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1.  Adult height and the risk of cause-specific death and vascular morbidity in 1 million people: individual participant meta-analysis 
Wormser, David | Angelantonio, Emanuele Di | Kaptoge, Stephen | Wood, Angela M | Gao, Pei | Sun, Qi | Walldius, Göran | Selmer, Randi | Verschuren, WM Monique | Bueno-de-Mesquita, H Bas | Engström, Gunnar | Ridker, Paul M | Njølstad, Inger | Iso, Hiroyasu | Holme, Ingar | Giampaoli, Simona | Tunstall-Pedoe, Hugh | Gaziano, J Michael | Brunner, Eric | Kee, Frank | Tosetto, Alberto | Meisinger, Christa | Brenner, Hermann | Ducimetiere, Pierre | Whincup, Peter H | Tipping, Robert W | Ford, Ian | Cremer, Peter | Hofman, Albert | Wilhelmsen, Lars | Clarke, Robert | de Boer, Ian H | Jukema, J Wouter | Ibañez, Alejandro Marín | Lawlor, Debbie A | D'Agostino, Ralph B | Rodriguez, Beatriz | Casiglia, Edoardo | Stehouwer, Coen DA | Simons, Leon A | Nietert, Paul J | Barrett-Connor, Elizabeth | Panagiotakos, Demosthenes B | Björkelund, Cecilia | Strandberg, Timo E | Wassertheil-Smoller, Sylvia | Blazer, Dan G | Meade, Tom W | Welin, Lennart | Svärdsudd, Kurt | Woodward, Mark | Nissinen, Aulikki | Kromhout, Daan | Jørgensen, Torben | Tilvis, Reijo S | Guralnik, Jack M | Rosengren, Annika | Taylor, James O | Kiechl, Stefan | Dagenais, Gilles R | Gerry, F | Fowkes, R | Wallace, Robert B | Khaw, Kay-Tee | Shaffer, Jonathan A | Visser, Marjolein | Kauhanen, Jussi | Salonen, Jukka T | Gallacher, John | Ben-Shlomo, Yoav | Kitamura, Akihiko | Sundström, Johan | Wennberg, Patrik | Kiyohara, Yutaka | Daimon, Makoto | de la Cámara, Agustin Gómez | Cooper, Jackie A | Onat, Altan | Devereux, Richard | Mukamal, Kenneth J | Dankner, Rachel | Knuiman, Matthew W | Crespo, Carlos J | Gansevoort, Ron T | Goldbourt, Uri | Nordestgaard, Børge G | Shaw, Jonathan E | Mussolino, Michael | Nakagawa, Hidaeki | Fletcher, Astrid | Kuller, Lewis H | Gillum, Richard F | Gudnason, Vilmundur | Assmann, Gerd | Wald, Nicholas | Jousilahti, Pekka R | Greenland, Philip | Trevisan, Maurizio | Ulmer, Hanno | Butterworth, Adam S | Folsom, Aaron R | Davey-Smith, George | Hu, Frank B | Danesh, John | Tipping, Robert W | Ford, Charles E | Simpson, Lara M | Walldius, Göran | Jungner, Ingmar | Folsom, Aaron R | Demerath, Ellen W | Franceschini, Nora | Lutsey, Pamela L | Panagiotakos, Demosthenes B | Pitsavos, Christos | Chrysohoou, Christina | Stefanadis, Christodoulos | Shaw, Jonathan E | Atkins, Robert | Zimmet, Paul Z | Barr, Elizabeth LM | Knuiman, Matthew W | Whincup, Peter H | Wannamethee, S Goya | Morris, Richard W | Willeit, Johann | Kiechl, Stefan | Weger, Siegfried | Oberhollenzer, Friedrich | Wald, Nicholas | Ebrahim, Shah | Lawlor, Debbie A | Gallacher, John | Ben-Shlomo, Yoav | Yarnell, John WG | Casiglia, Edoardo | Tikhonoff, Valérie | Greenland, Philip | Shay, Christina M | Garside, Daniel B | Nietert, Paul J | Sutherland, Susan E | Bachman, David L | Keil, Julian E | de Boer, Ian H | Kizer, Jorge R | Psaty, Bruce M | Mukamal, Kenneth J | Nordestgaard, Børge G | Tybjærg-Hansen, Anne | Jensen, Gorm B | Schnohr, Peter | Giampaoli, Simona | Palmieri, Luigi | Panico, Salvatore | Pilotto, Lorenza | Vanuzzo, Diego | de la Cámara, Agustin Gómez | Simons, Leon A | Simons, Judith | McCallum, John | Friedlander, Yechiel | Gerry, F | Fowkes, R | Price, Jackie F | Lee, Amanda J | Taylor, James O | Guralnik, Jack M | Phillips, Caroline L | Wallace, Robert B | Kohout, Frank J | Cornoni-Huntley, Joan C | Guralnik, Jack M | Blazer, Dan G | Guralnik, Jack M | Phillips, Caroline L | Phillips, Caroline L | Guralnik, Jack M | Khaw, Kay-Tee | Wareham, Nicholas J | Brenner, Hermann | Schöttker, Ben | Müller, Heiko | Rothenbacher, Dietrich | Wennberg, Patrik | Jansson, Jan-Håkan | Nissinen, Aulikki | Donfrancesco, Chiara | Giampaoli, Simona | Woodward, Mark | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | D'Agostino, Ralph B | Vasan, Ramachandran S | Fox, Caroline S | Pencina, Michael J | Daimon, Makoto | Oizumi, Toshihide | Kayama, Takamasa | Kato, Takeo | Bladbjerg, Else-Marie | Jørgensen, Torben | Møller, Lars | Jespersen, Jørgen | Dankner, Rachel | Chetrit, Angela | Lubin, Flora | Svärdsudd, Kurt | Eriksson, Henry | Welin, Lennart | Lappas, Georgios | Rosengren, Annika | Lappas, Georgios | Welin, Lennart | Svärdsudd, Kurt | Eriksson, Henry | Lappas, Georgios | Bengtsson, Calle | Lissner, Lauren | Björkelund, Cecilia | Cremer, Peter | Nagel, Dorothea | Strandberg, Timo E | Salomaa, Veikko | Tilvis, Reijo S | Miettinen, Tatu A | Tilvis, Reijo S | Strandberg, Timo E | Kiyohara, Yutaka | Arima, Hisatomi | Doi, Yasufumi | Ninomiya, Toshiharu | Rodriguez, Beatriz | Dekker, Jacqueline M | Nijpels, Giel | Stehouwer, Coen DA | Hu, Frank B | Sun, Qi | Rimm, Eric B | Willett, Walter C | Iso, Hiroyasu | Kitamura, Akihiko | Yamagishi, Kazumasa | Noda, Hiroyuki | Goldbourt, Uri | Vartiainen, Erkki | Jousilahti, Pekka R | Harald, Kennet | Salomaa, Veikko | Kauhanen, Jussi | Salonen, Jukka T | Kurl, Sudhir | Tuomainen, Tomi-Pekka | Poppelaars, Jan L | Deeg, Dorly JH | Visser, Marjolein | Meade, Tom W | De Stavola, Bianca Lucia | Hedblad, Bo | Nilsson, Peter | Engström, Gunnar | Verschuren, WM Monique | Blokstra, Anneke | de Boer, Ian H | Shea, Steven J | Meisinger, Christa | Thorand, Barbara | Koenig, Wolfgang | Döring, Angela | Verschuren, WM Monique | Blokstra, Anneke | Bueno-de-Mesquita, H Bas | Wilhelmsen, Lars | Rosengren, Annika | Lappas, Georgios | Fletcher, Astrid | Nitsch, Dorothea | Kuller, Lewis H | Grandits, Greg | Tverdal, Aage | Selmer, Randi | Nystad, Wenche | Mussolino, Michael | Gillum, Richard F | Hu, Frank B | Sun, Qi | Manson, JoAnn E | Rimm, Eric B | Hankinson, Susan E | Meade, Tom W | De Stavola, Bianca Lucia | Cooper, Jackie A | Bauer, Kenneth A | Davidson, Karina W | Kirkland, Susan | Shaffer, Jonathan A | Shimbo, Daichi | Kitamura, Akihiko | Iso, Hiroyasu | Sato, Shinichi | Holme, Ingar | Selmer, Randi | Tverdal, Aage | Nystad, Wenche | Nakagawa, Hidaeki | Miura, Katsuyuki | Sakurai, Masaru | Ducimetiere, Pierre | Jouven, Xavier | Bakker, Stephan JL | Gansevoort, Ron T | van der Harst, Pim | Hillege, Hans L | Crespo, Carlos J | Garcia-Palmieri, Mario R | Kee, Frank | Amouyel, Philippe | Arveiler, Dominique | Ferrières, Jean | Schulte, Helmut | Assmann, Gerd | Jukema, J Wouter | de Craen, Anton JM | Sattar, Naveed | Stott, David J | Cantin, Bernard | Lamarche, Benoît | Després, Jean-Pierre | Dagenais, Gilles R | Barrett-Connor, Elizabeth | Bergstrom, Jaclyn | Bettencourt, Richele R | Buisson, Catherine | Gudnason, Vilmundur | Aspelund, Thor | Sigurdsson, Gunnar | Thorsson, Bolli | Trevisan, Maurizio | Hofman, Albert | Ikram, M Arfan | Tiemeier, Henning | Witteman, Jacqueline CM | Tunstall-Pedoe, Hugh | Tavendale, Roger | Lowe, Gordon DO | Woodward, Mark | Devereux, Richard | Yeh, Jeun-Liang | Ali, Tauqeer | Calhoun, Darren | Ben-Shlomo, Yoav | Davey-Smith, George | Onat, Altan | Can, Günay | Nakagawa, Hidaeki | Sakurai, Masaru | Nakamura, Koshi | Morikawa, Yuko | Njølstad, Inger | Mathiesen, Ellisiv B | Løchen, Maja-Lisa | Wilsgaard, Tom | Sundström, Johan | Ingelsson, Erik | Michaëlsson, Karl | Cederholm, Tommy | Gaziano, J Michael | Buring, Julie | Ridker, Paul M | Gaziano, J Michael | Ridker, Paul M | Ulmer, Hanno | Diem, Günter | Concin, Hans | Rodeghiero, Francesco | Tosetto, Alberto | Wassertheil-Smoller, Sylvia | Manson, JoAnn E | Marmot, Michael | Clarke, Robert | Fletcher, Astrid | Brunner, Eric | Shipley, Martin | Kivimaki, Mika | Ridker, Paul M | Buring, Julie | Ford, Ian | Robertson, Michele | Ibañez, Alejandro Marín | Feskens, Edith | Geleijnse, Johanna M | Kromhout, Daan | Walker, Matthew | Watson, Sarah | Alexander, Myriam | Butterworth, Adam S | Angelantonio, Emanuele Di | Franco, Oscar H | Gao, Pei | Gobin, Reeta | Haycock, Philip | Kaptoge, Stephen | Seshasai, Sreenivasa R Kondapally | Lewington, Sarah | Pennells, Lisa | Rapsomaniki, Eleni | Sarwar, Nadeem | Thompson, Alexander | Thompson, Simon G | Walker, Matthew | Watson, Sarah | White, Ian R | Wood, Angela M | Wormser, David | Zhao, Xiaohui | Danesh, John
Background The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.
Methods We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual–participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.
Results For people born between 1900 and 1960, mean adult height increased 0.5–1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96–0.99) for death from any cause, 0.94 (0.93–0.96) for death from vascular causes, 1.04 (1.03–1.06) for death from cancer and 0.92 (0.90–0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12–1.42) for risk of melanoma death to 0.84 (0.80–0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.
Conclusion Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
doi:10.1093/ije/dys086
PMCID: PMC3465767  PMID: 22825588
Height; cardiovascular disease; cancer; cause-specific mortality; epidemiological study; meta-analysis
2.  Temporal Trends in Self-reported Functional Limitations and Physical Disability Among Community-dwelling Elders: The Framingham Heart Study 
American journal of public health  2008;98(7):1256-1262.
Objective
To determine change in the prevalence of functional limitations and physical disability in community-dwelling elders across three decades.
Methods
We studied original participants of the Framingham Study, aged 79 to 88 years, at exam 15 (1977–1979, 177 women, 103 men), exam 20 (1988–1990, 159 women, 98 men) and exam 25 (1997 to 1999, 174 women, 119 men). Self-reported 1) functional limitation defined using the Nagi scale and 2) physical disability defined using the Rosow-Breslau and Katz scales.
Results
Functional limitations declined across examinations from 74.6% to 60.5% to 37.9% (p< 0.001) in women and 54.2%, 37.8%, and 27.8% (p<0.001) in men. Physical disability declined from 74.5% to 48.5% to 34.6% (p< 0.001) in women and 42.3% to 33.3% to 22.8% (p=0.009) in men. Women had a greater decline in disability than men (p=0.03). In women, improvements in functional limitations (p=0.05) were greater from exam 20 to 25 whereas for physical disability (p=0.02) improvements were greater from exam 15 to 20. Improvements in function were constant across the three examinations in men.
Conclusions
Among community-dwelling elders the prevalence of functional limitations and physical disability declined significantly from the 1970s to the 1990s.
doi:10.2105/AJPH.2007.128132
PMCID: PMC2424084  PMID: 18511716
functional limitations; physical disability; trends; elders
3.  Cardiovascular Risk Estimation in 2012: Lessons Learned and Applicability to the HIV Population 
The Journal of Infectious Diseases  2012;205(Suppl 3):S362-S367.
