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1.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russell, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojensen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(20):4239.
doi:10.1093/hmg/ddt334
PMCID: PMC3871151
2.  Evaluating the Association of Workplace Psychosocial Stressors with Occupational Injury, Illness, and Assault 
Objective
This research project characterizes occupational injuries, illnesses, and assaults (OIIAs) as a negative outcome associated with worker exposure to generalized workplace abuse/harassment, sexual harassment, and job threat and pressure.
Methods
Data were collected in a nationwide random-digit-dial telephone survey conducted during 2003–2004. There were 2,151 study interviews conducted in English and Spanish. Analyses included cross tabulation with Pearson’s Chi-Square, and logistic regression analyses.
Results
Three hundred fifty-one (351) study participants reported having an OIIA during the 12 months preceding the study. Occurrences of generalized workplace harassment (O.R.= 1.53; CI = 1.33 – 1.75, p≤ 0.05), sexual harassment (O.R.= 1. 18; CI = 1.04 –1.34, p≤ 0.05), and job pressure and threat (O.R.=1.26; CI = 1.10–1.45, p≤ 0.05), were significantly associated with reporting an OIIA.
Conclusions
The psychosocial environment is significantly associated with an increased risk of OIIA. Further research is needed to understand causal pathways and to explore potential interventions.
doi:10.1080/15459624.2011.537985
PMCID: PMC3979455  PMID: 21154106
Psychosocial Stress; Occupational Injuries; Occupational Illnesses; Generalized Workplace Harassment; Sexual Harassment; Job Pressure and Threat
3.  Factors Associated With Fatigue After Surgery in Women With Early-Stage Invasive Breast Cancer 
The Oncologist  2013;18(4):467-475.
This study investigated factors correlated with cancer-related fatigue before surgery and just before subsequent adjuvant therapy in patients with breast cancer. Results suggest that worsening fatigue after surgery for breast cancer is associated with a decrease in physical functioning and an increase in psychological distress.
Learning Objectives
Describe the effect of worsening fatigue after breast cancer surgery on physical functioning and psychological distress.Better identify women at risk for developing cancer-related fatigue.Direct target interventions to patients most in need.
Purpose.
Fatigue is one of the most frequent symptoms in patients with cancer. However, the precise determinants of fatigue are still unknown. This study was conducted to investigate factors correlated with cancer-related fatigue before surgery and just before subsequent adjuvant therapy.
Methods.
Patients completed the Multidimensional Fatigue Inventory (MFI-20), the European Organization for Research and Treatment of Cancer 30-item quality-of-life questionnaire before and after surgery, the Trait Anxiety Inventory and the Life Orientation Test before surgery, and the State Anxiety Inventory before the start of adjuvant therapy. Multiple regression analysis of determinants of change in MFI-20 total score after surgery was conducted.
Results.
A series of 466 eligible patients with stage I–III breast cancer with planned surgery were recruited. An increase in MFI-20 total score after surgery was significantly correlated with higher preoperative fatigue and lower role functioning before surgery; a decrease in role functioning, physical functioning, and cognitive functioning after surgery; an increase in insomnia after surgery; and a higher state anxiety after surgery. Disease stage, lymph node metastases, surgical procedure, and demographic characteristics (e.g., age, marital status, having children, educational level) were not correlated with fatigue in multivariate analysis.
Conclusion.
These results suggest that worsening fatigue after surgery for breast cancer is associated with a decrease in physical functioning and an increase in psychological distress rather than with the cancer characteristics. Therefore, screening measures should be implemented at the time of diagnosis—before starting treatment—to identify psychologically vulnerable patients and to offer them professional support.
doi:10.1634/theoncologist.2012-0300
PMCID: PMC3639535  PMID: 23404818
4.  Changes in serum aldosterone are associated with changes in obesity-related factors in normotensive overweight and obese young adults 
Recent data suggest excess circulating aldosterone promotes cardiometabolic decline. Weight loss may lower aldosterone levels, but little longitudinal data is available in normotensive adults. We aimed to determine if, independent of changes in sodium excretion, reductions in serum aldosterone are associated with favorable changes in obesity-related factors in normotensive overweight/obese young adults. We studied 285 overweight/obese young adult participants (body mass index (BMI) ≥ 25 and < 40 kg/m2, age 20–45 years) in a clinical trial examining the effects of a one year diet and physical activity intervention with or without sodium restriction on vascular health. Body weight, serum aldosterone, 24-hr sodium and potassium excretion, and obesity-related factors were measured at baseline, 6, 12, and 24 months. Weight loss was significant at 6 (7%), 12 (6%), and 24 months (4%) (all p<0.0001). Decreases in aldosterone were associated with decreases in C-reactive protein, leptin, insulin, homeostasis assessment of insulin resistance, heart rate, tonic cardiac sympathovagal balance, and increases in adiponectin (all p<0.05) in models adjusting for baseline age, sex, race, intervention arm, time since baseline, and sodium and potassium excretion. Weight loss and reductions in thigh intermuscular fat (IMAT) were associated with decreases in aldosterone in the subgroup (n=98) with metabolic syndrome (MetS) at baseline (MetS x weight loss p=0.04, MetS x change in IMAT p=0.04). Favorable changes in obesity-related factors are associated with reductions in aldosterone in young adults with no risk factors besides excess weight, an important finding given aldosterone’s emergence as an important cardiometabolic risk factor.
