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1.  Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2010;30(1):382-386.
Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-β, has activity against pancreatic cancer in preclinical models. In a phase I trial of gemcitabine plus sorafenib, 57% of pancreatic cancer patients achieved stable disease.
Patients and methods
We conducted a multi-center phase II trial of sorafenib plus gemcitabine in chemo-naïve patients with histologicallyconfirmed, advanced pancreatic cancer. Patients received sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2 on days 1, 8 and 15 of a 28 day cycle.
Seventeen patients enrolled at 4 centers; 13 were evaluable for response. There were no objective responses; 18% had stable disease. Median overall survival was 4.0 months (95% CI: 3.4, 5.9); median progression-free survival was 3.2 months (95% CI: 1.6, 3.6). Grade 3/4 toxicities included thrombosis in 18% of patients, dehydration or hand-foot syndrome in 12%, and hypertension or gastrointestinal bleeding in 6%.
Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer.
PMCID: PMC4319645  PMID: 20803052
Pancreatic cancer; Phase II trial; Gemcitabine; Sorafenib
2.  Dasatinib in previously treated metastatic colorectal cancer: a phase II trial of the University of Chicago Phase II Consortium 
Investigational new drugs  2011;30(3):1211-1215.
Treatment options for metastatic colorectal cancer (CRC) are limited after a fluoropyrimi-dine, oxaliplatin and irinotecan; novel agents need to be explored in this setting. Dasatinib, an oral inhibitor of Src family kinases, inhibits proliferation in CRC cell lines and has antitumor activity in CRC xenograft models.
Patients and methods
We conducted a multi-center phase II trial of dasatinib in unresectable, previously-treated metastatic CRC patients. No more than 2 prior chemotherapy regimens were permitted, which must have contained a fluoropyrimidine, oxaliplatin and irinotecan. The primary endpoint was progression-free survival (PFS) at 4 months. The Simon two-stage design required that at least 5 of the first 19 patients be progression-free at 4 months to expand to a second stage.
Nineteen patients enrolled at 9 centers. The study was terminated after the first stage due to lack of efficacy. There were no objective responses; 1 patient (5%) had stable disease for 7.3 months. The PFS rate at 4 months was 5.3% (90% CI: 0.3, 22.6). Median PFS was 1.6 months (90% CI: 1.4, 1.8). Median overall survival was 5.1 months (90% CI: 2.4, 6.3). Grade 3/4 toxicities included fatigue in 16% of patients, and anemia, anorexia, nausea/vomiting and dyspnea in 11%.
Dasatinib is inactive as a single agent in previously treated metastatic CRC patients.
PMCID: PMC4317401  PMID: 21552992
Colorectal cancer; Phase II trial; Dasatinib
3.  GFI1B, EVI5, MYB—Additional genes that cooperate with the human BCL6 gene to promote the development of lymphomas 
The BCL6 gene, which is expressed in certain B- and T-cell human lymphomas, is involved with chromosomal rearrangements and mutations in a number of these neoplasms. Lymphomagenesis is believed to evolve through a multi-step accumulation of genetic alterations in these tumors. We used retroviral insertional mutagenesis in transgenic mice expressing the human BCL6 transgene in order to identify genes that cooperate with BCL6 during lymphomatous transformation. We previously reported PIM1 as the most frequently recurring cooperating gene in this model. We now report three newly identified cooperating genes—GFI1B, EVI5, and MYB—that we identified in the lymphomas of retroviral-injected BCL6 transgenic mice (but not in retroviral-injected non-transgenic controls); mRNA and protein expression of GFI1B and EVI5 were decreased in the murine tumors, whereas MYB mRNA and protein expression were increased or decreased. These findings correlated with protein expression in human lymphomas, both B- and T-cell. Improved therapy of lymphomas may necessitate the development of combinations of drugs that target the alterations specific to each neoplasm.
PMCID: PMC4272826  PMID: 23910958
BCL6 transgenic mice; Cooperating genes; Lymphoma development; GFI1B; EVI5; MYB
4.  Olfactory Dysfunction Predicts 5-Year Mortality in Older Adults 
PLoS ONE  2014;9(10):e107541.
Prediction of mortality has focused on disease and frailty, although antecedent biomarkers may herald broad physiological decline. Olfaction, an ancestral chemical system, is a strong candidate biomarker because it is linked to diverse physiological processes. We sought to determine if olfactory dysfunction is a harbinger of 5-year mortality in the National Social Life, Health and Aging Project [NSHAP], a nationally representative sample of older U.S. adults. 3,005 community-dwelling adults aged 57–85 were studied in 2005–6 (Wave 1) and their mortality determined in 2010–11 (Wave 2). Olfactory dysfunction, determined objectively at Wave 1, was used to estimate the odds of 5-year, all cause mortality via logistic regression, controlling for demographics and health factors. Mortality for anosmic older adults was four times that of normosmic individuals while hyposmic individuals had intermediate mortality (p<0.001), a “dose-dependent” effect present across the age range. In a comprehensive model that included potential confounding factors, anosmic older adults had over three times the odds of death compared to normosmic individuals (OR, 3.37 [95%CI 2.04, 5.57]), higher than and independent of known leading causes of death, and did not result from the following mechanisms: nutrition, cognitive function, mental health, smoking and alcohol abuse or frailty. Olfactory function is thus one of the strongest predictors of 5-year mortality and may serve as a bellwether for slowed cellular regeneration or as a marker of cumulative toxic environmental exposures. This finding provides clues for pinpointing an underlying mechanism related to a fundamental component of the aging process.
