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1.  Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers 
JMIR Research Protocols  2016;5(3):e182.
Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements.
The protocol described in this paper focuses on the validation of concepts based on biomarkers in blood in a major population screened by FIT.
In Part 1, participants will be identified and included through the Danish CRC Screening Program comprising initial FIT and subsequent colonoscopy to those with a positive result. Blood samples will be collected from 8000 FIT-positive participants, who are offered subsequent colonoscopy. Findings and interventions at colonoscopy together with personal data including co-morbidity will be recorded. Blood samples and data will also be collected from 6000 arbitrarily chosen participants with negative FIT. In Part 2, blood samples and data will be collected from 30,000 FIT-negative participants three times within 4 years. The blood samples will be analyzed using various in-house and commercially available manual and automated analysis platforms.
We anticipate Part 1 to terminate late August 2016 and Part 2 to terminate late September 2022. The results from Parts 1 and 2 will be presented within 12 to 18 months from termination.
The purpose of this study is to improve the efficacy of identifying participants with neoplastic bowel lesions, to identify false negative participants, to identify participants at risk of interval neoplastic lesions, to improve the compliance in screening sessions, and to establish guidelines for out-patient follow-up of at-risk participants based on combinations of blood-based biomarkers.
PMCID: PMC5039335  PMID: 27624815
colorectal neoplasms; genomics; epigenomics; transcriptome; proteomics; metabolomics; early detection of cancer
2.  Polymorphisms in the Toll-Like Receptor and the IL-23/IL-17 Pathways Were Associated with Susceptibility to Inflammatory Bowel Disease in a Danish Cohort 
PLoS ONE  2015;10(12):e0145302.
The inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Previous studies have shown that polymorphisms in the Toll-like receptor (TLR), the apoptosis, the IL-23/IL-17 and the interferon gamma (IFNG) pathways are associated with risk of both CD and UC.
Using a candidate gene approach, 21 functional single nucleotide polymorphisms (SNPs) in 15 genes were assessed in a clinical homogeneous group of severely diseased ethnic Danish patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.
The polymorphisms TLR5 (rs5744174) and IL12B (rs6887695) were associated with risk of CD, and TLR1 (rs4833095) and IL18 (rs187238) were associated with risk of both CD and UC (p<0.05). After Bonferroni correction for multiple testing, the homozygous variant genotype of TLR1 743 T>C (rs4833095) was associated with increased risk CD (OR: 3.15, 95% CI: 1.59–6.26, p = 0.02) and CD and UC combined (OR: 2.96, 95% CI: 1.64–5.32, p = 0.005).
Our results suggest that genetically determined high activity of TLR1 and TLR5 was associated with increased risk of both CD and UC and CD, respectively. This supports that the host microbial composition or environmental factors in the gut are involved in risk of IBD. Furthermore, genetically determined high activity of the IL-23/IL-17 pathway was associated with increased risk of CD and UC. Overall, our results support that genetically determined high inflammatory response was associated with increased risk of both CD and UC.
PMCID: PMC4689491  PMID: 26698117
3.  The Impact of Comorbid Depression on Educational Inequality in Survival after Acute Coronary Syndrome in a Cohort of 83 062 Patients and a Matched Reference Population 
PLoS ONE  2015;10(10):e0141598.
Patients with low socioeconomic position have higher rates of mortality after diagnosis of acute coronary syndrome (ACS), but little is known about the mechanisms behind this social inequality. The aim of the present study was to examine whether any educational inequality in survival after ACS was influenced by comorbid conditions including depression.
From 2001 to 2009 all first-time ACS patients were identified in the Danish National Patient Registry. This cohort of 83 062 ACS patients and a matched reference population were followed for incident depression and mortality until December 2012 by linkage to person, patients and prescription registries. Educational status was defined at study entry and the impact of potential confounders and mediators (age, gender, cohabitation status, somatic comorbidity and depression) on the relation between education and mortality were identified by drawing a directed acyclic graph and analysed using multiple Cox regression analyses.
During follow-up, 29 583(35.6%) of ACS patients and 19 105(22.9%) of the reference population died. Cox regression analyses showed an increased mortality in the lowest educated compared to those with high education in both ACS patients and the reference population. Adjustment for previous and incident depression or other covariables only attenuated the relations slightly. This pattern of associations was seen for mortality after 30 days, 1 year and during total follow-up.
In this study the relative excess mortality rate in lower educated ACS patients was comparable with the excess risk associated with low education in the background population. This educational inequality in survival remained after adjustment for somatic comorbidity and depression.
PMCID: PMC4626047  PMID: 26513652
4.  Chronic pain patients with possible co-morbid post-traumatic stress disorder admitted to multidisciplinary pain rehabilitation—a 1-year cohort study 
European Journal of Psychotraumatology  2014;5:10.3402/ejpt.v5.23235.
Although post-traumatic stress disorder (PTSD) is a common co-morbidity in chronic pain, little is known about the association between PTSD and pain in the context of chronic pain rehabilitation.
The aim of the present study was two-fold: (1) to investigate the association of a possible PTSD diagnosis with symptoms of pain, physical and mental functioning, as well as the use of opioids, and (2) to compare the outcome of multidisciplinary chronic pain rehabilitation for patients with a possible PTSD diagnosis at admission with patients without PTSD at admission.
A consecutively referred cohort of 194 patients completed a baseline questionnaire at admission covering post-traumatic stress, pain symptoms, physical and mental functioning, as well as self-reported sleep quality and cognitive difficulties. Medication use was calculated from their medical records. A total of 95 were admitted to further multidisciplinary treatment and included in the outcome study.
A high prevalence of possible PTSD was found (26.3%). Patients with possible co-morbid PTSD experienced significantly poorer general and mental health, poorer sleep quality, and more cognitive problems as well as inferior social functioning compared to patients without PTSD. Possible co-morbid PTSD did not result in higher use of opioids or sedatives. Surprisingly, possible co-morbid PTSD at admission was not associated with lower levels of symptom reduction from pre- to post-treatment.