Cardiovascular disease (CVD) risk assessment tools such as the Framingham Risk Functions, often called Framingham Risk Scores, are common in the evaluation of the CVD risk among individuals in the general population. These functions are multivariate risk algorithms that combine data on CVD risk factors, such as sex, age, systolic blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking behavior, and diabetes status, to produce an estimate (or risk) of developing CVD or a component of it (such as coronary heart disease, stroke, peripheral vascular disease, and heart failure) over a fixed period (eg, the next 10 years). These estimates of CVD risk are often major inputs in recommending drug treatments, such as agents to reduce cholesterol level. The Framingham Risk Functions are valid in diverse populations, at times requiring a calibration adjustment for proper applicability. With the realization that individuals with human immunodeficiency virus (HIV) infection often have elevated CVD risk factors, the evaluation of CVD risk for these individuals becomes a serious concern. Researchers have recently developed new CVD risk functions specifically for HIV-infected patients and have also examined the extension of existing Framingham Risk Functions to the HIV-infected population. This article first reviews briefly the Framingham Study and risk functions, covering their objectives, their components, evaluation of their performance, and transportability and validity on non-Framingham populations. It then reviews the development of CVD risk functions for HIV-infected individuals and comments on the usefulness of extending the Framingham risk equation to the HIV-infected population and the need to develop more-specific risk prediction equations uniquely tailored to this population.
doi:10.1093/infdis/jis196
PMCID: PMC3349294  PMID: 22577209
4.  Feasibility of Using a Community-Supported Agriculture Program to Improve Fruit and Vegetable Inventories and Consumption in an Underresourced Urban Community 
Introduction
Direct-to-consumer marketing efforts, such as community-supported agriculture (CSA), have been proposed as a solution for disparities in fruit and vegetable consumption. Evaluations of such efforts have been limited. The objective of this study was to test the feasibility of a CSA intervention to increase household inventory of fruits and vegetables and fruit and vegetable consumption of residents of an underresourced community.
Methods
For this randomized, controlled feasibility study, we recruited 50 low-income women with children. Intervention (n = 25) participants were offered 5 educational sessions and a box of fresh produce for 16 weeks; control participants were not offered the sessions nor were they included in the produce delivery. We collected data on participants’ home inventory of fruits and vegetables and on their consumption of fruits and vegetables at baseline (May 2012) and postintervention (August and September 2012).
Results
Of 55 potential participants, 50 were enrolled and 44 were reached for follow-up. We observed a significant increase in the number of foods in the household inventory of fruits and vegetables in the intervention group compared with the control group. The intervention group reported greater increases in fruit and vegetable consumption; however, these did not reach significance. Intervention participants picked up produce 9.2 (standard deviation = 4.58) of 16 weeks; challenges included transportation and work schedules. Most participants (20 of 21) expressed interest in continued participation; all stated a willingness to pay $10 per week, and some were willing to pay as much as $25 per week.
Conclusion
CSA is a feasible approach for providing fresh fruits and vegetables to an underresourced community. Future studies should evaluate the impact of such a program in a larger sample and should take additional steps to facilitate participation.
doi:10.5888/pcd10.130053
PMCID: PMC3748277  PMID: 23948337
5.  Quantifying Cardiometabolic Risk Using Modifiable Non–Self-Reported Risk Factors 
Background
Sensitive general cardiometabolic risk assessment tools of modifiable risk factors would be helpful and practical in a range of primary prevention interventions or for preventive health maintenance.
Purpose
To develop and validate a cumulative general cardiometabolic risk score that focuses on non–self-reported modifiable risk factors such as glycosylated hemoglobin (HbA1c) and BMI so as to be sensitive to small changes across a span of major modifiable risk factors, which may not individually cross clinical cut off points for risk categories.
Methods
We prospectively followed 2,359 cardiovascular disease (CVD)-free subjects from the Framingham offspring cohort over a 14–year follow-up. Baseline (fifth offspring examination cycle) included HbA1c and cholesterol measurements. Gender–specific Cox proportional hazards models were considered to evaluate the effects of non–self-reported modifiable risk factors (blood pressure, total cholesterol, high–density lipoprotein cholesterol, smoking, BMI, and HbA1c) on general CVD risk. We constructed 10–year general cardiometabolic risk score functions and evaluated its predictive performance in 2012–2013.
Results
HbA1c was significantly related to general CVD risk. The proposed cardiometabolic general CVD risk model showed good predictive performance as determined by cross-validated discrimination (male C-index=0.703, 95% CI=0.668, 0.734; female C-index=0.762, 95% CI=0.726, 0.801) and calibration (lack-of-fit χ2=9.05 [p=0.338] and 12.54 [p=0.128] for men and women, respectively).
Conclusions
This study presents a risk factor algorithm that provides a convenient and informative way to quantify cardiometabolic risk based on modifiable risk factors that can motivate an individual’s commitment to prevention and intervention.
doi:10.1016/j.amepre.2014.03.006
PMCID: PMC4107093  PMID: 24951039
6.  Assessing the incremental predictive performance of novel biomarkers over standard predictors 
Statistics in medicine  2014;33(15):2577-2584.
It is unclear to what extent the incremental predictive performance of a novel biomarker is impacted by the method used to control for standard predictors. We investigated whether adding a biomarker to a model with a published risk score overestimates its incremental performance as compared to adding it to a multivariable model with individual predictors (or a composite risk score estimated from the sample of interest), and to a null model. We used 1000 simulated datasets (with a range of risk factor distributions and event rates) to compare these methods, using the continuous Net Reclassification Index (NRI), the Integrated Discrimination Index (IDI), and change in the C-statistic as discrimination metrics. The new biomarker was added to a: null model; model including a published risk score; model including a composite risk score estimated from the sample of interest; and multivariable model with individual predictors. We observed a gradient in the incremental performance of the biomarker, with the null model resulting in the highest predictive performance of the biomarker and the model using individual predictors resulting in the lowest (mean increases in C-statistic between models without and with the biomarker: 0.261, 0.085, 0.030, and 0.031; NRI: 0.767, 0.621, 0.513, and 0.530; IDI: 0.153, 0.093, 0.053 and 0.057, respectively). These findings were supported by Framingham Study data predicting atrial fibrillation using novel biomarkers. We recommend that authors report the effect of a new biomarker after controlling for standard predictors modeled as individual variables.
doi:10.1002/sim.6165
PMCID: PMC4047140  PMID: 24719270
biomarkers; model discrimination; risk model; risk prediction
7.  Smoking and Arterial Stiffness in Youth with Type 1 Diabetes: The SEARCH CVD study 
The Journal of pediatrics  2014;165(1):110-116.
Objective
To evaluate the effects of smoking on early markers of cardiovascular (CV) disease (arterial stiffness) in adolescents with and without type 1 diabetes (T1D) in the SEARCH CVD study.
Study design
Participants included 606 youth [18.9 ± 3.3 years, 83% non-Hispanic white; 50% male]. Six groups were defined: (1) T1D smokers (n=80); (2) T1D former smokers (n=88); (3) T1D non-smokers (n=232); (4) non-T1D smokers (n=40); (5) non-T1D former smokers (n=51); and (6) non-T1D non-smokers (n=115). Arterial stiffness measurements included pulse wave velocity (PWV), augmentation index (AIX) and brachial distensibility (BrachD). Multivariate linear regression was used to assess the independent and joint effects of T1D and smoking on arterial stiffness.
Results
Nearly 20% of both T1D and non- T1D youth were smokers. In youth without T1D, smokers had higher trunk and arm PWV. After adjustment for potential confounders T1D but not smoking was an independent predictor of PWV(p<0.05). Moreover, smoking status did not modify the association between T1D and increased arterial stiffness.
