Current Role at Stanford

Senior Research Engineer (Biostatistician)


All Publications

  • Bupropion for the treatment of methamphetamine dependence in non-daily users: A randomized, double-blind, placebo-controlled trial DRUG AND ALCOHOL DEPENDENCE Anderson, A. L., Li, S., Markova, D., Holmes, T. H., Chiang, N., Kahn, R., Campbell, J., Dickerson, D. L., Galloway, G. P., Haning, W., Roache, J. D., Stock, C., Elkashef, A. M. 2015; 150: 170-174


    Bupropion was tested for efficacy to achieve methamphetamine (MA) abstinence in dependent, non-daily users.A randomized, double-blind, placebo-controlled trial, with 12-week treatment and 4-week follow-up, was conducted with 204 treatment-seeking participants having MA dependence per DSM-IV, who used MA on a less-than-daily basis. 104 were randomized to matched placebo and 100 to bupropion, sustained-release 150mg, twice daily. Participants were seen three times weekly to obtain urine for MA and bupropion assays, study assessments, and thrice weekly, 90-min, group psychotherapy. There was no biomarker for placebo adherence. The primary outcome was achievement of abstinence throughout the last two weeks of treatment; 'success' requiring at least two urine samples during each of Weeks 11 and 12, and all samples MA-negative (<300ng/mL).Bupropion and placebo groups did not differ significantly in the percentage achieving abstinence for the last 2 weeks of treatment (chi-square, p=0.32). Subgroup analysis of participants with lower baseline MA use (≤18 of last 30 days before consent) also revealed no difference in success between groups (p=0.73). Medication adherence per protocol (detectable bupropion, >5ng/mL, in ≥50% of urine samples from Study Weeks 1-10 and ≥66% of urine samples from Weeks 11 to 12) was achieved by 47% of participants taking bupropion.These data indicate that bupropion did not increase abstinence in dependent participants who were using MA less-than-daily. Medication non-adherence was a limitation in this trial. Psychosocial therapy remains the mainstay of treatment for MA dependence. Further research on subgroups who may respond to bupropion may be warranted.

    View details for DOI 10.1016/j.drugalcdep.2015.01.036

    View details for Web of Science ID 000353600900023

    View details for PubMedID 25818061

  • Abnormalities of Lipoprotein Concentrations in Obstructive Sleep Apnea Are Related to Insulin Resistance SLEEP Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-?

    View details for DOI 10.5665/sleep.4678

    View details for Web of Science ID 000353876600017

  • Abnormalities of lipoprotein concentrations in obstructive sleep apnea are related to insulin resistance. Sleep Liu, A., Cardell, J., Ariel, D., Lamendola, C., Abbasi, F., Kim, S. H., Holmes, T. H., Tomasso, V., Mojaddidi, H., Grove, K., Kushida, C. A., Reaven, G. M. 2015; 38 (5): 793-799


    Prevalence of cardiovascular disease (CVD) is increased in patients with obstructive sleep apnea (OSA), possibly related to dyslipidemia in these individuals. Insulin resistance is also common in OSA, but its contribution to dyslipidemia of OSA is unclear. The study’s aim was to define the relationships among abnormalities of lipoprotein metabolism, clinical measures of OSA, and insulin resistance.Cross-sectional study. OSA severity was defined by the apnea-hypopnea index (AHI) during polysomnography. Hypoxia measures were expressed as minimum and mean oxygen saturation, and the oxygen desaturation index. Insulin resistance was quantified by determining steady-state plasma glucose (SSPG) concentrations during the insulin suppression test. Fasting plasma lipid/ lipoprotein evaluation was performed by vertical auto profile methodology.Academic medical center.107 nondiabetic, overweight/ obese adults.Lipoprotein particles did not correlate with AHI or any hypoxia measures, nor were there differences noted by categories of OSA severity. By contrast, even after adjustment for age, sex, and BMI, SSPG was positively correlated with triglycerides (r = 0.30, P < 0.01), very low density lipoprotein (VLDL) and its subclasses (VLDL1+2) (r = 0.21-0.23, P < 0.05), and low density lipoprotein subclass 4 (LDL4) (r = 0.30, P < 0.01). SSPG was negatively correlated with high density lipoprotein (HDL) (r = -0.38, P < 0.001) and its subclasses (HDL2 and HDL3) (r = -0.32, -0.43, P < 0.01), and apolipoprotein A1 (r = -0.33, P < 0.01). Linear trends of these lipoprotein concentrations across SSPG tertiles were also significant.Pro-atherogenic lipoprotein abnormalities in OSA are related to insulin resistance, but not to OSA severity or degree of hypoxia. Insulin resistance may represent the link between OSA-related dyslipidemia and increased CVD risk.