doi:10.1038/hr.2013.45
PMCID: PMC3766434  PMID: 23657296
aldosterone; obesity; adipokines; metabolic syndrome; adipose tissue
5.  Gender, Power, and Intimate Partner Violence: A Study on Couples From Rural Malawi 
Journal of interpersonal violence  2013;29(5):866-888.
Gender-based power imbalances are perhaps the most compelling underlying explanation for intimate partner violence (IPV) among women in sub-Saharan Africa. However, an overemphasis on female victimization results in an incomplete understanding of men’s experiences as victims and the broader dyadic context in which violence occurs. This study examines the role of three domains of relationship power (power resources, processes, and outcomes) on sexual and physical IPV victimization in a unique sample of 466 young couples from Malawi. Two power resources were studied, namely, income and education level. Power processes were captured with a measure of couple communication and collaboration called unity. Power outcomes included a measure of relationship dominance (male dominated or female-dominated/egalitarian). Multilevel logistic regression using the Actor Partner Interpersonal Model framework was used to test whether respondent and partner data were predictive of IPV. The findings show that unity and male dominance were salient power factors that influenced young people’s risk for sexual IPV. Unity had a stronger protective effect on sexual IPV for women than for men. Involvement in a male-dominated relationship increased the risk of sexual IPV for women, but decreased the risk for men. The findings also showed that education level and unity were protective against physical IPV for both men and women. Contrary to what was expected, partner data did not play a role in the respondent’s experience of IPV. The consistency of these findings with the literature, theory, and study limitations are discussed.
doi:10.1177/0886260513505907
PMCID: PMC3946893  PMID: 24227592
physical abuse; sexual coercion; power; APIM; Malawi
6.  Suicide Risk Assessment Training for Psychology Doctoral Programs: Core Competencies and a Framework for Training 
Clinical and counseling psychology programs currently lack adequate evidence-based competency goals and training in suicide risk assessment. To begin to address this problem, this article proposes core competencies and an integrated training framework that can form the basis for training and research in this area. First, we evaluate the extent to which current training is effective in preparing trainees for suicide risk assessment. Within this discussion, sample and methodological issues are reviewed. Second, as an extension of these methodological training issues, we integrate empirically- and expert-derived suicide risk assessment competencies from several sources with the goal of streamlining core competencies for training purposes. Finally, a framework for suicide risk assessment training is outlined. The approach employs Objective Structured Clinical Examination (OSCE) methodology, an approach commonly utilized in medical competency training. The training modality also proposes the Suicide Competency Assessment Form (SCAF), a training tool evaluating self- and observer-ratings of trainee core competencies. The training framework and SCAF are ripe for empirical evaluation and potential training implementation.
doi:10.1037/a0031836
PMCID: PMC3963278  PMID: 24672588
suicide; risk assessment; competency; psychology training; OSCE
7.  Fluorinated N, N’-Diarylureas as AMPK Activators 
Adenosine monophosphate-activated kinase (AMPK) plays a central role in regulating energy homeostasis in eukaryotic cells. AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2. Due to its important roles in cell metabolism, AMPK is an attractive target for metabolic diseases, such as type II diabetes and obesity. AMPK activators, such as metformin, that are used for diabetes treatment are also effective anticancer agents. However, the efficacies of many known AMPK activators are relatively low. For example, metformin activates AMPK at millimolar levels. In this study, we identified a novel family of AMPK activators, namely fluorinated N,N’-diarylureas, that activate AMPK at 1–3µM concentrations. These novel agents strongly inhibit the proliferation of colon cancer cells. We studied the potential mechanisms of these agents, performed a structure-activity relationship (SAR) study and identified several fluorinated N,N’- diarylureas as potent AMPK activators.
doi:10.1016/j.bmcl.2013.01.096
PMCID: PMC3594501  PMID: 23414799
8.  CC12, a P450/Epoxygenase Inhibitor, Acts in the Rat Rostral Ventromedial Medulla to Attenuate Morphine Antinociception 
Brain research  2013;1499:1-11.
