Publications by authors named "Victoria Jenkins"

27 Publications

  • Page 1 of 1

Dose-Response of Paraxanthine on Cognitive Function: A Double Blind, Placebo Controlled, Crossover Trial.

Nutrients 2021 Dec 15;13(12). Epub 2021 Dec 15.

Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

Paraxanthine (PXN) is a metabolite of caffeine that has recently been reported to enhance cognition at a dose of 200 mg.

Objective: To determine the acute and short-term (7-day) effects of varying doses of PXN on cognitive function and side effects.

Methods: In a double blind, placebo-controlled, crossover, and counterbalanced manner, 12 healthy male and female volunteers (22.7 ± 4 years, 165 ± 7 cm, 66.5 ± 11 kg, 24.4 ± 3 kg/m) ingested 200 mg of a placebo (PLA), 50 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.) + 150 mg PLA, 100 mg PXN + 100 mg PLA, or 200 mg of PXN. With each treatment experiment, participants completed side effect questionnaires and donated a fasting blood sample. Participants then performed a series of tests assessing cognition, executive function, memory, and reaction time. Participants then ingested one capsule of PLA or PXN treatments. Participants then completed side effects and cognitive function tests after 1, 2, 3, 4, 5, and 6 h of treatment ingestion. Participants continued ingesting one dose of the assigned treatment daily for 6-days and returned to the lab on day 7 to donate a fasting blood sample, assess side effects, and perform cognitive function tests. Participants repeated the experiment while ingesting remaining treatments in a counterbalanced manner after at least a 7-day washout period until all treatments were assessed.

Results: The Sternberg Task Test (STT) 4-Letter Length Present Reaction Time tended to differ among groups ( = 0.06). Assessment of mean changes from baseline with 95% CI's revealed several significant differences among treatments in Berg-Wisconsin Card Sorting Correct Responses, Preservative Errors (PEBL), and Preservative Errors (PAR Rules). There was also evidence of significant differences among treatments in the Go/No-Go Task tests in Mean Accuracy as well as several time points of increasing complexity among STT variables. Finally, there was evidence from Psychomotor Vigilance Task Test assessment that response time improved over the series of 20 trials assessed as well as during the 6-h experiment in the PXN treatment. Acute and short-term benefits compared to PLA were seen with each dose studied but more consistent effects appeared to be at 100 mg and 200 mg doses. No significant differences were observed among treatments in clinical chemistry panels or the frequency or severity of reported side effects. Results provide evidence that acute ingestion of 100 mg and 200 mg of PXN may affect some measures of cognition, memory, reasoning, and response time as well as help sustain attention. Additionally, that acute and daily ingestion of PXN for 7 days is not associated with any clinically significant side effects.

Conclusions: PXN may serve as an effective nootropic agent at doses as low as 50 mg.
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http://dx.doi.org/10.3390/nu13124478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8708375PMC
December 2021

Acute Paraxanthine Ingestion Improves Cognition and Short-Term Memory and Helps Sustain Attention in a Double-Blind, Placebo-Controlled, Crossover Trial.

Nutrients 2021 Nov 9;13(11). Epub 2021 Nov 9.

Human Clinical Research Facility, Exercise & Sport Nutrition Lab, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

This study examined the effects of acute paraxanthine (PXN) ingestion on markers of cognition, executive function, and psychomotor vigilance. In a randomized, double blind, placebo-controlled, crossover, and counterbalanced manner, 13 healthy male and female participants were randomly assigned to consume a placebo (PLA) or 200 mg of PXN (ENFINITY™, Ingenious Ingredients, L.P.). Participants completed stimulant sensitivity and side effect questionnaires and then performed the Berg Wisconsin Card Sorting Test (BCST), the Go/No-Go test (GNG), the Sternberg task test (STT), and the psychomotor vigilance task test (PVTT). Participants then ingested one capsule of PLA or PXN treatment. Participants completed side effect and cognitive function tests after 1, 2, 3, 4, 5, and 6 h after ingestion of the supplement. After 7 days, participants repeated the experiment while consuming the alternative treatment. Data were analyzed by general linear model (GLM) univariate analyses with repeated measures using body mass as a covariate, and by assessing mean and percent changes from baseline with 95% confidence intervals (CIs) expressed as means (LL, UL). PXN decreased BCST errors (PXN -4.7 [-0.2, -9.20], = 0.04; PXN -17.5% [-36.1, 1.0], = 0.06) and perseverative errors (PXN -2.2 [-4.2, -0.2], = 0.03; PXN -32.8% [-64.4, 1.2], = 0.04) at hour 6. GNG analysis revealed some evidence that PXN ingestion better maintained mean accuracy over time and Condition R Round 2 response time (e.g., PXN -25.1 [-52.2, 1.9] ms, = 0.07 faster than PLA at 1 h), suggesting better sustained attention. PXN ingestion improved STT two-letter length absent and present reaction times over time as well as improving six-letter length absent reaction time after 2 h (PXN -86.5 ms [-165, -7.2], = 0.03; PXN -9.0% [-18.1, 0.2], = 0.05), suggesting that PXN enhanced the ability to store and retrieve random information of increasing complexity from short-term memory. A moderate treatment x time effect size (η = 0.08) was observed in PVTT, where PXN sustained vigilance during Trial 2 after 2 h (PXN 840 ms [103, 1576], = 0.03) and 4 h (PXN 1466 ms [579, 2353], = 0.002) compared to PL. As testing progressed, the response time improved during the 20 trials and over the course of the 6 h experiment in the PXN treatment, whereas it significantly increased in the PL group. The results suggest that acute PXN ingestion (200 mg) may affect some measures of short-term memory, reasoning, and response time to cognitive challenges and help sustain attention.
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http://dx.doi.org/10.3390/nu13113980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8622427PMC
November 2021

Effects of Inositol-Enhanced Bonded Arginine Silicate Ingestion on Cognitive and Executive Function in Gamers.