PMCID: PMC4182669  PMID: 25271633
5.  Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion 
The Journal of Clinical Investigation  2014;124(10):4614-4628.
Ovarian cancer (OvCa) metastasizes to organs in the abdominal cavity, such as the omentum, which are covered by a single layer of mesothelial cells. Mesothelial cells are generally thought to be “bystanders” to the metastatic process and simply displaced by OvCa cells to access the submesothelial extracellular matrix. Here, using organotypic 3D cultures, we found that primary human mesothelial cells secrete fibronectin in the presence of OvCa cells. Moreover, we evaluated the tumor stroma of 108 human omental metastases and determined that fibronectin was consistently overexpressed in these patients. Blocking fibronectin production in primary mesothelial cells in vitro or in murine models, either genetically (fibronectin 1 floxed mouse model) or via siRNA, decreased adhesion, invasion, proliferation, and metastasis of OvCa cells. Using a coculture model, we determined that OvCa cells secrete TGF-β1, which in turn activates a TGF-β receptor/RAC1/SMAD-dependent signaling pathway in the mesothelial cells that promotes a mesenchymal phenotype and transcriptional upregulation of fibronectin. Additionally, blocking α5 or β1 integrin function with antibodies reduced metastasis in an orthotopic preclinical model of OvCa metastasis. These findings indicate that cancer-associated mesothelial cells promote colonization during the initial steps of OvCa metastasis and suggest that mesothelial cells actively contribute to metastasis.
PMCID: PMC4191043  PMID: 25202979
6.  Statin Therapy Is Associated with Improved Survival in Patients with Non-Serous-Papillary Epithelial Ovarian Cancer: A Retrospective Cohort Analysis 
PLoS ONE  2014;9(8):e104521.
To determine whether statin use is associated with improved epithelial ovarian cancer (OvCa) survival.
This is a single-institution retrospective cohort review of patients treated for OvCa between 1992 and 2013. Inclusion criteria were International Federation of Gynecology and Obstetrics (FIGO) stage I–IV OvCa. The primary exposures analyzed were hyperlipidemia and statin use. The primary outcomes were progression-free survival (PFS) and disease-specific survival (DSS).
442 patients met inclusion criteria. The cohort was divided into three groups: patients with hyperlipidemia who used statins (n = 68), patients with hyperlipidemia who did not use statins (n = 28), and patients without hyperlipidemia (n = 346). OvCa outcomes were evaluated. When we analyzed the entire cohort, we found no significant differences in PFS or DSS among the groups. The median PFS for hyperlipidemics using statins, hyperlipidemics not using statins, and non-hyperlipidemics was 21.7, 13.6, and 14.7 months, respectively (p = 0.69). Median DSS for hyperlipidemics using statins, hyperlipidemics not using statins, and non-hyperlipidemics was 44.2, 75.7, and 41.5 months, respectively (p = 0.43). These findings did not change after controlling for confounders. However, a secondary analysis revealed that, among patients with non-serous-papillary subtypes of OvCa, statin use was associated with a decrease in hazards of both disease recurrence (adjusted HR = 0.23, p = 0.02) and disease-specific death (adjusted HR = 0.23, p = 0.04). To augment the findings in the retrospective cohort, the histology-specific effects of statins were also evaluated in vitro using proliferation assays. Here, statin treatment of cell lines resulted in a variable level of cytotoxicity.
Statin use among patients with non-serous-papillary OvCa was associated with improvement in both PFS and DSS.
PMCID: PMC4131884  PMID: 25118694
7.  Effects of Vascular Endothelial Growth Factor Signaling Inhibition on Human Erythropoiesis 
The Oncologist  2013;18(8):965-970.
Vascular endothelial growth factor (VEGF) signaling inhibition is associated with increased red blood cell (RBC) counts and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors. We analyzed RBC measurements in patients enrolled in three studies of VEGF signaling inhibition, but we noted no significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status.
Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/μL [95% confidence interval (CI), 1.5–3.9]) and axitinib (4.3 M/μL [95% CI, 2.2–6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (−12.8 M/μL per day [95% CI, −15.7 to −9.8]) but less so with added bevacizumab (−7.2 M/μL per day [95% CI, −9.5 to −4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.
PMCID: PMC3755935  PMID: 23900000
Vascular endothelial growth factor A; Biological markers; Erythrocyte count; Erythropoietin; Axitinib; Bevacizumab; Sorafenib
8.  Evaluation of a novel rash scale and a serum proteomic predictor in a randomized phase II trial of sequential or concurrent cetuximab and pemetrexed in previously treated non-small cell lung cancer 
BMC Cancer  2014;14:5.