Brain cytochrome P450 epoxygenases were recently shown to play an essential role in mediating the pain-relieving properties of morphine. To identify the CNS sites containing the morphine-relevant P450s, the effects of intracerebral (ic) microinjections of the P450 inhibitor CC12 were determined on morphine antinociception in rats. CC12 inhibited morphine antinociception when both drugs were injected into the rostral ventromedial medulla (RVM), but not following co-injections into the periaqueductal gray (PAG) or into the spinal subarachnoid space. In addition, intra-RVM CC12 pretreatment nearly completely blocked the effects of morphine following intracerebroventricular (icv) administration. Although morphine is thought to act in both the PAG and RVM by pre-synaptic inhibition of inhibitory GABAergic transmission, the present findings show that 1) the mechanism of morphine action differs between these two brainstem areas, and 2) P450 activity within the RVM is important for supraspinal morphine antinociception. Characterization of morphine-P450 interactions within RVM circuits will further enhance the understanding of the biochemistry of pain relief.
doi:10.1016/j.brainres.2012.12.030
PMCID: PMC3570688  PMID: 23298831
morphine; opioids; pain; cytochrome P450; RVM
9.  Non-Hodgkin Lymphoma and circulating markers of inflammation and adiposity in a nested case-control study: The Multiethnic Cohort 
Objective
Since immune dysfunction is thought to underlie the development of Non-Hodgkin Lymphoma (NHL), obesity and chronic inflammation may be involved in its etiology. We examined the association of pre-diagnostic inflammatory markers and adipokines with NHL risk.
Methods
We conducted a nested case-control analysis (272 cases and 541 matched controls) within the Multiethnic Cohort. Luminex technology was used to measure a 10-plex panel of cytokines, ELISA assays for adipokines, and an autoanalyzer for C-reactive protein (CRP). Odds ratios (ORs) and 95% confidence intervals (CIs) for tertiles of analytes were estimated by conditional logistic regression.
Results
After a median time of 2.7 years from phlebotomy to diagnosis, interleukin (IL)-10 was significantly related to NHL risk (ORT3 vs T1=3.07; 95%CI: 2.02–4.66; ptrend <0.001). TNF-α and IL-8 showed borderline elevated risks, while IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, and CRP were not associated with NHL. Leptin but not adiponectin was related to NHL risk (ORT3 vs T1=0.48, 95%CI: 0.30–0.76; ptrend<0.001). Adjustment for body mass index did not substantially affect the risk estimates. Stratification by subtype indicated significant associations with IL-10 and leptin for follicular but not for diffuse large B-cell lymphoma. Excluding cases diagnosed <1 year after phlebotomy attenuated all associations.
Conclusions
IL-10 was the only cytokine and leptin the only adipokine associated with NHL, but, due to the short follow-up time, pre-clinical effects cannot be excluded.
Impact
Although markers of inflammation and adiposity may provide new insights into the etiology of NHL, they need to be assessed many years before clinical diagnosis.
doi:10.1158/1055-9965.EPI-12-0947
PMCID: PMC3596426  PMID: 23300021
Non-Hodgkin Lymphoma; inflammatory markers; adiponectin; leptin; nested case-control study; prospective cohort; ethnicity
10.  Frontal gray matter reduction after breast cancer chemotherapy and association with executive symptoms: A replication and extension study 
Brain, behavior, and immunity  2012;30(0):S117-S125.
Cognitive changes related to cancer and its treatment have been intensely studied, and neuroimaging has begun to demonstrate brain correlates. In the first prospective longitudinal neuroimaging study of breast cancer (BC) patients we recently reported decreased gray matter density one month after chemotherapy completion, particularly in frontal regions. These findings helped confirm a neural basis for previously reported cognitive symptoms, which most commonly involve executive and memory processes in which the frontal lobes are a critical component of underlying neural circuitry. Here we present data from an independent, larger, more demographically diverse cohort that is more generalizable to the BC population. BC patients treated with (N = 27) and without (N = 28) chemotherapy and matched healthy controls (N = 24) were scanned at baseline (prior to systemic treatment) and one month following chemotherapy completion (or yoked intervals for non-chemotherapy and control groups) and APOE-genotyped. Voxel-based morphometry (VBM) showed decreased frontal gray matter density after chemotherapy, as observed in the prior cohort, which was accompanied by self-reported difficulties in executive functioning. Gray matter and executive symptom changes were not related to APOE ε4 status, though a somewhat greater percentage of BC patients who received chemotherapy were ε4 allele carriers than patients not treated with chemotherapy or healthy controls. These findings provide confirmatory evidence of frontal morphometric changes that may be a pathophysiological basis for cancer and treatment-related cognitive dysfunction. Further research into individual risk factors for such changes will be critical for development of treatment and prevention strategies.
doi:10.1016/j.bbi.2012.05.007
PMCID: PMC3629547  PMID: 22613170
Adjuvant chemotherapy; APOE genotype; Brain; Breast cancer; BRIEF-A; Executive function; Frontal lobes; Magnetic resonance imaging; Neuroimaging; Voxel-based morphometry
11.  What Does It Take? Comparing Intensive Rehabilitation to Outpatient Treatment for Children With Significant Pain-Related Disability 
Journal of Pediatric Psychology  2012;38(2):213-223.
