, Gillian S. Dite, Laura Baglietto, Malcolm C. Pike, Christopher F. Evans, Ho N. Trinh, Ye Kyaw Aung, Pierre Antoine Dugué, Shuai Li, John L. Hopper, Dallas R. English, Tuong L. Nguyen, Melissa C. Southey, Graham G. Giles, Jennifer Stone, Roger L. Milne, and Joohon Sung
Subjects: Adult, Cancer Research, medicine.medical_specialty, interval breast cancer, Breast Neoplasms, body mass index, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Surveys and Questionnaires, medicine, Humans, Mammography, Family history, Medical History Taking, breast density, skin and connective tissue diseases, Progesterone, Aged, Pike's model of breast tissue aging, family history, medicine.diagnostic_test, Obstetrics, business.industry, Australia, Case-control study, Cancer, Estrogens, Odds ratio, Middle Aged, medicine.disease, Logistic Models, ROC Curve, Oncology, Case-Control Studies, 030220 oncology & carcinogenesis, Relative risk, Female, business, Body mass index, Cancer Epidemiology
Abstract: Interval breast cancers (those diagnosed between recommended mammography screens) generally have poorer outcomes and are more common among women with dense breasts. We aimed to develop a risk model for interval breast cancer. We conducted a nested case–control study within the Melbourne Collaborative Cohort Study involving 168 interval breast cancer patients and 498 matched control subjects. We measured breast density using the CUMULUS software. We recorded first‐degree family history by questionnaire, measured body mass index (BMI) and calculated age‐adjusted breast tissue aging, a novel measure of exposure to estrogen and progesterone based on the Pike model. We fitted conditional logistic regression to estimate odds ratio (OR) or odds ratio per adjusted standard deviation (OPERA) and calculated the area under the receiver operating characteristic curve (AUC). The stronger risk associations were for unadjusted percent breast density (OPERA = 1.99; AUC = 0.66), more so after adjusting for age and BMI (OPERA = 2.26; AUC = 0.70), and for family history (OR = 2.70; AUC = 0.56). When the latter two factors and their multiplicative interactions with age‐adjusted breast tissue aging (p = 0.01 and 0.02, respectively) were fitted, the AUC was 0.73 (95% CI 0.69–0.77), equivalent to a ninefold interquartile risk ratio. In summary, compared with using dense breasts alone, risk discrimination for interval breast cancers could be doubled by instead using breast density, BMI, family history and hormonal exposure. This would also give women with dense breasts, and their physicians, more information about the major consequence of having dense breasts—an increased risk of developing an interval breast cancer., What's new? Breast cancers that are detected between regular screening intervals are more aggressive and have poorer outcomes than screen‐detected tumors but no valid risk model exists to predict “interval” breast cancers. Here the authors combined breast density with other breast cancer risk factors such as body mass index, family history and a novel measure of age‐adjusted hormonal exposure. Applying this to more than 150 women with interval breast cancer, they find that risk discrimination can be doubled with the combination of factors as compared with just using breast density alone, thus improving risk predictions and clinical recommendations for breast screening procedures.
Published: 2019
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21. Performance of Dual-Energy Contrast-enhanced Digital Mammography for Screening Women at Increased Risk of Breast Cancer

Author: Donna D’Alessio, Lizza Lebron, Elizabeth A. Morris, Malcolm C. Pike, Janice S. Sung, Delia M. Keating, Christopher Comstock, Miranda Ayhan, Carol H. Lee, Maxine S. Jochelson, and Chaya S. Moskowitz
Subjects: Adult, Risk, Oncology, medicine.medical_specialty, Digital mammography, Contrast Media, Breast Neoplasms, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Radiography, Dual-Energy Scanned Projection, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Internal medicine, medicine, Contrast Enhanced Digital Mammography, Humans, Mammography, Radiology, Nuclear Medicine and imaging, Breast, Original Research, Aged, Retrospective Studies, Aged, 80 and over, medicine.diagnostic_test, Dual energy, business.industry, Reproducibility of Results, Middle Aged, medicine.disease, Radiographic Image Enhancement, Editorial Commentary, Increased risk, 030220 oncology & carcinogenesis, Female, business, human activities
Abstract: BACKGROUND: Contrast agent–enhanced digital mammography (CEDM) has been shown to be more sensitive and specific than two-dimensional full-field digital mammography in the diagnostic setting. Few studies have reported on its performance in the screening setting. PURPOSE: To evaluate the performance of CEDM for breast cancer screening. MATERIALS AND METHODS: This retrospective study included women who underwent dual-energy CEDM for breast cancer screening from December 2012 through April 2016. Medical records were reviewed for age, risk factors, short-interval follow-up and biopsies recommended, and cancers detected. Sensitivity, specificity, positive predictive value of abnormal findings at screening (PPV(1)), positive predictive value of biopsy performed (PPV(3)), and negative predictive value were determined. RESULTS: In the study period 904 baseline CEDMs were performed. Mean age was 51.8 years ± 9.4 (standard deviation). Of 904 patients, 700 (77.4%) had dense breasts, 247 (27.3%) had a family history of breast cancer in a first-degree relative age 50 years or younger, and 363 (40.2%) a personal history of breast cancer. The final Breast Imaging Reporting and Data System score was 1 or 2 in 832 of 904 (92.0%) patients, score of 3 in 25 of 904 (2.8%) patients, and score of 4 or 5 in 47 of 904 (5.2%) patients. By using CEDM, 15 cancers were diagnosed in 14 of 904 women (cancer detection rate, 15.5 of 1000). PPV(3) was 29.4% (15 of 51). At least 1-year follow up was available in 858 women. There were two interval cancers. Sensitivity was 50.0% (eight of 16; 95% confidence interval [CI]: 24.7%, 75.3%) on the low-energy images compared with 87.5% (14 of 16; 95% CI: 61.7%, 98.4%) for the entire study (low-energy and iodine images; P = .03). Specificity was 93.7% (789 of 842; 95% CI: 91.8%, 95.2%); PPV(1) was 20.9% (14 of 67; 95% CI: 11.9%, 32.6%), and negative predictive value was 99.7% (789 of 791; 95% CI: 99.09%, 99.97%). CONCLUSION: Contrast-enhanced digital mammography is a promising technique for screening women with higher-than-average risk for breast cancer. © RSNA, 2019
Published: 2019
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22. Going to extremes: determinants of extraordinary response and survival in patients with cancer

Author: Paul D.P. Pharoah, Alan Herschtal, Anna deFazio, Susan J. Ramus, Ellen L. Goode, Sian Fereday, Flurina Saner, Dale W. Garsed, Ahwan Pandey, Stephanie Lheureux, David D.L. Bowtell, Malcolm C. Pike, Brad H. Nelson, Jessica A. Beach, Andrew Berchuck, and Celeste Leigh Pearce
Subjects: Treatment response, medicine.medical_specialty, Future studies, Accrual, General Mathematics, Disease, Article, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Cancer Survivors, Neoplasms, medicine, Humans, In patient, Intensive care medicine, Survival analysis, business.industry, Applied Mathematics, Clinical study design, Cancer, medicine.disease, Survival Analysis, Treatment Outcome, 030220 oncology & carcinogenesis, Mutation, business
Abstract: Research into factors affecting treatment response or survival in patients with cancer frequently involves cohorts that span the most common range of clinical outcomes, as such patients are most readily available for study. However, attention has turned to highly unusual patients who have exceptionally favourable or atypically poor responses to treatment and/or overall survival, with the expectation that patients at the extremes may provide insights that could ultimately improve the outcome of individuals with more typical disease trajectories. While clinicians can often recount surprising patients whose clinical journey was very unusual, given known clinical characteristics and prognostic indicators, there is a lack of consensus among researchers on how best to define exceptional patients and little has been proposed for the optimal design of studies to identify factors that dictate unusual outcome. In this Opinion article, we review different approaches to identifying exceptional patients with cancer, and possible study designs to investigate extraordinary clinical outcomes. We discuss pitfalls with finding these rare patients, including challenges associated with accrual of patients across different treatment centres and time periods. We describe recent molecular and immunological factors that have been identified as contributing to unusual patient outcome, and make recommendations for future studies on these intriguing patients.
Published: 2019
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23. Genetic Data from Nearly 63,000 Women of European Descent Predicts DNA Methylation Biomarkers and Epithelial Ovarian Cancer Risk