Possible co-morbid PTSD in chronic pain is a major problem associated with significantly poorer functioning on several domains. Nevertheless, our results indicate that pain-related symptoms could be treated with success despite possible co-morbid PTSD. However, since PTSD was only measured at admission it is not known whether rehabilitation actually reduced PTSD.
PMCID: PMC4127830  PMID: 25147628
Post-traumatic stress; chronic pain; rehabilitation; distress; physical functioning; opioids
5.  Polymorphisms in the Inflammatory Pathway Genes TLR2, TLR4, TLR9, LY96, NFKBIA, NFKB1, TNFA, TNFRSF1A, IL6R, IL10, IL23R, PTPN22, and PPARG Are Associated with Susceptibility of Inflammatory Bowel Disease in a Danish Cohort 
PLoS ONE  2014;9(6):e98815.
The inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.
Using a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.
Sixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p≤0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (ORCD,adj: 0.38, 95% CI: 0.21–0.67, p = 0.03; ORIBD,adj 0.43, 95% CI: 0.28–0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (ORCD,unadj 0.54, 95% CI: 0.41–0.72, p = 7*10−4; ORIBD,unadj: 0.61, 95% CI: 0.48–0.77, p = 0.001) were associated with reduced risk of CD.
The biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.
PMCID: PMC4074037  PMID: 24971461
6.  Trends in Prevalence of Overweight and Obesity in Danish Infants, Children and Adolescents – Are We Still on a Plateau? 
PLoS ONE  2013;8(7):e69860.
After the worldwide steep increase in child and adolescent overweight and obesity during the last decades, there is now evidence of a levelling off in the prevalence in many countries in the Western world.
To examine whether there still is a plateau in the prevalence of overweight and obesity in Danish children and adolescents, or whether the prevalence is decreasing or rising again.
The trends in the prevalence rates were based on three data sets providing comparable repeated estimates: 1) the Danish Health Visitors Child Health Database (DHVCHD) with measurements on infant and childhood height and weight from 2002 to 2011 (n up to 39,984), 2) the Danish National Birth Cohort (DNBC) with maternal reports of measured infant and childhood height and weight from 1998 to 2010 (n up to 56,826) and 3) the Danish part of the Health Behaviour in School-aged Children survey (HBSC) with self-reported information on adolescent height and weight from the years 2002 to 2010 (n = 16,557). Overweight and obesity were categorized according to WHO growth standards. Trends were assessed by repeated point estimates and linear regression analyses providing regression coefficients for changes in per cent per year with 95% confidence intervals (CI).
The prevalence rates of overweight and obesity for infants, children and adolescents showed a mixed pattern of decline, stability and increase (ranging from -1.10 through 0.29 per cent per year with CI’s from -3.10 through 2.37). Overall, there were no consistent statistically significant trends upwards or downwards, although some significant downward trends in childhood and adolescence were observed.
This study, based on data from 1998 through 2011, showed that the prevalence rates of overweight and obesity among Danish infants, children and adolescents were largely still on a plateau with tendencies for a decline among children and adolescents.
PMCID: PMC3722196  PMID: 23894553
7.  The effect of early measles vaccination at 4.5 months of age on growth at 9 and 24 months of age in a randomized trial in Guinea-Bissau 
BMC Pediatrics  2016;16:199.
Providing an early, additional measles vaccine (MV) at 4.5 months of age has been shown to reduce child mortality in low-income countries. We studied the effects on growth at 9 and 24 months of age.
A randomized controlled trial was conducted in Guinea-Bissau from 2003–2007 including 6,648 children. Children were randomized 1:1:1 to receive Edmonston-Zagreb measles vaccine at 4.5 and 9 months of age (group A), no vaccine at 4.5 months and Edmonston-Zagreb measles vaccine at 9 months (group B), or no vaccine at 4.5 months and Schwarz measles vaccine at 9 months (group C) Data on anthropometrics were obtained at enrolment at 4.5 months of age and again at 9 and 24 months of age. Analyses were stratified by sex, season of enrolment, and neonatal vitamin A supplementation (NVAS) status, as all these factors have been shown to modify the effect of early MV on mortality.
Overall there was no effect of early MV on anthropometry at 9 months. At 24 months children who had received early MV had a significantly larger mid-upper-arm-circumference (MUAC/in cm) (Difference = 0.08; 95% CI (0.02;0.14)) compared with children in the control group; this effect was most pronounced among girls (0.12 (0.03;0.20)). The effect of early MV on MUAC remained significant in the dry season and in girls who received placebo rather than NVAS.
Early MV was associated with a larger MUAC particularly in girls. These results indicate that a two-dose measles vaccination schedule might not only reduce child mortality but also improve growth.
Trial registration NCT00168558. Registered September 9, 2005, retrospectively registered
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-016-0738-z) contains supplementary material, which is available to authorized users.
PMCID: PMC5135799  PMID: 27912735
Early measles vaccination; Growth; Non-specific effects; Sex-differential effects; Neonatal vitamin A supplementation; Season
8.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
PMCID: PMC5123387
9.  The Danish Registry of Diabetic Retinopathy 
Clinical Epidemiology  2016;8:613-619.
Aim of database
To monitor the development of diabetic eye disease in Denmark and to evaluate the accessibility and effectiveness of diabetic eye screening programs with focus on interregional variations.
Target population
The target population includes all patients diagnosed with diabetes. Denmark (5.5 million inhabitants) has ~320,000 diabetes patients with an annual increase of 27,000 newly diagnosed patients. The Danish Registry of Diabetic Retinopathy (DiaBase) collects data on all diabetes patients aged ≥18 years who attend screening for diabetic eye disease in hospital eye departments and in private ophthalmological practice. In 2014–2015, DiaBase included data collected from 77,968 diabetes patients.