Objectives This study compared outcomes between day hospital pain rehabilitation patients and patients engaged in outpatient multidisciplinary pain treatment. Methods This study included 100 children who presented for an initial tertiary care pain clinic evaluation. 50 patients enrolled in intensive day hospital pain rehabilitation and 50 patients pursued outpatient multidisciplinary treatment. Across 2 time points, children completed measures of functional disability, pain-related fear, and readiness to change and parents completed measures of pain-related fear and readiness to change. Results Across both treatment modalities, patients and parents reported improvements. Patients enrolled in intensive pain rehabilitation had significantly larger improvements in functional disability, pain-related fear, and readiness to change. Parents of day hospital patients reported larger declines in child pain-related fear and increased readiness to change compared with their outpatient counterparts. Discussion For patients with high levels of pain-related disability and distress, intensive pain rehabilitation provides rapid, dramatic improvements in functioning.
doi:10.1093/jpepsy/jss109
PMCID: PMC3695659  PMID: 23104827
child and adolescent; chronic pain; pain rehabilitation; treatment response
12.  PREDICTORS OF ATTEMPTED WEIGHT LOSS AND PHYSICIAN ADVICE FOR WEIGHT LOSS IN A GROUP OF OVERWEIGHT AND OBESE PATIENTS IN TOGO 
Ethnicity & disease  2013;23(1):83-86.
Despite a worldwide increase in obesity, little is known about obesity in Africa and factors related to attempting weight loss (AWL) in high-risk populations. The aims of this study were to determine the prevalence of obesity among patients in a Togolese cardiology clinic and determine predictors of reporting AWL and physician advice for weight loss. We recruited French-speaking men and women, aged ≥ 18 years from this academic cardiology clinic to complete a questionnaire and anthropometric measurements. Among 135 patients, 33% were overweight and 24% were obese. Among overweight and obese patients (n=76), logistic regression was used to calculate odds ratios (OR) for predictors of AWL and physician advice. 53% reported AWL and 49% received physician advice. Obese participants were 11 times more likely than overweight participants to report AWL (OR= 11.14; P=<.0001). AWL was more common in those reporting physician advice (OR=7.58; P=.0001) and women (OR=2.78; P=.04). Obesity and female sex were also associated with reporting physician advice to lose weight. Age and education were not associated with AWL or physician advice. Physician advice highly correlates with AWL; however only half of participants received it. Physicians should make efforts to incorporate weight loss advice in their routine care.
PMCID: PMC3934629  PMID: 23495627
Togo; West Africa; Obesity; Overweight; Weight Loss; Physician Advice; BMI
13.  Behavioral Landscapes and Change in Behavioral Landscapes: A Multiple Time-Scale Density Distribution Approach 
Research in human development  2013;10(1):88-110.
In developmental arenas, it is well accepted that multiple observations are needed to obtain a robust characterization of individuals’ behavioral tendencies across time and context. In this paper, we fuse core ideas from the study of lifespan development with intraindividual variability based approaches to personality and methods used to characterize the topography of geographic landscapes. We generalize the notion of density distributions into bivariate and multivariate space and draw parallels between the resulting behavioral landscapes and geographic landscapes. We illustrate through an empirical example how multiple time-scale study designs, measures of intraindividual variability, and methods borrowed from geography can be used to describe both an individual’s behavioral landscape and changes in the behavioral landscape.
doi:10.1080/15427609.2013.760262
PMCID: PMC3728905  PMID: 23914142
longitudinal analysis; ecological momentary assessment; intensive longitudinal data; emotional variability
14.  Olfactory processing in schizophrenia, non-ill first-degree family members, and young people at-risk for psychosis 
Objectives
While deficits in odor identification and discrimination have been reported in schizophrenia, few studies have examined the relative specificity of these deficits in patients and at-risk youth.
Method
Sniffin’ Sticks odor identification and discrimination were assessed in schizophrenia outpatients and non-ill first-degree relatives (Study One), as well as youth at clinical (CR) or genetic (GR) risk for schizophrenia (Study Two). Scores were z-transformed, using the performance of a demographically-matched adult or adolescent comparison group.
Results
Patients and relatives were impaired on odor identification, but odor discrimination impairment was limited to the patient group. A similar pattern of impairment emerged in at-risk youth. GR youth were impaired on odor identification but not discrimination, while CR youth were impaired on both tasks. In patients, olfactory impairment was correlated with negative symptomatology.
Conclusions
To our knowledge, this is the first study to show that CR youth are impaired on both olfactory tasks, as observed in adult schizophrenia patients. GR youth were impaired only on odor identification like their adult counterparts. These data suggest that odor identification impairment, in isolation, may represent a genetic marker of vulnerability for schizophrenia, while odor discrimination deficits may be a biomarker associated with the development of psychosis.
doi:10.3109/15622975.2011.615862
PMCID: PMC3922881  PMID: 22070564
olfaction; smell; prodrome; negative symptoms; psychosis prone
15.  First implication of STRA6 mutations in isolated anophthalmia, microphthalmia and coloboma: a new dimension to the STRA6 phenotype 
Human mutation  2011;32(12):1417-1426.