    View details for DOI 10.5665/sleep.4678

    View details for PubMedID 25348129

  • Distinct Patterns of B-Cell Activation and Priming by Natural Influenza Virus Infection Versus Inactivated Influenza Vaccination JOURNAL OF INFECTIOUS DISEASES He, X., Holmes, T. H., Sanyal, M., Albrecht, R. A., Garcia-Sastre, A., Dekker, C. L., Davis, M. M., Greenberg, H. B. 2015; 211 (7): 1051-1059


    The human B-cell response to natural influenza virus infection has not been extensively investigated at the polyclonal level.The overall B-cell response of patients acutely infected with the 2009 pandemic influenza A(H1N1)pdm09 virus (A[H1N1]pdm09) was analyzed by determining the reactivity of plasmablast-derived polyclonal antibodies (PPAbs) to influenza proteins. Recipients of inactivated influenza vaccine containing the same A(H1N1)pdm09 strain were studied for comparison.During acute infection, robust plasmablast responses to the infecting virus were detected, characterized by a greater PPAb reactivity to the conserved influenza virus nuclear protein and to heterovariant and heterosubtypic hemagglutinins, in comparison to responses to the inactivated A(H1N1)pdm09 vaccine. In A(H1N1)pdm09 vaccinees, the presence of baseline serum neutralizing antibodies against A(H1N1)pdm09, suggesting previous exposure to natural A(H1N1)pdm09 infection, did not affect the plasmablast response to vaccination, whereas repeated immunization with inactivated A(H1N1)pdm09 vaccine resulted in significantly reduced vaccine-specific and cross-reactive PPAb responses.Natural A(H1N1)pdm09 infection and inactivated A(H1N1)pdm09 vaccination result in very distinct patterns of B-cell activation and priming. These differences are likely to be associated with differences in protective immunity, especially cross-protection against heterovariant and heterosubtypic influenza virus strains.

    View details for DOI 10.1093/infdis/jiu580

    View details for Web of Science ID 000354697500005

  • SMART DOCS: A New Patient-Centered Outcomes and Coordinated-Care Management Approach for the Future Practice of Sleep Medicine SLEEP Kushida, C. A., Nichols, D. A., Holmes, T. H., Miller, R., Griffin, K., Cardell, C., Hyde, P. R., Cohen, E., Manber, R., Walsh, J. K. 2015; 38 (2): 315-?

    View details for DOI 10.5665/sleep.4422

    View details for Web of Science ID 000348757800020

  • SMART DOCS: a new patient-centered outcomes and coordinated-care management approach for the future practice of sleep medicine. Sleep Kushida, C. A., Nichols, D. A., Holmes, T. H., Miller, R., Griffin, K., Cardell, C., Hyde, P. R., Cohen, E., Manber, R., Walsh, J. K. 2015; 38 (2): 315-326


    The practice of medicine is currently undergoing a transformation to become more efficient, cost-effective, and patient centered in its delivery of care. The aim of this article is to stimulate discussion within the sleep medicine community in addressing these needs by our approach as well as other approaches to sleep medicine care. The primary goals of the Sustainable Methods, Algorithms, and Research Tools for Delivering Optimal Care Study (SMART DOCS) are: (1) to introduce a new Patient-Centered Outcomes and Coordinated-Care Management (PCCM) approach for the future practice of sleep medicine, and (2) to test the PCCM approach against a Conventional Diagnostic and Treatment Outpatient Medical Care (CONV) approach in a randomized, two-arm, single-center, long-term, comparative effectiveness trial. The PCCM approach is integrated into a novel outpatient care delivery model for patients with sleep disorders that includes the latest technology, allowing providers to obtain more accurate and rapid diagnoses and to make evidence-based treatment recommendations, while simultaneously enabling patients to have access to personalized medical information and reports regarding their diagnosis and treatment so that they can make more informed health care decisions. Additionally, the PCCM approach facilitates better communication between patients, referring primary care physicians, sleep specialists, and allied health professionals so that providers can better assist patients in achieving their preferred outcomes. A total of 1,506 patients 18 y or older will be randomized to either the PCCM or CONV approach and will be followed for at least 1 y with endpoints of improved health care performance, better health, and cost control., NCT02037438.

    View details for DOI 10.5665/sleep.4422

    View details for PubMedID 25409112

  • Multimorbidity and healthcare utilisation among high-cost patients in the US Veterans Affairs Health Care System BMJ OPEN Zulman, D. M., Chee, C. P., Wagner, T. H., Yoon, J., Cohen, D. M., Holmes, T. H., Ritchie, C., Asch, S. M. 2015; 5 (4)
  • Multimorbidity and healthcare utilisation among high-cost patients in the US Veterans Affairs Health Care System. BMJ open Zulman, D. M., Pal Chee, C., Wagner, T. H., Yoon, J., Cohen, D. M., Holmes, T. H., Ritchie, C., Asch, S. M. 2015; 5 (4)


    To investigate the relationship between multimorbidity and healthcare utilisation patterns among the highest cost patients in a large, integrated healthcare system.In this retrospective cross-sectional study of all patients in the U.S. Veterans Affairs (VA) Health Care System, we aggregated costs of individuals' outpatient and inpatient care, pharmacy services and VA-sponsored contract care received in 2010. We assessed chronic condition prevalence, multimorbidity as measured by comorbidity count, and multisystem multimorbidity (number of body systems affected by chronic conditions) among the 5% highest cost patients. Using multivariate regression, we examined the association between multimorbidity and healthcare utilisation and costs, adjusting for age, sex, race/ethnicity, marital status, homelessness and health insurance status.USA VA Health Care System.5.2 million VA patients.Annual total costs; absolute and share of costs generated through outpatient, inpatient, pharmacy and VA-sponsored contract care; number of visits to primary, specialty and mental healthcare; number of emergency department visits and hospitalisations.The 5% highest cost patients (n=261 699) accounted for 47% of total VA costs. Approximately two-thirds of these patients had chronic conditions affecting ≥3 body systems. Patients with cancer and schizophrenia were less likely to have documented comorbid conditions than other high-cost patients. Multimorbidity was generally associated with greater outpatient and inpatient utilisation. However, increased multisystem multimorbidity was associated with a higher outpatient share of total costs (1.6 percentage points per affected body system, p<0.01) but a lower inpatient share of total costs (-0.6 percentage points per affected body system, p<0.01).Multisystem multimorbidity is common among high-cost VA patients. While some patients might benefit from disease-specific programmes, for most patients with multimorbidity there is a need for interventions that coordinate and maximise efficiency of outpatient services across multiple conditions.