Nutrients 2021 Oct 24;13(11). Epub 2021 Oct 24.

Exercise & Sport Nutrition Laboratory, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX 77843, USA.

Inositol stabilized arginine silicate (ASI) ingestion has been reported to increase nitric oxide levels while inositol (I) has been reported to enhance neurotransmission. The current study examined whether acute ASI + I (Inositol-enhanced bonded arginine silicate) ingestion affects cognitive function in e-sport gamers. In a double blind, randomized, placebo controlled, and crossover trial, 26 healthy male (n = 18) and female (n = 8) experienced gamers (23 ± 5 years, 171 ± 11 cm, 71.1 ± 14 kg, 20.7 ± 3.5 kg/m) were randomly assigned to consume 1600 mg of ASI + I (nooLVL, Nutrition 21) or 1600 mg of a maltodextrin placebo (PLA). Prior to testing, participants recorded their diet, refrained from consuming atypical amounts of stimulants and foods high in arginine and nitrates, and fasted for 8 h. During testing sessions, participants completed stimulant sensitivity questionnaires and performed cognitive function tests (i.e., Berg-Wisconsin Card Sorting task test, Go/No-Go test, Sternberg Task Test, Psychomotor Vigilance Task Test, Cambridge Brain Sciences Reasoning and Concentration test) and a light reaction test. Participants then ingested treatments in a randomized manner. Fifteen minutes following ingestion, participants repeated tests (Pre-Game). Participants then played their favorite video game for 1-h and repeated the battery of tests (Post-Game). Participants observed a 7-14-day washout period and then replicated the study with the alternative treatment. Data were analyzed by General Linear Model (GLM) univariate analyses with repeated measures using weight as a covariate, paired -tests (not adjusted to weight), and mean changes from baseline with 95% Confidence Intervals (CI). Pairwise comparison revealed that there was a significant improvement in Sternberg Mean Present Reaction Time (ASI + I vs. PLA; < 0.05). In Post-Game assessments, 4-letter Absent Reaction Time ( < 0.05), 6-letter Present Reaction Time ( < 0.01), 6-letter Absent Reaction Time ( < 0.01), Mean Present Reaction Time ( < 0.02), and Mean Absent Reaction Time ( < 0.03) were improved with ASI + I vs. PLA. There was a non-significant trend in Pre-Game Sternberg 4-letter Present Reaction time in ASI + I vs. PLA ( < 0.07). ASI + I ingestion better maintained changes in Go/No-Go Mean Accuracy and Reaction Time, Psychomotor Vigilance Task Reaction Time, and Cambridge Post-Game Visio-spatial Processing and Planning. Results provide evidence that ASI + I ingestion prior to playing video games may enhance some measures of short-term and working memory, reaction time, reasoning, and concentration in experienced gamers.
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http://dx.doi.org/10.3390/nu13113758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618773PMC
October 2021

An RNAi screen of the kinome in epithelial follicle cells of the Drosophila melanogaster ovary reveals genes required for proper germline death and clearance.

G3 (Bethesda) 2021 02;11(2)

Department of Biology, Boston University, Boston, MA 02215, USA.

Programmed cell death and cell corpse clearance are an essential part of organismal health and development. Cell corpses are often cleared away by professional phagocytes such as macrophages. However, in certain tissues, neighboring cells known as nonprofessional phagocytes can also carry out clearance functions. Here, we use the Drosophila melanogaster ovary to identify novel genes required for clearance by nonprofessional phagocytes. In the Drosophila ovary, germline cells can die at multiple time points. As death proceeds, the epithelial follicle cells act as phagocytes to facilitate the clearance of these cells. We performed an unbiased kinase screen to identify novel proteins and pathways involved in cell clearance during two death events. Of 224 genes examined, 18 demonstrated severe phenotypes during developmental death and clearance while 12 demonstrated severe phenotypes during starvation-induced cell death and clearance, representing a number of pathways not previously implicated in phagocytosis. Interestingly, it was found that several genes not only affected the clearance process in the phagocytes, but also non-autonomously affected the process by which germline cells died. This kinase screen has revealed new avenues for further exploration and investigation.
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http://dx.doi.org/10.1093/g3journal/jkaa066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022946PMC
February 2021

A systematic review of the burden of pertussis disease in infants and the effectiveness of maternal immunization against pertussis.

Expert Rev Vaccines 2020 07 9;19(7):621-638. Epub 2020 Aug 9.

GSK , Wavre, Belgium.

Introduction Infants too young to be fully immunized are the most vulnerable to severe pertussis disease. To close this susceptibility gap, passive infant immunization through vaccination of pregnant women against pertussis was first introduced in 2011 in the United States and has been extended since then to more than 40 countries. Areas covered We conducted two systematic literature searches to describe the worldwide burden of pertussis disease in infants <6 months of age since 2005, and the effectiveness and impact of maternal pertussis vaccination in preventing infant pertussis since 2011. Expert opinion Pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Virtually all pertussis deaths occurred in this age group. Data from Africa, Eastern Mediterranean, and Asia were limited, but suggest a similar or higher disease burden than in Europe or the Americas. Estimates of effectiveness of second/third trimester pertussis vaccination in preventing pertussis disease in <2-3 months old infants were consistently high (69%-93%) across the observational studies reviewed, conducted in various settings with different designs. Maternal vaccination programs appear to be achieving their goal of reducing the burden of disease in very young infants. Plain language summary What is the context? Pertussis, also known as whooping cough, is a highly contagious disease of the respiratory tract. Infants too young to be fully vaccinated are at the highest risk of severe pertussis disease, hospitalization, and death. Vaccinating pregnant women against pertussis with a Tdap vaccine is recommended in more than 40 countries as a safe and effective strategy to protect infants for the first months of life. What is new? This review summarizes recent literature describing the burden of pertussis disease in infants worldwide prior to the introduction of maternal vaccination programs; pertussis disease incidence rates in infants aged <2-3 months were substantial in all countries with available data, exceeding 1000 cases per 100,000 population during outbreaks. Immunization of pregnant women with a Tdap vaccine can prevent about 70-90% of pertussis disease and up to 90.5% of pertussis hospitalizations in infants under 3 months of age. What is the impact? Limited available data suggest that incidence rates of pertussis disease after the introduction of Tdap maternal immunization have declined in infants. Current knowledge supports the implementation of Tdap maternal immunization programs.
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http://dx.doi.org/10.1080/14760584.2020.1791092DOI Listing
July 2020