Microphthalmia, anophthalmia and coloboma (MAC) are structural congenital eye malformations that cause a significant proportion of childhood visual impairments. Several disease genes have been identified but do not account for all MAC cases, suggesting that additional risk loci exist. We used SNP homozygosity mapping (HM) and targeted next-generation sequencing to identify the causative mutation for autosomal recessive isolated colobomatous micro-anophthalmia (MCOPCB) in a consanguineous Irish Traveller family. We identified a double nucleotide polymorphism (g.1157G>A and g.1156G>A; p.G304K) in STRA6 that was homozygous in all of the MCOPCB patients. The STRA6 p.G304K mutation was subsequently detected in additional MCOPCB patients, including one individual with Matthew-Wood syndrome (MWS; MCOPS9). STRA6 encodes a transmembrane receptor involved in vitamin A uptake, a process essential to eye development and growth. We have shown that the G304K mutant STRA6 protein is mislocalised and has severely reduced vitamin A uptake activity. Furthermore, we reproduced the MCOPCB phenotype in a zebrafish disease model by inhibiting retinoic acid synthesis, suggesting that diminished retinoic acid levels account for the eye malformations in STRA6 p.G304K patients. The current study demonstrates that STRA6 mutations can cause isolated eye malformations in addition to the congenital anomalies observed in MWS.
doi:10.1002/humu.21590
PMCID: PMC3918001  PMID: 21901792
STRA6; homozygosity mapping; Matthew-Wood syndrome; MWS
16.  Use of a three-band HRP2/pLDH combination rapid diagnostic test increases diagnostic specificity for falciparum malaria in Ugandan children 
Malaria Journal  2014;13:43.
Background
Rapid diagnostic tests (RDTs) for malaria provide a practical alternative to light microscopy for malaria diagnosis in resource-limited settings. Three-band RDTs incorporating two parasite antigens may have enhanced diagnostic specificity, relative to two-band RDTs with a single parasite antigen (typically histidine-rich protein 2 [HRP2]).
Methods
Phase 1: 2,000 children, two months to five years of age, admitted to a referral hospital in Jinja, Uganda, with acute febrile illness were enrolled. A WHO highly rated three-band RDT was compared to light microscopy of thick peripheral blood films read by local expert microscopists.
Phase 2: the three-band RDT was used as a screening tool for inclusion of patients in a clinical trial, and subjects with three positive RDT bands were tested by microscopy using blood samples drawn in parallel. Discordant results were adjudicated by PCR.
Results
Phase 1: 1,648 children had both a RDT and peripheral blood smear performed. The specificity of a RDT with all three bands positive was 82% (95% CI: 79-85%) compared to 62% (95% CI: 59-66%) for HRP2 alone. The sensitivity was 88% (95% CI: 85-89%) and 94% (95% CI: 92-95%) for three-band positive RDT and HRP2 antigen, respectively. 119 patients (7.2%) had a positive HRP2 band, but negative parasite lactate dehydrogenase (pLHD) band and negative peripheral smear, and 72 (61%) of these had received pre-treatment with anti-malarials, suggesting a false positive HRP2 result (p = 0.002).
Phase 2: the positive predictive value (PPV) of the three-band RDT was 94% (95% CI 89%-97%) using microscopy as the reference standard. However, microscopy-discordant results were shown to be positive for P. falciparum by PCR in all cases, suggesting that the PPV was in fact higher.
Conclusion
The pLDH antigen on three-band RDTs, used in combination with HRP2, provides added diagnostic specificity for malaria parasitaemia and may be useful to distinguish acute infection from recently treated infection. In situations where diagnostic specificity is desirable (e.g., for selection of malaria-infected participants in clinical trials), a three-band RDT should be considered in a sub-Saharan African setting.
doi:10.1186/1475-2875-13-43
PMCID: PMC3922073  PMID: 24484540
Malaria; Rapid diagnostic test; Sensitivity; Specificity
17.  Gene Expression Profiling Identifies Important Genes Affected by R2 Compound Disrupting FAK and P53 Complex 
Cancers  2014;6(1):166-178.