Author: Usha Menon, Ralf Bützow, Siddhartha Kar, Jonathan Tyrer, Francesmary Modugno, Ellen L. Goode, Diana Eccles, Cristina Rodríguez-Antona, Renée T. Fortner, Linda E. Kelemen, Elio Riboli, Javier Benitez, Taymaa May, Kexin Chen, David G. Huntsman, Susana Banerjee, Penelope M. Webb, Rosalind Glasspool, Hoda Anton-Culver, Andrew Berchuck, Emily White, Thilo Dörk, Lang Wu, Douglas A. Levine, Heli Nevanlinna, Anita Koushik, Joe Dennis, Veronica Wendy Setiawan, Walter C. Willett, Yingchang Lu, Håkan Olsson, Nicolas Wentzensen, Kang Shan, Holly R. Harris, N. Charlotte Onland-Moret, Claus Høgdall, Jennifer A. Doherty, Fei Ye, Yaohua Yang, Qiuyin Cai, Linda S. Cook, Jacek Gronwald, Keitaro Matsuo, Joellen M. Schildkraut, James D. Brenton, Isabelle Romieu, Shelley S. Tworoger, Anna H. Wu, Alvaro N.A. Monteiro, Roberta B. Ness, Paul D.P. Pharoah, James Paul, Alicia Beeghly-Fadiel, Wei Zheng, Lambertus A. Kiemeney, Rebecca Sutphen, Thomas A. Sellers, Michelle A.T. Hildebrandt, Yin Ling Woo, Simon A. Gayther, Meir J. Stampfer, Diether Lambrechts, Marc T. Goodman, Weiva Sieh, Line Bjørge, Lukasz Szafron, Leon F.A.G. Massuger, Daniel W. Cramer, Bingshan Li, Susan J. Ramus, Nadeem Siddiqui, Dale P. Sandler, Jirong Long, Peter A. Fasching, Tanja Pejovic, Drakoulis Yannoukakos, Florian Heitz, Beth Y. Karlan, Estrid Høgdall, Malcolm C. Pike, Anthony J. Swerdlow, Georgia Chenevix-Trench, Catherine M. Phelan, Xiang Shu, Digna R. Velez Edwards, Celeste Leigh Pearce, Sue K. Park, Patricia G. Moorman, Soo-Hwang Teo, Nhu D. Le, Susanne K. Kjaer, Kirsten B. Moysich, Graham G. Giles, Alicja Wolk, Iain A. McNeish, Xiao-Ou Shu, Jenny Chang-Claude, L Yan, Anna deFazio, Ian G. Campbell, HUSLAB, Department of Pathology, Medicum, HUS Gynecology and Obstetrics, Department of Obstetrics and Gynecology, and Clinicum
Subjects: 0301 basic medicine, Cancer Research, endocrine system diseases, Medizin, PROTEIN, Genome-wide association study, Carcinoma, Ovarian Epithelial, VARIANTS, THERAPY, DISEASE, Cohort Studies, Models, Ovarian Epithelial, MAPT, WIDE ASSOCIATION, GWAS, 2.1 Biological and endogenous factors, Aetiology, Cancer, Ovarian Neoplasms, Regulation of gene expression, Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Tumor, Methylation, female genital diseases and pregnancy complications, Ovarian Cancer, 3. Good health, Oncology, CpG site, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], DNA methylation, Female, Life Sciences & Biomedicine, Risk, SUSCEPTIBILITY LOCI, 3122 Cancers, Oncology and Carcinogenesis, Biology, Article, White People, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Rare Diseases, Genetic, Predictive Value of Tests, Clinical Research, Genetic model, Biomarkers, Tumor, Genetics, medicine, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Epigenetics, Science & Technology, Models, Genetic, IDENTIFICATION, Prevention, Carcinoma, Human Genome, DNA Methylation, medicine.disease, 030104 developmental biology, TISSUE, Cancer research, Women's Health, 1112 Oncology And Carcinogenesis, Biomarkers
Abstract: DNA methylation is instrumental for gene regulation. Global changes in the epigenetic landscape have been recognized as a hallmark of cancer. However, the role of DNA methylation in epithelial ovarian cancer (EOC) remains unclear. In this study, high-density genetic and DNA methylation data in white blood cells from the Framingham Heart Study (N = 1,595) were used to build genetic models to predict DNA methylation levels. These prediction models were then applied to the summary statistics of a genome-wide association study (GWAS) of ovarian cancer including 22,406 EOC cases and 40,941 controls to investigate genetically predicted DNA methylation levels in association with EOC risk. Among 62,938 CpG sites investigated, genetically predicted methylation levels at 89 CpG were significantly associated with EOC risk at a Bonferroni-corrected threshold of P < 7.94 × 10−7. Of them, 87 were located at GWAS-identified EOC susceptibility regions and two resided in a genomic region not previously reported to be associated with EOC risk. Integrative analyses of genetic, methylation, and gene expression data identified consistent directions of associations across 12 CpG, five genes, and EOC risk, suggesting that methylation at these 12 CpG may influence EOC risk by regulating expression of these five genes, namely MAPT, HOXB3, ABHD8, ARHGAP27, and SKAP1. We identified novel DNA methylation markers associated with EOC risk and propose that methylation at multiple CpG may affect EOC risk via regulation of gene expression. Significance: Identification of novel DNA methylation markers associated with EOC risk suggests that methylation at multiple CpG may affect EOC risk through regulation of gene expression.
Published: 2019
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24. Cardiovascular medications and survival in people with ovarian cancer: A population-based cohort study from British Columbia, Canada

Author: Paramdeep Kaur, Malcolm C. Pike, Kathryn L. Terry, C. Leigh Pearce, Cindy McKinnon Deurloo, Penelope M. Webb, Andrew Berchuck, Gillian E. Hanley, Anne Chase, Jean L. Richardson, and Bronwyn Grout
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, Statin, medicine.drug_class, Population, Adrenergic beta-Antagonists, Carcinoma, Ovarian Epithelial, Drug Prescriptions, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Internal medicine, medicine, Humans, education, Aged, Retrospective Studies, Ovarian Neoplasms, education.field_of_study, British Columbia, Proportional hazards model, business.industry, Hazard ratio, Obstetrics and Gynecology, Middle Aged, medicine.disease, Survival Analysis, 3. Good health, Serous fluid, 030104 developmental biology, Cardiovascular Diseases, 030220 oncology & carcinogenesis, Cohort, Female, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ovarian cancer, business, Administrative Claims, Healthcare, Follow-Up Studies
Abstract: Objectives Research examining survival among people with ovarian cancer following use of statins or β-blockers has been conflicting. Many studies to date have suffered from immortal time bias and/or had limited power. To address these limitations, we used time-dependent analyses to study the association between statin or β-blocker use among all people diagnosed with an epithelial ovarian cancer in British Columbia, Canada between 1997 and 2015. Methods Population-based administrative data were linked for 4207 people with ovarian cancer. Statin or β-blocker use was examined using time-dependent variables for any use, cumulative duration of use and by user-group according to whether use was initiated before or after their ovarian cancer diagnosis. Cox proportional hazards models were run to estimate the association between statin or β-blocker use and survival. Results Any postdiagnosis use of statins was associated with better ovarian cancer survival in the full cohort (adjusted hazard ratio (aHR) = 0.76, 95% CI 0.64, 0.89) and among women with serous cancers (aHR = 0.80, 95%CI 0.67–0.96). This was primarily driven by new use post-diagnosis (aHR = 0.67, 95%CI, 0.51-0.89), but there was a trend towards better survival among those who continued use from before diagnosis (aHR 0.83, 95%CI, 0.68-1.00). There was no statistically significant association between β-blocker use and survival. Conclusion Postdiagnosis statin use was associated with improved survival among people with ovarian cancer. Given the consistency of this finding in the literature, we recommend a randomized clinical trial of statin use in people with ovarian cancer.
Published: 2021

25. Development and Validation of a Breast Cancer Risk Prediction Model for Childhood Cancer Survivors Treated With Chest Radiation: A Report From the Childhood Cancer Survivor Study and the Dutch Hodgkin Late Effects and LATER Cohorts

Author: Danielle Novetsky Friedman, Flora E. van Leeuwen, Cécile M. Ronckers, Leslie L. Robison, Berthe M.P. Aleman, Chaya S. Moskowitz, Joanne F. Chou, Tara O. Henderson, Susan A. Smith, Cecile P.M. Janus, Joseph P. Neglia, Simone de Vries, Dana Barnea, Colin B. Begg, Suzanne L. Wolden, Birgitta Versluys, Helena J H van der Pal, Judith L. Kok, Gregory T. Armstrong, Wendy M. Leisenring, Charles A. Sklar, Michael Arnold, Lucie M. Turcotte, Rebecca M. Howell, Michael Schaapveld, Malcolm C. Pike, Kevin C. Oeffinger, and Leontien C. M. Kremer
Subjects: Oncology, Adult, Cancer Research, medicine.medical_specialty, Neoplasms, Radiation-Induced, Childhood cancer, MEDLINE, Breast Neoplasms, Childhood Cancer Survivor Study, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Cancer Survivors, Risk Factors, Internal medicine, medicine, Humans, 030212 general & internal medicine, business.industry, ORIGINAL REPORTS, Middle Aged, medicine.disease, 030220 oncology & carcinogenesis, Female, business
Abstract: PURPOSE Women treated with chest radiation for childhood cancer have one of the highest risks of breast cancer. Models producing personalized breast cancer risk estimates applicable to this population do not exist. We sought to develop and validate a breast cancer risk prediction model for childhood cancer survivors treated with chest radiation incorporating treatment-related factors, family history, and reproductive factors. METHODS Analyses were based on multinational cohorts of female 5-year survivors of cancer diagnosed younger than age 21 years and treated with chest radiation. Model derivation was based on 1,120 participants in the Childhood Cancer Survivor Study diagnosed between 1970 and 1986, with median attained age 42 years (range 20-64) and 242 with breast cancer. Model validation included 1,027 participants from three cohorts, with median age 32 years (range 20-66) and 105 with breast cancer. RESULTS The model included current age, chest radiation field, whether chest radiation was delivered within 1 year of menarche, anthracycline exposure, age at menopause, and history of a first-degree relative with breast cancer. Ten-year risk estimates ranged from 2% to 23% for 30-year-old women (area under the curve, 0.63; 95% CI, 0.50 to 0.73) and from 5% to 34% for 40-year-old women (area under the curve, 0.67; 95% CI, 0.54 to 0.84). The highest risks were among premenopausal women older than age 40 years treated with mantle field radiation within a year of menarche who had a first-degree relative with breast cancer. It showed good calibration with an expected-to-observed ratio of the number of breast cancers of 0.92 (95% CI, 0.74 to 1.16). CONCLUSION Breast cancer risk varies among childhood cancer survivors treated with chest radiation. Accurate risk prediction may aid in refining surveillance, counseling, and preventive strategies in this population.
Published: 2021

26. Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies

Author: Francesmary Modugno, Minh Tung Phung, Bhramar Mukherjee, Jennifer A. Doherty, Paul D.P. Pharoah, Weiva Sieh, Penelope M. Webb, Usha Menon, Linda Titus, Valerie McGuire, Alice W. Lee, Malcolm C. Pike, Harvey A. Risch, Hoda Anton-Culver, Mary Anne Rossing, Susan J. Jordan, Katharine Brieger, Ashley Wiensch, Joellen M. Schildkraut, Holly R. Harris, Marc T. Goodman, Kirsten B. Moysich, Roberta B. Ness, Pamela J. Thompson, Joseph H. Rothstein, Argyrios Ziogas, Lilah Khoja, Nicolas Wentzensen, Allan Jensen, Bo Qin, Alice S. Whittemore, Anna H. Wu, Stacey Rosenzweig, Celeste Leigh Pearce, Susan J. Ramus, Susanne K. Kjaer, Aliya Alimujiang, Kathryn L. Terry, Daniel W. Cramer, Michael E. Carney, Andrew Berchuck, Elisa V. Bandera, Ellen L. Goode, Aleksandra Gentry-Maharaj, and Jenny Chang-Claude
Subjects: Risk, Cancer Research, medicine.medical_specialty, Reduced risk, Carcinoma, Ovarian Epithelial, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Medicine, Humans, Epithelial ovarian cancer, 030212 general & internal medicine, Gynecology, Ovarian Neoplasms, business.industry, Abortion, Induced, Odds ratio, Articles, medicine.disease, United Kingdom, United States, Large sample, Abortion, Spontaneous, Parity, Contraceptive use, Pooled analysis, Oncology, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business, Ovarian cancer
Abstract: Author(s): Lee, Alice W; Rosenzweig, Stacey; Wiensch, Ashley; Australian Ovarian Cancer Study Group; Ramus, Susan J; Menon, Usha; Gentry-Maharaj, Aleksandra; Ziogas, Argyrios; Anton-Culver, Hoda; Whittemore, Alice S; Sieh, Weiva; Rothstein, Joseph H; McGuire, Valerie; Wentzensen, Nicolas; Bandera, Elisa V; Qin, Bo; Terry, Kathryn L; Cramer, Daniel W; Titus, Linda; Schildkraut, Joellen M; Berchuck, Andrew; Goode, Ellen L; Kjaer, Susanne K; Jensen, Allan; Jordan, Susan J; Ness, Roberta B; Modugno, Francesmary; Moysich, Kirsten; Thompson, Pamela J; Goodman, Marc T; Carney, Michael E; Chang-Claude, Jenny; Rossing, Mary Anne; Harris, Holly R; Doherty, Jennifer Anne; Risch, Harvey A; Khoja, Lilah; Alimujiang, Aliya; Phung, Minh Tung; Brieger, Katharine; Mukherjee, Bhramar; Pharoah, Paul DP; Wu, Anna H; Pike, Malcolm C; Webb, Penelope M; Pearce, Celeste Leigh | Abstract: BackgroundParity is associated with decreased risk of invasive ovarian cancer; however, the relationship between incomplete pregnancies and invasive ovarian cancer risk is unclear. This relationship was examined using 15 case-control studies from the Ovarian Cancer Association Consortium (OCAC). Histotype-specific associations, which have not been examined previously with large sample sizes, were also evaluated.MethodsA pooled analysis of 10 470 invasive epithelial ovarian cancer cases and 16 942 controls was conducted. Odds ratios (ORs) and 95% confidence intervals (CIs) for the association between incomplete pregnancies and invasive epithelial ovarian cancer were estimated using logistic regression. All models were conditioned on OCAC study, race and ethnicity, age, and education level and adjusted for number of complete pregnancies, oral contraceptive use, and history of breastfeeding. The same approach was used for histotype-specific analyses.ResultsEver having an incomplete pregnancy was associated with a 16% reduction in ovarian cancer risk (OR = 0.84, 95% CI = 0.79 to 0.89). There was a trend of decreasing risk with increasing number of incomplete pregnancies (2-sided Ptrend l .001). An inverse association was observed for all major histotypes; it was strongest for clear cell ovarian cancer.ConclusionsIncomplete pregnancies are associated with a reduced risk of invasive epithelial ovarian cancer. Pregnancy, including incomplete pregnancy, was associated with a greater reduction in risk of clear cell ovarian cancer, but the result was broadly consistent across histotypes. Future work should focus on understanding the mechanisms underlying this reduced risk.
Published: 2021
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27. Dynamic conduction and repolarisation changes in early arrhythmogenic right ventricular cardiomyopathy versus benign outflow tract ectopy demonstrated by high density mapping & paced surface ECG analysis.

Author: Malcolm C Finlay, Akbar K Ahmed, Alan Sugrue, Justine Bhar-Amato, Giovanni Quarta, Antonis Pantazis, Edward J Ciaccio, Petros Syrris, Srijita Sen-Chowdhry, Ron Ben-Simon, Anthony W Chow, Martin D Lowe, Oliver R Segal, William J McKenna, and Pier D Lambiase
Subjects: Medicine, Science
Abstract: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy.22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol.Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43 ± 20 ms) more than RVOT ectopy patients (36 ± 14 ms, p = 0.03) or Normals (25 ± 16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18 ± 20 ms; RVOT ectopy: 5 ± 14, Normal: 1 ± 18, p
Published: 2014
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28. Phylogenomics of white-eyes, a ‘great speciator’, reveals Indonesian archipelago as the center of lineage diversity

Author: Balaji Chattopadhyay, Keren R. Sadanandan, Rauri C. K. Bowie, Dewi M. Prawiradilaga, Teuku Reza Ferasyi, Karen M. C. Rowe, Mohammad Irham, Martin Irestedt, Kelvin S.-H. Peh, Tri Haryoko, Jessica G. H. Lee, Chyi Yin Gwee, Fumin Lei, Kritika M. Garg, Shaoyuan Wu, Malcolm C. K. Soh, Luke M. Bloch, Guinevere O. U. Wogan, and Frank E. Rheindt
Subjects: Gene Flow, 0106 biological sciences, 0301 basic medicine, bird, Asia, QH301-705.5, Genetic Speciation, Science, Lineage (evolution), phylogeny, 010603 evolutionary biology, 01 natural sciences, General Biochemistry, Genetics and Molecular Biology, Coalescent theory, Gene flow, Songbirds, 03 medical and health sciences, Phylogenetics, Phylogenomics, parasitic diseases, Animals, Biology (General), Evolutionary Biology, geography.geographical_feature_category, General Immunology and Microbiology, biology, avian, General Neuroscience, white-eye, General Medicine, biology.organism_classification, Zosterops, 030104 developmental biology, Geography, Indonesia, Evolutionary biology, Archipelago, Medicine, Other, White-eye, target enrichment, Research Article
Abstract: Archipelagoes serve as important ‘natural laboratories’ which facilitate the study of island radiations and contribute to the understanding of evolutionary processes. The white-eye genus Zosterops is a classical example of a ‘great speciator’, comprising c. 100 species from across the Old World, most of them insular. We achieved an extensive geographic DNA sampling of Zosterops by using historical specimens and recently collected samples. Using over 700 genome-wide loci in conjunction with coalescent species tree methods and gene flow detection approaches, we untangled the reticulated evolutionary history of Zosterops, which comprises three main clades centered in Indo-Africa, Asia, and Australasia, respectively. Genetic introgression between species permeates the Zosterops phylogeny, regardless of how distantly related species are. Crucially, we identified the Indonesian archipelago, and specifically Borneo, as the major center of diversity and the only area where all three main clades overlap, attesting to the evolutionary importance of this region.
Published: 2020
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29. BIFoR FACE: Water-soil-vegetation-atmosphere research in a temperate deciduous forest catchment, including under elevated CO2

Author: Sophie Comer-Warner, Angus Robert MacKenzie, Angeliki Kourmouli, Susan Quick, Sami Ullah, Richard M. Thomas, Malcolm C. Press, Giulio Curioni, David M. Hannah, Nicolai Brekenfeld, Stefan Krause, Ronald L. Hamilton, P. Blaen, and Kris Hart
Subjects: Hydrology, Atmosphere, geography, geography.geographical_feature_category, medicine, Drainage basin, Environmental science, medicine.symptom, Vegetation (pathology), Temperate deciduous forest
Published: 2020
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30. Association of breast cancer with MRI background parenchymal enhancement: the IMAGINE case-control study

Author: Gordon P. Watt, Despina Kontos, Jennifer D. Brooks, Angela R. Bradbury, Malcolm C. Pike, Janice S. Sung, Jonine L. Bernstein, Sarah Colonna, Xiaolin Liang, Meghan Woods, Emily F. Conant, Saundra S. Buys, Matthew Stein, Elizabeth A. Morris, and Susan P. Weinstein
Subjects: Oncology, Adult, medicine.medical_specialty, Contrast Media, Breast Neoplasms, lcsh:RC254-282, Risk Assessment, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Young Adult, 0302 clinical medicine, Breast cancer, Surgical oncology, Predictive Value of Tests, Internal medicine, Epidemiology, Background parenchymal enhancement, medicine, Breast MRI, Humans, Mass Screening, Breast, Family history, skin and connective tissue diseases, Aged, Breast Density, Retrospective Studies, medicine.diagnostic_test, business.industry, Confounding, Case-control study, Odds ratio, Middle Aged, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Magnetic Resonance Imaging, Risk factors, 030220 oncology & carcinogenesis, Case-Control Studies, Female, business, Follow-Up Studies, Research Article
Abstract: Background Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. Methods The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years’ experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. Results The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05–2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92–2.27; p = 0.1). Conclusions BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.
Published: 2020

31. SAT-583 Assessment of Thermoregulatory Pathways Induced in Male and Female Mice Lacking Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) in Response to Cold Acclimation