Perceptions of vaccine preventable diseases in Australian healthcare: focus on pertussis.

Hum Vaccin Immunother 2021 02 22;17(2):344-350. Epub 2020 Jul 22.

Medical Affairs, GSK , Singapore, Singapore.

Adult vaccination in Australia is suboptimal. For instance, as few as one in nine people have received a pertussis vaccine in adolescence or adulthood, despite increasing disease burden and evidence of a positive correlation between older age and hospitalization rates. The objectives of this study were to describe general practitioners' (GPs) and adult consumers' knowledge and attitudes toward adult vaccination, with an emphasis on pertussis. Australian GPs and consumers were recruited in two nationally representative online surveys repeated annually between 2014 and 2018. Vaccination discussions occurred in a minority of adult/GP encounters. Pertussis was among the five most frequently identified vaccine preventable diseases but was unlikely to be proactively discussed with adults not in contact with young children. Among consumers, only one in three recalled ever receiving a pertussis vaccination. GPs are a strong predictor of adults receiving a pertussis vaccine. Possible factors contributing to low uptake are misconceptions around pertussis disease, vaccination requirements and lack of GP recommendation for adult vaccination. GPs have a key role to play in increasing adult vaccination coverage with their recommendation.
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http://dx.doi.org/10.1080/21645515.2020.1780848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899657PMC
February 2021

An Examination of a Novel Weight Loss Supplement on Anthropometry and Indices of Cardiovascular Disease Risk.

J Diet Suppl 2021 21;18(5):478-506. Epub 2020 Jul 21.

Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX, USA.

Purpose: This study examined whether adding (DG; 300 mg/d) to thermogenic supplements with (DG + C) and without (DG) caffeine and other nutrients affects weight loss, changes in body composition, and/or markers of health.

Methods: Sixty-eight participants (female, 54%) were grouped in a double-blind, parallel, stratified random, placebo-controlled manner to supplement their diet with a placebo, DG, or DG + C for 12 weeks while maintaining their normal diet and physical activity. Diet, physical activity, body weight, body composition, anthropometric measures, resting energy expenditure, fasting blood samples, and questionnaires were obtained at 0, 4, 8, and 12 weeks and analyzed using general linear models with repeated measures. Data are reported as mean (±SD) and change from baseline (mean, 95% confidence interval) for weeks 4, 8, and 12, respectively, with values showing changes from baseline.

Results: DG treatment promoted significant but minor reductions in fat mass (-0.56 [-1.02, -0.14],  = 0.01; -0.63 [-1.23, -0.02],  = 0.04; -0.71 [-1.47, 0.09] kg,  = 0.08) and percent body fat (-0.46 [-0.96, -0.04],  = 0.07; -0.63 [-1.16, -0.10],  = 0.02; -0.78 [-1.45, 0.07] %,  = 0.03). There was some evidence that DG + C increased resting energy expenditure, decreased hunger, increased satiety, and improved sleep quality (diminished in DG + C). No other significant effects were observed.

Conclusions: Ingestion of thermogenic supplements containing DG (300 mg/d) with and without caffeine and other nutrients in overweight but otherwise healthy participants who did not alter diet or physical activity promoted clinically insignificant changes in body weight and composition.
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http://dx.doi.org/10.1080/19390211.2020.1786207DOI Listing
October 2021

The Certificate of Advanced Studies (CAS) course adapted to a pandemic.

Eur Heart J 2020 05;41(18):1716-1718

CAS in Structural Cardiac Interventions Training Team, University of Zürich and Department of Cardiac Surgery, University Hospital Zürich, Zürich, Switzerland.

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http://dx.doi.org/10.1093/eurheartj/ehaa284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239246PMC
May 2020

Pertussis in high-risk groups: an overview of the past quarter-century.

Hum Vaccin Immunother 2020 11 16;16(11):2609-2617. Epub 2020 Apr 16.

Vaccines, GSK , Wavre, Belgium.

Infectious diseases can impact chronic medical conditions. However, it is currently not clear how pertussis correlates with preexisting or underlying disorders. We reviewed literature from the last 25 years to describe the burden and impact of pertussis infection in specific risk groups in individuals aged ≥11 years. Our literature search returned 543 hits, of which 18 were eligible for this review. Adolescents and adults with underlying conditions, such as asthma, chronic obstructive pulmonary disease (COPD), or obesity are potentially at increased risk of pertussis infection. Immunodeficiency and smoking have also been associated with worsened pertussis symptoms and an increased pertussis-related hospitalization rate. In patients with pertussis and preexisting asthma or COPD, symptoms were worsened, and health-care costs were consequently increased. Further efforts are needed to close the knowledge gap and to understand the burden of pertussis in at-risk adolescent and adult populations to help inform vaccination strategies and recommendations.
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http://dx.doi.org/10.1080/21645515.2020.1738168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746252PMC
November 2020

Comparison of ingesting a food bar containing whey protein and isomalto-oligosaccharides to carbohydrate on performance and recovery from an acute bout of resistance-exercise and sprint conditioning: an open label, randomized, counterbalanced, crossover pilot study.