Main variables
The main variables provide data for calculation of performance indicators to monitor the quality of diabetic eye screening and development of diabetic retinopathy. Data with respect to age, sex, best corrected visual acuity, screening frequency, grading of diabetic retinopathy and maculopathy at each visit, progression/regression of diabetic eye disease, and prevalence of blindness were obtained. Data analysis from DiaBase’s latest annual report (2014–2015) indicates that the prevalence of no diabetic retinopathy, nonproliferative diabetic retinopathy, and proliferative diabetic retinopathy is 78%, 18%, and 4%, respectively. The percentage of patients without diabetic maculopathy is 97%. The proportion of patients with regression of diabetic retinopathy (20%) is greater than the proportion of patients with progression of diabetic retinopathy (10%).
The collection of data from diabetic eye screening is still expanding in Denmark. Analysis of the data collected during the period 2014–2015 reveals an overall decrease of diabetic retinopathy compared to the previous year, although the number of patients newly diagnosed with diabetes has been increasing in Denmark. DiaBase is a useful tool to observe the quality of screening, prevalence, and progression/regression of diabetic eye disease.
PMCID: PMC5094648  PMID: 27822108
diabetes; DiaBase; Danish Diabetes Database; national annual report; quality of care; database; registry; quality indicator
10.  Prosthetic valve endocarditis after transcatheter aortic valve implantation-diagnostic and surgical considerations 
Journal of Thoracic Disease  2016;8(10):E1213-E1218.
Prosthetic valve endocarditis (PVE) after transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR) is a potential life threatening complication. Better understanding of the incidence, predictors, clinical presentation, diagnostic measures, complications and management of PVE may help improve TAVI long-term outcome. We report a case of TAVI-PVE in an 80-year-old high risk patient in whom SAVR was successfully performed. We have reviewed literature regarding TAVI-PVE.
PMCID: PMC5107464  PMID: 27867590
Transcatheter aortic valve implantation (TAVI); prosthetic Valve endocarditis (PVE)
11.  12th International Conference on Conservative Management of Spinal Deformities – SOSORT 2015 Annual Meeting 
Parent, Eric | Richter, Alan | Aulisa, Angelo Gabriele | Guzzanti, Vincenzo | Pizzetti, Paolo | Poscia, Andrea | Aulisa, Lorenzo | Simony, Ane | Christensen, Steen Bach | Andersen, Mikkel O. | Negrini, Alessandra | Donzelli, Sabrina | Maserati, Laura | Zaina, Fabio | Villafane, Jorge H | Negrini, Stefano | Fortin, Carole | Grunstein, Erin | Labelle, Hubert | Parent, Stefan | Feldman, Debbie Ehrmann | Lou, Edmond | Zheng, Rui | Hill, Doug | Donauer, Andreas | Tilburn, Melissa | Raso, Jim | Schreiber, Sanja | Parent, Eric | Kawchuk, Greg | Hedden, Douglas | Sánchez-Raya, Judith | Adrover, Antonia Matamalas | D’Agata, Elisabetta | Granell, Joan Bagó | Kluszczynski, Marek | Kluszczyńska, Anna | Wąsik, Jacek | Motow-Czyż, Marta | Kluszczyński, Adam | Simony, Ane | Hansen, Karen Hojmark | Thomsen, Hanne | Andersen, Mikkel Meyer | Vuust, Morten | Blicharska, Irmina | Durmała, Jacek | Wnuk, Bartosz | Matyja, Małgorzata | Szopa, Andrzej | Domagalska-Szopa, Małgorzata | Gallert-Kopyto, Weronika | Łosień, Tomasz | Plintla, Ryszard | Landauer, Franz | Vanas, Karl | Gur, Gozde | Altun, Necdet Sukru | Yakut, Yavuz | Gawda, Piotr | Majcher, Piotr | Sulam, Lior Neuhaus | Bradley, Michael | Glynn, David | Hughes, Alex | Maude, Erika | Pilcher, Christine | Lebel, Andrea | Lebel, Victoria Ashley | Orbán, Judit | Stępień, Agnieszka | Graff, Krzysztof | Speers, D. | Aulisa, Angelo Gabriele | Guzzanti, Vincenzo | Mastantuoni, Giuseppe | Poscia, Andrea | Aulisa, Lorenzo | Aulisa, Angelo Gabriele | Guzzanti, Vincenzo | Falciglia, Francesco | Poscia, Andrea | Aulisa, Lorenzo | Karavidas, Nikos | Etemadifar, Mohammadreza | Donzelli, Sabrina | Zaina, Fabio | Lusini, Monia | Minnella, Salvatore | Balzarini, Luca | Respizzi, Stefano | Negrini, Stefano | Güttinger, Kathrin | Durmała, Jacek | Blicharska, Irmina | Drosdzol–Cop, Agnieszka | Skrzypulec–Plinta, Violetta | D’Agata, Elisabetta | Sánchez-Raya, Judith | Sánchez-Raya, Judith | D’Agata, Elisabetta | Paśko, Sławomir | Glinkowski, Wojciech | Michoński, Jakub | Walesiak, Katarzyna | Pakuła, Anna | Sitnik, Robert | Glinkowski, Wojciech | Diers, Helmut | Majcher, Piotr | Gawda, Piotr | Lebel, Andrea | Lebel, Victoria Ashley | van Loon, Piet | van Erve, Ruud | Grotenhuis, Andre | Zapata, Karina | Parent, Eric | Sucato, Dan | Korbel, Krzysztof | Kozinoga, Mateusz | Stoliński, Łukasz | Kotwicki, Tomasz | Lebel, Andrea | Lebel, Victoria Ashley | Diers, Helmut | Berdishevsky, Hagit | Berdishevsky, Hagit
Scoliosis and Spinal Disorders  2016;11(Suppl 1):23.
O1 The functional properties of paraspinal muscles in adolescents with idiopathic scoliosis (AIS): A systematic review of the literature
Eric Parent, Alan Richter
O2 The importance of the lateral profile in the treatment of idiopathic scoliosis
Angelo Gabriele Aulisa, Vincenzo Guzzanti, Paolo Pizzetti, Andrea Poscia, Lorenzo Aulisa
O3 Radiological outcome in Adolescent idiopathic scoliosis patients 20 years after treatment
Ane Simony, Steen Bach Christensen, Mikkel O Andersen
O4 Junctional Kyphosis, how can we detect and monitor it during growth?