Candidate predictive biomarkers for epidermal growth factor receptor inhibitors (EGFRi), skin rash and serum proteomic assays, require further qualification to improve EGFRi therapy in non-small cell lung cancer (NSCLC). In a phase II trial that was closed to accrual because of changes in clinical practice we examined the relationships among candidate biomarkers, quantitative changes in tumor size, progression-free and overall survival.
55 patients with progressive NSCLC after platinum therapy were randomized to receive (Arm A) cetuximab, followed by pemetrexed at progression, or (Arm B) concurrent cetuximab and pemetrexed. All received cetuximab monotherapy for the first 14 days. Pre-treatment serum and weekly rash assessments by standard and EGFRi-induced rash (EIR) scales were collected.
43 patients (20-Arm A, 23-Arm B) completed the 14-day run-in. Median survival was 9.1 months. Arm B had better median overall (Arm B = 10.3 [95% CI 7.5, 16.8]; Arm A = 3.5 [2.8, 11.7] months P = 0.046) and progression-free survival (Arm B = 2.3 [1.6, 3.1]; Arm A = 1.6 [0.9, 1.9] months P = 0.11). The EIR scale distributed ratings among 6 rather than 3 categories but ordinal scale rash severity did not predict outcomes. The serum proteomic classifier and absence of rash after 21 days of cetuximab did.
Absence of rash after 21 days of cetuximab therapy and the serum proteomic classifier, but not ordinal rash severity, were associated with NSCLC outcomes. Although in a small study, these observations were consistent with results from larger retrospective analyses.
Trial registration Identifier NCT00203931
PMCID: PMC3893521  PMID: 24386952
Pemetrexed; Lung Cancer; Cetuximab; Rash; EGFR; Proteomics
9.  Varied manifestations of persistent hyperplastic primary vitreous with graded somatic mosaic deletion of a single gene 
Molecular Vision  2014;20:215-230.
Persistent hyperplastic primary vitreous (PHPV) represents a developmental eye disease known to have diverse manifestations ranging from a trivial remnant of hyaloid vessels to a dense fibrovascular mass causing lens opacity and retinal detachment. PHPV can be modeled in mice lacking individual genes, but certain features of such models differ from the clinical realm. For example, mice lacking the Arf gene have uniformly severe disease with consistent autosomal recessive disease penetrance. We tested whether the graded somatic loss of Arf in a subset of cells in chimeric mice mimics the range of disease in a non-heritable manner.
Wild type ↔ Arf −/− mouse chimeras were generated by morulae fusion, and when the mice were 10 weeks old, fundoscopic, slit-lamp, and histological evaluations were performed. The relative fraction of cells of the Arf −/− lineage was assessed with visual, molecular genetic, and histological analysis. Objective quantification of various aspects of the phenotype was correlated with the genotype.
Sixteen chimeras were generated and shown to have low, medium, and high contributions of Arf −/− cells to tail DNA, the cornea, and the retinal pigment epithelium (RPE), with excellent correlation between chimerism in the tail DNA and the RPE. Phenotypic differences (coat color and severity of eye disease) were evident, objectively quantified, and found to correlate with the contribution of Arf −/− cells to the RPE and tail-derived DNA, but not the cornea.
Generating animals composed of different numbers of Arf −/− cells mimicked the range of disease severity observed in patients with PHPV. This establishes the potential for full manifestations of PHPV to be caused by somatic mutations of a single gene during development.
PMCID: PMC3945809  PMID: 24623965
10.  Obstructive Sleep Apnea in Young Lean Men 
Diabetes Care  2012;35(11):2384-2389.
To assess whether the presence of obstructive sleep apnea (OSA) affects glucose metabolism in young, lean individuals who are healthy and free of cardiometabolic disease.
In a prospective design, 52 healthy men (age 18–30 years; BMI 18–25 kg/m2) underwent laboratory polysomnogram followed by a morning oral glucose tolerance test (OGTT). We stratified all subjects according to the presence or absence of ethnicity-based diabetes risk and family history of diabetes. We then used a frequency-matching approach and randomly selected individuals without OSA, yielding a total of 20 control men without OSA and 12 men with OSA. Indices of glucose tolerance, insulin sensitivity, and insulin secretion (early phase and total) were compared between men with OSA and control subjects. The incremental areas under the glucose (incAUCglu) and insulin (incAUCins) curves were calculated using the trapezoidal method from 0 to 120 min during the OGTT.
Men with OSA and control subjects were similar in terms of age, BMI, ethnicity-based diabetes risk, family history of diabetes, and level of exercise. Both groups had normal systolic and diastolic blood pressure and fasting lipid levels. After ingestion of a glucose load, men with OSA had 27% lower insulin sensitivity (estimated by Matsuda index) and 37% higher total insulin secretion (incAUCins) than the control subjects, despite comparable glucose levels (incAUCglu).
In young, lean, and healthy men who are free of cardiometabolic disease, the presence of OSA is associated with insulin resistance and a compensatory rise in insulin secretion to maintain normal glucose tolerance. Thus, OSA may increase the risk of type 2 diabetes independently of traditional cardiometabolic risk factors.