J Int Soc Sports Nutr 2019 Aug 13;16(1):34. Epub 2019 Aug 13.

Exercise & Sport Nutrition Lab, Human Clinical Research Facility, Department of Health & Kinesiology, Texas A&M University, College Station, TX, 77843-4243, USA.

Background: We previously reported that consuming a food bar (FB) containing whey protein and the plant fiber isomalto-oligosaccharides [IMO] had a lower glycemic (GI) but similar insulinemic response as a high GI carbohydrate. Therefore, we hypothesized that ingestion of this FB before, during, and following intense exercise would better maintain glucose homeostasis and performance while hastening recovery in comparison to the common practice of ingesting carbohydrate alone.

Methods: Twelve resistance-trained males participated in an open label, randomized, counterbalanced, crossover trial with a 7-d washout period. Participants consumed a carbohydrate matched dextrose comparitor (CHO) or a FB containing 20 g of whey, 25 g of IMO, and 7 g of fat 30-min before, mid-way, and following intense exercise. Participants performed 11 resistance-exercises (3 sets of 10 repetitions at 70% of 1RM) followed by agility and sprint conditioning drills for time. Participants donated blood to assess catabolic and inflammatory markers, performed isokinetic strength tests, and rated perceptions of muscle soreness, hypoglycemia before, and following exercise and after 48 h of recovery. Data were analyzed using general linear models (GLM) for repeated measures and mean changes from baseline with 95% confidence intervals (CI) with a one-way analysis of variance. Data are reported as mean change from baseline with 95% CI.

Results: GLM analysis demonstrated that blood glucose was significantly higher 30-min post-ingestion for CHO (3.1 [2.0, 4.3 mmol/L,] and FB (0.8 [0.2, 1.5, mmol/L, p = 0.001) while the post-exercise ratio of insulin to glucose was greater with FB (CHO 0.04 [0.00, 0.08], FB 0.11 [0.07, 0.15], p = 0.013, η = 0.25). GLM analysis revealed no significant interaction effects between treatments in lifting volume of each resistance-exercise or total lifting volume. However, analysis of mean changes from baseline with 95% CI's revealed that leg press lifting volume (CHO -130.79 [- 235.02, - 26.55]; FB -7.94 [- 112.17, 96.30] kg, p = 0.09, η = 0.12) and total lifting volume (CHO -198.26 [- 320.1, - 76.4], FB -81.7 [- 203.6, 40.1] kg, p = 0.175, η = 0.08) from set 1 to 3 was significantly reduced for CHO, but not for the FB. No significant interaction effects were observed in ratings of muscle soreness. However, mean change analysis revealed that ratings of soreness of the distal vastus medialis significantly increased from baseline with CHO while being unchanged with FB (CHO 1.88 [0.60, 3.17]; FB 0.29 [- 0.99, 1.57] cm, p = 0.083, η = 0.13). No significant GLM interaction or mean change analysis effects were seen between treatments in sprint performance, isokinetic strength, markers of catabolism, stress and sex hormones, or inflammatory markers.

Conclusion: Pilot study results provide some evidence that ingestion of this FB can positively affect glucose homeostasis, help maintain workout performance, and lessen perceptions of muscle soreness.

Trial Registration: clinicaltrials.gov, # NCT03704337 . Retrospectively registered 12, July 2018.
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http://dx.doi.org/10.1186/s12970-019-0301-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693099PMC
August 2019

An unusual presentation of silent pulmonary embolism.

Br J Hosp Med (Lond) 2018 Jan;79(1):48-49

Consultant in Anaesthesia and Intensive Care Medicine, Department of Anaesthesia, Barking Havering and Redbridge University Hospitals NHS Trust, London.

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http://dx.doi.org/10.12968/hmed.2018.79.1.48DOI Listing
January 2018

Squamous Cell Carcinoma of the Penis with Pulmonary Metastasis and Paraneoplastic Hypertrophic Osteopathy in a Dog.

J Am Anim Hosp Assoc 2017 Sep/Oct;53(5):277-280. Epub 2017 Aug 9.

From the University of Florida, Gainesville, Florida (V.J., C.H.d.M.S.); Hôpital Vétérinaire Rive-Sud, Brossard, Quebec, Canada (L-P.d.L.); IPEV, Rio de Janeiro, Brazil (E.d.T-P.).

Squamous cell carcinoma of the penis was diagnosed by incisional biopsy of a penile mass in a 12 yr old intact male beagle dog presenting with hemorrhagic discharge from the prepuce. Penile amputation, orchiectomy with scrotal ablation, and scrotal urethrostomy were performed. Hypertrophic osteopathy secondary to pulmonary metastatic disease occurred 10 mo after the surgery. Palliative treatment with piroxicam was administered and led to complete resolution of the clinical signs of the pain. Sixteen months following surgery, the dog presented with significant dyspnea and anorexia and was euthanized due to poor prognosis. This case report describes a rare penile tumor, squamous cell carcinoma. Consequent paraneoplastic hypertrophic osteopathy and its palliative treatment are also reviewed.
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http://dx.doi.org/10.5326/JAAHA-MS-6425DOI Listing
January 2019

Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.

Sci Rep 2017 03 29;7(1):502. Epub 2017 Mar 29.

Research Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.