Alessandra Negrini, Sabrina Donzelli, Laura Maserati, Fabio Zaina, Jorge H Villafane, Stefano Negrini
O5 Usefulness of the clinical measure of trunk imbalance in adolescent idiopathic scoliosis
Carole Fortin, Erin Grunstein, Hubert Labelle, Stefan Parent, Debbie Ehrmann Feldman
O6 Can ultrasound imaging be used to determine curve flexibility when designing spinal orthoses?
Edmond Lou, Rui Zheng, Doug Hill, Andreas Donauer, Melissa Tilburn, Jim Raso
O7 Reliability of the Schroth curve type classification in adolescents with idiopathic scoliosis (AIS)
Sanja Schreiber, Eric Parent, Greg Kawchuk, Douglas Hedden
O8 Can Trunk Appearance Perception Scale (TAPS) be used as a descriptive tool of scoliosis severity?
Judith Sánchez-Raya, Antonia Matamalas Adrover, Elisabetta D’Agata, Joan Bagó Granell
O9 Magnitude of the Cobb angle on an X-ray in relation to the angle of trunk rotation in children who come to the “Troniny” Scoliosis Treatment Centre
Marek Kluszczynski, Anna Kluszczyńska, Jacek Wąsik, Marta Motow-Czyż, Adam Kluszczyński
O10 Cobb angel measurement without X-ray, a novel method
Ane Simony, Karen Hojmark Hansen; Hanne Thomsen; Mikkel Meyer Andersen; Morten Vuust
O11 The postural tone magnitude and distribution in patients diagnosed with an adolescent idiopathic scoliosis: a preliminary study
Irmina Blicharska, Jacek Durmała, Bartosz Wnuk, Małgorzata Matyja
O12 From studies on the function of the respiratory system in children with body posture defects
Andrzej Szopa, Małgorzata Domagalska-Szopa, Weronika Gallert-Kopyto, Tomasz Łosień, Ryszard Plintla
O13 Scoliosis as the “first” sign of various diseases
Franz Landauer, Karl Vanas
O14 The effectiveness of core stabilization exercises versus conventional exercises in addition to brace wearing in patients with adolescent idiopathic acoliosis
Gozde Gur, Necdet Sukru Altun, Yavuz Yakut
O15 The effect of physiotherapy techniques on the body balance in patients with scoliosis treated with corrective appliances
Piotr Gawda, Piotr Majcher
O16 New combine method treating AIS – preliminary results
Lior Neuhaus Sulam
O17 Does a 4-week intensive course of ScolioGold therapy reduce angle of trunk rotation in scoliotic patients: a retrospective case series.
Michael Bradley, David Glynn, Alex Hughes, Erika Maude, Christine Pilcher
O18 Schroth physiotherapy method without bracing is an effective treatment for scoliosis in improving curves and avoiding surgery and should be offered as a treatment option for scoliosis in Canada: case series
Andrea Lebel, Victoria Ashley Lebel, Judit Orbán
O19 Rotation of the trunk and pelvis and coupled movements in the sagittal plane in double support stance in adolescent girls with idiopathic scoliosis
Agnieszka Stępień, Krzysztof Graff
O20 Curve progression analysis in Risser 0 patients orthotically managed with compliance monitors
D. Speers
O21 Conservative treatment in Scheuermann’s kyphosis: comparison between lateral curve and variation of the vertebral geometry
Angelo Gabriele Aulisa, Vincenzo Guzzanti, Giuseppe Mastantuoni, Andrea Poscia, Lorenzo Aulisa
O22 The plaster cast in the conservative treatment of idiopathic scoliosis can still play a positive role?
Angelo Gabriele Aulisa, Vincenzo Guzzanti, Francesco Falciglia, Andrea Poscia, Lorenzo Aulisa
O23 Bracing for Adolescent Idiopathic Scoliosis (AIS) and Scheuermann Kyphosis : The issue of overtreatment in Greece
Nikos Karavidas
O24 Efficacy of Milwaukee brace for correction of scheurmann kyphosis
Mohammadreza Etemadifar
O25 The three dimensional analysis of the Sforzesco brace correction
Sabrina Donzelli, Fabio Zaina, Monia Lusini, Salvatore Minnella, Luca Balzarini, Stefano Respizzi, Stefano Negrini
O26 Quality of Life in adolescents with idiopathic scoliosis: A comparison measured by the Kidscreen 27 between scoliotic patients and healthy controls
Kathrin Güttinger
O27 The degree of illness acceptance in young women with idiopathic scoliosis treated with orthopedic braces: a preliminary study
Jacek Durmała, Irmina Blicharska, Agnieszka Drosdzol–Cop, Violetta Skrzypulec–Plinta
O28 Which are the personality traits of the patients with Adolescent Idiopathic Scoliosis?