PMCID: PMC3476882  PMID: 22912423
11.  Antimüllerian hormone levels are independently related to ovarian hyperandrogenism and polycystic ovaries 
Fertility and sterility  2012;98(1):242-249.
To determine the relationship of antimüllerian hormone (AMH) levels to polycystic ovaries and ovarian androgenic function.
Prospective case-control study.
General clinical research center.
Eumenorrheic asymptomatic volunteers without (V-NO; n = 19; reference population) or with (V-PCO; n = 28) a polycystic ovary and hyperandrogenemic anovulatory subjects grouped according to ovarian function into typical PCOS (PCOS-T; n = 37) and atypical PCOS (PCOS-A; n = 18).
Pelvic ultrasonography, short dexamethasone androgen-suppression test (SDAST), and GnRH agonist (GnRHag) test.
Main Outcome Measure(s)
Baseline AMH levels were related to polycystic ovary status, testosterone response to SDAST, and 17-hydroxyprogesterone response to GnRHag test.
AMH levels correlated with SDAST and GnRHag test outcomes. AMH was elevated (>6.2 ng/mL) in 32% of V-PCO versus 5% V-NO. The 21% of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyperandrogenism, but AMH levels were similar to nonhyperandrogenic V-PCO. AMH >10.7 ng/mL discriminated V-PCO from PCOS with 96% specificity and 41% sensitivity for PCOS-T, and insignificantly for PCOS-A.
AMH levels are independently related to ovarian androgenic function and polycystic ovaries. Very high AMH levels are specific but insensitive for PCOS. In the absence of hyperandrogenism, moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool.
PMCID: PMC3597099  PMID: 22541936
Antimüllerian hormone; dexamethasone suppression test; functional ovarian hyperandrogenism; GnRH agonist test; obesity; ovarian reserve; polycystic ovary
The Journal of parasitology  2011;97(2):328-337.
Reduction of risk of human and food animal infection with Toxoplasma gondii is hampered by the lack of epidemiological data documenting the predominant routes of infection (oocyst versus tissue cyst consumption) in horizontally transmitted toxoplasmosis. Existing serological assays can determine previous exposure to the parasite, but not the route of infection. We have used difference gel electrophoresis in combination with tandem mass spectroscopy and Western blot to identify a sporozoite-specific protein (Toxoplasma gondii embryogenesis-related protein, TgERP) which elicited antibody and differentiated oocyst- versus tissue cyst-induced infection in pigs and mice. The recombinant protein was selected from a cDNA library constructed from T. gondii sporozoites, and this protein was used in Western blots and probed with sera from T. gondii infected humans. Serum antibody to TgERP was detected in humans within 6–8 mo of initial oocyst-acquired infection. Of 163 individuals in the acute stage of infection (anti-Toxoplasma IgM detected in sera, or <30 in the IgG avidity test), 103 (63.2%) had detectable antibodies that reacted with TgERP. Of 176 individuals with unknown infection route and in the chronic stage of infection (no anti-Toxoplasma IgM detected in sera, or >30 in the IgG avidity test), antibody to TgERP was detected in 31 (17.6%). None of the 132 uninfected individuals tested had detectable antibody to TgERP. These data suggest that TgERP may be useful in detecting exposure to sporozoites in early Toxoplasma infection and implicates oocysts as the agent of infection.
PMCID: PMC3684278  PMID: 21506817
13.  Prematurity and Severity Are Associated With Toxoplasma gondii Alleles (NCCCTS, 1981–2009) 
Type II and NE-II parasite alleles are present in persons with congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severity at birth. Both II and NE-II infections improved with treatment.
Background. Congenital toxoplasmosis is a severe, life-altering disease in the United States. A recently developed enzyme-linked immunosorbent assay (ELISA) distinguishes Toxoplasma gondii parasite types (II and not exclusively II [NE-II]) by detecting antibodies in human sera that recognize allelic peptide motifs of distinct parasite types.
Methods. ELISA determined parasite serotype for 193 congenitally infected infants and their mothers in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS), 1981–2009. Associations of parasite serotype with demographics, manifestations at birth, and effects of treatment were determined.
Results. Serotypes II and NE-II occurred in the United States with similar proportions during 3 decades. For persons diagnosed before or at birth and treated in infancy, and persons diagnosed after 1 year of age who missed treatment in infancy, proportions were similar (P = .91). NE-II serotype was more common in hot, humid regions (P = .02) but was also present in other regions. NE-II serotype was associated with rural residence (P < .01), lower socioeconomic status (P < .001), and Hispanic ethnicity (P < .001). Prematurity (P = .03) and severe disease at birth (P < .01) were associated with NE-II serotype. Treatment with lower and higher doses of pyrimethamine with sulfadizine improved outcomes relative to those outcomes of persons in the literature who did not receive such treatment.
Conclusions. Type II and NE-II parasites cause congenital toxoplasmosis in North America. NE-II serotype was more prevalent in certain demographics and associated with prematurity and severe disease at birth. Both type II and NE-II infections improved with treatment.