    View details for DOI 10.1136/bmjopen-2015-007771

    View details for PubMedID 25882486

  • Bayesian immunological model development from the literature: Example investigation of recent thymic emigrants. Journal of immunological methods Holmes, T. H., Lewis, D. B. 2014; 414: 32-50


    Bayesian estimation techniques offer a systematic and quantitative approach for synthesizing data drawn from the literature to model immunological systems. As detailed here, the practitioner begins with a theoretical model and then sequentially draws information from source data sets and/or published findings to inform estimation of model parameters. Options are available to weigh these various sources of information differentially per objective measures of their corresponding scientific strengths. This approach is illustrated in depth through a carefully worked example for a model of decline in T-cell receptor excision circle content of peripheral T cells during development and aging. Estimates from this model indicate that 21years of age is plausible for the developmental timing of mean age of onset of decline in T-cell receptor excision circle content of peripheral T cells.

    View details for DOI 10.1016/j.jim.2014.08.001

    View details for PubMedID 25179832

  • Mental illness and intensification of diabetes medications: an observational cohort study BMC HEALTH SERVICES RESEARCH Frayne, S. M., Holmes, T. H., Berg, E., Goldstein, M. K., Berlowitz, D. R., Miller, D. R., Pogach, L. M., Laungani, K. J., Lee, T. T., Moos, R. 2014; 14
  • Immune Profiling of Pregnant Toxoplasma-Infected US and Colombia Patients Reveals Surprising Impacts of Infection on Peripheral Blood Cytokines JOURNAL OF INFECTIOUS DISEASES Pernas, L., Ramirez, R., Holmes, T. H., Montoya, J. G., Boothroyd, J. C. 2014; 210 (6): 923-931


    In North America (NA) and Europe, the majority of toxoplasmosis cases are benign and generally asymptomatic, while in South America (SA) toxoplasmosis is associated with much more severe symptoms in adults and congenitally infected children. The reasons for these differences remain unknown and, currently, there is little information from patients in either region on how the immune system responds to infection with Toxoplasma gondii. Here, we report the relative abundance of 51 serum cytokines from acute and chronic toxoplasmosis cohorts of pregnant women from the United States (US), where approximately one-half of clinical isolates are Type II, and Colombia, where clinical isolates are generally "atypical" or Type I-like strains. Surprisingly, the results showed notably lower levels of 23 cytokines in acutely infected patients from the US, relative to uninfected US controls. In acutely infected Colombian patients, however, only 8 cytokine levels differed detectably with four being lower and four higher relative to uninfected controls. Strikingly, there were also differences in the cytokine profiles of the chronically infected patients relative to uninfected controls in the US cohort. Hence, Toxoplasma appears to specifically impact levels of circulating cytokines and our results may partly explain region-specific differences in the clinical spectrum of toxoplasmosis.

    View details for DOI 10.1093/infdis/jiu189

    View details for Web of Science ID 000344608300011

  • Distinct Cross-reactive B-Cell Responses to Live Attenuated and Inactivated Influenza Vaccines JOURNAL OF INFECTIOUS DISEASES Sasaki, S., Holmes, T. H., Albrecht, R. A., Garcia-Sastre, A., Dekker, C. L., He, X., Greenberg, H. B. 2014; 210 (6): 865-874


    Background. The immunological bases for the efficacies of the two currently licensed influenza vaccines, the live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV), are not fully understood. The goal of this study was to identify specific B-cell responses correlated with the known efficacies of these two vaccines.Methods. We compared the B-cell and antibody responses after immunization with 2010/2011 IIV versus LAIV in young adults, focusing on peripheral plasmablasts at days 6-8 post-vaccination.Results. The quantities of vaccine-specific plasmablasts and plasmablast-derived polyclonal antibodies (PPAb) were significantly higher in IIV recipients than in LAIV recipients. No significant difference was detected in the avidity of vaccine-specific PPAb between the two vaccine groups. Proportionally, LAIV induced a greater vaccine-specific IgA plasmablast response as well as a greater plasmablast response to the conserved influenza nuclear protein than did IIV. The cross-reactive plasmablast response to heterovariant strains, as indicated by the relative levels of cross-reactive plasmablasts and the cross-reactive PPAb binding reactivity, was also greater in the LAIV group.Conclusions. Distinct quantitative and qualitative patterns of plasmablast responses were induced by LAIV and IIV in young adults; a proportionally greater cross-reactive response was induced by LAIV.