Tuberculosis (TB) treatment is long and complex, typically involving a combination of drugs taken for 6 months. Improved drug regimens to shorten and simplify treatment are urgently required, however a major challenge to TB drug development is the lack of predictive pre-clinical tools. To address this deficiency, we have adopted a new high-content imaging-based approach capable of defining the killing kinetics of first line anti-TB drugs against intracellular Mycobacterium tuberculosis (Mtb) residing inside macrophages. Through use of this pharmacokinetic-pharmacodynamic (PK-PD) approach we demonstrate that the killing dynamics of the intracellular Mtb sub-population is critical to predicting clinical TB treatment duration. Integrated modelling of intracellular Mtb killing alongside conventional extracellular Mtb killing data, generates the biphasic responses typical of those described clinically. Our model supports the hypothesis that the use of higher doses of rifampicin (35 mg/kg) will significantly reduce treatment duration. Our described PK-PD approach offers a much needed decision making tool for the identification and prioritisation of new therapies which have the potential to reduce TB treatment duration.
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http://dx.doi.org/10.1038/s41598-017-00529-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428680PMC
March 2017

Building Successful Relationships in the PLCO Cancer Screening Trial.

Rev Recent Clin Trials 2015 ;10(3):181-6

Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, Maryland, USA.

Biomedical research cannot succeed without funding, knowledgeable staff, and appropriate infrastructure. There are however equally important but intangible factors that are rarely considered in planning large multidisciplinary endeavors or evaluating their success. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial required extensive collaborations between individuals from many fields, including clinicians, clinical trialists, and administrators; it also addressed questions across the spectrum of cancer prevention and control. In this manuscript, we examine the experiences and opinions of trial staff regarding the building of successful relationships in PLCO. We summarize, in narrative form, data collected using open-ended questionnaires that were administered to the National Cancer Institute project officers, coordinating center staff, screening center principal investigators, and screening center coordinators in 2015, about 3 years after publication of the final primary trial manuscript. Trust, respect, listening to others, and in-person interaction were frequently mentioned as crucial to building successful relationships.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571759PMC
http://dx.doi.org/10.2174/1574887110666150731131743DOI Listing
July 2016

Deciphering the metabolic response of Mycobacterium tuberculosis to nitrogen stress.

Mol Microbiol 2015 Sep 17;97(6):1142-57. Epub 2015 Jul 17.

MRC Centre for Molecular Bacteriology and Infection, Department of Medicine, Imperial College London, London, SW7 2AZ, UK.

A key component to the success of Mycobacterium tuberculosis as a pathogen is the ability to sense and adapt metabolically to the diverse range of conditions encountered in vivo, such as oxygen tension, environmental pH and nutrient availability. Although nitrogen is an essential nutrient for every organism, little is known about the genes and pathways responsible for nitrogen assimilation in M. tuberculosis. In this study we have used transcriptomics and chromatin immunoprecipitation and high-throughput sequencing to address this. In response to nitrogen starvation, a total of 185 genes were significantly differentially expressed (96 up-regulated and 89 down regulated; 5% genome) highlighting several significant areas of metabolic change during nitrogen limitation such as nitrate/nitrite metabolism, aspartate metabolism and changes in cell wall biosynthesis. We identify GlnR as a regulator involved in the nitrogen response, controlling the expression of at least 33 genes in response to nitrogen limitation. We identify a consensus GlnR binding site and relate its location to known transcriptional start sites. We also show that the GlnR response regulator plays a very different role in M. tuberculosis to that in non-pathogenic mycobacteria, controlling genes involved in nitric oxide detoxification and intracellular survival instead of genes involved in nitrogen scavenging.
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http://dx.doi.org/10.1111/mmi.13091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950008PMC
September 2015

Diversity of cell death pathways: insight from the fly ovary.

Trends Cell Biol 2013 Nov 19;23(11):567-74. Epub 2013 Aug 19.

Department of Biology, Boston University, 5 Cummington Mall, Boston, MA, USA.

Multiple types of cell death exist including necrosis, apoptosis, and autophagic cell death. The Drosophila ovary provides a valuable model to study the diversity of cell death modalities, and we review recent progress to elucidate these pathways. At least five distinct types of cell death occur in the ovary, and we focus on two that have been studied extensively. Cell death of mid-stage egg chambers occurs through a novel caspase-dependent pathway that involves autophagy and triggers phagocytosis by surrounding somatic epithelial cells. For every egg, 15 germline nurse cells undergo developmental programmed cell death, which occurs independently of most known cell death genes. These forms of cell death are strikingly similar to cell death observed in the germlines of other organisms.
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http://dx.doi.org/10.1016/j.tcb.2013.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3839102PMC
November 2013

Deciphering the response of Mycobacterium smegmatis to nitrogen stress using bipartite active modules.

BMC Genomics 2013 Jul 2;14:436. Epub 2013 Jul 2.

Department of Medicine, MRC Centre for Molecular Bacteriology and Infection, South Kensington, London SW7 2AZ, UK.

Background: The ability to adapt to environments with fluctuating nutrient availability is vital for bacterial survival. Although essential for growth, few nitrogen metabolism genes have been identified or fully characterised in mycobacteria and nitrogen stress survival mechanisms are unknown.

Results: A global transcriptional analysis of the mycobacterial response to nitrogen stress, showed a significant change in the differential expression of 16% of the Mycobacterium smegmatis genome. Gene expression changes were mapped onto the metabolic network using Active Modules for Bipartite Networks (AMBIENT) to identify metabolic pathways showing coordinated transcriptional responses to the stress. AMBIENT revealed several key features of the metabolic response not identified by KEGG enrichment alone. Down regulated reactions were associated with the general reduction in cellular metabolism as a consequence of reduced growth rate. Up-regulated modules highlighted metabolic changes in nitrogen assimilation and scavenging, as well as reactions involved in hydrogen peroxide metabolism, carbon scavenging and energy generation.

Conclusions: Application of an Active Modules algorithm to transcriptomic data identified key metabolic reactions and pathways altered in response to nitrogen stress, which are central to survival under nitrogen limiting environments.
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http://dx.doi.org/10.1186/1471-2164-14-436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3706326PMC
July 2013

Genome wide analysis of the complete GlnR nitrogen-response regulon in Mycobacterium smegmatis.