Clinical Trials Registration. NCT00004317.
PMCID: PMC3348955  PMID: 22499837
14.  Patterns and Loss of Sexual Activity in the Year Following Hospitalization for Acute Myocardial Infarction (A U.S. National, Multi-Site Observational Study) 
The American Journal of Cardiology  2012;109(10):1439-1444.
A multi-site, observational study of sexual activity-related outcomes among patients enrolled in the TRIUMPH Registry during hospitalization for an acute myocardial infarction (AMI) was conducted to identify patterns and loss of sexual activity 1 year following hospitalization for AMI. Gender-specific multivariable hierarchical models were used to identify correlates of loss of sexual activity, including physician counseling. Main outcome measures included “loss of sexual activity” (less frequent or no sexual activity one year after an AMI in those who were sexually active in the year before the AMI) and 1-year mortality. Mean age (years) was 61.1 for women (n=605) and 58.6 for men (n=1274). Many were sexually active in the year before and 1 year after hospitalization (44% and 40% of women, 74% and 68% of men, respectively). A third of women and 47% of men reported receiving hospital discharge instructions about resuming sex. Those who did not receive instructions were more likely to report loss of sexual activity (women: adjusted RR 1.44, 95% CI 1.16–1.79; men: adjusted RR 1.27, 95% CI 1.11–1.46). One year post-AMI mortality was similar among those who reported sexual activity in the first month after their AMI (2.1%) and those who were sexually inactive (4.1%) (p=0.08). In conclusion, although many patients were sexually active prior to AMI, only a minority received discharge counseling about resuming sexual activity. Lack of counseling was associated with loss of sexual activity 1 year later. Mortality was not significantly elevated among individuals who were sexually active soon after their AMI.
PMCID: PMC3341956  PMID: 22546209
acute myocardial infarction; sexuality; quality of life; physician-patient communication
15.  Do Physician Organizations Located in Lower Socioeconomic Status Areas Score Lower on Pay-for-Performance Measures? 
Physician organizations (POs)—independent practice associations and medical groups—located in lower socioeconomic status (SES) areas may score poorly in pay-for-performance (P4P) programs.
To examine the association between PO location and P4P performance.
Cross-sectional study; Integrated Healthcare Association’s (IHA’s) P4P Program, the largest non-governmental, multi-payer program for POs in the U.S.
160 POs participating in 2009.
We measured PO SES using established methods that involved geo-coding 11,718 practice sites within 160 POs to their respective census tracts and weighting tract-specific SES according to the number of primary care physicians at each site. P4P performance was defined by IHA’s program and was a composite mainly representing clinical quality, but also including measures of patient experience, information technology and registry use.
The area-based PO SES measure ranged from −11 to +11 (mean 0, SD 5), and the IHA P4P performance score ranged from 23 to 86 (mean 69, SD 15). In bivariate analysis, there was a significant positive relationship between PO SES and P4P performance (p < 0.001). In multivariate analysis, a one standard deviation increase in PO SES was associated with a 44% increase (relative risk 1.44, 95%CI, 1.22-1.71) in the likelihood of a PO being ranked in the top two quintiles of performance (p < 0.001).
Physician organizations’ performance scores in a major P4P program vary by the SES of the areas in which their practice sites are located. P4P programs that do not account for this are likely to pay higher bonuses to POs in higher SES areas, thus increasing the resource gap between these POs and POs in lower SES areas, which may increase disparities in the care they provide.
PMCID: PMC3326117  PMID: 22160817
physician organizations; independent practice associations; medical groups; pay-for-performance; quality; disparities
16.  Clinical Use of U-500 Regular Insulin: Review and Meta-Analysis 
The use of U-500 regular insulin (U-500R) to treat diabetic patients with severe insulin resistance has increased. In this review, we performed a meta-analysis of PubMed studies reporting the use of U-500R to evaluate the effects of U-500R on hemoglobin A1c (HbA1c), body weight, and total daily insulin dose (TDD). These studies included 310 patients using U-500R as multiple daily injections (MDI) and 55 patients using U-500R via continuous subcutaneous insulin infusion (CSII). Overall, the use of U-500R as MDI resulted in a significant HbA1c reduction of 1.59%, a significant weight gain of 4.38 kg, and a significant increase in TDD by 51.9 units. The use of U-500R via CSII resulted in a similarly significant HbA1c reduction of 1.64% but a nonsignificant weight gain and a nonsignificant change in TDD.
The use of U-500 regular insulin both as MDI and via CSII was not reported to be associated with severe hypoglycemia but was associated with an increase in patient satisfaction as well as in cost savings. Suggestions in initiating U-500R in the outpatient setting using U-500R in hospitalized patients are reviewed. In addition, precautions for avoiding prescription and patient errors are discussed.