    View details for DOI 10.1093/infdis/jiu190

    View details for Web of Science ID 000344608300005

  • Association Between Success Rate and Citation Count of Studies of Radiofrequency Catheter Ablation for Atrial Fibrillation Possible Evidence of Citation Bias CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Perino, A. C., Hoang, D. D., Holmes, T. H., Santangeli, P., Heidenreich, P. A., Perez, M. V., Wang, P. J., Turakhia, M. P. 2014; 7 (5): 687-692
  • Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation Findings From the TREAT-AF Study JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Turakhia, M. P., Santangeli, P., Winkelmayer, W. C., Xu, X., Ullal, A. J., Than, C. T., Schmitt, S., Holmes, T. H., Frayne, S. M., Phibbs, C. S., Yang, F., Hoang, D. D., Ho, P. M., Heidenreich, P. A. 2014; 64 (7): 660-668


    Despite endorsement of digoxin in clinical practice guidelines, there exist limited data on its safety in atrial fibrillation/flutter (AF).The goal of this study was to evaluate the association of digoxin with mortality in AF.Using complete data of the TREAT-AF (The Retrospective Evaluation and Assessment of Therapies in AF) study from the U.S. Department of Veterans Affairs (VA) healthcare system, we identified patients with newly diagnosed, nonvalvular AF seen within 90 days in an outpatient setting between VA fiscal years 2004 and 2008. We used multivariate and propensity-matched Cox proportional hazards to evaluate the association of digoxin use with death. Residual confounding was assessed by sensitivity analysis.Of 122,465 patients with 353,168 person-years of follow-up (age 72.1 ± 10.3 years, 98.4% male), 28,679 (23.4%) patients received digoxin. Cumulative mortality rates were higher for digoxin-treated patients than for untreated patients (95 vs. 67 per 1,000 person-years; p < 0.001). Digoxin use was independently associated with mortality after multivariate adjustment (hazard ratio [HR]: 1.26, 95% confidence interval [CI]: 1.23 to 1.29, p < 0.001) and propensity matching (HR: 1.21, 95% CI: 1.17 to 1.25, p < 0.001), even after adjustment for drug adherence. The risk of death was not modified by age, sex, heart failure, kidney function, or concomitant use of beta-blockers, amiodarone, or warfarin.Digoxin was associated with increased risk of death in patients with newly diagnosed AF, independent of drug adherence, kidney function, cardiovascular comorbidities, and concomitant therapies. These findings challenge current cardiovascular society recommendations on use of digoxin in AF.

    View details for DOI 10.1016/j.jacc.2014.03.060

    View details for Web of Science ID 000340243300005

    View details for PubMedID 25125296

  • Chest CT in children: anesthesia and atelectasis PEDIATRIC RADIOLOGY Newman, B., Krane, E. J., Gawande, R., Holmes, T. H., Robinson, T. E. 2014; 44 (2): 164-172


    There has been an increasing tendency for anesthesiologists to be responsible for providing sedation or anesthesia during chest CT imaging in young children. Anesthesia-related atelectasis noted on chest CT imaging has proven to be a common and troublesome problem, affecting image quality and diagnostic sensitivity.To evaluate the safety and effectiveness of a standardized anesthesia, lung recruitment, controlled-ventilation technique developed at our institution to prevent atelectasis for chest CT imaging in young children.Fifty-six chest CT scans were obtained in 42 children using a research-based intubation, lung recruitment and controlled-ventilation CT scanning protocol. These studies were compared with 70 non-protocolized chest CT scans under anesthesia taken from 18 of the same children, who were tested at different times, without the specific lung recruitment and controlled-ventilation technique. Two radiology readers scored all inspiratory chest CT scans for overall CT quality and atelectasis. Detailed cardiorespiratory parameters were evaluated at baseline, and during recruitment and inspiratory imaging on 21 controlled-ventilation cases and 8 control cases.Significant differences were noted between groups for both quality and atelectasis scores with optimal scoring demonstrated in the controlled-ventilation cases where 70% were rated very good to excellent quality scans compared with only 24% of non-protocol cases. There was no or minimal atelectasis in 48% of the controlled ventilation cases compared to 51% of non-protocol cases with segmental, multisegmental or lobar atelectasis present. No significant difference in cardiorespiratory parameters was found between controlled ventilation and other chest CT cases and no procedure-related adverse events occurred.Controlled-ventilation infant CT scanning under general anesthesia, utilizing intubation and recruitment maneuvers followed by chest CT scans, appears to be a safe and effective method to obtain reliable and reproducible high-quality, motion-free chest CT images in children.

    View details for DOI 10.1007/s00247-013-2800-4

    View details for Web of Science ID 000330987900005

    View details for PubMedID 24202432

  • Regarding "feasibility and safety of same-day discharge after implantable cardioverter defibrillator placement for primary prevention". Pacing and clinical electrophysiology : PACE Turakhia, M. P., Holmes, T. 2014; 37 (1): 131-?

    View details for DOI 10.1111/pace.12273

    View details for PubMedID 24033450

  • Do Benzodiazepines Reduce the Effectiveness of Exposure Therapy for Posttraumatic Stress Disorder? JOURNAL OF CLINICAL PSYCHIATRY Rosen, C. S., Greenbaum, M. A., Schnurr, P. P., Holmes, T. H., Brennan, P. L., Friedman, M. J. 2013; 74 (12): 1241-1247


    Benzodiazepines, other anxiolytics, or sedative hypnotics are prescribed for 30%-50% of posttraumatic stress disorder (PTSD) patients. Prior data and theory suggest that these medications may inhibit response to exposure therapy, one of the most effective PTSD treatments. The present post hoc study reanalyzed results from a psychotherapy trial to assess whether benzodiazepine use was associated with reduced response to exposure therapy.Between August 2002 and October 2005, 283 female veterans and soldiers meeting DSM-IV criteria for PTSD were randomly assigned to 10 weekly 90-minute sessions of either prolonged exposure (n = 140) or present-centered psychotherapy (n = 143). Benzodiazepine use (n = 57) or non-use (n = 226) at intake was not randomly assigned. Multilevel modeling was used to assess the effects of benzodiazepine status, psychotherapy condition, and their interaction on changes on the Clinician-Administered PTSD Scale and the PTSD Checklist during the treatment and 6-month follow-up periods.Consistent with prior reports from these data, prolonged exposure psychotherapy produced greater reductions per week in PTSD symptoms than did present-centered psychotherapy (b = -0.48, P = .02). Patients prescribed benzodiazepines did not have weaker response to prolonged exposure, but demonstrated poorer posttreatment maintenance of gains from present-centered psychotherapy (b = -0.78, P < .001).Prolonged exposure is a sufficiently robust treatment that patients who are taking benzodiazepines can benefit from it. It is unclear whether benzodiazepine use or other patient factors accounted for benzodiazepine recipients' poorer maintenance of gains in present-centered identifier: NCT00032617.