Author: Malcolm C Hughes, Landon I. Short, Erik N Schien, Sarah L. Gray, Maeghan A. M. Forster, Simon S Harris, Ekaterina Filatov, Daemon L. Cline, and Colin J Appleby
Subjects: endocrine system, medicine.medical_specialty, Adipose Tissue, Appetite, and Obesity, Chemistry, Endocrinology, Diabetes and Metabolism, Adenylate kinase, Cyclase, Endocrinology, Adipose Tissue Biology and Obesity, Internal medicine, medicine, Cold acclimation, AcademicSubjects/MED00250, hormones, hormone substitutes, and hormone antagonists
Abstract: Pituitary Adenylate Cyclase Activating Polypetptide (PACAP) is a peptide hormone known to regulate energy homeostasis1. Mice lacking PACAP are cold sensitive and have impaired adrenergic-induced thermogenesis2-4. Interestingly, Pacap null mice can survive cold housing if acclimated slowly, similar to what was observed in UCP1 deficient mice4,5. We hypothesized that Pacap-/- mice employ alternate thermogenic pathways to compensate for impaired adaptive thermogenesis and assessed shivering thermogenesis and UCP1-dependent and UCP1-independent adaptive thermogenesis in male and female Pacap-/- and Pacap+/+ with cold acclimation (4°C). Assessment of oxidative fibres in skeletal muscles and behavioural observations did not show evidence of prolonged shivering in male or female Pacap-/- mice during cold acclimation compared to Pacap+/+ mice. We did however observe morphological and molecular differences in adipose tissues of Pacap-/- mice compared to Pacap+/+ mice that were distinct in males and females. Cold-acclimated, female Pacap-/- mice had decreased induction of UCP1 protein in intrascapular brown fat (iBAT), yet had a significantly higher beiging and UCP1 immunoreactivity (ir) in gonadal white fat (gWAT) compared to female Pacap+/+ mice. Furthermore, beiging was observed in inguinal white fat (ingWAT) and gWAT of female Pacap-/- mice housed at thermoneutrality (30°C), a finding not observed in Pacap+/+ control mice. Unlike female mice, we did not observe impaired UCP1 induction in iBAT of male Pacap-/- mice compared to Pacap+/+ mice, and this was associated with negligible UCP1-ir in male gWAT similar to wildtype controls. Despite previous work that has established impaired adaptive thermogenesis in Pacap-/- mice4, we show here that UCP1 protein can be induced in adipose tissues of Pacap-/- mice during cold acclimation, although to a lesser degree or in a different pattern compared to Pacap+/+ control mice. Taken together, this work suggests that while PACAP is clearly involved in regulating thermoregulation, it is not required for cold-induced UCP1 expression. In addition, this work highlights sexual dimorphism in adipose tissue remodeling and induction of thermogenesis with cold acclimation. References: (1) Rudecki AP, et al. Trends Endocrinol Metab. 2016;27(9), 620–632. (2) Gray SL, et al. J Mol Endocrinol. 2001;15(10), 1739–1747. (3) Gray SL, et al. J Endocrinol. 2002;143(10), 3946–3954. (4) Diané A, et al. J Endocrinol. 2014;222, 327–339. (5) Golozoubova V, et al. FASEB J. 2001;15, 2048–2050.
Published: 2020
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32. Assessment of the Research Interests and Perceptions of First-Year Medical Students at 4 Colleges of Osteopathic Medicine

Author: Victoria Nguyen, Dana Ziegler, Conor Kirby, Malcolm C. Modrzakowski, Kyle Messer, Sarah Zahl, Kelly Kaneshiro, Tim Cho, Julia M. Hum, Olivia Pipitone, Glen Kisby, Daniel Atchley, Jonathan W. Lowery, and Hinduja Nallamala
Subjects: Complementary and Manual Therapy, Response rate (survey), Medical education, Students, Medical, business.industry, Compensation (psychology), MEDLINE, Context (language use), 030230 surgery, Osteopathic medicine in the United States, 030205 complementary & alternative medicine, 03 medical and health sciences, 0302 clinical medicine, Incentive, Clinical research, Complementary and alternative medicine, Coursework, Surveys and Questionnaires, Medicine, Humans, Perception, business, Osteopathic Medicine, Schools, Medical
Abstract: Context There are limited data regarding the experiences of and attitudes toward research participation among osteopathic medical students despite rapidly increasing enrollment and expansion of the number of osteopathic medical schools. Objective To assess first-year osteopathic medical students’ experience with research, their interest in it, their perceptions of its value, and barriers to participation. Methods An anonymous, online survey was sent to 868 medical students in the class of 2021 at 4 colleges of osteopathic medicine. The survey consisted of 14 multiple-choice items (7 of which offered the option of a written response) and 1 open-ended item that asked them to report their age. The survey remained open for 2 weeks, with 1 reminder email sent on the last day of the survey. Incomplete responses were excluded from the analysis. Results A total of 328 participants were included, for a response rate of 38%. A majority of respondents reported previous research experience (261 [79.6%]), consistent with a strong perception that research participation is important (315 [96.0%]). Fewer students (177 [54.0%]) were either currently participating in research or affirmed interest in performing research during medical school, with the highest level of interest in clinical research (259 [79.0%]) followed by basic science (166 [50.6%]). Regarding incentives that might encourage participation in research, students preferred monetary compensation (213 [64.9%]) or extra credit in courses (195 [59.5%]). A commonly reported barrier to performing research during medical school was the possibility of a negative impact on performance in coursework (289 [88.1%]). Conclusion First-year osteopathic medical students are interested in research, view research experience as valuable, and consider research experience as beneficial to future career development. This study's findings highlight opportunities for increasing student participation in research through incentives or removal of perceived barriers.
Published: 2020

33. Stromal invasion pattern identifies patients at lowest risk of lymph node metastasis in HPV-associated endocervical adenocarcinomas, but is irrelevant in adenocarcinomas unassociated with HPV

Author: Simona Stolnicu, Robert A. Soslow, Iulia Barsan, Lynn Hoang, Anna Pesci, Takako Kiyokawa, Sarit Aviel-Ronen, Malcolm C. Pike, Cristina Terinte, Isabel Alvarado-Cabrero, Kay J. Park, Esther Oliva, Nadeem R. Abu-Rustum, and Prusha Patel
Subjects: Pathology, medicine.medical_specialty, Lymphovascular invasion, Uterine Cervical Neoplasms, Lymph node metastasis, Adenocarcinoma, Article, Metastasis, Stromal Invasion, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, Usual type, Humans, Medicine, Papillomaviridae, Cervical cancer, 030219 obstetrics & reproductive medicine, business.industry, Cervical adenocarcinoma, Papillomavirus Infections, Obstetrics and Gynecology, medicine.disease, Survival Rate, Oncology, Lymphatic Metastasis, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, business, Clinical record
Abstract: OBJECTIVE: The Silva invasion pattern-based classification system stratifies endocervical adenocarcinomas (ECAs) into 3 categories corresponding to risk of metastasis and recurrence, but has only been evaluated for HPV-associated ECAs of usual type. We examined whether the Silva system is applicable to all endocervical adenocarcinomas, especially those not associated with HPV. METHODS: Complete slide sets from 341 surgical specimens of ECA were collected from 7 institutions worldwide. All specimens were associated with clinical records covering at least 5 years of follow-up. Tumors were classified as HPV-associated (HPVA) or not (NHPVA) by both morphology and detection of HPV using in situ hybridization. Recurrence and survival were analyzed by multivariate Mantel-Haenszel methods. RESULTS: Most specimens (292; 85.6%) were HPVA, while 49 (14.3%) were NHPVA. All NHPVAs were Silva pattern C, while 76.0% of HPVAs were pattern C, 14.7% pattern A, and 9.3% pattern B. Including both HPVAs and NHPVAs, lymphovascular invasion (LVI) was detected in 0% of pattern A, 18.5% of pattern B and 62.6% of pattern C cases (p < 0.001). None of the pattern A or B cases were associated with lymph node metastases (LNM), in contrast to pattern C cases (21.8%). Among patients with Silva pattern C ECA, those with HPVA tumors had a lower recurrence rate and better survival than those with NHPVA; however, when adjusted for stage at diagnosis, the difference in recurrence and mortality was small and not statistically significant. CONCLUSIONS: Application of the Silva system is only relevant in HPVA cervical adenocarcinoma.
Published: 2018
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34. MRI background parenchymal enhancement, breast density and serum hormones in postmenopausal women

Author: Elizabeth A. Morris, Jennifer D. Brooks, Jonine L. Bernstein, Malcolm C. Pike, Frank Z. Stanczyk, Janice S. Sung, and Irene Orlow
Subjects: Cancer Research, medicine.medical_specialty, medicine.drug_class, Estrone, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Breast Cancer Risk Factor, Breast cancer, Internal medicine, Medicine, Breast MRI, medicine.diagnostic_test, business.industry, Magnetic resonance imaging, medicine.disease, 3. Good health, Endocrinology, Oncology, chemistry, Estrogen, 030220 oncology & carcinogenesis, business, Body mass index, Hormone
Abstract: Background parenchymal enhancement (BPE) is the degree to which normal breast tissue enhances on contrast-enhanced magnetic resonance imaging (MRI). MRI-density is a volumetric measure of breast density that is highly correlated with mammographic density, an established breast cancer risk factor. Endogenous estrogen concentrations are positively associated with postmenopausal breast cancer risk and BPE has been shown to be sensitive to hormonal exposures. The objective of our study was to examine the relationship between BPE and MRI-density and serum hormone concentrations in postmenopausal women. This was a study of cancer-free postmenopausal women undergoing contrast-enhanced breast MRI (N = 118). At the time of MRI all women completed a self-administered questionnaire and blood samples were collected for hormone analyses. Serum concentrations of estrone (E1), estradiol (E2) and bioavailable E2 were examined by category of BPE and MRI-density. Compared to women with "minimal" BPE, those who had "marked" BPE had significantly higher serum concentrations of E1, E2 and bioavailable E2 (90% increase, ptrend across all categories = 0.001; 150% increase, ptrend = 0.001; and 158% increase, ptrend = 0.001, respectively). These associations were only affected to a minor extent by adjustment for BMI and other variables. After adjustment for BMI, no significant associations between MRI-density and serum E1, E2 and bioavailable E2 were observed. Serum estrogen concentrations were significantly positively associated with BPE. Our study provides further evidence of the hormone-sensitive nature of BPE, indicating a potential role for BPE as an imaging marker of endogenous and exogenous hormonal exposures in the breast.
Published: 2018
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35. Estrogen receptor beta rs1271572 polymorphism and invasive ovarian carcinoma risk: pooled analysis within the Ovarian Cancer Association Consortium.