Elisabetta D’Agata, Judith Sánchez-Raya
O29 How many Scolioses do exist in the same person? A zoom vision on the perception of the patient
Judith Sánchez-Raya, Elisabetta D’Agata
P1 The algorithm for the automatic detection of the pelvic obliquity based on analysis of the PA viev of the x-ray image
Sławomir Paśko, Wojciech Glinkowski
P2 Monitoring of spine curvatures and posture during pregnancy using surface topography – case study and method assessment
Jakub Michoński, Katarzyna Walesiak, Anna Pakuła, Robert Sitnik, Wojciech Glinkowski
P3 Spinal rotation under static and dynamic conditions: a prospective study comparing normative data vs. scoliosis
Helmut Diers
P4 The principle of non-surgical treatment of idiopathic scoliosis right-sided breast depending on the volatility of the formation of the intervertebral discs and vertebral bodies
Piotr Majcher, Piotr Gawda
P5 Unexpected late progression of adolescent idiopathic scoliosis treated with short-term, aggressive, full-time bracing and Schroth physiotherapy with excellent preliminary result: case study
Andrea Lebel, Victoria Ashley Lebel
P6 Visible posture in relation to the neuroanatomical and neurodynamical features in spinal deformations
Piet van Loon, Ruud van Erve, Andre Grotenhuis
P7 Immediate effects of scoliosis-specific corrective exercises on the Cobb angle after 1 week and after 1 year of practice
Karina Zapata, Eric Parent, Dan Sucato
P8 Retrospective analysis of idiopathic scoliosis medical records coming from one out-patient clinic for compatibility with Scoliosis Research Society criteria of brace treatment studies
Krzysztof Korbel, Mateusz Kozinoga, Łukasz Stoliński, Tomasz Kotwicki
P9 Adult female with severe progressive scoliosis possibly secondary to benign tumor removal at age 3 treated with scoliosis specific Schroth physiotherapy after refusing surgery: case study
Andrea Lebel, Victoria Ashley Lebel
P10 New aspects of scoliosis therapy planning and monitoring
Helmut Diers
P11 Outcome of intensive outpatient rehabilitation in an adult patient with M. Scheuermann evaluated by radiologic imaging – a case report
Hagit Berdishevsky
P12 The effectiveness of a Scoliosis Specific Home Exercise Program and bracing to reduce an idiopathic scoliosis curve with more than 90 % success in less than a year of exercises. Case report.
Hagit Berdishevsky
PMCID: PMC5001244
12.  Effect of Marriage and Spousal Criminality on Recidivism 
The authors analyzed whether the effect of marriage on recidivism varied by spousal criminality. For this purpose, they used propensity score matching and full population data from Statistics Denmark on all unmarried and previously convicted men from birth cohorts 1965–1985 (N = 102,839). The results showed that marriage reduced recidivism compared to nonmarriage only when the spouse had no criminal record. Similarly, marriage to a nonconvicted spouse reduced recidivism significantly more than marriage to a convicted spouse. These findings not only underline how important marriage is for social integration but also stress the heterogeneous nature of the protective effects of marriage.
PMCID: PMC4964922  PMID: 27524833
crime; marital quality; marriage; quantitative methodology; sociology
13.  Right Ventricular Myocardial Stiffness in Experimental Pulmonary Arterial Hypertension 
Circulation. Heart Failure  2016;9(7):e002636.
Supplemental Digital Content is available in the text.
The purpose of this study was to determine the relative contribution of fibrosis-mediated and myofibril-mediated stiffness in rats with mild and severe right ventricular (RV) dysfunction.
Methods and Results—
By performing pulmonary artery banding of different diameters for 7 weeks, mild RV dysfunction (Ø=0.6 mm) and severe RV dysfunction (Ø=0.5 mm) were induced in rats. The relative contribution of fibrosis- and myofibril-mediated RV stiffness was determined in RV trabecular strips. Total myocardial stiffness was increased in trabeculae from both mild and severe RV dysfunction in comparison to controls. In severe RV dysfunction, increased RV myocardial stiffness was explained by both increased fibrosis-mediated stiffness and increased myofibril-mediated stiffness, whereas in mild RV dysfunction, only myofibril-mediated stiffness was increased in comparison to control. Histological analyses revealed that RV fibrosis gradually increased with severity of RV dysfunction, whereas the ratio of collagen I/III expression was only elevated in severe RV dysfunction. Stiffness measurements in single membrane-permeabilized RV cardiomyocytes demonstrated a gradual increase in RV myofibril stiffness, which was partially restored by protein kinase A in both mild and severe RV dysfunction. Increased expression of compliant titin isoforms was observed only in mild RV dysfunction, whereas titin phosphorylation was reduced in both mild and severe RV dysfunction.
RV myocardial stiffness is increased in rats with mild and severe RV dysfunction. In mild RV dysfunction, stiffness is mainly determined by increased myofibril stiffness. In severe RV dysfunction, both myofibril- and fibrosis-mediated stiffness contribute to increased RV myocardial stiffness.
PMCID: PMC4956674  PMID: 27370069
collagen; fibrosis; heart failure; hypertension; right ventricular dysfunction
14.  Determinants related to gender differences in general practice utilization: Danish Diet, Cancer and Health Cohort 
This study aims to describe the determinants related to gender differences in the GP utilization in Danish population aged 50–65 years.
Cohort-based cross-sectional study.
Danish general practice.
Totally, 54,849 participants of the Danish Diet, Cancer and Health cohort (50–65 years).
Main outcome measures
The sum of cohort members’ face-to-face consultations with general practitioner (GP) at the cohort baseline year (1993–1997). We obtained data on GP visits from the Danish National Health Service Register at the cohort baseline (1993–1997), when information on lifestyle (smoking, body mass index (BMI), alcohol use, physical activity), medical conditions (somatic and mental), employment, education, gravidity, and hormone therapy (HT) use was collected by questionnaire.
Women had on average 4.1 and men 2.8 consultations per year. In a crude model, women had 47% higher rate of GP visits than men (incidence rate ratio: 1.47; 95% Confidence Interval: 1.45–1.50), which remained unchanged after adjustment for lifestyle, socio-demographic and medical factors, but attenuated to 18% (1.18; 1.13–1.24) after adjustment for female factors (gravidity and post-menopausal HT. In a fully adjusted model, subjects with hypertension (1.63; 1.59–1.67), mental illness (1.63; 1.61–1.66), diabetes (1.56; 1.47–1.65), angina pectoris (1.28; 1.21–1.34), and unemployed persons (1.19; 1.18–1.21) had highest rates of GP visits.
Gravidity and HT use explain a large proportion, but not all of the gender difference in GP utilization. Medical conditions (somatic and mental) and unemployment are the main determinants of GP utilization in men and women, while lifestyle has minor effect.