    View details for DOI 10.4088/JCP.13m08592

    View details for Web of Science ID 000330187000014

    View details for PubMedID 24434093

  • Effects of Continuous Positive Airway Pressure on Neurocognitive Function in Obstructive Sleep Apnea Patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES) SLEEP Kushida, C. A., Nichols, D. A., Holmes, T. H., Quan, S. F., Walsh, J. K., Gottlieb, D. J., Simon, R. D., Guilleminault, C., White, D. P., Goodwin, J. L., Schweitzer, P. K., Leary, E. B., Hyde, P. R., Hirshkowitz, M., Green, S., McEvoy, L. K., Chan, C., Gevins, A., Kay, G. G., Bloch, D. A., Crabtree, T., Dement, W. C. 2012; 35 (12): 1593-U40


    To determine the neurocognitive effects of continuous positive airway pressure (CPAP) therapy on patients with obstructive sleep apnea (OSA).The Apnea Positive Pressure Long-term Efficacy Study (APPLES) was a 6-month, randomized, double-blind, 2-arm, sham-controlled, multicenter trial conducted at 5 U.S. university, hospital, or private practices. Of 1,516 participants enrolled, 1,105 were randomized, and 1,098 participants diagnosed with OSA contributed to the analysis of the primary outcome measures.Active or sham CPAP MEASUREMENTS: THREE NEUROCOGNITIVE VARIABLES, EACH REPRESENTING A NEUROCOGNITIVE DOMAIN: Pathfinder Number Test-Total Time (attention and psychomotor function [A/P]), Buschke Selective Reminding Test-Sum Recall (learning and memory [L/M]), and Sustained Working Memory Test-Overall Mid-Day Score (executive and frontal-lobe function [E/F])The primary neurocognitive analyses showed a difference between groups for only the E/F variable at the 2 month CPAP visit, but no difference at the 6 month CPAP visit or for the A/P or L/M variables at either the 2 or 6 month visits. When stratified by measures of OSA severity (AHI or oxygen saturation parameters), the primary E/F variable and one secondary E/F neurocognitive variable revealed transient differences between study arms for those with the most severe OSA. Participants in the active CPAP group had a significantly greater ability to remain awake whether measured subjectively by the Epworth Sleepiness Scale or objectively by the maintenance of wakefulness test.CPAP treatment improved both subjectively and objectively measured sleepiness, especially in individuals with severe OSA (AHI > 30). CPAP use resulted in mild, transient improvement in the most sensitive measures of executive and frontal-lobe function for those with severe disease, which suggests the existence of a complex OSA-neurocognitive relationship.Registered at Identifier: NCT00051363. CITATION: Kushida CA; Nichols DA; Holmes TH; Quan SF; Walsh JK; Gottlieb DJ; Simon RD; Guilleminault C; White DP; Goodwin JL; Schweitzer PK; Leary EB; Hyde PR; Hirshkowitz M; Green S; McEvoy LK; Chan C; Gevins A; Kay GG; Bloch DA; Crabtree T; Demen WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: the Apnea Positive Pressure Long-term Efficacy Study (APPLES). SLEEP 2012;35(12):1593-1602.

    View details for DOI 10.5665/sleep.2226

    View details for Web of Science ID 000313000600005

    View details for PubMedID 23204602

  • High-Anxious Individuals Show Increased Chronic Stress Burden, Decreased Protective Immunity, and Increased Cancer Progression in a Mouse Model of Squamous Cell Carcinoma PLOS ONE Dhabhar, F. S., Saul, A. N., Holmes, T. H., Daugherty, C., Neri, E., Tillie, J. M., Kusewitt, D., Oberyszyn, T. M. 2012; 7 (4)


    In spite of widespread anecdotal and scientific evidence much remains to be understood about the long-suspected connection between psychological factors and susceptibility to cancer. The skin is the most common site of cancer, accounting for nearly half of all cancers in the US, with approximately 2-3 million cases of non-melanoma cancers occurring each year worldwide. We hypothesized that a high-anxious, stress-prone behavioral phenotype would result in a higher chronic stress burden, lower protective-immunity, and increased progression of the immuno-responsive skin cancer, squamous cell carcinoma. SKH1 mice were phenotyped as high- or low-anxious at baseline, and subsequently exposed to ultraviolet-B light (1 minimal erythemal dose (MED), 3 times/week, 10-weeks). The significant strengths of this cancer model are that it uses a normal, immunocompetent, outbred strain, without surgery/injection of exogenous tumor cells/cell lines, and produces lesions that resemble human tumors. Tumors were counted weekly (primary outcome), and tissues collected during early and late phases of tumor development. Chemokine/cytokine gene-expression was quantified by PCR, tumor-infiltrating helper (Th), cytolytic (CTL), and regulatory (Treg) T cells by immunohistochemistry, lymph node T and B cells by flow cytometry, adrenal and plasma corticosterone and tissue vascular-endothelial-growth-factor (VEGF) by ELISA. High-anxious mice showed a higher tumor burden during all phases of tumor development. They also showed: higher corticosterone levels (indicating greater chronic stress burden), increased CCL22 expression and Treg infiltration (increased tumor-recruited immuno-suppression), lower CTACK/CCL27, IL-12, and IFN-? gene-expression and lower numbers of tumor infiltrating Th and CTLs (suppressed protective immunity), and higher VEGF concentrations (increased tumor angiogenesis/invasion/metastasis). These results suggest that the deleterious effects of high trait anxiety could be: exacerbated by life-stressors, accentuated by the stress of cancer diagnosis/treatment, and mediate increased tumor progression and/or metastasis. Therefore, it may be beneficial to investigate the use of chemotherapy-compatible anxiolytic treatments immediately following cancer diagnosis, and during cancer treatment/survivorship.