Author: Galina Lurie, Lynne R Wilkens, Pamela J Thompson, Yurii B Shvetsov, Rayna K Matsuno, Michael E Carney, Rachel T Palmieri, Anna H Wu, Malcolm C Pike, Celeste L Pearce, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Susan J Ramus, Alice S Whittemore, Valerie McGuire, Weiva Sieh, Paul D P Pharoah, Honglin Song, Jacek Gronwald, Anna Jakubowska, Cezary Cybulski, Jan Lubinski, Joellen M Schildkraut, Andrew Berchuck, Susanne Krüger Kjær, Estrid Høgdall, Peter A Fasching, Matthias W Beckmann, Arif B Ekici, Alexander Hein, Georgia Chenevix-Trench, Penelope M Webb, Jonathan Beesley, Australian Ovarian Cancer Study Group, Australian Cancer Study Group, Marc T Goodman, and Ovarian Cancer Association Consortium
Subjects: Medicine, Science
Abstract: The association of ovarian carcinoma risk with the polymorphism rs1271572 in the estrogen receptor beta (ESR2) gene was examined in 4946 women with primary invasive ovarian carcinoma and 6582 controls in a pooled analysis of ten case-control studies within the Ovarian Cancer Association Consortium (OCAC). All participants were non-Hispanic white women. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression adjusted for site and age. Women with the TT genotype were at increased risk of ovarian carcinoma compared to carriers of the G allele (OR = 1.10; 95%; CI: 1.01-1.21; p = 0.04); the OR was 1.09 (CI: 0.99-1.20; p = 0.07) after excluding data from the center (Hawaii) that nominated this SNP for OCAC genotyping A stronger association of rs1271572 TT versus GT/GG with risk was observed among women aged ≤50 years versus older women (OR = 1.35; CI: 1.12-1.62; p = 0.002; p for interaction = 0.02) that remained statistically significant after excluding Hawaii data (OR = 1.34; CI: 1.11-1.61; p = 0.009). No heterogeneity of the association was observed by study, menopausal status, gravidity, parity, use of contraceptive or menopausal hormones, tumor histological type, or stage at diagnosis. This pooled analysis suggests that rs1271572 might influence the risk of ovarian cancer, in particular among younger women.
Published: 2011
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36. IGF-1, IGFBP-1, and IGFBP-3 polymorphisms predict circulating IGF levels but not breast cancer risk: findings from the Breast and Prostate Cancer Cohort Consortium (BPC3).

Author: Alpa V Patel, Iona Cheng, Federico Canzian, Loïc Le Marchand, Michael J Thun, Christine D Berg, Julie Buring, Eugenia E Calle, Stephen Chanock, Francoise Clavel-Chapelon, David G Cox, Miren Dorronsoro, Laure Dossus, Christopher A Haiman, Susan E Hankinson, Brian E Henderson, Robert Hoover, David J Hunter, Rudolf Kaaks, Laurence N Kolonel, Peter Kraft, Jakob Linseisen, Eiliv Lund, Jonas Manjer, Catherine McCarty, Petra H M Peeters, Malcolm C Pike, Michael Pollak, Elio Riboli, Daniel O Stram, Anne Tjonneland, Ruth C Travis, Dimitrios Trichopoulos, Rosario Tumino, Meredith Yeager, Regina G Ziegler, Heather Spencer Feigelson, and Breast and Prostate Cancer Cohort Consortium
Subjects: Medicine, Science
Abstract: IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women.
Published: 2008
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37. Established risk factors account for most of the racial differences in cardiovascular disease mortality.

Author: Sean O Henderson, Christopher A Haiman, Lynne R Wilkens, Laurence N Kolonel, Peggy Wan, and Malcolm C Pike
Subjects: Medicine, Science
Abstract: Cardiovascular disease (CVD) mortality varies across racial and ethnic groups in the U.S., and the extent that known risk factors can explain the differences has not been extensively explored.We examined the risk of dying from acute myocardial infarction (AMI) and other heart disease (OHD) among 139,406 African-American (AA), Native Hawaiian (NH), Japanese-American (JA), Latino and White men and women initially free from cardiovascular disease followed prospectively between 1993-1996 and 2003 in the Multiethnic Cohort Study (MEC). During this period, 946 deaths from AMI and 2,323 deaths from OHD were observed. Relative risks of AMI and OHD mortality were calculated accounting for established CVD risk factors: body mass index (BMI), hypertension, diabetes, smoking, alcohol consumption, amount of vigorous physical activity, educational level, diet and, for women, type and age at menopause and hormone replacement therapy (HRT) use.Established CVD risk factors explained much of the observed racial and ethnic differences in risk of AMI and OHD mortality. After adjustment, NH men and women had greater risks of OHD than Whites (69% excess, P
Published: 2007
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38. Timing of births and oral contraceptive use influences ovarian cancer risk

Author: Celeste Leigh Pearce, Chiu-Chen Tseng, Anjali R. Jotwani, Prusha Patel, Alice W. Lee, Malcolm C. Pike, and Anna H. Wu
Subjects: Cancer Research, Pregnancy, medicine.medical_specialty, business.industry, Obstetrics, Cancer, medicine.disease, Lower risk, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Ovarian carcinoma, medicine, Etiology, 030212 general & internal medicine, Young adult, Age of onset, Ovarian cancer, business
Abstract: Increasing parity and duration of combined oral contraceptive (COC) use provide substantial protection against ovarian carcinoma (cancer). There are limited data on the impact of the age of the births or age of COC use on reducing ovarian cancer risk. Here, we examined the effects of age at first and last births and age at use of COCs using data from studies conducted in Los Angeles County, California, USA (1,632 cases, 2,340 controls). After adjusting for the number of births, every 5 years that a first birth was delayed reduced the risk of ovarian cancer by 13% (95% CI 5-21%; p = 0.003); a first birth after age 35 was associated with a 47% lower risk than a first birth before age 25. COC use before age 35 was associated with greater protection per year of use than COC use at older ages. Considering previously published results as well as the results presented here, increasing parity and a later age at births are both important protective factors against ovarian cancer and the protection extends over 30 or more years from last birth. Current models of the etiology of ovarian cancer do not encompass an effect of late age at births. Our result of an attenuation of the protective effect with COC use after around age 35 needs further investigation as it has not been seen in all studies.
Published: 2017
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39. The MOCOG study: Learning from extraordinary responders to improve treatment outcomes for women with ovarian cancer

Author: David D.L. Bowtell, Katy Milne, Dale W. Garsed, Anna de Fazio, Flurina Saner, Sian Fereday, Susan J. Ramus, Maartje C.A. Wouters, Malcolm C. Pike, Celeste Leigh Pearce, Jessica A. Beach, Ellen L. Goode, Bronwyn Gibson-Wright, Kathryn Alsop, Martin Köbel, Nadia Traficante, Catherine J. Kennedy, Ahwan Pandey, Brad H. Nelson, and Joy Hendley
Subjects: Oncology, medicine.medical_specialty, business.industry, Internal medicine, Treatment outcome, Medicine, business, Ovarian cancer, medicine.disease, Pathology and Forensic Medicine
Published: 2020
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40. Inertance-Integrated Primary Suspension Optimisation on an Industrial Railway Vehicle Model

Author: Neil Dinmore, Simon A Neild, Simon Iwnicki, Yuan Li, Jason Zheng Jiang, Tim D Lewis, Roger M. Goodall, Gareth Tucker, and Malcolm C. Smith
Subjects: Cost effectiveness, Stiffness, Track (rail transport), Automotive engineering, law.invention, Inertance, Vehicle dynamics, law, Inerter, medicine, Environmental science, medicine.symptom, Suspension (vehicle), Reduction (mathematics)
Abstract: Improving the track friendliness of a railway vehicle is highly beneficial to the rail industry, as it substantially increases its cost effectiveness. Rail surface damage under curving conditions can be reduced by using vehicles with a reduced Primary Yaw Stiffness (PYS); however, a lower PYS often leads to a reduction in high-speed stability and can negatively impact ride comfort. Previous studies have suggested that this trade-off, between track friendliness and passenger comfort, can be successfully improved by using an inerter in the primary suspension; however, these studies used simplified two-axle vehicles and simplified contact models, and track inputs. Considering a more realistic four-axle passenger vehicle model, this paper investigates the extent to which the PYS can be reduced using inertance-integrated primary lateral suspensions without increasing Root Mean Square (RMS) lateral carbody accelerations when running over a 5 km example track (with a number of vertical, lateral and longitudinal irregularities, and gauge variations). The vehicle, with inertance-integrated primary lateral suspensions, has been modelled in \(\mathrm{VAMPIRE}^{\textregistered }\), and the vehicle dynamics are captured over a range of different velocities and wheel-rail equivalent conicities. Several inertance-integrated suspensions are optimised, leading to permissible PYS reductions of up to 47% compared to the original vehicle, whilst lateral carbody accelerations remain at acceptable levels. This level of PYS reduction would result in a potential Network Rail Variable Usage Charge saving of 26%.
Published: 2020
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41. P147 Long-term survival in women with high-grade serous ovarian cancer: interplay between RB1 and BRCA1/2