Focal Adhesion Kinase (FAK) is a non-receptor kinase that plays an important role in many cellular processes: adhesion, proliferation, invasion, angiogenesis, metastasis and survival. Recently, we have shown that Roslin 2 or R2 (1-benzyl-15,3,5,7-tetraazatricyclo[3.3.1.1~3,7~]decane) compound disrupts FAK and p53 proteins, activates p53 transcriptional activity, and blocks tumor growth. In this report we performed a microarray gene expression analysis of R2-treated HCT116 p53+/+ and p53−/− cells and detected 1484 genes that were significantly up- or down-regulated (p < 0.05) in HCT116 p53+/+ cells but not in p53−/− cells. Among up-regulated genes in HCT p53+/+ cells we detected critical p53 targets: Mdm-2, Noxa-1, and RIP1. Among down-regulated genes, Met, PLK2, KIF14, BIRC2 and other genes were identified. In addition, a combination of R2 compound with M13 compound that disrupts FAK and Mmd-2 complex or R2 and Nutlin-1 that disrupts Mdm-2 and p53 decreased clonogenicity of HCT116 p53+/+ colon cancer cells more significantly than each agent alone in a p53-dependent manner. Thus, the report detects gene expression profile in response to R2 treatment and demonstrates that the combination of drugs targeting FAK, Mdm-2, and p53 can be a novel therapy approach.
doi:10.3390/cancers6010166
PMCID: PMC3980603  PMID: 24452144
Focal Adhesion Kinase; p53; Mdm-2; Nutlin; gene expression profiling; microarrays; combination therapy
18.  Host biomarkers distinguish dengue from leptospirosis in Colombia: a case–control study 
Background
Dengue fever and leptospirosis have partially overlapping geographic distributions, similar clinical presentations and potentially life-threatening complications but require different treatments. Distinguishing between these cosmopolitan emerging pathogens represents a diagnostic dilemma of global importance. We hypothesized that perturbations in host biomarkers can differentiate between individuals with dengue fever and leptospirosis during the acute phase of illness.
Methods
We randomly selected subjects from a prospective cohort study of acute febrile illness in Bucaramanga, Colombia and tested 19 serum biomarkers by ELISA in dengue fever (DF, n = 113) compared to subjects with leptospirosis (n = 47). Biomarkers were selected for further analysis if they had good discriminatory ability (area under the ROC curve (AUC) >0.80) and were beyond a reference range (assessed using local healthy controls).
Results
Nine biomarkers differed significantly between dengue fever and leptospirosis, with higher levels of Angptl3, IL-18BP, IP-10/CXCL10, Platelet Factor 4, sICAM-1, Factor D, sEng and sKDR in dengue and higher levels of sTie-2 in leptospirosis (p < 0.001 for all comparisons). Two biomarkers, sEng and IL18BP, showed excellent discriminatory ability (AUROC >0.90). When incorporated into multivariable models, sEng and IL18BP improved the diagnostic accuracy of clinical information alone.
Conclusions
These results suggest that host biomarkers may have utility in differentiating between dengue and leptospirosis, clinically similar conditions of different etiology.
doi:10.1186/1471-2334-14-35
PMCID: PMC3909480  PMID: 24444080
Dengue fever; Leptospirosis; Acute febrile illness; Host biomarkers; Clinical discrimination; Combinatorial models
19.  The Microarray Gene Profiling Analysis of Glioblastoma Cancer Cells Reveals Genes Affected by FAK Inhibitor Y15 and Combination of Y15 and Temozolomide 
Focal adhesion is known to be highly expressed and activated in glioma cells. Recently, we demonstrated that FAK autophosphorylation inhibitor, Y15 significantly decreased tumor growth of DBTRG and U87 cells, especially in combination with temozolomide. In the present report, we performed gene expression analysis in these cells to reveal genes affected by Y15, temozolomide and combination of Y15 and temozolomide. We tested the effect of Y15 on gene expression by Illumina Human HT12v4 microarray assay and detected 8087 and 6555 genes, which were significantly either up- or down-regulated by Y15-treatment in DBTRG and U87 cells, respectively (p<0.05). Moreover, DBTRG and U87 cells treated with Y15 changed expression of 1332 and 462 genes more than 1.5 fold, p<0.05, respectively and had 237 common genes affected by Y15. The common genes up-regulated by Y15 included GADD45A, HSPA6 (heat-shock 70); DUSP1, DUSP 5 (dual-phosphatase 5); CDKN1A (p21) and common down-regulated genes included kinesins, such as KIF11, 14, 20A, 20B; topoisomerase II, TOP2A; cyclin F; cell cycle protein: BUB1; PARP1, POLA1. In addition, we detected genes affected by temozolomide and by combination of Y15 and temozolomide treatment in U87 cells. Among genes up-regulated by Y15 and temozolomide more significantly than by each agent alone were: COX7B; interferon, gamma-inducible transcript: IFI16; DDIT4; GADD45G and down-regulated: KIF3A, AKT1; ABL; JAK1, GLI3 and ALDH1A3. Thus, microarray gene expression analysis can be effective in establishing genes affected in response to FAK inhibitor alone and in response to combination of Y15 with temozolomide that is important for glioblastoma therapy.
PMCID: PMC3883957  PMID: 23387973
Focal Adhesion Kinase; Y397 site; autophosphorylation; brain; glioblastoma; inhibitor
20.  Changes in willingness to self-manage pain among children and adolescents and their parents enrolled in an intensive interdisciplinary pediatric pain treatment program 
Pain  2012;153(9):10.1016/j.pain.2012.05.027.