BMC Genomics 2013 May 4;14:301. Epub 2013 May 4.

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, South Kensington, London SW7 2AZ, UK.

Background: Nitrogen is an essential element for bacterial growth and an important component of biological macromolecules. Consequently, responding to nitrogen limitation is critical for bacterial survival and involves the interplay of signalling pathways and transcriptional regulation of nitrogen assimilation and scavenging genes. In the soil dwelling saprophyte Mycobacterium smegmatis the OmpR-type response regulator GlnR is thought to mediate the transcriptomic response to nitrogen limitation. However, to date only ten genes have been shown to be in the GlnR regulon, a vastly reduced number compared to other organisms.

Results: We investigated the role of GlnR in the nitrogen limitation response and determined the entire GlnR regulon, by combining expression profiling of M. smegmatis wild type and glnR deletion mutant, with GlnR-specific chromatin immunoprecipitation and high throughput sequencing. We identify 53 GlnR binding sites during nitrogen limitation that control the expression of over 100 genes, demonstrating that GlnR is the regulator controlling the assimilation and utilisation of nitrogen. We also determine a consensus GlnR binding motif and identify key residues within the motif that are required for specific GlnR binding.

Conclusions: We have demonstrated that GlnR is the global nitrogen response regulator in M. smegmatis, directly regulating the expression of more than 100 genes. GlnR controls key nitrogen stress survival processes including primary nitrogen metabolism pathways, the ability to utilise nitrate and urea as alternative nitrogen sources, and the potential to use cellular components to provide a source of ammonium. These studies further our understanding of how mycobacteria survive nutrient limiting conditions.
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http://dx.doi.org/10.1186/1471-2164-14-301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662644PMC
May 2013

Adenylylation of mycobacterial Glnk (PII) protein is induced by nitrogen limitation.

Tuberculosis (Edinb) 2013 Mar 24;93(2):198-206. Epub 2013 Jan 24.

MRC Centre for Molecular Bacteriology and Infection, Imperial College London, Exhibition Road, South Kensington, London SW7 2AZ, UK.

PII proteins are pivotal regulators of nitrogen metabolism in most prokaryotes, controlling the activities of many targets, including nitrogen assimilation enzymes, two component regulatory systems and ammonium transport proteins. Escherichia coli contains two PII-like proteins, PII (product of glnB) and GlnK, both of which are uridylylated under nitrogen limitation at a conserved Tyrosine-51 residue by GlnD (a uridylyl transferase). PII-uridylylation in E. coli controls glutamine synthetase (GS) adenylylation by GlnE and mediates the NtrB/C transcriptomic response. Mycobacteria contain only one PII protein (GlnK) which in environmental Actinomycetales is adenylylated by GlnD under nitrogen limitation. However in mycobacteria, neither the type of GlnK (PII) covalent modification nor its precise role under nitrogen limitation is known. In this study, we used LC-Tandem MS to analyse the modification state of mycobacterial GlnK (PII), and demonstrate that during nitrogen limitation GlnK from both non-pathogenic Mycobacterium smegmatis and pathogenic Mycobacterium tuberculosis is adenylylated at the Tyrosine-51 residue; we also show that GlnD is the adenylyl transferase enzyme responsible. Further analysis shows that in contrast to E. coli, GlnK (PII) adenylylation in M. tuberculosis does not regulate GS adenylylation, nor does it mediate the transcriptomic response to nitrogen limitation.
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http://dx.doi.org/10.1016/j.tube.2012.12.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3612183PMC
March 2013

Upregulation of brain-derived neurotrophic factor expression in nodose ganglia and the lower brainstem of hypertensive rats.

J Neurosci Res 2013 Feb 22;91(2):220-9. Epub 2012 Nov 22.

Department of Integrative Biosciences, Oregon Health & Science University, Portland, Oregon 97239, USA.

Hypertension leads to structural and functional changes at baroreceptor synapses in the medial nucleus tractus solitarius (NTS), but the underlying molecular mechanisms remain unknown. Our previous studies show that brain-derived neurotrophic factor (BDNF) is abundantly expressed by rat nodose ganglion (NG) neurons, including baroreceptor afferents and their central terminals in the medial NTS. We hypothesized that hypertension leads to upregulation of BDNF expression in NG neurons. To test this hypothesis, we used two mechanistically distinct models of hypertension, the spontaneously hypertensive rat (SHR) and the deoxycorticosterone acetate (DOCA)-salt rat. Young adult SHRs, whose blood pressure was significantly elevated compared with age-matched Wistar-Kyoto (WKY) control rats, exhibited dramatic upregulation of BDNF mRNA and protein in the NG. BDNF transcripts from exon 4, known to be regulated by activity, and exon 9 (protein-coding region) showed the largest increases. Electrical stimulation of dispersed NG neurons with patterns that mimic baroreceptor activity during blood pressure elevations led to increases in BDNF mRNA that were also mediated through promoter 4. The increase in BDNF content of the NG in vivo was associated with a significant increase in the percentage of BDNF-immunoreactive NG neurons. Moreover, upregulation of BDNF in cell bodies of NG neurons was accompanied by a significant increase in BDNF in the NTS region, the primary central target of NG afferents. A dramatic increase in BDNF in the NG was also detected in DOCA-salt hypertensive rats. Together, our study identifies BDNF as a candidate molecular mediator of activity-dependent changes at baroafferent synapses during hypertension.
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http://dx.doi.org/10.1002/jnr.23158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927140PMC
February 2013

Free glucosylglycerate is a novel marker of nitrogen stress in Mycobacterium smegmatis.

J Proteome Res 2012 Jul 11;11(7):3888-96. Epub 2012 Jun 11.