Author: Fam Saner, Brad H. Nelson, Sian Fereday, Martin Köbel, Dale W. Garsed, Nadia Traficante, A de Fazio, Mca Wouters, Ddl Bowtell, CL Pearce, Malcolm C. Pike, Kathryn Alsop, Ahwan Pandey, Ellen L. Goode, Jessica A. Beach, and Susan J. Ramus
Subjects: Oncology, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Cancer, medicine.disease, Germline, Internal medicine, Cohort, Serous ovarian cancer, medicine, Immunohistochemistry, Stage IIIC, Ovarian cancer, business
Abstract: Introduction/Background Only ∼15% of patients with high-grade serous ovarian cancer (HGSC) survive >10 years. Those patients with a more typical disease trajectory may benefit from insights gained from long-term survivors (LTS). Here, we investigated genomic and immunologic determinants of exceptional survival in vivo and in vitro with a focus on the tumour suppressor RB1. Methodology Whole-genome sequencing (WGS) was performed on a unique set of primary tumors and germline samples from a cohort of 55 women with >10-year survival following a diagnosis of advanced stage (Stage IIIC/IV) HGSC. Tumors were also characterised by RNA sequencing and immunohistochemistry (IHC). RB1 was depleted in HGSC cell lines through CRISPR-Cas9 knockout (KO). The impact of RB1 loss was analysed in assays of chemosensitivity, clonogenicity, immunogenicity and transcriptomics. Results WGS showed that somatic inactivation of RB1 was common in LTS, with 33% of tumours showing loss of RB1 protein by IHC compared to 13% of unselected HGSC controls (n=207; P=0.001). IHC revealed that RB1 loss was associated with increased numbers of PD-1+ tumour-infiltrating lymphocytes (P=0.015) and MHC class I on tumor cells (P=0.002). In an independent HGSC cohort (n=847) from the OTTA consortium, co-occurrence of germline BRCA1/2 mutations and RB1 loss was associated with a significantly longer overall survival than patients with intact BRCA1/2 and RB1 (HR: 0.44, P Conclusion In HGSC, concurrent loss of RB1 and BRCA1/2 mutation is associated with significantly longer overall survival. RB1 loss appears to result in impaired self-renewal after standard chemotherapy and enhanced host immune response. Disclosure F.A.M.S is supported by a Swiss National Foundation Early Postdoc Mobility Fellowship, a Swiss Cancer Research Foundation grant and the Prof. Dr. Max Cloetta foundation. D.W.G. is supported by U.S. Army Medical Research and Materiel Command grant. AOCS receives funding support from Astra Zeneca and Ovarian Cancer Australia. C.L.P. and M.C.P. acknowledge support from the US Congressionally Directed Ovarian Cancer Research Program administered by the US Army Medical research and Materiel Command, grant number W81XWH-16-2-0010. D.D.L.B. is supported by U.S. Army Medical Research and Materiel Command grant, by the National Health and Medical Research Council of Australia (NHMRC) grants APP1092856 and APP1117044, the US National Cancer Institute U54 program, and receives research funding from Astra Zeneca, Beigene and Genentech-Roche. A.deF. is supported by grants from the U.S. Army Medical Research and Materiel Command, NHMRC, Cancer Institute NSW, Cancer Council New South Wales and AstraZeneca.
Published: 2019
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42. Principles of lossless adjustable one-ports

Author: Faryar Jabbari, Malcolm C. Smith, Tryphon T. Georgiou, and Apollo - University of Cambridge Repository
Subjects: mechanical network, 0209 industrial biotechnology, business.product_category, Computer science, Passivity, Acceleration, Systems and Control (eess.SY), 02 engineering and technology, Data_CODINGANDINFORMATIONTHEORY, Capacitors, semiactive, lossless, variable stiffness, law.invention, 020901 industrial engineering & automation, law, Control theory, FOS: Electrical engineering, electronic engineering, information engineering, Inerter, medicine, passivity, 93A99, 70Q99, 70E99, Electrical and Electronic Engineering, Force, Lossless compression, Lever, Control systems, Stiffness, Valves, Computer Science Applications, Power (physics), Inertance, Springs, Shock absorber, Capacitor, Shock absorbers, Control and Systems Engineering, Spring (device), Control system, Computer Science - Systems and Control, medicine.symptom, business
Abstract: This paper explores the possibility to construct two-terminal mechanical devices (one-ports) which are lossless and adjustable. To be lossless, the device must be passive (i.e. not requiring a power supply) and non-dissipative. To be adjustable, a parameter of the device should be freely variable in real time as a control input. For the simplest lossless one ports, the spring and inerter, the question is whether the stiffness and inertance may be varied freely in a lossless manner. We will show that the typical laws which have been proposed for adjustable springs and inerters are necessarily active and that it is not straightforward to modify them to achieve losslessness, or indeed passivity. By means of a physical construction using a lever with moveable fulcrum we will derive device laws for adjustable springs and inerters which satisfy a formal definition of losslessness. We further provide a construction method which does not require a power supply for physically realisable translational and rotary springs and inerters. The analogous questions for lossless adjustable electrical devices are examined., Comment: 10 pages, 8 figures
Published: 2019
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43. Assessing the Effect of Middle Ear Effusions on Wideband Acoustic Immittance Using Optical Coherence Tomography

Author: Jungeun Won, Ronit Barkalifa, Pin-Chieh Huang, Guillermo L. Monroy, Eric J. Chaney, Stephen A. Boppart, Michael A. Novak, Darold R. Spillman, Malcolm C. Hill, and Ryan G. Porter
Subjects: Male, medicine.medical_specialty, Acoustic immittance, Ear, Middle, Imaging, Absorbance, Speech and Hearing, Middle Ear Effusions, Optical coherence tomography, stomatognathic system, Ophthalmology, Middle ear effusion, medicine, otorhinolaryngologic diseases, Humans, Child, Otitis media, medicine.diagnostic_test, business.industry, Otitis Media with Effusion, Wideband acoustic immittance, Acoustics, Tympanometry, stomatognathic diseases, Otitis, medicine.anatomical_structure, Cross-Sectional Studies, Otorhinolaryngology, Acoustic Impedance Tests, Child, Preschool, Middle ear, Female, Tomography, sense organs, medicine.symptom, business, Tomography, Optical Coherence, Research Article
Abstract: Objectives: Wideband acoustic immittance (WAI) noninvasively assesses middle ear function by measuring the sound conduction over a range of audible frequencies. Although several studies have shown the potential of WAI for detecting the presence of middle ear effusions (MEEs), determining the effects of MEE type and amount on WAI in vivo has been challenging due to the anatomical location of middle ear cavity. The purpose of this study is to correlate WAI measurements with physical characteristics of the middle ear and MEEs determined by optical coherence tomography (OCT), a noninvasive optical imaging technique. Design: Sixteen pediatric subjects (average age of 7 ± 4 years) were recruited from the primary care clinic at Carle Foundation Hospital (Urbana, IL). A total of 22 ears (normal: 15 ears, otitis media with effusion: 6 ears, and acute otitis media: 1 ear, based on physician’s diagnosis) were examined via standard otoscopy, tympanometry, OCT imaging, and WAI measurements in a busy, community-based clinical setting. Cross-sectional OCT images were analyzed to quantitatively assess the presence, type (relative turbidity based on the amount of scattering), and amount (relative fluid level) of MEEs. These OCT metrics were utilized to categorize subject ears into no MEE (control), biofilm without a MEE, serous-scant, serous-severe, mucoid-scant, and mucoid-severe MEE groups. The absorbance levels in each group were statistically evaluated at α = 0.05. Results: The absorbance of the control group showed a similar trend when compared with a pediatric normative dataset, and the presence of an MEE generally decreased the power absorbance. The mucoid MEE group showed significantly less power absorbance from 2.74 to 4.73 kHz (p < 0.05) when compared with the serous MEE group, possibly due to the greater mass impeding the middle ear system. Similarly, the greater amount of middle ear fluid contributed to the lower power absorbance from 1.92 to 2.37 kHz (p< 0.05), when compared with smaller amounts of fluid. As expected, the MEEs with scant fluid only significantly affected the power absorbance at frequencies greater than 4.85 kHz. A large variance in the power absorbance was observed between 2 and 5 kHz, suggesting the dependence on both the type and amount of MEE. Conclusions: Physical characteristics of the middle ear and MEEs quantified from noninvasive OCT images can be helpful to understand abnormal WAI measurements. Mucoid MEEs decrease the power absorbance more than serous MEEs, and the greater amounts of MEE decreases the power absorbance, especially at higher (>2 kHz) frequencies. As both the type and amount of MEE can significantly affect WAI measurements, further investigations to correlate acoustic measurements with physical characteristics of middle ear conditions in vivo is needed.
Published: 2019

44. A comprehensive gene-environment interaction analysis in Ovarian Cancer using genome-wide significant common variants