Conclusions
We found a high prevalence of smoking among youth with and without T1D; however, smoking status was not independently associated with increased arterial stiffness in youth with T1D.
doi:10.1016/j.jpeds.2014.02.024
PMCID: PMC4074551  PMID: 24681182
pediatrics; cigarette; vascular disease; cardiovascular disease
8.  Impact of Farnesylation Inhibitors on Survival in Hutchinson-Gilford Progeria Syndrome 
Circulation  2014;130(1):27-34.
Background
Hutchinson-Gilford progeria syndrome is an ultra-rare segmental premature aging disease resulting in early death from heart attack or stroke. There is no approved treatment, but starting in 2007, several recent single arm clinical trials have administered inhibitors of protein farnesylation aimed at reducing toxicity of the disease-producing protein progerin. No study has assessed whether treatments influence patient survival. The key elements necessary for this analysis are a robust natural history of survival and comparison with a sufficiently large patient population that has been treated for a sufficient time period with disease-targeting medications.
Methods and Results
We generated survival Kaplan-Meier survival analyses for the largest untreated Hutchinson-Gilford progeria syndrome cohort to date. Mean survival was 14.6 years. Comparing survival for treated versus age-and-gender-matched untreated cohorts, hazard ratio was 0.13 (95% CI 0.04-0.37; P<0.001) with median follow-up of 5.3 years from time of treatment initiation. There were 21/43 deaths in untreated versus 5/43 deaths among treated subjects. Treatment increased mean survival by 1.6 years.
Conclusions
This study provides a robust untreated disease survival profile, which can be utilized for comparisons now and in the future to assess changes in survival with treatments for HGPS. The current comparisons estimating increased survival with protein farnesylation inhibitors provide the first evidence of treatments influencing survival for this fatal disease.
Clinical Trial Registration Information
www.clinicaltrials.gov. Indentifiers: NCT00425607, NCT00879034 and NCT00916747.
doi:10.1161/CIRCULATIONAHA.113.008285
PMCID: PMC4082404  PMID: 24795390
progeria; Hutchinson-Gilford progeria syndrome; lamin; farnesylation; FTI; aging; atherosclerosis
9.  F10 Inhibits Growth of PC3 Xenografts and Enhances the Effects of Radiation Therapy 
Chemotherapy remains of limited use for the treatment of prostate cancer with only one drug, docetaxel, demonstrating a modest survival advantage for treatment of late-stage disease. Data from the NCI 60 cell line screen indicated that the castration-resistant prostate cancer cell lines PC3 and DU145 were more sensitive than average to the novel polymeric fluoropyrimidine (FP), F10, despite displaying less than average sensitivity to the widely-used FP, 5FU. Here, we show that F10 treatment of PC3 xenografts results in a significant survival advantage (treatment to control ratio (T/C) days = 18; p < 0.001; n = 16) relative to control mice treated with saline. F10 (40 mg/kg/dose) was administered via jugular vein catheterization 3-times per week for five weeks. This aggressive dosing regimen was completed with no drug-induced weight loss and with no evidence of toxicity. F10 was also shown to sensitize PC3 cells to radiation and F10 was also shown to be a potent radiosensitizer of PC3 xenografts in vivo with F10 in combination with radiation resulting in significantly greater regression of PC3 xenografts than radiation alone. The results indicate that F10 in this pre-clinical setting is an effective chemotherapeutic agent and possesses significant radiosensitizing properties.
PMCID: PMC4442609  PMID: 26020060
Radiosensitization; Prostate cancer; Fluoropyrimidine; Thymidylate synthase
10.  One-Year Outcomes of Out-of-Hospital Administration of Intravenous Glucose, Insulin, and Potassium (GIK) in Patients with Suspected Acute Coronary Syndromes (from the IMMEDIATE [Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care] Trial) 
The American journal of cardiology  2014;113(10):1599-1605.
The IMMEDIATE Trial of very early intravenous glucose-insulin-potassium (GIK) for acute coronary syndromes (ACS) in out-of-hospital emergency medical service (EMS) settings showed 80% reduction in infarct size at 30 days, suggesting potential longer-term benefit. Here we report 1-year outcomes. Pre-specified 1-year endpoints of this randomized, placebo-controlled, double-blind, effectiveness trial included all-cause mortality, and composites including cardiac arrest, mortality, or hospitalization for heart failure (HF). Among 871 participants randomized to GIK vs. placebo, respectively, death occurred within 1 year in 11.6% vs. 13.5% (unadjusted hazard ratio [HR] 0.83; 95% CI 0.57, 1.23, P=0.36). The composite of cardiac arrest or 1-year mortality was 12.8% vs. 17.0% (HR 0.71; 95% CI 0.50, 1.02, P=0.06). The composite of hospitalization for HF or mortality within 1 year was 17.2% vs. 17.2% (HR 0.98; 95% CI 0.70, 1.37, P=0.92). The composite of mortality, cardiac arrest, or HF hospitalization within 1 year was 18.1% vs. 20.4% (HR 0.85; 95% CI 0.62, 1.16, P=0.30). Among patients presenting with suspected ST elevation myocardial infarction (STEMI), hazard ratios for 1-year mortality and the 3 composites were, respectively, 0.65 (95% CI 0.33, 1.27, P=0.21); 0.52 (95% CI 0.30, 0.92, P=0.03); 0.63 (95% CI 0.35, 1.16, P=0.14); and 0.51 (95% CI 0.30, 0.87, P=0.01). Among patients with suspected ACS, serious endpoints generally were lower with GIK than placebo, but the differences were not statistically significant. However, among those with STEMI, the composites of cardiac arrest or 1-year mortality, and of cardiac arrest, mortality, or HF hospitalization within 1 year, were significantly reduced.
doi:10.1016/j.amjcard.2014.02.010
PMCID: PMC4043184  PMID: 24792735
acute myocardial infarction; acute coronary syndromes; emergency medical services; glucose-insulin-potassium; ACS; GIK
11.  No association of dietary fiber intake with inflammation or arterial stiffness in youth with type 1 diabetes 
Aim
To examine the association of dietary fiber intake with inflammation and arterial stiffness among youth with type 1 diabetes (T1D) in the US.
Methods
Data are from youth ≥ 10 years old with clinically diagnosed T1D for ≥ 3 months and ≥ 1 positive diabetes autoantibody in the SEARCH for Diabetes in Youth Study. Fiber intake was assessed by food frequency questionnaire with measurement error (ME) accounted for by structural sub-models derived using additional 24-hour dietary recall data in a calibration sample and the respective exposure-disease model covariates. Markers of inflammation, measured at baseline, included IL-6 (n=1405), CRP (n=1387), and fibrinogen (n=1340); markers of arterial stiffness, measured approximately 19 months post-baseline, were available in a subset of participants and included augmentation index (n=180), pulse wave velocity (n=184), and brachial distensibility (n=177).
Results
Mean (SD) T1D duration was 47.9 (43.2) months; 12.5% of participants were obese. Mean (SD) ME-adjusted fiber intake was 15 (2.8) g/day. In multivariable analyses, fiber intake was not associated with inflammation or arterial stiffness.