PMCID: PMC3380787  PMID: 22538155
continuous subcutaneous insulin infusion; insulin resistance; multiple daily injections; U-500 regular insulin
17.  Unrecognized Ingestion of Toxoplasma gondii Oocysts Leads to Congenital Toxoplasmosis and Causes Epidemics in North America 
Undetected contamination of food and water by oocysts causes human infections in North America. Risks often are unrecognized. Education alone cannot prevent suffering and economic consequences associated with congenital toxoplasmosis. Prenatal screening can facilitate prevention and treatment of congenital toxoplasmosis.
(See the Editorial Commentary by Linn, on pages 1090–1.)
Background. Congenital toxoplasmosis presents as severe, life-altering disease in North America. If mothers of infants with congenital toxoplasmosis could be identified by risks, it would provide strong support for educating pregnant women about risks, to eliminate this disease. Conversely, if not all risks are identifiable, undetectable risks are suggested. A new test detecting antibodies to sporozoites demonstrated that oocysts were the predominant source of Toxoplasma gondii infection in 4 North American epidemics and in mothers of children in the National Collaborative Chicago-based Congenital Toxoplasmosis Study (NCCCTS). This novel test offered the opportunity to determine whether risk factors or demographic characteristics could identify mothers infected with oocysts.
Methods. Acutely infected mothers and their congenitally infected infants were evaluated, including in-person interviews concerning risks and evaluation of perinatal maternal serum samples.
Results. Fifty-nine (78%) of 76 mothers of congenitally infected infants in NCCCTS had primary infection with oocysts. Only 49% of these mothers identified significant risk factors for sporozoite acquisition. Socioeconomic status, hometown size, maternal clinical presentations, and ethnicity were not reliable predictors.
Conclusions. Undetected contamination of food and water by oocysts frequently causes human infections in North America. Risks are often unrecognized by those infected. Demographic characteristics did not identify oocyst infections. Thus, although education programs describing hygienic measures may be beneficial, they will not suffice to prevent the suffering and economic consequences associated with congenital toxoplasmosis. Only a vaccine or implementation of systematic serologic testing of pregnant women and newborns, followed by treatment, will prevent most congenital toxoplasmosis in North America.
PMCID: PMC3246875  PMID: 22021924
18.  Determination of the source of androgen excess in functionally atypical polycystic ovary syndrome by a short dexamethasone androgen-suppression test and a low-dose ACTH test 
Human Reproduction (Oxford, England)  2011;26(11):3138-3146.
Polycystic ovary syndrome (PCOS) patients typically have 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHa) (PCOS-T). The objective of this study was to determine the source of androgen excess in the one-third of PCOS patients who atypically lack this type of ovarian dysfunction (PCOS-A).
Aged-matched PCOS-T (n= 40), PCOS-A (n= 20) and controls (n= 39) were studied prospectively in a General Clinical Research Center. Short (4 h) and long (4–7 day) dexamethasone androgen-suppression tests (SDAST and LDAST, respectively) were compared in subsets of subjects. Responses to SDAST and low-dose adrenocorticotropic hormone (ACTH) were then evaluated in all.
Testosterone post-SDAST correlated significantly with testosterone post-LDAST and 17OHP post-GnRHa (r = 0.671–0.672), indicating that all detect related aspects of ovarian dysfunction. An elevated dehydroepiandrosterone peak in response to ACTH, which defined functional adrenal hyperandrogenism, was similarly prevalent in PCOS-T (27.5%) and PCOS-A (30%) and correlated significantly with baseline dehydroepiandrosterone sulfate (DHEAS) (r = 0.708). Functional ovarian hyperandrogenism was detected by subnormal testosterone suppression by SDAST in most (92.5%) PCOS-T, but significantly fewer PCOS-A (60%, P< 0.01). Glucose intolerance was absent in PCOS-A, but present in 30% of PCOS-T (P < 0.001). Most of the PCOS-A cases with normal testosterone suppression in response to SDAST (5/8) lacked evidence of adrenal hyperandrogenism and were obese.
Functional ovarian hyperandrogenism was not demonstrable by SDAST in 40% of PCOS-A. Most of these cases had no evidence of adrenal hyperandrogenism. Obesity may account for most hyperandrogenemic anovulation that lacks a glandular source of excess androgen, and the SDAST seems useful in making this distinction.
PMCID: PMC3196876  PMID: 21908468
glucose intolerance; functional adrenal hyperandrogenism; functional ovarian hyperandrogenism; obesity
19.  Sleep Disturbances and Their Relationship to Glucose Tolerance in Pregnancy 
Diabetes Care  2011;34(11):2454-2457.
To explore relationships among sleep disturbances, glucose tolerance, and pregnancy outcomes.
Four validated sleep questionnaires were administered to 169 pregnant women at the time of 50-g oral glucose tolerance testing (OGTT) during the second trimester. Pregnancy outcomes were analyzed in 108 women with normal glucose tolerance (NGT).