    View details for DOI 10.1371/journal.pone.0033069

    View details for Web of Science ID 000305345200001

    View details for PubMedID 22558071

  • A method for estimating normative distributions for study-specific populations of clinical trials CONTEMPORARY CLINICAL TRIALS Holmes, T. H., Nichols, D. A., Thomander, D., Kushida, C. A. 2012; 33 (2): 445-449


    For any particular psychological instrument, published normative distributions have been derived in one to at most a few specific "reference" populations. Here a method is provided for estimating a normative distribution pertinent to the specific population being evaluated in a randomized clinical trial. Normative quantiles are obtained using quantile regression, a method chosen for its flexibility in that no assumptions are made about the parametric form (e.g., Gaussian) of the normative distribution to be estimated. Outcome is regressed on disease severity for the ?th quantile using that sample of consented participants who were not randomized because they fell below the trial's disease severity entry criterion. The ?th quantile of the normative distribution is then estimated by the intercept of this fitted regression function, which corresponds to severity of zero. Additional covariates that explain variation in outcome may be included to permit adjustment for shifts in their distributions between the randomized and non-randomized samples. The method is illustrated using data on a depression instrument (GRID Hamilton Rating Scale for Depression) and a neurocognitive instrument (CogScreen Pathfinder Number) from a multicenter clinical trial in sleep apnea patients.

    View details for DOI 10.1016/j.cct.2011.11.014

    View details for Web of Science ID 000300962000025

    View details for PubMedID 22138103

  • Modafinil for the treatment of methamphetamine dependence DRUG AND ALCOHOL DEPENDENCE Anderson, A. L., Li, S., Biswas, K., McSherry, F., Holmes, T., Iturriaga, E., Kahn, R., Chiang, N., Beresford, T., Campbell, J., Haning, W., Mawhinney, J., McCann, M., Rawson, R., Stock, C., Weis, D., Yu, E., Elkashef, A. M. 2012; 120 (1-3): 135-141


    Modafinil was tested for efficacy in decreasing use in methamphetamine-dependent participants, compared to placebo.This was a randomized, double-blind, placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Eight outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, who all had a DSM-IV diagnosis of methamphetamine dependence; 68 participants to placebo, 72 to modafinil 200mg, and 70 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments, urine drug screens, and group psychotherapy. The primary outcome measure was a methamphetamine non-use week, which required all the week's qualitative urine drug screens to be negative for methamphetamine.Regression analysis showed no significant difference between either modafinil group (200 or 400mg) or placebo in change in weekly percentage having a methamphetamine non-use week over the 12-week treatment period (p=0.53). Similarly, a number of secondary outcomes did not show significant effects of modafinil. However, an ad-hoc analysis of medication compliance, by urinalysis for modafinil and its metabolite, did find a significant difference in maximum duration of abstinence (23 days vs. 10 days, p=0.003), between those having the top quartile of compliance (>85% of urines were positive for modafinil, N=36), and the lower three quartiles of modafinil 200 and 400mg groups (N=106).Although these data suggest that modafinil, plus group behavioral therapy, was not effective for decreasing methamphetamine use, the study is probably inconclusive because of inadequate compliance with taking medication.

    View details for DOI 10.1016/j.drugalcdep.2011.07.007

    View details for Web of Science ID 000299499800019

    View details for PubMedID 21840138

  • Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies JOURNAL OF CLINICAL INVESTIGATION Sasaki, S., Sullivan, M., Narvaez, C. F., Holmes, T. H., Furman, D., Zheng, N., Nishtala, M., Wrammert, J., Smith, K., James, J. A., Dekker, C. L., Davis, M. M., Wilson, P. C., Greenberg, H. B., He, X. 2011; 121 (8): 3109-3119


    During seasonal influenza epidemics, disease burden is shouldered predominantly by the very young and the elderly. Elderly individuals are particularly affected, in part because vaccine efficacy wanes with age. This has been linked to a reduced ability to induce a robust serum antibody response. Here, we show that this is due to reduced quantities of vaccine-specific antibodies, rather than a lack of antibody avidity or affinity. We measured levels of vaccine-specific plasmablasts by ELISPOT 1 week after immunization of young and elderly adults with inactivated seasonal influenza vaccine. Plasmablast-derived polyclonal antibodies (PPAbs) were generated from bulk-cultured B cells, while recombinant monoclonal antibodies (re-mAbs) were produced from single plasmablasts. The frequency of vaccine-specific plasmablasts and the concentration of PPAbs were lower in the elderly than in young adults, whereas the yields of secreted IgG per plasmablast were not different. Differences were not detected in the overall vaccine-specific avidity or affinity of PPAbs and re-mAbs between the 2 age groups. In contrast, reactivity of the antibodies induced by the inactivated seasonal influenza vaccine toward the 2009 pandemic H1N1 virus, which was not present in the vaccine, was higher in the elderly than in the young. These results indicate that the inferior antibody response to influenza vaccination in the elderly is primarily due to reduced quantities of vaccine-specific antibodies. They also suggest that exposure history affects the cross-reactivity of vaccination-induced antibodies.