The importance of willingness to adopt a self-management approach to chronic pain has been demonstrated in the context of cognitive-behaviorally oriented interdisciplinary pain treatment programs for adults, both as a treatment outcome and as a process that facilitates functional improvements. Willingness to self-manage pain has not been studied in pediatric interdisciplinary pain treatment settings. Study aims were (1) to investigate willingness to self-manage pain among children and parents undergoing intensive interdisciplinary pain treatment and (2) to determine whether increased willingness to self-manage pain influenced functional treatment outcomes. 157 children ages 10-18 and their parents enrolled in a pediatric pain rehabilitation program completed the Pain Stages of Change Questionnaire (PSOCQ youth and parent versions) at pre-treatment, post-treatment, and short-term follow up. They also reported on pain, functional disability, depressive symptoms, fear of pain, and use of passive and accommodative coping strategies. Results show that willingness to self-manage pain increased during treatment among both children and parents, with gains maintained at follow-up. Increases in children’s readiness to self-manage pain from pre- to post-treatment were associated with decreases in functional disability, depressive symptoms, fear of pain, and use of adaptive coping strategies. Increases in parents’ readiness to adopt a pain-self management approach were associated with changes in parent-reported fear of pain but not with other child outcomes. Few associations emerged between pre-treatment willingness to self-manage pain and post-treatment outcomes. Findings suggest that interdisciplinary pediatric pain rehabilitation may facilitate increased willingness to self-manage pain, which is associated with improvements in function and psychological well-being.
doi:10.1016/j.pain.2012.05.027
PMCID: PMC3884572  PMID: 22749194
Chronic pain; Multidisciplinary Treatment, Parents; Pediatric Pain; Readiness to change
21.  Alterations in brain structure and function in breast cancer survivors: effect of post-chemotherapy interval and relation to oxidative DNA damage 
Neuroimaging studies have begun to uncover the neural substrates of cancer and treatment-related cognitive dysfunction, but the time course of these changes in the years following chemotherapy is unclear. This study analyzed multimodality 3T MRI scans to examine the structural and functional effects of chemotherapy and post-chemotherapy interval (PCI) in a cohort of breast cancer survivors (BCS; n=24; PCI mean 6, range 3–10 y) relative to age- and education-matched healthy controls (HC; n=23). Assessments included voxel-based morphometry (VBM) for gray matter density (GMD) and fMRI for activation profile during a 3-back working memory task. The relationships between brain regions associated with PCI and neuropsychological performance, self-reported cognition, and oxidative and direct DNA damage as measured in peripheral lymphocytes were assessed in secondary analyses. PCI was positively associated with GMD and activation on fMRI in the right anterior frontal region (Brodmann Areas 9 and 10) independent of participant age. GMD in this region was also positively correlated with global neuropsychological function. Memory dysfunction, cognitive complaints, and oxidative DNA damage were increased in BCS compared to HC. Imaging results indicated lower fMRI activation in several regions in the BCS group. BCS also had lower GMD than HC in several regions, and in these regions GMD was inversely related to oxidative DNA damage and learning and memory neuropsychological domain scores. This is the first study to show structural and functional effects of PCI and to relate oxidative DNA damage to brain alterations in BCS. The relationship between neuroimaging and cognitive function indicates the potential clinical relevance of these findings. The relationship with oxidative DNA damage provides a mechanistic clue warranting further investigation.
doi:10.1007/s10549-012-2385-x
PMCID: PMC3543695  PMID: 23263697
breast cancer; voxel-based morphometry; functional MRI; chemotherapy; DNA damage
22.  The Effects of Soy Consumption before Diagnosis on Breast Cancer Survival: the Multiethnic Cohort Study 
Nutrition and cancer  2013;65(4):10.1080/01635581.2013.776694.
This study tested the hypothesis that prediagnostic soy intake was inversely associated with all-cause and breast cancer-specific mortality. The analyses included 3,842 female in the Multiethnic Cohort (MEC) study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and Caucasians, who completed a quantitative food frequency questionnaire, aged ≥50 years at cohort entry, and diagnosed with primary invasive breast cancer following cohort entry (1993-2007). Hazard ratios (HR) and 95% confidence intervals (CI) were estimated from Cox proportional hazards regression with adjustment for known clinical and lifestyle factors. During a mean follow-up after diagnosis of invasive breast cancer of 6.2±3.8 years, there were 804 deaths including 376 breast cancer-specific deaths. The HR (95%CI) for all-cause and breast cancer-specific morality comparing the highest versus lowest tertiles were 1.03 (0.81-1.33) and 1.03 (0.71-1.50) for soy products and 0.99 (0.82-1.20) and 0.95 (0.71-1.28) for total isoflavones, respectively (Ptrend > 0.60 for all). There was limited evidence of differences by hormone receptor status, tumor stage, or ethnic group. Prediagnostic soy intake was unrelated to mortality in postmenopausal women. Our findings are consistent with the literature that soy consumption does not adversely affect breast cancer survival in women.
doi:10.1080/01635581.2013.776694
PMCID: PMC3821969  PMID: 23659444
Breast neoplasms; ethnic groups; soy foods; isoflavones; survival; postmenopause
23.  Programmatic Cost Evaluation of Nontargeted Opt-Out Rapid HIV Screening in the Emergency Department 
PLoS ONE  2013;8(12):e81565.