Biomolecular Medicine, Department of Surgery and Cancer, Department of Medicine, Imperial College, London SW7 2AZ, UK.

Nitrogen is an essential element for bacterial growth, and as such, bacteria have evolved several pathways to assimilate nitrogen and adapt to situations of nitrogen limitation. However, the adaptation of mycobacteria to nitrogen stress and the regulation of the stress response pathways is unknown. Identification of key metabolites produced by mycobacteria during nitrogen stress could therefore provide important insights into mycobacterial survival strategies. Here we used NMR-based metabolomics to monitor and quantify intracellular and extracellular metabolite levels (metabolic footprinting) in Mycobacterium smegmatis grown under nitrogen-limiting and nitrogen-rich conditions. There were several metabolic differences between the two conditions: following nitrogen run-out, there was an increase in intracellular α-ketoglutarate and a decrease in intracellular glutamine and glutamate levels. In addition, a sugar-derived compound accumulated in nitrogen-starved cells that was subsequently assigned as glucosylglycerate (GGA). Free GGA production was responsive to nitrogen stress in M. smegmatis but not to oxidative or osmotic stress; lack of a functional GGA synthesis pathway slightly reduced growth and decreased ammonium uptake rates under nitrogen-limiting conditions. Hence, GGA could contribute to the fitness of mycobacteria under nitrogen limitation.
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http://dx.doi.org/10.1021/pr300371bDOI Listing
July 2012

Aspartate D48 is essential for the GlnR-mediated transcriptional response to nitrogen limitation in Mycobacterium smegmatis.

FEMS Microbiol Lett 2012 May 12;330(1):38-45. Epub 2012 Mar 12.

Department of Medicine, Centre for Molecular Medicine and Infection, Imperial College London, London, UK.

Nitrogen is an essential element required for bacterial growth and consequently bacteria must adapt to situations of nitrogen limitation for survival. The transcriptional response to nitrogen limitation in Mycobacterium smegmatis is thought to be regulated by GlnR, although, to date, only five nitrogen metabolism genes have been shown to be under its direct control. GlnR belongs to the OmpR family of two-component response regulators that are typically activated by phosphorylation of a conserved aspartate residue. The M. smegmatis GlnR protein contains the highly conserved aspartate residue (D48) corresponding to the phosphorylation sites identified in other OmpR family regulators. In this study, we replaced GlnR D48 with alanine and constructed a GlnR deletion mutant. Under nitrogen-limiting conditions, both the GlnR_D48A and GlnR deletion mutants exhibited reduced growth rates compared with wild type. Transcriptional analysis showed both mutants failed to up-regulate the expression of GlnR-controlled genes under nitrogen-limiting conditions. We therefore demonstrate that the GlnR aspartate (D48) residue is essential for its function as a nitrogen-stress transcriptional response regulator in M. smegmatis.
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http://dx.doi.org/10.1111/j.1574-6968.2012.02530.xDOI Listing
May 2012

Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity.

J Biol Chem 2010 Jan 28;285(1):541-54. Epub 2009 Oct 28.

Division of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London W2 1PG, United Kingdom and.

Lens epithelium-derived growth factor (LEDGF) is an important co-factor of human immunodeficiency virus DNA integration; however, its cellular functions are poorly characterized. We now report identification of the Cdc7-activator of S-phase kinase (ASK) heterodimer as a novel interactor of LEDGF. Both kinase subunits co-immunoprecipitated with endogenous LEDGF from human cell extracts. Truncation analyses identified the integrase-binding domain of LEDGF as essential and minimally sufficient for the interaction with Cdc7-ASK. Reciprocally, the interaction required autophosphorylation of the kinase and the presence of 50 C-terminal residues of ASK. The kinase phosphorylated LEDGF in vitro, with Ser-206 being the major target, and LEDGF phosphorylated at this residue could be detected during S phase of the cell cycle. LEDGF potently stimulated the enzymatic activity of Cdc7-ASK, increasing phosphorylation of MCM2 in vitro by more than 10-fold. This enzymatic stimulation as well as phosphorylation of LEDGF depended on the protein-protein interaction. Intriguingly, removing the C-terminal region of ASK, involved in the interaction with LEDGF, resulted in a hyperactive kinase. Our results indicate that the interaction with LEDGF relieves autoinhibition of Cdc7-ASK kinase, imposed by the C terminus of ASK.
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http://dx.doi.org/10.1074/jbc.M109.036491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804203PMC
January 2010

Recruitment methods employed in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.

Clin Trials 2009 Feb;6(1):52-9

University of Utah, USA.

Background: The Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) is a US National Cancer Institute (NCI)-funded randomized controlled trial designed to evaluate whether certain screening tests reduce mortality from prostate, lung, colorectal, and ovarian cancer. To obtain adequate statistical power, it was necessary to enroll over 150,000 healthy volunteers. Recruitment began in 1993 and ended in 2001.

Purpose: Our goal is to evaluate the success of recruitment methods employed by the 10 PLCO screening centers. We also provide estimates of recruitment yield and cost for our most successful strategy, direct mail.

Methods: Each screening center selected its own methods of recruitment. Methods changed throughout the recruitment period as needed. For this manuscript, representatives from each screening center provided information on methods utilized and their success.

Results: In the United States between 1993 and 2001, ten screening centers enrolled 154,934 study participants. Based on participant self-report, an estimated 95% of individuals were recruited by direct mail. Overall, enrollment yield for direct mail was 1.0%. Individual center enrollment yield ranged from 0.7% to 3.8%. Cost per enrolled participant was $9.64-35.38 for direct mail, excluding personnel costs.

Limitations: Numeric data on recruitment processes were not kept consistently at individual screening centers. Numeric data in this manuscript are based on the experiences of 5 of the 10 centers.