    View details for DOI 10.1172/JCI57834

    View details for Web of Science ID 000293495500022

    View details for PubMedID 21785218

  • Anemia in older persons: Etiology and evaluation BLOOD CELLS MOLECULES AND DISEASES Price, E. A., Mehra, R., Holmes, T. H., Schrier, S. L. 2011; 46 (2): 159-165


    The aim of this study was to prospectively determine the etiology of anemia in a cohort of community-dwelling older outpatients with a comprehensive hematologic evaluation. Participants were men and women age 65 and older with anemia as defined by World Health Organization criteria recruited from outpatient hematology clinics at Stanford Hospital and Clinics (SHC) and Veterans Affairs Palo Alto Health Care System (VAPAHCS). Each participant underwent a history and physical examination, followed by a comprehensive hematologic evaluation, which in all participants included complete blood count, red cell indices, review of the blood smear, and assessment of vitamin B12, folate, iron status and renal function. Additional evaluation was obtained by clinical providers as per their discretion. 190 participants enrolled and completed the evaluation. Twelve percent of participants had iron deficiency anemia. Of those with iron deficiency in whom there was follow-up information, half normalized their hemoglobin in response to iron repletion, and half did not. Thirty-five percent of participants had unexplained anemia. Those with unexplained anemia had mildly increased inflammatory markers compared to non-anemic controls, and, at the lower hemoglobin ranges had relatively low erythropoietin levels. Sixteen percent of participants were categorized as being "suspicious for myelodysplastic syndrome." Thus, even with comprehensive hematologic evaluation, unexplained anemia is common in older anemic outpatients. Iron deficiency anemia is also common and can be difficult to diagnose, and frequently the anemia is not fully corrected with iron repletion.

    View details for DOI 10.1016/j.bcmd.2010.11.004

    View details for Web of Science ID 000287267100007

    View details for PubMedID 21208814

  • Advantages of Joint Modeling of Component HIV Risk Behaviors and Non-Response: Application to Randomized Trials in Cocaine-Dependent and Methamphetamine-Dependent Populations. Frontiers in psychiatry / Frontiers Research Foundation Holmes, T. H., Anderson, A. L., Li, S., Elkashef, A. M. 2011; 2: 41-?


    The HIV risk-taking behavior scale (HRBS) is an 11-item instrument designed to assess the risks of HIV infection due to self-reported injection-drug use and sexual behavior. A retrospective analysis was performed on HRBS data collected from approximately 1,000 participants pooled across seven clinical trials of pharmacotherapies for either the treatment of cocaine dependence or methamphetamine dependence. Analysis faced three important challenges. The sample contained a high proportion of missing assessments after randomization. Also, the HRBS scale consists of two distinct behavioral components which may or may not coincide in response patterns. In addition, distributions of responses on the subscales were highly concentrated at just a few values (e.g., 0, 6). To address these challenges, a single probit regression model was fit to three outcomes variables simultaneously - the two subscale totals plus an indicator variable for assessments not obtained (non-response). This joint-outcome regression model was able to identify that those who left assessment early had higher self-reported risk of injection-drug use and lower self-reported risky sexual behavior because the model was able to draw on information on associations among the three outcomes collectively. These findings were not identified in analyses performed on each outcome separately. No evidence for an effect of pharmacotherapies was observed, except to reduce missing assessments. Univariate-outcome modeling is not recommended for the HRBS.

    View details for DOI 10.3389/fpsyt.2011.00041

    View details for PubMedID 21779253

  • Military-Related Sexual Trauma Among Veterans Health Administration Patients Returning From Afghanistan and Iraq AMERICAN JOURNAL OF PUBLIC HEALTH Kimerling, R., Street, A. E., Pavao, J., Smith, M. W., Cronkite, R. C., Holmes, T. H., Frayne, S. M. 2010; 100 (8): 1409-1412


    We examined military-related sexual trauma among deployed Operation Enduring Freedom and Operation Iraqi Freedom veterans. Of 125 729 veterans who received Veterans Health Administration primary care or mental health services, 15.1% of the women and 0.7% of the men reported military sexual trauma when screened. Military sexual trauma was associated with increased odds of a mental disorder diagnosis, including posttraumatic stress disorder, other anxiety disorders, depression, and substance use disorders. Sexual trauma is an important postdeployment mental health issue in this population.