Background
The Centers for Disease Control and Prevention recommends nontargeted opt-out HIV screening in healthcare settings. Cost effectiveness is critical when considering potential screening methods. Our goal was to compare programmatic costs of nontargeted opt-out rapid HIV screening with physician-directed diagnostic rapid HIV testing in an urban emergency department (ED) as part of the Denver ED HIV Opt-Out Trial.
Methods
This was a prospective cohort study nested in a larger quasi-experiment. Over 16 months, nontargeted rapid HIV screening (intervention) and diagnostic rapid HIV testing (control) were alternated in 4-month time blocks. During the intervention phase, patients were offered HIV testing using an opt-out approach during registration; during the control phase, physicians used a diagnostic approach to offer HIV testing to patients. Each method was fully integrated into ED operations. Direct program costs were determined using the perspective of the ED. Time-motion methodology was used to estimate personnel activity costs. Costs per patient newly-diagnosed with HIV infection by intervention phase, and incremental cost effectiveness ratios were calculated.
Results
During the intervention phase, 28,043 eligible patients were included, 6,933 (25%) completed testing, and 15 (0.2%, 95% CI: 0.1%–0.4%) were newly-diagnosed with HIV infection. During the control phase, 29,925 eligible patients were included, 243 (0.8%) completed testing, and 4 (1.7%, 95% CI: 0.4%–4.2%) were newly-diagnosed with HIV infection. Total annualized costs for nontargeted screening were $148,997, whereas total annualized costs for diagnostic HIV testing were $31,355. The average costs per HIV diagnosis were $9,932 and $7,839, respectively. Nontargeted HIV screening identified 11 more HIV infections at an incremental cost of $10,693 per additional infection.
Conclusions
Compared to diagnostic testing, nontargeted HIV screening was more costly but identified more HIV infections. More effective and less costly testing strategies may be required to improve the identification of patients with undiagnosed HIV infection in the ED.
doi:10.1371/journal.pone.0081565
PMCID: PMC3877399  PMID: 24391706
24.  Fast, Exact Model Selection and Permutation Testing for ℓ2-Regularized Logistic Regression 
Regularized logistic regression is a standard classification method used in statistics and machine learning. Unlike regularized least squares problems such as ridge regression, the parameter estimates cannot be computed in closed-form and instead must be estimated using an iterative technique. This paper addresses the computational problem of regularized logistic regression that is commonly encountered in model selection and classifier statistical significance testing, in which a large number of related logistic regression problems must be solved for. Our proposed approach solves the problems simultaneously through an iterative technique, which also garners computational efficiencies by leveraging the redundancies across the related problems. We demonstrate analytically that our method provides a substantial complexity reduction, which is further validated by our results on real-world datasets.
PMCID: PMC3875235  PMID: 24382986
25.  Fluorescence Intensity and Lifetime Cell Imaging with Luminescent Gold Nanoclusters 
In this article, luminescent properties of gold nanoclusters (AuNCs) were studied at the single nanoparticle level and also used as novel imaging agents in cell media. Two types of water-soluble AuNCs which were stabilized with a monolayer composed of either mercaptosuccinic acid (MSA) or tiopronin thiolate ligands were synthesized by a chemical reduction reaction. These AuNCs were determined to have an average core diameter of less than 2 nm. On a time-resolved confocal microscope, the emission signals from the single AuNCs were distinctly recordable. The quantum yields of these AuNCs were measured to be ca. 5%. The lifetime of these AuNCs is also much longer than the lifetime of cellular autofluorescence in lifetime cell imaging as well as the lifetime of organic dye Alexa Fluor 488. After being derivatized with polyethylene glycol (PEG) moieties, the AuNCs were uploaded efficiently in the HeLa cells. Fluorescence intensity and lifetime cell images were recorded on the time-resolved confocal microscope in which the emission from the AuNCs was readily differentiated from the cellular autofluorescence background because of their relatively stronger emission intensities and longer lifetimes. These loaded nanoclusters in the cells were observed to widely distribute throughout the cells and especially densely loaded near the cell nucleuses. The AuNCs in the cells were also tested to have a better photostability relative to the organic fluorophores under the same conditions. We thus conclude that the AuNCs have a great potential as novel nanoparticle imaging agents, especially as lifetime imaging agents, in fluorescence imaging applications. We also prospect much broader applications of these AuNCs after further improvements of their luminescence quantum yields.
doi:10.1021/jp306036y
PMCID: PMC3868212  PMID: 24363815

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