Conclusion
Among youth with T1D, fiber intake does not meet recommendations and is not associated with measures of systemic inflammation or vascular stiffness. Further research is needed to evaluate whether fiber is associated with these outcomes in older individuals with T1D or among individuals with higher intakes than those observed in the present study.
doi:10.1016/j.jdiacomp.2014.01.005
PMCID: PMC4011131  PMID: 24613131
type 1 diabetes; youth; dietary fiber; inflammation; arterial stiffness
12.  Glycated Hemoglobin Measurement and Prediction of Cardiovascular Disease 
Angelantonio, Emanuele Di | Gao, Pei | Khan, Hassan | Butterworth, Adam S. | Wormser, David | Kaptoge, Stephen | Kondapally Seshasai, Sreenivasa Rao | Thompson, Alex | Sarwar, Nadeem | Willeit, Peter | Ridker, Paul M | Barr, Elizabeth L.M. | Khaw, Kay-Tee | Psaty, Bruce M. | Brenner, Hermann | Balkau, Beverley | Dekker, Jacqueline M. | Lawlor, Debbie A. | Daimon, Makoto | Willeit, Johann | Njølstad, Inger | Nissinen, Aulikki | Brunner, Eric J. | Kuller, Lewis H. | Price, Jackie F. | Sundström, Johan | Knuiman, Matthew W. | Feskens, Edith J. M. | Verschuren, W. M. M. | Wald, Nicholas | Bakker, Stephan J. L. | Whincup, Peter H. | Ford, Ian | Goldbourt, Uri | Gómez-de-la-Cámara, Agustín | Gallacher, John | Simons, Leon A. | Rosengren, Annika | Sutherland, Susan E. | Björkelund, Cecilia | Blazer, Dan G. | Wassertheil-Smoller, Sylvia | Onat, Altan | Marín Ibañez, Alejandro | Casiglia, Edoardo | Jukema, J. Wouter | Simpson, Lara M. | Giampaoli, Simona | Nordestgaard, Børge G. | Selmer, Randi | Wennberg, Patrik | Kauhanen, Jussi | Salonen, Jukka T. | Dankner, Rachel | Barrett-Connor, Elizabeth | Kavousi, Maryam | Gudnason, Vilmundur | Evans, Denis | Wallace, Robert B. | Cushman, Mary | DAgostino, Ralph B. | Umans, Jason G. | Kiyohara, Yutaka | Nakagawa, Hidaeki | Sato, Shinichi | Gillum, Richard F. | Folsom, Aaron R. | van der Schouw, Yvonne T. | Moons, Karel G. | Griffin, Simon J. | Sattar, Naveed | Wareham, Nicholas J. | Selvin, Elizabeth | Thompson, Simon G. | Danesh, John
JAMA  2014;311(12):1225-1233.
IMPORTANCE
The value of measuring levels of glycated hemoglobin (HbA1c) for the prediction of first cardiovascular events is uncertain.
OBJECTIVE
To determine whether adding information on HbA1c values to conventional cardiovascular risk factors is associated with improvement in prediction of cardiovascular disease (CVD) risk.
DESIGN, SETTING, AND PARTICIPANTS
Analysis of individual-participant data available from 73 prospective studies involving 294 998 participants without a known history of diabetes mellitus or CVD at the baseline assessment.
MAIN OUTCOMES AND MEASURES
Measures of risk discrimination for CVD outcomes (eg, C-index) and reclassification (eg, net reclassification improvement) of participants across predicted 10-year risk categories of low (<5%), intermediate (5%to <7.5%), and high (≥7.5%) risk.
RESULTS
During a median follow-up of 9.9 (interquartile range, 7.6-13.2) years, 20 840 incident fatal and nonfatal CVD outcomes (13 237 coronary heart disease and 7603 stroke outcomes) were recorded. In analyses adjusted for several conventional cardiovascular risk factors, there was an approximately J-shaped association between HbA1c values and CVD risk. The association between HbA1c values and CVD risk changed only slightly after adjustment for total cholesterol and triglyceride concentrations or estimated glomerular filtration rate, but this association attenuated somewhat after adjustment for concentrations of high-density lipoprotein cholesterol and C-reactive protein. The C-index for a CVD risk prediction model containing conventional cardiovascular risk factors alone was 0.7434 (95% CI, 0.7350 to 0.7517). The addition of information on HbA1c was associated with a C-index change of 0.0018 (0.0003 to 0.0033) and a net reclassification improvement of 0.42 (−0.63 to 1.48) for the categories of predicted 10-year CVD risk. The improvement provided by HbA1c assessment in prediction of CVD risk was equal to or better than estimated improvements for measurement of fasting, random, or postload plasma glucose levels.
CONCLUSIONS AND RELEVANCE
In a study of individuals without known CVD or diabetes, additional assessment of HbA1c values in the context of CVD risk assessment provided little incremental benefit for prediction of CVD risk.
doi:10.1001/jama.2014.1873
PMCID: PMC4386007  PMID: 24668104
13.  Trends in the Prevalence of Ketoacidosis at Diabetes Diagnosis: The SEARCH for Diabetes in Youth Study 
Pediatrics  2014;133(4):e938-e945.
OBJECTIVE:
To estimate temporal changes in the prevalence of diabetic ketoacidosis (DKA) at diagnosis of type 1 or type 2 diabetes in youth and to explore factors associated with its occurrence.
METHODS:
Five centers identified incident cases of diabetes among youth aged 0 to 19 years starting in 2002. DKA presence was defined as a bicarbonate level <15 mmol/L and/or a pH <7.25 (venous) or <7.30 (arterial or capillary) or mention of DKA in the medical records. We assessed trends in the prevalence of DKA over 3 time periods (2002–2003, 2004–2005, and 2008–2010). Logistic regression was used to determine factors associated with DKA.
RESULTS:
In youth with type 1 diabetes (n = 5615), the prevalence of DKA was high and stable over time (30.2% in 2002–2003, 29.1% in 2004–2005, and 31.1% in 2008–2010; P for trend = .42). Higher prevalence was associated with younger age at diagnosis (P < .0001), minority race/ethnicity (P = .019), income (P = .019), and lack of private health insurance (P = 008). Among youth with type 2 diabetes (n = 1425), DKA prevalence decreased from 11.7% in 2002–2003 to 5.7% in 2008–2010 (P for trend = .005). Higher prevalence was associated with younger age at diagnosis (P = .001), minority race/ethnicity (P = .013), and male gender (P = .001).
CONCLUSIONS:
The frequency of DKA in youth with type 1 diabetes, although stable, remains high, indicating a persistent need for increased awareness of signs and symptoms of diabetes and better access to health care. In youth with type 2 diabetes, DKA at onset is less common and is decreasing over time.
doi:10.1542/peds.2013-2795
PMCID: PMC4074618  PMID: 24685959
diabetic ketoacidosis; youth; diabetes type
14.  Biomarkers of Cardiovascular Stress and Subclinical Atherosclerosis in the Community 
Clinical chemistry  2014;60(11):1402-1408.
BACKGROUND
Biomarkers of cardiovascular stress have been associated with incident cardiovascular outcomes. Their relations with measures of subclinical atherosclerosis, as assessed by carotid intima-media thickness, have not been well described.