Key Points
Female gender remained a dominant determinant of GP utilization, after adjustment for lifestyle, socio-demography, medical and gender specific factors, with females consulting their GP 18% more often than males.Female reproductive factors (use of postmenopausal hormone therapy and gravidity) explained a large proportion of the gender variation in use of GP.Strongest determinants for GP use among Danish adults aged 50–65 years were the presence of medical conditions (somatic and mental) and unemployment, while lifestyle factors (e.g., body mass index, alcohol consumption and smoking) had minor effect.
PMCID: PMC5036013  PMID: 27421064
Cohort; Denmark; gender; general practice; health service use; lifestyle; unemployment
15.  Increasing incidence of base of tongue cancers from 2000 to 2010 due to HPV: the largest demographic study of 210 Danish patients 
British Journal of Cancer  2015;113(1):131-134.
We assessed the development in the number of new base of tongue squamous-cell carcinoma (BSCC) cases per year in eastern Denmark from 2000 to 2010 and whether HPV may explain any observable increased incidence.
We performed HPV DNA PCR and p16 immunohistochemistry analysis for all (n=210) BSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and the Danish Pathology Data Bank, and genotyped all HPV-positive specimens with amplicon-based next-generation sequencing.
The overall crude incidence of BSCCs increased significantly (5.4% per year) during the study period. This was explained by a significant increase in the number of HPV-positive BSCCs (8.1% per year), whereas the number of HPV-negative BSCCs did not increase significantly. The overall HPV prevalence was 51%, with HPV16 as the predominant HPV type.
The increased number of HPV-positive BSCCs may explain the increasing incidence of BSCCs in eastern Denmark, 2000–2010.
PMCID: PMC4647522  PMID: 26042932
base of tongue cancer; oropharyngeal cancer; HPV; p16
16.  Bone regenerating effect of surface-functionalized titanium implants with sustained-release characteristics of strontium in ovariectomized rats 
Since strontium (Sr) is known for its anabolic and anticatabolic effect on bone, research has been focused on its potential impact on osseointegration. The objective of this study was to investigate the performance of nanotopographic implants with a Sr-functionalized titanium (Ti) coating (Ti–Sr–O) with respect to osseointegration in osteoporotic bone. The trial was designed to examine the effect of sustained-release characteristics of Sr in poor-quality bone. Three Ti–Sr–O groups, which differed from each other in coating thickness, Sr contents, and Sr release, were examined. These were prepared by a magnetron sputtering process and compared to uncoated grade 4 Ti. Composition, morphology, and mechanical stability of the coatings were analyzed, and Sr release data were gained from in vitro washout experiments. In vivo investigation was carried out in an osteoporotic rat model and analyzed histologically, 6 weeks and 12 weeks after implantation. Median values of bone-to-implant contact and new bone formation after 6 weeks were found to be 84.7% and 54.9% (best performing Sr group) as compared to 65.2% and 23.8% (grade 4 Ti reference), respectively. The 12-week observation period revealed 84.3% and 56.5% (best performing Sr group) and 81.3% and 39.4% (grade 4 Ti reference), respectively, for the same measurements. The increase in new bone formation was found to correlate with the amount of Sr released in vitro. The results indicate that sputtered nanostructured Ti–Sr–O coatings showed sustained release of Sr and accelerate osseointegration even in poor-quality bone, and thus, may have impact on practical applications for medical implants.
PMCID: PMC4892864  PMID: 27313456
nanotopography; osteoinduction; osseointegration; osteoporosis; rodent
17.  Competence Classification of Cumulus and Granulosa Cell Transcriptome in Embryos Matched by Morphology and Female Age 
PLoS ONE  2016;11(4):e0153562.
By focussing on differences in the mural granulosa cell (MGC) and cumulus cell (CC) transcriptomes from follicles resulting in competent (live birth) and non-competent (no pregnancy) oocytes the study aims on defining a competence classifier expression profile in the two cellular compartments. Design: A case-control study. Setting: University based facilities for clinical services and research. Patients: MGC and CC samples from 60 women undergoing IVF treatment following the long GnRH-agonist protocol were collected. Samples from 16 oocytes where live birth was achieved and 16 age- and embryo morphology matched incompetent oocytes were included in the study.
MGC and CC were isolated immediately after oocyte retrieval. From the 16 competent and non-competent follicles, mRNA was extracted and expression profile generated on the Human Gene 1.0 ST Affymetrix array. Live birth prediction analysis using machine learning algorithms (support vector machines) with performance estimation by leave-one-out cross validation and independent validation on an external data set.
We defined a signature of 30 genes expressed in CC predictive of live birth. This live birth prediction model had an accuracy of 81%, a sensitivity of 0.83, a specificity of 0.80, a positive predictive value of 0.77, and a negative predictive value of 0.86. Receiver operating characteristic analysis found an area under the curve of 0.86, significantly greater than random chance. When applied on 3 external data sets with the end-point outcome measure of blastocyst formation, the signature resulted in 62%, 75% and 88% accuracy, respectively. The genes in the classifier are primarily connected to apoptosis and involvement in formation of extracellular matrix. We were not able to define a robust MGC classifier signature that could classify live birth with accuracy above random chance level.
We have developed a cumulus cell classifier, which showed a promising performance on external data. This suggests that the gene signature at least partly include genes that relates to competence in the developing blastocyst.
PMCID: PMC4851390  PMID: 27128483
18.  Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter 
Nature Communications  2016;7:11261.
Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode photocrosslinking unnatural amino acids (UAAs) into 75 different positions in hSERT. UAAs are incorporated with high specificity, and functionally active transporters have similar transport properties and pharmacological profiles compared with wild-type transporters. We employ ultraviolet-induced crosslinking with p-azido-L-phenylalanine (azF) at selected positions in hSERT to map the binding site of imipramine, a prototypical tricyclic antidepressant, and vortioxetine, a novel multimodal antidepressant. We find that the two antidepressants crosslink with azF incorporated at different positions within the central substrate-binding site of hSERT, while no crosslinking is observed at the vestibular-binding site. Taken together, our data provide direct evidence for defining the high-affinity antidepressant binding site in hSERT.