Author: Angela Brooks-Wilson, Linda S. Cook, Elisa V. Bandera, Alice S. Whittemore, Roger L. Milne, Francesmary Modugno, Estrid Høgdall, Marc T. Goodman, N. Wentzensen, Simon A. Gayther, Georgia Chenevix-Trench, Shelley S. Tworoger, Jennifer A. Doherty, Allan Jensen, Graham G. Giles, Daniel W. Cramer, Joellen M. Schildkraut, Jenny Chang-Claude, Celeste Leigh Pearce, Ashley Wiensch, Argyrios Ziogas, Sara H. Olson, Gang Liu, Bhramar Mukherjee, Roberta B. Ness, David G. Huntsman, Susanne K. Kjaer, Britton Trabert, Sehee Kim, Hoda Anton-Culver, Pamela J. Thompson, Jonathan Tyrer, Usha Menon, Nhu D. Le, Miao Wang, Honglin Song, Penelope M. Webb, Mary Anne Rossing, Andrew Berchuck, Renée T. Fortner, Paul D.P. Pharoah, Ellen L. Goode, Weiva Sieh, Anna H. Wu, Maxwell Salvatore, Holly R. Harris, Kathryn L. Terry, Alice W. Lee, Malcolm C. Pike, Stacey J. Winham, Tyrer, Jonathan [0000-0003-3724-4757], Song, Honglin [0000-0001-5076-7371], Pharoah, Paul [0000-0001-8494-732X], and Apollo - University of Cambridge Repository
Subjects: Oncology, additive interaction, Cancer Research, Genome-wide association study, 0302 clinical medicine, Genotype, 2.1 Biological and endogenous factors, genetics, Gene–environment interaction, Aetiology, Cancer, Ovarian Neoplasms, education.field_of_study, Contraceptives, Environmental exposure, Single Nucleotide, 3. Good health, Ovarian Cancer, ovarian cancer, 030220 oncology & carcinogenesis, Female, Patient Safety, G x E, Oral, Risk, medicine.medical_specialty, Population, Oncology and Carcinogenesis, Environment, Polymorphism, Single Nucleotide, Article, Contraceptives, Oral, Hormonal, 03 medical and health sciences, G × E, Rare Diseases, Clinical Research, Internal medicine, medicine, Genetics, Humans, Genetic Predisposition to Disease, Oncology & Carcinogenesis, Polymorphism, education, Hormonal, business.industry, Prevention, Human Genome, Case-control study, Odds ratio, Environmental Exposure, medicine.disease, Good Health and Well Being, Case-Control Studies, Gene-Environment Interaction, business, Genome-Wide Association Study
Abstract: As a follow-up to genome-wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well-known ovarian cancer risk factors and their interactions with 28 genome-wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case-control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10-4 ). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46-0.60) compared to 0.71 (95%CI = 0.66-0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1-5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene-environment analysis in ovarian cancer.
Published: 2019

45. Automated classification platform for the identification of otitis media using optical coherence tomography

Author: Jungeun Won, Stephen A. Boppart, Roshan Dsouza, Ryan G. Porter, Michael A. Novak, Guillermo L. Monroy, Malcolm C. Hill, Paritosh Pande, and Darold R. Spillman
Subjects: medicine.medical_specialty, Computer science, Medicine (miscellaneous), Health Informatics, Primary care, lcsh:Computer applications to medicine. Medical informatics, Paediatric research, Article, 03 medical and health sciences, 0302 clinical medicine, Health Information Management, Optical coherence tomography, Clinical information, Machine learning, medicine, Medical physics, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, Imaging and sensing, Translational research, 3. Good health, Computer Science Applications, Identification (information), Otitis, Workflow, lcsh:R858-859.7, sense organs, medicine.symptom, Middle ear fluid, Biomedical engineering, 030217 neurology & neurosurgery, Healthcare system
Abstract: The diagnosis and treatment of otitis media (OM), a common childhood infection, is a significant burden on the healthcare system. Diagnosis relies on observer experience via otoscopy, although for non-specialists or inexperienced users, accurate diagnosis can be difficult. In past studies, optical coherence tomography (OCT) has been used to quantitatively characterize disease states of OM, although with the involvement of experts to interpret and correlate image-based indicators of infection with clinical information. In this paper, a flexible and comprehensive framework is presented that automatically extracts features from OCT images, classifies data, and presents clinically relevant results in a user-friendly platform suitable for point-of-care and primary care settings. This framework was used to test the discrimination between OCT images of normal controls, ears with biofilms, and ears with biofilms and middle ear fluid (effusion). Predicted future performance of this classification platform returned promising results (90%+ accuracy) in various initial tests. With integration into patient healthcare workflow, users of all levels of medical experience may be able to collect OCT data and accurately identify the presence of middle ear fluid and/or biofilms.
Published: 2019

46. Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study

Author: Charles A. Sklar, Tara O. Henderson, Lucie M. Turcotte, Danielle Novetsky Friedman, Gregory T. Armstrong, Wendy M. Leisenring, Kevin C. Oeffinger, Flora E. van Leeuwen, Cécile M. Ronckers, Leslie L. Robison, Joseph P. Neglia, Malcolm C. Pike, Dana Barnea, Rebecca M. Howell, Joanne F. Chou, Chaya S. Moskowitz, CCA - Cancer Treatment and Quality of Life, Paediatric Oncology, CCA -Cancer Center Amsterdam, and ARD - Amsterdam Reproduction and Development
Subjects: 0301 basic medicine, Oncology, Adult, Cancer Research, medicine.medical_specialty, Neoplasms, Radiation-Induced, Anthracycline, pediatric malignancy, Epidemiology, Hormone Replacement Therapy, medicine.medical_treatment, supradiaphragmatic radiotherapy, Breast Neoplasms, Childhood Cancer Survivor Study, Premature ovarian insufficiency, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, Medicine, late effects, Humans, Survivors, Child, Radiotherapy, business.industry, Hazard ratio, Estrogen Receptor alpha, second malignancies, Hormone replacement therapy (menopause), Middle Aged, medicine.disease, 3. Good health, Radiation therapy, 030104 developmental biology, 030220 oncology & carcinogenesis, Female, Hormone therapy, business, Gonadal Hormones
Abstract: Background: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. Methods: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970–1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. Results: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs 1 year from menarche (HR=1.80, CI 1.19–2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause
Published: 2017
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47. A splicing variant ofTERTidentified by GWAS interacts with menopausal estrogen therapy in risk of ovarian cancer

Author: Usha Menon, Kathryn L. Terry, Allan Jensen, Georgia Chenevix-Trench, Francesmary Modugno, Bhramar Mukherjee, Ashley Bomkamp, Aleksandra Gentry-Maharaj, Jenny Chang-Claude, Mary Anne Rossing, Daniel O. Stram, Kirsten B. Moysich, Roberta B. Ness, Lynda D. Roman, Celeste Leigh Pearce, Daniel W. Cramer, Jennifer A. Doherty, Sara H. Olson, Elisa V. Bandera, Marc T. Goodman, Estrid Høgdall, Alice W. Lee, Anja Rudolph, Malcolm C. Pike, Susanne K. Kjaer, Susan J. Ramus, Joellen M. Schildkraut, Andrew Berchuck, Anna H. Wu, Simon A. Gayther, and Paul D.P. Pharoah
Subjects: 0301 basic medicine, Gynecology, Oncology, Cancer Research, medicine.medical_specialty, endocrine system diseases, Case-control study, Cancer, Single-nucleotide polymorphism, Genome-wide association study, Odds ratio, Biology, medicine.disease, female genital diseases and pregnancy complications, 03 medical and health sciences, Serous fluid, 030104 developmental biology, Internal medicine, medicine, Risk factor, Ovarian cancer
Abstract: Menopausal estrogen-alone therapy (ET) is a well-established risk factor for serous and endometrioid ovarian cancer. Genetics also plays a role in ovarian cancer, which is partly attributable to 18 confirmed ovarian cancer susceptibility loci identified by genome-wide association studies. The interplay among these loci, ET use and ovarian cancer risk has yet to be evaluated. We analyzed data from 1,414 serous cases, 337 endometrioid cases and 4,051 controls across 10 case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Conditional logistic regression was used to determine the association between the confirmed susceptibility variants and risk of serous and endometrioid ovarian cancer among ET users and non-users separately and to test for statistical interaction. A splicing variant in TERT, rs10069690, showed a statistically significant interaction with ET use for risk of serous ovarian cancer (pint = 0.013). ET users carrying the T allele had a 51% increased risk of disease (OR = 1.51, 95% CI 1.19-1.91), which was stronger for long-term ET users of 10+ years (OR = 1.85, 95% CI 1.28-2.66, pint = 0.034). Non-users showed essentially no association (OR = 1.08, 95% CI 0.96-1.21). Two additional genomic regions harboring rs7207826 (C allele) and rs56318008 (T allele) also had significant interactions with ET use for the endometrioid histotype (pint = 0.021 and pint = 0.037, respectively). Hence, three confirmed susceptibility variants were identified whose associations with ovarian cancer risk are modified by ET exposure; follow-up is warranted given that these interactions are not adjusted for multiple comparisons. These findings, if validated, may elucidate the mechanism of action of these loci.
Published: 2016
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48. Chronic Recreational Physical Inactivity and Epithelial Ovarian Cancer Risk: Evidence from the Ovarian Cancer Association Consortium