METHODS
Plasma growth differentiation factor-15 (GDF-15), soluble ST2 (sST2), and high-sensitivity troponin I (hsTnI) were measured in 3111 Framingham Offspring participants who also underwent carotid ultrasonography during the sixth examination (1995 – 1998, mean age 58 years, 54% women). Carotid measurements included maximal internal carotid artery (ICA) intima-media thickness (IMT), plaque presence (defined as ICA IMT > 1.5 mm), and mean common carotid artery IMT. Multivariable regressions for carotid measurements versus biomarkers were carried out using linear and logistic models; P < 0.0056 was deemed statistically significant.
RESULTS
Maximal ICA IMT was significantly associated with plasma GDF-15 (β-estimate 0.04 per 1 unit increase in log-GDF-15 SE 0.01, P < 0.0001). Similarly, the odds of having carotid plaque increased 33% (OR 1.33 per 1-unit increase in log-GDF-15, 95% CI 1.20-1.48, P < 0.0001). In contrast, there was no significant association of maximal ICA IMT or plaque presence with sST2 or hsTnI, and none of the three biomarkers was significantly associated with mean CCA IMT. GDF-15 was a stronger predictor of maximal ICA thickness and plaque presence compared with BNP and CRP when these conventional biomarkers were tested together.
CONCLUSION
Higher GDF-15 concentrations are associated with subclinical atherosclerosis, including maximal ICA IMT and carotid plaque presence. Future studies investigating the role of GDF-15 for screening and management of patients with subclinical atherosclerosis are warranted.
doi:10.1373/clinchem.2014.227116
PMCID: PMC4376479  PMID: 25237063
carotid intima-media thickness; atherosclerosis; biomarkers
15.  Chronic Kidney Disease Defined by Cystatin C Predicts Mobility Disability and Changes in Gait Speed: The Framingham Offspring Study 
Background.
As creatinine-based estimates of renal function are inaccurate in older adults, an alternative is an estimated glomerular filtration rate (eGFRcys) based on cystatin C. We examined the prospective association between chronic kidney disease (CKDcys) as determined by eGFRcys with the primary outcome of incident mobility disability and the secondary outcome of change in gait speed.
Methods.
Framingham Offspring Study participants older than 60 years and free of mobility disability at baseline (1998–2001) were eligible. Baseline CKDcys was defined as eGFRcys less than 60 mL/min/1.73 m2. At follow-up (2005–2008), the outcomes of mobility disability, defined as self-reported inability to walk 1/2 mile and/or climb a flight of stairs, and gait speed were measured. Logistic and linear regression models were adjusted for age, sex, body mass index, smoking, diabetes, C reactive protein, and physical activity.
Results.
Of 1,226 participants, 230 (19%) had CKDcys at baseline. After a mean follow-up of 6.6 years, 185 (15%) developed mobility disability. Of those with CKDcys, 60 (26%) developed mobility disability. Those with CKDcys had greater odds of mobility disability in the age- and sex-adjusted (odds ratio [OR] 1.91, 95% CI 1.32, 2.75) and fully adjusted (OR 1.55, 95% CI 1.05, 2.31) models compared with those without CKDcys. In fully adjusted models, participants with CKDcys had greater gait speed declines than those without CKDcys (β = 0.07 [SE 0.02], p = .0022).
Conclusion.
CKDcys was associated with higher odds of incident mobility disability and greater decline in gait speed, highlighting the loss of physical independence in elders with CKD.
doi:10.1093/gerona/glt096
PMCID: PMC3976137  PMID: 23913929
Chronic kidney disease; Cystatin C; Disability; Gait speed.
16.  Urinary F2-Isoprostanes and Metabolic Markers of Fat Oxidation 
Metabolomic studies of increased fat oxidation showed increase in circulating acylcarnitines C2, C8, C10, and C12 and decrease in C3, C4, and C5. We hypothesize that urinary F2-isoprostanes reflect intensity of fatty acid oxidation and are associated with circulating C2, C8, C10, and C12 directly and with C3, C4, and C5 inversely. Four urinary F2-isoprostane isomers and serum acylcarnitines are quantified using LC-MS/MS within the Insulin Resistance Atherosclerosis Study nondiabetic cohort (n = 682). Cross-sectional associations between fasting urinary F2-isoprostanes (summarized as a composite index) and the selected acylcarnitines are examined using generalized linear models. F2-isoprostane index is associated with C2 and C12 directly and with C5 inversely: the adjusted beta coefficients are 0.109, 0.072, and −0.094, respectively (P < 0.05). For these acylcarnitines and for F2-isoprostanes, the adjusted odds ratios (ORs) of incident diabetes are calculated from logistic regression models: the ORs (95% CI) are 0.77 (0.60–0.97), 0.79 (0.62–1.01), 1.18 (0.92–1.53), and 0.51 (0.35–0.76) for C2, C12, C5, and F2-isoprostanes, respectively. The direction of the associations between urinary F2-isoprostanes and three acylcarnitines (C2, C5, and C12) supports our hypothesis. The inverse associations of C2 and C12 and with incident diabetes are consistent with the suggested protective role of efficient fat oxidation.
doi:10.1155/2015/729191
PMCID: PMC4352765  PMID: 25802683
17.  Impact of Breathing 100% Oxygen on Radiation-Induced Cognitive Impairment 
Radiation research  2014;182(5):580-585.
Future space missions are expected to include increased extravehicular activities (EVAs) during which astronauts are exposed to high-energy space radiation while breathing 100% oxygen. Given that brain irradiation can lead to cognitive impairment, and that oxygen is a potent radiosensitizer, there is a concern that astronauts may be at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA. To address this concern, unanesthetized, unrestrained, young adult male Fischer 344 × Brown Norway rats were allowed to breathe 100% O2 for 30 min prior to, during and 2 h after whole-body irradiation with 0, 1, 3, 5 or 7 Gy doses of 18 MV X rays delivered from a medical linear accelerator at a dose rate of ~425 mGy/min. Irradiated and unirradiated rats breathing air (~21% O2) served as controls. Cognitive function was assessed 9 months postirradiation using the perirhinal cortex-dependent novel object recognition task. Cognitive function was not impaired until the rats breathing either air or 100% O2 received a whole-body dose of 7 Gy. However, at all doses, cognitive function of the irradiated rats breathing 100% O2 was improved over that of the irradiated rats breathing air. These data suggest that astronauts are not at greater risk of developing cognitive impairment when exposed to space radiation while breathing 100% O2 during an EVA.
doi:10.1667/RR13643.1
PMCID: PMC4321947  PMID: 25338095
18.  IRP2 regulates breast tumor growth 
Cancer research  2013;74(2):497-507.