Molecular details of how antidepressant drugs bind to the human serotonin transporter are not currently clear. Here, the authors introduce photo-cross-linkers into the protein and map the binding site of several antidepressants.
PMCID: PMC4838859  PMID: 27089947
19.  Occupational Tuberculosis in Denmark through 21 Years Analysed by Nationwide Genotyping 
PLoS ONE  2016;11(4):e0153668.
Tuberculosis (TB) is a well-known occupational hazard. Based on more than two decades (1992–2012) of centralized nationwide genotyping of all Mycobacterium tuberculosis culture-positive TB patients in Denmark, we compared M. tuberculosis genotypes from all cases notified as presumed occupational (N = 130) with M. tuberculosis genotypes from all TB cases present in the country (N = 7,127). From 1992 through 2006, the IS6110 Restriction Fragment Length Polymorphism (RFLP) method was used for genotyping, whereas from 2005 to present, the 24-locus-based Mycobacterial Interspersed Repetitive Unit-Variable Number of Tandem Repeat (MIRU-VNTR) was used. An occupational TB case was classified as clustered if the genotype was 100% identical to at least one other genotype. Subsequently, based on genotype, time period, smear positivity, geography, susceptibility pattern, and any reported epidemiological links between the occupational cases and any potential source cases, the occupational case was categorized as confirmed, likely, possible or unlikely occupationally infected. Among the 130 notified presumed occupational cases, 12 (9.2%) could be classified as confirmed and 46 (35.4%) as unlikely, accounting for nearly half of all cases (44.6%). The remaining 72 cases (55.4%) were categorized as possible. Within this group, 15 cases (11.5%) were assessed to be likely occupational. Our study shows that genotyping can serve as an important tool for disentangle occupational TB in high-income low incidence settings, but still needs to be combined with good epidemiological linkage information.
PMCID: PMC4833408  PMID: 27082745
20.  Importance of nonsynonymous OCA2 variants in human eye color prediction 
The color of the eyes is one of the most prominent phenotypes in humans and it is often used to describe the appearance of an individual. The intensity of pigmentation in the iris is strongly associated with one single‐nucleotide polymorphism (SNP), rs12913832:A>G that is located in the promotor region of OCA2 (OMIM #611409). Nevertheless, many eye colors cannot be explained by only considering rs12913832:A>G.
In this study, we searched for additional variants in OCA2 to explain human eye color by sequencing a 500 kbp region, encompassing OCA2 and its promotor region.
We identified three nonsynonymous OCA2 variants as important for eye color, including rs1800407:G>A (p.Arg419Gln) and two variants, rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile), not previously described as important for eye color variation. It was shown that estimated haplotypes consisting of four variants (rs12913832:A>G, rs1800407:G>A (p.Arg419Gln), rs74653330:A>T (p.Ala481Thr), and rs121918166:G>A (p.Val443Ile)) explained 75.6% (adjusted R 2 = 0.76) of normal eye color variation, whereas rs12913832:A>G alone explained 68.8% (adjusted R 2 = 0.69). Moreover, rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile) had a measurable effect on quantitative skin color (P = 0.008).
Our data showed that rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile) have a measurable effect on normal pigmentation variation.
PMCID: PMC4947861  PMID: 27468418
Eye color; forensic DNA phenotyping; nonsynonymous variants; OCA2; pigmentation; rs74653330 and rs121918166; skin color
21.  Tryptophan 2,3-dioxygenase (TDO)-reactive T cells differ in their functional characteristics in health and cancer 
Oncoimmunology  2015;4(1):e968480.
Tryptophan-2,3-dioxygenase (TDO) physiologically regulates systemic tryptophan levels in the liver. However, numerous studies have linked cancer with activation of local and systemic tryptophan metabolism. Indeed, similar to other heme dioxygenases TDO is constitutively expressed in many cancers. In the present study, we detected the presence of both CD8+ and CD4+ T-cell reactivity toward TDO in peripheral blood of patients with malignant melanoma (MM) or breast cancer (BC) as well as healthy subjects. However, TDO-reactive CD4+ T cells constituted distinct functional phenotypes in health and disease. In healthy subjects these cells predominately comprised interferon (IFN)γ and tumor necrosis factor (TNF)-α producing Th1 cells, while in cancer patients TDO-reactive CD4+ T-cells were more differentiated with release of not only IFNγ and TNFα, but also interleukin (IL)-17 and IL-10 in response to TDO-derived MHC-class II restricted peptides. Hence, in healthy donors (HD) a Th1 helper response was predominant, whereas in cancer patients CD4+ T-cell responses were skewed toward a regulatory T cell (Treg) response. Furthermore, MM patients hosting a TDO-specific IL-17 response showed a trend toward an improved overall survival (OS) compared to MM patients with IL-10 producing, TDO-reactive CD4+ T cells. For further characterization, we isolated and expanded both CD8+ and CD4+ TDO-reactive T cells in vitro. TDO-reactive CD8+ T cells were able to kill HLA-matched tumor cells of different origin. Interestingly, the processed and presented TDO-derived epitopes varied between different cancer cells. With respect to CD4+ TDO-reactive T cells, in vitro expanded T-cell cultures comprised a Th1 and/or a Treg phenotype. In summary, our data demonstrate that the immune modulating enzyme TDO is a target for CD8+ and CD4+ T cell responses both in healthy subjects as well as patients with cancer; notably, however, the functional phenotype of these T-cell responses differ depending on the respective conditions of the host.
PMCID: PMC4368150  PMID: 25949861
immune regulation; T cells; TDO; Th17; Tregs
22.  Determinants of frequent attendance in Danish general practice: a cohort-based cross-sectional study 
BMC Family Practice  2016;17:9.
Previous studies addressing determinants of frequent attendance have mainly focused on socio-demographic, psychosocial and medical factors, and few had data on lifestyle and gender-specific factors. This study aims to describe determinants of general practice frequent attendance in Danish adult population, by examining lifestyle, socio-demographic, medical and gender-specific factors.