Of the participants, 41% had excessive daytime sleepiness (Epworth Sleepiness Scale [ESS] >8); 64% had poor sleep quality; 25% snored frequently; 29% had increased risk of sleep-disordered breathing (SDB); 52% experienced short sleep (SS); 19% had both increased SDB risk and SS (SDB/SS); and 14% had daytime dysfunction. Reported sleep duration inversely correlated with glucose values from 50-g OGTT (r = −0.21, P < 0.01). Each hour of reduced sleep time was associated with a 4% increase in glucose levels. Increased likelihood of gestational diabetes mellitus (GDM) was found in subjects with increased SDB risk (odds ratio 3.0 [95% CI 1.2–7.4]), SS (2.4 [1.0–5.9]), SDB/SS (3.4 [1.3–8.7]), and frequent snoring (3.4 [1.3–8.8], after adjustment for BMI). Among NGT subjects, preterm delivery was more frequent in those with increased ESS (P = 0.02), poor sleep quality (P = 0.02), and SS (P = 0.03). Neonatal intensive care unit admissions were associated with increased ESS (P = 0.03), SDB/SS (P = 0.03), and daytime dysfunction (P < 0.01) in mothers.
Pregnant women experience significant sleep disturbances that are associated with increased risk of GDM and unfavorable pregnancy outcomes. Pregnant women with increased SDB risk, frequent snoring, and sleep duration of <7 h/night have increased risk of developing GDM.
PMCID: PMC3198297  PMID: 21926292
20.  Dual Inhibition of VEGFR and EGFR is an Effective Chemopreventive Strategy in the Mouse 4-NQO Model of Oral Carcinogenesis 
Despite recent therapeutic advances, several factors, including field cancerization, have limited improvements in long-term survival for oral squamous cell carcinoma (OSCC). Therefore, comprehensive treatment plans must include improved chemopreventive strategies. Using the 4-Nitroquinoline 1-Oxide (4-NQO) mouse model, we tested the hypothesis that ZD6474 (Vandetanib, ZACTIMA) is an effective chemopreventive agent. CBA mice were fed 4-NQO (100 ug/ml) in their drinking water for 8 weeks and then randomized to no treatment or oral ZD6474 (25 mg/Kg/day) for 24 weeks. The percentage of animals with OSCC was significantly different between the two groups (71% in control and 12% in ZD6474 group; p≤0.001). The percentage of mice with dysplasia or OSCC was significantly different (96% in the control and 28% in the ZD6474 group; p≤0.001). Proliferation and MVD scores were significantly decreased in the ZD6474 group (p<=0.001 for both). While proliferation and MVD increased with histologic progression in control and treatment cohorts, EGFR and VEGFR-2 phosphorylation was decreased in the treatment group for each histologic diagnosis, including mice harboring tumors. OSCC from ZD6474-treated mice exhibited features of epithelial to mesenchymal transition (EMT), as demonstrated by loss E-cadherin and gain of vimentin protein expression. These data suggest that ZD6474 holds promise as an OSCC chemopreventive agent. They further suggest that acquired resistance to ZD6474 may be mediated by the expression of an EMT phenotype. Finally, the data suggests that this model is a useful pre-clinical platform to investigate the mechanisms of acquired resistance in the chemopreventive setting.
PMCID: PMC3408865  PMID: 20978113
oral cancer; angiogenesis; ZD6474; mouse model; 4-NQO
21.  Assessing Gynecologic and Breast Cancer Survivors’ Sexual Health Care Needs (Sexual Care Needs of Cancer Survivors) 
Cancer  2010;117(12):2643-2651.
To identify patterns of female cancer survivors’ interest in receiving care for sexual concerns.
Survey and medical record data were collected June 2008 to March 2009 from 261 gynecologic and breast cancer patients. Logistic regression was used to estimate the effect of age and months since treatment on interest in receiving sexual health care.
Participants’ mean age was 55 years (range 21–88). Only 7% had recently sought medical help for sexual issues, yet 41.6% were interested in receiving care. More than 30% responded that they would be likely to see a physician to address sexual matters and 35% of all women were willing to be contacted if a formal program was offered. When compared to older women (>65 years), younger women (18–47 years) were significantly more likely to report interest in receiving care to address sexual issues (OR 2.94, 95% CI 1.14–7.54), to see a physician to address sexual matters (OR 4.51, 95% CI 1.51–13.43) and more willing to be contacted for a formal program (AOR 5.00, 95% CI 1.63–15.28). Compared to those currently in treatment, women who last received treatment more than 12 months prior were significantly more interested in receiving care (AOR 2.02, 95% CI 1.02–4.01) and more willing to be contacted (AOR 2.49, 95% CI 1.18–5.26).
More than 40% of survivors expressed interest in receiving sexual health care, but few had ever sought such care. There is an unmet need for attention to sexual concerns among women with gynecologic and breast cancer.
PMCID: PMC3084902  PMID: 21656742
gynecologic neoplasms; breast neoplasms; sexuality; sexual dysfunction psychological; sexually dysfunction physiological; needs assessment; quality of life
22.  Chorioretinal lesions in mothers of children with congenital toxoplasmosis in the National Collaborative Chicago-based, Congenital Toxoplasmosis Study 
Scientia medica  2010;20(1):20-26.
To determine whether mothers of children with congenital toxoplasmosis have chorioretinal lesions consistent with toxoplasmosis.