Author: Andrew Berchuck, Nicolas Wentzensen, Jennifer A. Doherty, Brooke L. Fridley, Albina N. Minlikeeva, Daniel W. Cramer, J. Brian Szender, Mary Anne Rossing, Chi Chen Hong, Anna H. Wu, Stacey J. Winham, Estrid Høgdall, Barbara Schmalfeldt, Elizabeth A. Szamreta, Marc T. Goodman, Robert P. Edwards, Joellen M. Schildkraut, Allan Jensen, Rikki Cannioto, Chiu-Chen Tseng, Harvey A. Risch, Jenny Chang-Claude, Celeste Leigh Pearce, Robert A. Vierkant, Kristine G. Wicklund, Michael J. LaMonte, Satoyo Hosono, Penelope M. Webb, Keitaro Matsuo, Francesmary Modugno, Susanne K. Kjaer, R Klapdor, Ellen L. Goode, Pamela J. Thompson, Kirsten B. Moysich, Emily Gower, Roberta B. Ness, Kathryn L. Terry, Linda E. Kelemen, Kevin H. Eng, Elisa V. Bandera, Catherine M. Olsen, Sara H. Olson, Malcolm C. Pike, Susan J. Jordan, Gary Zirpoli, and Lara E. Sucheston-Campbell
Subjects: Adult, Oncology, medicine.medical_specialty, endocrine system diseases, Epidemiology, Physical fitness, Carcinoma, Ovarian Epithelial, Logistic regression, Article, 03 medical and health sciences, Breast cancer, 0302 clinical medicine, Uterine cancer, Risk Factors, Internal medicine, medicine, Humans, Neoplasms, Glandular and Epithelial, 030212 general & internal medicine, Risk factor, Recreation, Exercise, Ovarian Neoplasms, Gynecology, business.industry, Case-control study, Obstetrics and Gynecology, Cancer, General Medicine, Odds ratio, medicine.disease, female genital diseases and pregnancy complications, Systematic review, Logistic Models, Case-Control Studies, 030220 oncology & carcinogenesis, Meta-analysis, Female, Sedentary Behavior, Ovarian cancer, business, Body mass index
Abstract: Background: Despite a large body of literature evaluating the association between recreational physical activity and epithelial ovarian cancer (EOC) risk, the extant evidence is inconclusive, and little is known about the independent association between recreational physical inactivity and EOC risk. We conducted a pooled analysis of nine studies from the Ovarian Cancer Association Consortium to investigate the association between chronic recreational physical inactivity and EOC risk. Methods: In accordance with the 2008 Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. Multivariable logistic regression was utilized to estimate the ORs and 95% confidence intervals (CI) for the association between inactivity and EOC risk overall and by subgroups based upon histotype, menopausal status, race, and body mass index. Results: The current analysis included data from 8,309 EOC patients and 12,612 controls. We observed a significant positive association between inactivity and EOC risk (OR = 1.34; 95% CI, 1.14–1.57), and similar associations were observed for each histotype. Conclusions: In this large pooled analysis examining the association between recreational physical inactivity and EOC risk, we observed consistent evidence of an association between chronic inactivity and all EOC histotypes. Impact: These data add to the growing body of evidence suggesting that inactivity is an independent risk factor for cancer. If the apparent association between inactivity and EOC risk is substantiated, additional work via targeted interventions should be pursued to characterize the dose of activity required to mitigate the risk of this highly fatal disease. Cancer Epidemiol Biomarkers Prev; 25(7); 1114–24. ©2016 AACR.
Published: 2016
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49. Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium

Author: Kunle Odunsi, Janine M. Joseph, Satoyo Hosono, Brahm H. Segal, Francesmary Modugno, Robert P. Edwards, Joseph L. Kelley, Chiu-Chen Tseng, Peter Hillemanns, Brenda Diergaarde, Barbara Schmalfeldt, Allan Jensen, Michael J. LaMonte, Kathryn L. Terry, Albina N. Minlikeeva, Kevin H. Eng, Nicolas Wentzensen, Penelope M. Webb, Harvey A. Risch, Andrew Berchuck, Stacey J. Winham, J. Brian Szender, Keitaro Matsuo, Robert A. Vierkant, Anna H. Wu, Joellen M. Schildkraut, Marc T. Goodman, Brooke L. Fridley, Christina M. Nagle, Mary Anne Rossing, Thilo Dörk, Elizabeth A. Szamreta, Pamela J. Thompson, Celeste Leigh Pearce, Kristine G. Wicklund, Grace Friel, Chi-Chen Hong, Susanne K. Kjaer, Estrid Høgdall, Malcolm C. Pike, Rüdiger Klapdor, Jenny Chang-Claude, Ellen L. Goode, Lisa E. Paddock, Kirsten B. Moysich, Jennifer A. Doherty, Daniel W. Cramer, Anna deFazio, Roberta B. Ness, Linda E. Kelemen, Elisa V. Bandera, Catherine M. Olsen, Lara E. Sucheston-Campbell, and Rikki Cannioto
Subjects: epithelial ovarian cancer, Oncology, endocrine system, Cancer Research, medicine.medical_specialty, endocrine system diseases, Colorectal cancer, Short Communication, Carcinoma, Ovarian Epithelial, survival, recreational physical activity, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Breast cancer, Risk Factors, Internal medicine, Humans, Medicine, Neoplasms, Glandular and Epithelial, 030212 general & internal medicine, Exercise, Proportional Hazards Models, Ovarian Neoplasms, Cervical cancer, business.industry, Cancer, Middle Aged, medicine.disease, female genital diseases and pregnancy complications, 3. Good health, inactivity, 030220 oncology & carcinogenesis, mortality risk, Recreation, Female, Skin cancer, business, Liver cancer, Ovarian cancer
Abstract: Background: Little is known about modifiable behaviours that may be associated with epithelial ovarian cancer (EOC) survival. We conducted a pooled analysis of 12 studies from the Ovarian Cancer Association Consortium to investigate the association between pre-diagnostic physical inactivity and mortality. Methods: Participants included 6806 women with a primary diagnosis of invasive EOC. In accordance with the Physical Activity Guidelines for Americans, women reporting no regular, weekly recreational physical activity were classified as inactive. We utilised Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) representing the associations of inactivity with mortality censored at 5 years. Results: In multivariate analysis, inactive women had significantly higher mortality risks, with (HR=1.34, 95% CI: 1.18–1.52) and without (HR=1.22, 95% CI: 1.12–1.33) further adjustment for residual disease, respectively. Conclusion: In this large pooled analysis, lack of recreational physical activity was associated with increased mortality among women with invasive EOC.
Published: 2016
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50. Abstract 3498: Ovarian cancer risk factors multiply to create high risk in pre-menopausal women

Author: Argyrios Ziogas, Allan Jensen, Jennifer A. Doherty, Minh Tung Phung, Hoda Anton-Culver, Anna H. Wu, Harvey A. Risch, Marc T. Goodman, Francesmary Modugno, Kathryn L. Terry, Penelope M. Webb, Bhramar Mukherjee, Alice W. Lee, Malcolm C. Pike, Holly R. Harris, Daniel W. Cramer, Roberta B. Ness, Celeste Leigh Pearce, and Susanne K. Kjaer
Subjects: Cancer Research, Framingham Risk Score, business.industry, Cancer, Odds ratio, Logistic regression, medicine.disease, Oncology, Quartile, Medicine, Population study, Family history, business, Body mass index, Demography
Abstract: Background: Ovarian cancer is the eighth-most common cancer among women. Although a number of established risk factors exist for this disease, analyses of these exposures have largely not taken into account potential interactions. We present an interaction analysis of eight ovarian cancer risk factors, followed by the creation of modifiable and non-modifiable risk scores for the disease. Methods: Data used in this analysis come from nine studies in the Ovarian Cancer Association Consortium (OCAC): one from Australia, one from Europe and seven from the US. Analyses were restricted to pre-menopausal women without first-degree family histories of ovarian cancer, leading to a final study population of 1504 cases and 3515 controls. Five potentially modifiable predictors (oral contraceptive (OC) use duration, body mass index, tubal ligation, hysterectomy and breastfeeding) and three non-modifiable predictors (parity, incomplete pregnancies and history of endometriosis) were considered. A complete analysis of interactions between the eight variables as well as with age, race/ethnicity, education level and study site was conducted. No statistically significant pairwise interactions were found with likelihood ratio statistics, thus suggesting no departure from multiplicativity in the odds ratios. The modifiable and non-modifiable risk scores were calculated as the product of the odds ratios for each group of exposures. Logistic regression was used to model the association between ovarian cancer and the risk scores. Age, race/ethnicity, education level and study site were included in the model. Results: The associations between the second, third and fourth quartiles of the modifiable risk score compared to the lowest quartile were 1.67 (95% CI 1.35-2.09), 2.18 (95% CI 1.76-2.71) and 3.72 (95% CI 3.04-4.57), respectively. The odds ratios for the non-modifiable risk score were 1.17 (95% CI 0.95-1.44), 1.24 (95% CI 0.99-1.54) and 2.06 (95% CI 1.68-2.53), respectively for the second, third and fourth quartiles compared to the first. Women in the highest quartiles of both the modifiable and non-modifiable risk scores, representing 14.6% of the women, had a 7.67-fold increased risk of ovarian cancer (95% CI 4.68-11.39) compared to women in the lowest quartiles for both risk scores (3.6% of the women). Conclusions: Pre-menopausal women in the highest risk quartiles have a substantially elevated risk of ovarian cancer based on these eight exposures. Modifiable factors contribute more than non-modifiable factors to ovarian cancer risk among pre-menopausal women with no family history in our study. Women in the highest risk group (fourth quartile of both risk scores) could reduce their risk by intervening on the modifiable exposures; for example, 63% of women in this group had not used oral contraceptives and 93% had not had tubal ligation. However, careful consideration of the risks and benefits of such prevention measures is needed. Citation Format: Minh Tung Phung, Bhramar Mukherjee, Alice W. Lee, Penelope M. Webb, Harvey A. Risch, Jennifer Anne Doherty, Holly R. Harris, Marc T. Goodman, Roberta B. Ness, Francesmary Modugno, Allan Jensen, Susanne K. Kjaer, Kathryn L. Terry, Daniel W. Cramer, Argyrios Ziogas, Hoda Anton-Culver, Malcolm C. Pike, Anna H. Wu, Celeste Leigh Pearce. Ovarian cancer risk factors multiply to create high risk in pre-menopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3498.
Published: 2020
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