For 54,849 participants of the Danish Diet, Cancer and Health cohort (50–65 year old) we obtained data on visits to general practitioner (GP) from the Danish National Health Service Register at cohort baseline (1993–97), when information on medical conditions and lifestyle, socio-demographic and gender-specific factors was collected by questionnaire. Logistic regression was used to identify determinants of frequent attendance, defined as top 10 % GP users at the year of recruitment into the cohort (baseline) in the period between 1993 and 1997.
Frequent attenders accounted for 40 % of all face-to-face GP consultations with a mean 12 visits/year. Women were more likely to be frequent attenders, in crude (Odds ratio: 1.95; 95 % Confidence Interval: 1.85–2.06) and fully adjusted (1.26; 1.09–1.47) model. In a fully adjusted model, strongest determinants of frequent attendance were pre-existing medical conditions, with hypertension (2.58; 2.42–2.75), diabetes (2.24; 1.94–2.59), and mental illness (2.29; 2.09–2.52) more than doubling the odds of being FA. High education (0.63; 0.57–0.69, >4 years higher education vs. no vocational training) and employment (0.61; 0.57–0.65) were inversely associated with frequent attendance. Finally, obesity (1.54; 1.14–2.08), smoking (1.21; 1.12–1.30, current vs. never), physical activity (0.84; 0.80–89), alcohol consumption (0.83; 0.78–0.87 above vs. below recommended level), and hormone therapy in women (1.52; 1.42–1.63) were all significant determinants of frequent attendance.
In addition to pre-existing medical conditions, gender, socio-demographic and gender-specific factors, lifestyle (obesity, smoking, exercise and alcohol use) is also an independent determinant of frequent attendance at general practitioner.
PMCID: PMC4730631  PMID: 26821807
Frequent attendance; General practice; Gender; Lifestyle; Unemployment; Cohort
23.  Does physical exposure throughout working life influence chair-rise performance in midlife? A retrospective cohort study of associations between work and physical function in Denmark 
BMJ Open  2015;5(11):e009873.
Our aim was to study associations between physical exposures throughout working life and physical function measured as chair-rise performance in midlife.
The Copenhagen Aging and Midlife Biobank (CAMB) provided data about employment and measures of physical function. Individual job histories were assigned exposures from a job exposure matrix. Exposures were standardised to ton-years (lifting 1000 kg each day in 1 year), stand-years (standing/walking for 6 h each day in 1 year) and kneel-years (kneeling for 1 h each day in 1 year). The associations between exposure-years and chair-rise performance (number of chair-rises in 30 s) were analysed in multivariate linear and non-linear regression models adjusted for covariates.
Mean age among the 5095 participants was 59 years in both genders, and, on average, men achieved 21.58 (SD=5.60) and women 20.38 (SD=5.33) chair-rises in 30 s. Physical exposures were associated with poorer chair-rise performance in both men and women, however, only associations between lifting and standing/walking and chair-rise remained statistically significant among men in the final model. Spline regression analyses showed non-linear associations and confirmed the findings.
Higher physical exposure throughout working life is associated with slightly poorer chair-rise performance. The associations between exposure and outcome were non-linear.
PMCID: PMC4636598  PMID: 26537502
24.  Local infiltration analgesia is not improved by postoperative intra-articular bolus injections for pain after total hip arthroplasty 
Acta Orthopaedica  2015;86(6):647-653.
Background and purpose — The effect of postoperative intra-articular bolus injections after total hip arthroplasty (THA) remains unclear. We tested the hypothesis that intra-articular bolus injections administered every 6 hours after surgery during the first 24 hours would significantly improve analgesia after THA.
Patients and methods — 80 patients undergoing THA received high-volume local infiltration analgesia (LIA; 200 mg ropivacaine and 30 mg ketorolac) followed by 4 intra-articular injections with either ropivacaine (100 mg) and ketorolac (15 mg) (the treatment group) or saline (the control group). The intra-articular injections were combined with 4 intravenous injections of either saline (treatment group) or 15 mg ketorolac (control group). All patients received morphine as patient-controlled analgesia (PCA). The primary outcome was consumption of intravenous morphine PCA and secondary outcomes were consumption of oral morphine, pain intensity, side effects, readiness for hospital discharge, length of hospital stay, and postoperative consumption of analgesics at 3, 6, and 12 weeks after surgery.
Results — There were no statistically significant differences between the 2 groups regarding postoperative consumption of intravenous morphine PCA. Postoperative pain scores during walking were higher in the treatment group from 24–72 hours after surgery, but other pain scores were similar between groups. Time to readiness for hospital discharge was longer in the treatment group. Other secondary outcomes were similar between groups.
Interpretation — Postoperative intra-articular bolus injections of ropivacaine and ketorolac cannot be recommended as analgesic method after THA.
PMCID: PMC4750761  PMID: 26312445
25.  Binding site residues control inhibitor selectivity in the human norepinephrine transporter but not in the human dopamine transporter 
Scientific Reports  2015;5:15650.
The transporters for norepinephrine and dopamine (NET and DAT, respectively) constitute the molecular targets for recreational drugs and therapeutics used in the treatment of psychiatric disorders. Despite a strikingly similar amino acid sequence and predicted topology between these transporters, some inhibitors display a high degree of selectivity between NET and DAT. Here, a systematic mutational analysis of non-conserved residues within the extracellular entry pathway and the high affinity binding site in NET and DAT was performed to examine their role for selective inhibitor recognition. Changing the six diverging residues in the central binding site of NET to the complementary residues in DAT transferred a DAT-like pharmacology to NET, showing that non-conserved binding site residues in NET are critical determinants for inhibitor selectivity. In contrast, changing the equivalent residues in the central site of DAT to the corresponding residues in NET had modest effects on the same inhibitors, suggesting that non-conserved binding site residues in DAT play a minor role for selective inhibitor recognition. Our data points towards distinct structural determinants governing inhibitor selectivity in NET and DAT, and provide important new insight into the molecular basis for NET/DAT selectivity of therapeutic and recreational drugs.
PMCID: PMC4621520  PMID: 26503701

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