Experimental and epidemiological evidence suggest that dysregulation of proteins involved in iron metabolism plays a critical role in cancer. The mechanisms by which cancer cells alter homeostatic iron regulation are just beginning to be understood. Here we demonstrate that iron regulatory protein 2 (IRP2) plays a key role in iron accumulation in breast cancer. Although both IRP1 and IRP2 are over-expressed in breast cancer, the overexpression of IRP2, but not IRP1, is associated with decreased ferritin H and increased transferrin receptor 1 (TfR1). Knock-down of IRP2 in triple negative MDA-MB-231 human breast cancer cells increases ferritin H expression and decreases TfR1 expression, resulting in a decrease in the labile iron pool. Further, IRP2 knockdown reduces growth of MDA-MB-231 cells in the mouse mammary fat pad. Gene expression microarray profiles of breast cancer patients demonstrate that increased IRP2 expression is associated with high grade cancer. Increased IRP2 expression is observed in luminal A, luminal B and basal breast cancer subtypes, but not in breast tumors of the ERBB2 molecular subtype. These results suggest that dysregulation of IRP2 is an early nodal point underlying altered iron metabolism in breast cancer and may contribute to poor outcome of some breast cancer patients.
doi:10.1158/0008-5472.CAN-13-1224
PMCID: PMC3989290  PMID: 24285726
breast cancer; iron; metabolism; iron regulatory proteins; molecular subtypes
19.  Left Ventricular Hypertrophy Patterns and Incidence of Heart Failure with Preserved versus Reduced Ejection Fraction 
The American journal of cardiology  2013;113(1):10.1016/j.amjcard.2013.09.028.
Higher left ventricular (LV) mass, wall thickness and internal dimension are associated with increased heart failure (HF) risk. Whether different LV hypertrophy patterns vary with respect to rates and types of HF incidence is unclear. We classified 4768 Framingham Heart Study participants (mean age 50 years; 56% women) into 4 mutually exclusive LV hypertrophy pattern groups (normal, concentric remodeling, concentric hypertrophy, eccentric hypertrophy) using American Society of Echocardiography recommended thresholds of echocardiographic LV mass/body surface area and relative wall thickness, and related them to HF incidence. We evaluated if risk for HF types (HF with reduced [<45%; HFREF] versus preserved [≥45%; HFPEF] ejection fraction) varied by hypertrophy pattern. On follow-up (mean 21 years), 458 participants (9.6%; 250 women) developed new-onset HF. The age-and-sex-adjusted 20-year HF incidence rose from 6.96% in normal LV group to 8.67%, 13.38% and 15.27% in the concentric remodeling, concentric hypertrophy and eccentric hypertrophy groups, respectively. After adjustment for co-morbidities and incident myocardial infarction, LV hypertrophy patterns were associated with higher HF incidence relative to normal LV (p=0.0002); eccentric hypertrophy carried the greatest risk (hazards ratio [HR] 1.89, 95% confidence interval [CI] 1.41-2.54), followed by concentric hypertrophy (HR [CI] 1.40 [1.04-1.87]). Participants with eccentric hypertrophy had a higher propensity for HFREF (HR 2.23; CI 1.48-3.37, whereas those with concentric hypertrophy were more prone to HFPEF (HR 1.66; CI 1.09-2.51). In conclusion, in our large community-based sample, HF risk varied by LV hypertrophy pattern, with eccentric and concentric hypertrophy predisposing to HFREF and HFPEF, respectively.
doi:10.1016/j.amjcard.2013.09.028
PMCID: PMC3881171  PMID: 24210333
Concentric hypertrophy; eccentric hypertrophy; left ventricular hypertrophy; heart failure; risk
20.  Impact of Glycemic Control on Heart Rate Variability in Youth with Type 1 Diabetes: The SEARCH CVD Study 
Diabetes Technology & Therapeutics  2013;15(12):977-983.
Abstract
Aim: This study explored the role of glycemic control on cardiac autonomic function, measured by heart rate variability (HRV), in youth with type 1 diabetes.
Patients and Methods: A retrospective cohort of 345 youth with type 1 diabetes (mean age, 18.5 years; duration, 10 years) participating in the SEARCH for Diabetes in Youth study were enrolled in the ancillary SEARCH Cardiovascular Disease (CVD) study. Anthropometric, metabolic, and HRV parameters were collected at the current research visit. Glycemic control over time was assessed by the mean glycated hemoglobin (A1c) levels collected over the past 6 years. Multiple linear regression analysis assessed the association between A1c over time and HRV parameters, independent of demographic and CVD risk factors. Participants were categorized into four glycemic control categories based on their mean A1c over time: Group 1, optimal (mean A1c, ≤7.4%); Group 2 (mean A1c, 7.5–8.4%); Group 3 (mean A1c, 8.5–9.4%), and Group 4, poor (mean A1c, ≥9.5%), and a linear trend was explored across these categories.
Results: For every 1% increase in the average A1c over 6 years there was a 5% decrease in the SD of the normal RR interval (SDNN) (P=0.02) and 7% decrease in the root mean square successive difference of the RR interval (RMSSD) (P=0.02), independent of demographic and traditional CVD risk factors. A dose–response relationship between worsening glucose control categories and measures of overall reduced HRV was found.
Conclusions: Chronic hyperglycemia is the main determinant of early cardiac autonomic dysfunction, manifested as reduced overall HRV and parasympathetic loss, among youth with type 1 diabetes.
doi:10.1089/dia.2013.0147
PMCID: PMC3868395  PMID: 24010960
21.  Association of Pain and Itch With Depth of Invasion and Inflammatory Cell Constitution in Skin Cancer 
JAMA dermatology  2014;150(11):1160-1166.
IMPORTANCE
This study highlights a simple bedside evaluation of itch and pain for suspicious skin lesions.
OBJECTIVE
To examine the correlation of pain and itch with histologic features of skin cancers.
DESIGN, SETTING, AND PARTICIPANTS
This large, prospective, clinicopathologic study enrolled patients who filled out questionnaires that assessed itch and pain intensity of their skin tumors at the time of excision. Study participants were from the patient population presenting to the Department of Dermatology surgical unit at Wake Forest University Baptist Medical Center from July 1, 2010, through March 31, 2011. Study participants included 268 patients, representing 339 histopathologically confirmed cutaneous neoplasms. The following skin cancer subtypes were represented in this analysis: 166 basal cell carcinomas, 146 squamous cell carcinomas, and 27 melanomas.
MAIN OUTCOMES AND MEASURES
Itch and pain associated with skin cancer at the time of excision ranked on an 11-point (score range, 0-10) numerical visual analog scale and histopathologic analysis for each neoplasm (assessment of the amount and type of inflammation, ulceration, perineural invasion, and depth of invasion).
RESULTS
The prevalence of itch and pain across all skin cancers was 36.9% and 28.2%, respectively. However, these symptoms were mostly absent in melanomas. Pain intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P < .001), presence of neutrophils in the inflammatory infiltrate (predominantly mononuclear vs mixed or neutrophilic; P = .003), presence of eosinophils (present vs absent; P = .007), ulceration (yes vs no; P = .003), perineural invasion (yes vs no; P < .001), depth of invasion (P = .001), and largest diameter length of skin lesion (P < .003). Itch intensity was significantly associated with the degree of inflammation (mild or none vs moderate or marked; P = .001) and the presence of eosinophils (present vs absent; P = .02).
CONCLUSIONS AND RELEVANCE
These findings support the theory that itch emanates from the upper layers of the skin, whereas pain is associated with deeper processes. This study also reports that a simple bedside assessment for the presence and intensity of pain or itch is an easily implementable tool for physicians evaluating suspicious skin lesions.
doi:10.1001/jamadermatol.2014.895
PMCID: PMC4229457  PMID: 25055194
22.  Impact of Correlation on Predictive Ability of Biomarkers 
Statistics in medicine  2013;32(24):4196-4210.