Conclusions: Direct mail, using rosters of names and addresses from profit and not-for-profit (including government) organizations, was the most successful and most often used recruitment method. Other recruitment strategies, such as community outreach and use of mass media, can be an important adjunct to direct mail in recruiting minority populations.
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http://dx.doi.org/10.1177/1740774508100974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651181PMC
February 2009

Brain-derived neurotrophic factor in arterial baroreceptor pathways: implications for activity-dependent plasticity at baroafferent synapses.

J Neurochem 2009 Jan 29;108(2):450-64. Epub 2008 Nov 29.

Department of Integrative Biosciences, Oregon Health and Science University, Portland, OR 97239, USA.

Functional characteristics of the arterial baroreceptor reflex change throughout ontogenesis, including perinatal adjustments of the reflex gain and adult resetting during hypertension. However, the cellular mechanisms that underlie these functional changes are not completely understood. Here, we provide evidence that brain-derived neurotrophic factor (BDNF), a neurotrophin with a well-established role in activity-dependent neuronal plasticity, is abundantly expressed in vivo by a large subset of developing and adult rat baroreceptor afferents. Immunoreactivity to BDNF is present in the cell bodies of baroafferent neurons in the nodose ganglion, their central projections in the solitary tract, and terminal-like structures in the lower brainstem nucleus tractus solitarius. Using ELISA in situ combined with electrical field stimulation, we show that native BDNF is released from cultured newborn nodose ganglion neurons in response to patterns that mimic the in vivo activity of baroreceptor afferents. In particular, high-frequency bursting patterns of baroreceptor firing, which are known to evoke plastic changes at baroreceptor synapses, are significantly more effective at releasing BDNF than tonic patterns of the same average frequency. Together, our study indicates that BDNF expressed by first-order baroreceptor neurons is a likely mediator of both developmental and post-developmental modifications at first-order synapses in arterial baroreceptor pathways.
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http://dx.doi.org/10.1111/j.1471-4159.2008.05781.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605776PMC
January 2009

Endomorphin-2 is released from newborn rat primary sensory neurons in a frequency- and calcium-dependent manner.

Eur J Neurosci 2008 May 29;27(10):2629-42. Epub 2008 May 29.

Department of Integrative Biosciences, Oregon Health and Science University, Portland, OR 97239, USA.

Recent evidence indicates that endomorphins, endogenous mu-opioid receptor (MOR) agonists, modulate synaptic transmission in both somatic and visceral sensory pathways. Here we show that endomorphin-2 (END-2) is expressed in newborn rat dorsal root ganglion (DRG) and nodose-petrosal ganglion complex (NPG) neurons, and rarely co-localizes with brain-derived neurotrophic factor (BDNF). In order to examine activity-dependent release of END-2 from neurons, we established a model using dispersed cultures of DRG and NPG cells activated by patterned electrical field stimulation. To detect release of END-2, we developed a novel rapid capture enzyme-linked immunosorbent assay (ELISA), in which END-2 capture antibody was added to neuronal cultures shortly before their electrical stimulation. The conventional assay was effective at reliably detecting END-2 only when the cells were stimulated in the presence of CTAP, a MOR-selective antagonist. This suggests that the strength of the novel assay is related primarily to rapid capture of released END-2 before it binds to endogenous MORs. Using the rapid capture ELISA, we found that stimulation protocols known to induce plastic changes at sensory synapses were highly effective at releasing END-2. Removal of extracellular calcium or blocking voltage-activated calcium channels significantly reduced the release. Together, our data provide the first evidence that END-2 is expressed by newborn DRG neurons of all sizes found in this age group, and can be released from these, as well as from NPG neurons, in an activity-dependent manner. These results point to END-2 as a likely mediator of activity-dependent plasticity in sensory pathways.
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http://dx.doi.org/10.1111/j.1460-9568.2008.06238.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2575094PMC
May 2008

Enrollment of racial and ethnic minorities in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

J Natl Med Assoc 2008 Mar;100(3):291-8

Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA.

Background: Minority populations in the United States, especially blacks and Hispanics, are generally underrepresented among participants in clinical trials. Here, we report the experience of enrolling ethnic minorities in a large cancer screening trial.

Methods: The Prostate, Colorectal, Lung and Ovarian (PLCO) Cancer Screening Trial is a multicenter randomized trial designed to evaluate the effectiveness of screening for the PLCO cancers. Subjects were recruited at 10 U.S. centers between 1993 and 2001. One screening center had a major special recruitment effort for blacks and another center had a major special recruitment effort for Hispanics.

Results: Among almost 155,000 subjects enrolled in PLCO, minority enrollment was as follows: black (5.0%), Hispanic (1.8%) and Asian (3.6%). This compares to an age-eligible population in the combined catchment areas of the PLCO centers that was 14.0% black, 2.9% Hispanic and 5.4% Asian, and an age-eligible population across the U.S. that was 9.5% black, 6.5% Hispanic and 3.0% Asian. About half (45%) of Hispanics were recruited at the center with the special Hispanic recruitment effort. Seventy percent of blacks were recruited at two centers; the one with the major special recruitment effort and a center in Detroit whose catchment area was 20% black among age-eligibles. Blacks, Hispanics and (non-Hispanic) whites were all more highly educated, less likely to currently smoke and more likely to get regular exercise than their counterparts in the general population.

Conclusion: Significant efforts were made to recruit racial/ ethnic minorities into PLCO, and these efforts resulted in enrollment levels that were comparable to those seen in many recent cancer screening or prevention trials. Blacks and Hispanics were nonetheless underrepresented in PLCO compared to their levels among age-eligibles in the overall U.S. population or in the aggregate PLCO catchment areas.
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http://dx.doi.org/10.1016/s0027-9684(15)31241-4DOI Listing
March 2008
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