Prospective cohort study. Ophthalmologists in our study have examined 173 children with congenital toxoplasmosis in a hospital outpatient setting. These children were referred to us by their primary care physicians. One hundred and thirty mothers of these children had retina examinations of both eyes at least once. Main outcome measure was lesion(s) consistent with ocular toxoplasmosis.
Of 130 mothers examined between 1991–2005, 10 (7.7%, 95% Confidence Interval 3.8%, 13.7%) had chorioretinal lesions which likely represent resolved toxoplasmic chorioretinitis. Most of these were small peripheral chorioretinal lesions. None reactivated between 1991–2005.
Chorioretinal lesions consistent with quiescent ocular toxoplasmosis occur in mothers of children with congenital toxoplasmosis in the United States.
PMCID: PMC3347882  PMID: 22577474
23.  Predictors of C-Reactive Protein in the National Social Life, Health, and Aging Project 
Inflammation plays an important role in many chronic degenerative diseases associated with aging, and social, economic, and behavioral factors that contribute to inflammation may lead to differential burdens of morbidity and mortality in later life. This study examines socioeconomic status and race/ethnicity as predictors of C-reactive protein (CRP) among older adults in the United States and considers the degree to which health behaviors, medical conditions and medication use, and psychosocial factors account for these associations.
Multiple linear regression analysis of survey data for 1,580 participants, 57–85 years of age, in a population-based nationally representative sample of community-residing older adults in the United States.
Educational attainment, household wealth, and race/ethnicity were independently associated with CRP, with limited evidence for interactions with age. Health-related behaviors and usage of medications related to inflammation accounted for substantial proportions of these associations.
These results highlight the fundamental causes of inflammation among older adults and suggest pathways through which social disparities in inflammation may be reduced.
PMCID: PMC3001750  PMID: 20172904
Aging; Health disparities; Inflammation; Social determinants of health
24.  Physician Preferences and Knowledge Gaps Regarding the Care of Childhood Cancer Survivors: A Mailed Survey of Pediatric Oncologists 
Journal of Clinical Oncology  2009;28(5):878-883.
Little is known about physicians' attitudes and knowledge regarding the health care needs of childhood cancer survivors (CCS). We sought to obtain pediatric cancer physicians' self-reported attitudes and knowledge regarding this population.
A mailed survey was sent to 1,159 pediatric oncologists in the United States.
A total of 655 surveys were returned (ie, 57% response rate). Median age of respondents was 47 years (range, 31 to 82 years); 57% were men. Respondents practiced for a median 14 years (range, 1 to 50 years) and reported seeing a median of 21 patients per week (range, 0 to 250 patients per week). When comfort levels in caring for CCS were described (ie, 1 = very uncomfortable; 7 = very comfortable), respondents were most comfortable with survivors ≤ 21 years (mean ± standard deviation, 6.2 ± 1.3 level), were less comfortable (5.0 ± 1.5 level) with those older than 21 years but less than 30 years old, and were uncomfortable with CCS ≥ 30 years (2.9 ± 1.7 level). In response to a clinical vignette of a 29-year-old woman treated with mantle radiation for Hodgkin's lymphoma at 16 years of age, and on the basis of available guidelines, 34% of respondents did not appropriately recommend yearly breast cancer surveillance; 43% of respondents did not appropriately recommend cardiac surveillance; and 24% of respondents did not appropriately recommend yearly thyroid surveillance. Those with greater self-reported familiarity with available long-term follow-up (LTFU) guidelines (odds ratio [OR], 1.33; 95% CI, 1.15 to 1.54) and with receipt of training in the care of CCS (OR, 1.73; 95% CI, 1.18 to 2.52) were more likely to have answered all three questions correctly.
Pediatric oncologists express a range of preferences with regard to LTFU of CCS. Many appear unfamiliar with LTFU surveillance guidelines.
PMCID: PMC3040043  PMID: 20038717
25.  Age of onset, symptom threshold, and expansion of the nosology of conduct disorder for girls 
Journal of abnormal psychology  2010;119(4):689-698.
The study of conduct disorder (CD) in girls is characterized by several nosologic controversies that center on the most common age of onset, the most valid symptom threshold, and potentially including other manifestations of antisocial behavior and dimensions of personality as part of the definition of CD. Data from a prospective, longitudinal study of a community sample of 2,451 racially diverse girls were used to empirically inform these issues. Results revealed that adolescent-onset CD is rare in girls. There was mixed support for the threshold at which symptoms are associated with impairment: parent-reported impairment provided the clearest evidence of maintaining the current DSM-IV threshold of 3 symptoms. The impact of callousness and relational aggression on impairment varied by informant, with small effects for parent-and youth-reported impairment, and larger effects for teacher-rated impairment relative to the effects for CD. These results support arguments for revising the typical age of onset of CD for girls, but for maintaining the current symptom threshold. The results also suggest the need to consider sub-typing according to the presence or absence of callousness. Given its content validity relational aggression requires further study in the context of ODD and CD.
PMCID: PMC2991491  PMID: 20853913
conduct disorder; girls; diagnosis; validity; phenotype

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