Summary
In this paper we investigate how the correlation structure of independent variables affects the discrimination of risk prediction model. Using multivariate normal data and binary outcome we prove that zero correlation among predictors is often detrimental for discrimination in a risk prediction model and negatively correlated predictors with positive effect sizes are beneficial. A very high multiple R-squared from regressing the new predictor on the old ones can also be beneficial. As a practical guide to new variable selection, we recommend to select predictors that have negative correlation with the risk score based on the existing variables. This step is easy to implement even when the number of new predictors is large. Our results are illustrated using real-life Framingham data suggesting that the conclusions hold outside of normality. The findings presented in this paper might be useful for preliminary selection of potentially important predictors, especially is situations where the number of predictors is large.
doi:10.1002/sim.5824
PMCID: PMC4177016  PMID: 23640729
AUC; discrimination; risk prediction model; correlation; linear discriminant analysis; logistic regression
23.  Albuminuria According to Status of Autoimmunity and Insulin Sensitivity Among Youth With Type 1 and Type 2 Diabetes 
Diabetes Care  2013;36(11):3633-3638.
OBJECTIVE
To evaluate whether etiologic diabetes type is associated with the degree of albuminuria in children with diabetes.
RESEARCH DESIGN AND METHODS
SEARCH is an observational, longitudinal study of children with diabetes. Youth with newly diagnosed diabetes were classified according to diabetes autoantibody (DAA) status and presence of insulin resistance. We defined insulin resistance as an insulin sensitivity score <25th percentile for the United States general youth population. DAA status was based on positivity for the 65-kD isoform of glutamate decarboxylase and insulinoma-associated protein 2 antigens. The four etiologic diabetes type groups were as follows: DAA+/insulin-sensitive (IS) (n = 1,351); DAA+/insulin-resistant (IR) (n = 438); DAA−/IR (n = 379); and DAA−/IS (n = 233). Urinary albumin:creatinine ratio (UACR) was measured from a random urine specimen. Multivariable regression analyses assessed the independent relationship between the four diabetes type groups and magnitude of UACR.
RESULTS
Adjusted UACR means across the four groups were as follows: DAA+/IS = 154 μg/mg; DAA+/IR = 137 μg/mg; DAA−/IR = 257 μg/mg; and DAA−/IS = 131 μg/mg (P < 0.005). Only DAA−/IR was significantly different. We performed post hoc multivariable regression analysis restricted to the two IR groups to explore the contribution of DAA status and insulin sensitivity (continuous) to the difference in UACR between the IR groups. Only insulin sensitivity was significantly associated with UACR (β = −0.54; P < 0.0001).
CONCLUSIONS
In youth with diabetes, the DAA−/IR group had a greater UACR than all other groups, possibly because of the greater magnitude of insulin resistance. Further exploration of the relationships between severity of insulin resistance, autoimmunity, and albuminuria in youth with diabetes is warranted.
doi:10.2337/dc13-0568
PMCID: PMC3816857  PMID: 23846811
24.  Correlates of Medical Nutrition Therapy and Cardiovascular Outcomes in Youth with Type 1 Diabetes 
Objective
To examine whether the types of medical nutrition therapies (MNTs) taught to and used by youth with type 1 diabetes (T1D) varies by socio-demographic characteristics and cardiovascular (CVD) risk factors
Design
Cross-sectional study
Setting
The SEARCH for Diabetes in Youth study is a population-based cohort of individuals with clinical diagnosed diabetes
Participants
1,191 individuals with T1D
Main Outcome Measures
Types of MNTs and frequency of use
Analysis
Bivariate analysis and multivariate linear regression (P<0.05)
Results
More race/ethnic minorities (vs. whites), individuals with parents
Conclusions and Implications
In individuals with T1D, race/ethnic minorities, individuals with parents
doi:10.1016/j.jneb.2013.06.003
PMCID: PMC3825757  PMID: 23891147
medical nutrition therapy; type 1 diabetes; cardiovascular risk
JAMA  2012;307(18):1925-1933.
Context
Laboratory studies suggest that in the setting of cardiac ischemia, immediate intravenous glucose-insulin-potassium (GIK) reduces ischemia-related arrhythmias and myocardial injury. Clinical trials have not consistently shown these benefits, possibly due to delayed administration.
Objective
To test out-of hospital emergency medical service (EMS) administration of GIK in the first hours of suspected acute coronary syndromes (ACS).
Design, Setting, and Participants
Randomized, placebo-controlled, double-blind effectiveness trial in 13 US cities (36 EMS agencies), from December 2006 through July 31, 2011, in which paramedics, aided by electrocardiograph (ECG)-based decision support, randomized 911 (871 enrolled) patients (mean age, 63.6 years; 71.0% men) with high probability of ACS.
Intervention
Intravenous GIK solution (n=411) or identical-appearing 5% glucose placebo (n=460) administered by paramedics in the out-of-hospital setting and continued for 12 hours.
Main Outcome Measures
The prespecified primary end point was progression of ACS to myocardial infarction (MI) within 24 hours, as assessed by biomarkers and ECG evidence. Prespecified secondary end points included survival at 30 days and a composite of prehospital or in-hospital cardiac arrest or in-hospital mortality, analyzed by intent-to-treat and by presentation with ST-segment elevation.
Results
There was no significant difference in the rate of progression to MI among patients who received GIK (n=200; 48.7%) vs those who received placebo (n=242; 52.6%) (odds ratio [OR], 0.88; 95% CI, 0.66–1.13; P=.28). Thirty-day mortality was 4.4% with GIK vs 6.1% with placebo (hazard ratio [HR], 0.72; 95% CI, 0.40–1.29; P=.27). The composite of cardiac arrest or in-hospital mortality occurred in 4.4% with GIK vs 8.7% with placebo (OR, 0.48; 95% CI, 0.27–0.85; P=.01). Among patients with ST-segment elevation (163 with GIK and 194 with placebo), progression to MI was 85.3% with GIK vs 88.7% with placebo (OR, 0.74; 95% CI, 0.40–1.38; P=.34); 30-day mortality was 4.9% with GIK vs 7.7% with placebo (HR, 0.63; 95% CI, 0.27–1.49; P=.29). The composite outcome of cardiac arrest or in-hospital mortality was 6.1% with GIK vs 14.4% with placebo (OR, 0.39; 95% CI, 0.18–0.82; P=.01). Serious adverse events occurred in 6.8% (n=28) with GIK vs 8.9% (n=41) with placebo (P=.26).
Conclusions
Among patients with suspected ACS, out-of-hospital administration of intravenous GIK, compared with glucose placebo, did not reduce progression to MI. Compared with placebo, GIK administration was not associated with improvement in 30-day survival but was associated with lower rates of the composite outcome of cardiac arrest or in-hospital mortality.
Trial Registration
clinicaltrials.gov Identifier: NCT00091507
doi:10.1001/jama.2012.426
PMCID: PMC4167391  PMID: 22452807

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