    View details for DOI 10.2105/AJPH.2009.171793

    View details for Web of Science ID 000282354800015

    View details for PubMedID 20558808

  • MENTAL ILLNESS AND GLYCEMIC CONTROL: DRILLING DEEPER Frayne, S., Moos, R., Berg, E., Laungani, K., Goldstein, M., Berlowitz, D., Miller, D., Holmes, T., Pogach, L. SPRINGER. 2010: 333-333
  • Mental illness-related disparities in length of stay. Algorithm choice influences results JOURNAL OF REHABILITATION RESEARCH AND DEVELOPMENT Frayne, S. M., Berg, E., Holmes, T. H., Laungani, K., Berlowitz, D. R., Miller, D. R., Pogach, L., Jackson, V. W., Moos, R. 2010; 47 (8): 709-718


    Methodological challenges arise when one uses various Veterans Health Administration (VHA) data sources, each created for distinct purposes, to characterize length of stay (LOS). To illustrate this issue, we examined how algorithm choice affects conclusions about mental health condition (MHC)-related differences in LOS for VHA patients with diabetes nationally (n = 784,321). We assembled a record-level database of all fiscal year (FY) 2003 inpatient care. In 10 steps, we sequentially added instances of inpatient care from various VHA sources. We processed databases in three stages, truncating stays at the beginning and end of FY03 and consolidating overlapping stays. For patients with MHCs versus those without MHCs, mean LOS was 17.7 versus 13.6 days, respectively (p < 0.001), for the crudest algorithm and 37.2 versus 21.7 days, respectively (p < 0.001), for the most refined algorithm. Researchers can improve the quality of data applied to VHA systems redesign by applying methodological considerations raised by this study to inform LOS algorithm choice.

    View details for DOI 10.1682/JRRD.2009.08.0112

    View details for Web of Science ID 000285074300006

    View details for PubMedID 21110246

  • Association between Genotype of the Serotonin Transporter-Linked Polymorphic Region of the Serotonin Transporter Gene and Age of Onset of Methamphetamine Use: a Preliminary Analysis. Frontiers in psychiatry / Frontiers Research Foundation Johnson, B. A., Elkashef, A. M., Seneviratne, C., Ait-Daoud, N., Kahn, R. C., Li, S., Bloch, D. A., Holmes, T. H., Wang, X., Vocci, F. J., Li, M. D. 2010; 1: 145-?


    Early-onset methamphetamine use increases the lifetime prevalence of methamphetamine dependence. An earlier onset of methamphetamine use leads to greater damage to the terminal ends of serotonin neurons, more reduction in serotonin transporter (5-HTT) density, and an increased propensity toward further methamphetamine use. Because the 5-HTT-linked polymorphic region (5'-HTTLPR) within the promoter region of the 5-HTT gene leads to differential expression of the 5-HTT, we examined, for the first time, whether there is a differential association between the long (L) and short (S) alleles of the 5'-HTTLPR and the age of first methamphetamine use (AMU). The study included 120 methamphetamine-dependent adults of European descent. Diagnosis of methamphetamine dependence and AMU were collected using structured questionnaires, and the 5'-HTTLPR genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism method. Statistical analysis with the general linear model detected a significant interactive effect of 5'-HTTLPR genotypes (SS vs. L-carriers) and gender, associated with AMU (F?=?3.99; p?=?0.048). Further analysis of 5'-HTTLPR effects on AMU in males and females separately showed that the SS genotype compared with L-carriers had about two times greater risk of an earlier onset of methamphetamine use in men (hazard ratio?=?1.839; 95% confidence interval?=?1.042-3.246; p?=?0.036) but not in women. Together, our findings in this preliminary study suggest a greater risk for earlier onset methamphetamine use associated with the SS genotype of the 5'-HTTLPR among methamphetamine-dependent Caucasian males.

    View details for DOI 10.3389/fpsyt.2010.00145

    View details for PubMedID 21423453

  • Short-term stress enhances cellular immunity and increases early resistance to squamous cell carcinoma BRAIN BEHAVIOR AND IMMUNITY Dhabhar, F. S., Saul, A. N., Daugherty, C., Holmes, T. H., Bouley, D. M., Oberyszyn, T. M. 2010; 24 (1): 127-137


    In contrast to chronic/long-term stress that suppresses/dysregulates immune function, an acute/short-term fight-or-flight stress response experienced during immune activation can enhance innate and adaptive immunity. Moderate ultraviolet-B (UV) exposure provides a non-invasive system for studying the naturalistic emergence, progression and regression of squamous cell carcinoma (SCC). Because SCC is an immunoresponsive cancer, we hypothesized that short-term stress experienced before UV exposure would enhance protective immunity and increase resistance to SCC. Control and short-term stress groups were treated identically except that the short-term stress group was restrained (2.5h) before each of nine UV-exposure sessions (minimum erythemal dose, 3-times/week) during weeks 4-6 of the 10-week UV exposure protocol. Tumors were measured weekly, and tissue collected at weeks 7, 20, and 32. Chemokine and cytokine gene expression was quantified by real-time PCR, and CD4+ and CD8+ T cells by flow cytometry and immunohistochemistry. Compared to controls, the short-term stress group showed greater cutaneous T-cell attracting chemokine (CTACK)/CCL27, RANTES, IL-12, and IFN-gamma gene expression at weeks 7, 20, and 32, higher skin infiltrating T cell numbers (weeks 7 and 20), lower tumor incidence (weeks 11-20) and fewer tumors (weeks 11-26). These results suggest that activation of short-term stress physiology increased chemokine expression and T cell trafficking and/or function during/following UV exposure, and enhanced Type 1 cytokine-driven cell-mediated immunity that is crucial for resistance to SCC. Therefore, the physiological fight-or-flight stress response and its adjuvant-like immuno-enhancing effects, may provide a novel and important mechanism for enhancing immune system mediated tumor-detection/elimination that merits further investigation.

    View details for DOI 10.1016/j.bbi.2009.09.004

    View details for Web of Science ID 000272676400017

    View details for PubMedID 19765644

  • Modafinil for the treatment of cocaine dependence DRUG AND ALCOHOL DEPENDENCE Anderson, A. L., Reid, M. S., Li, S., Holmes, T., Shemanski, L., Slee, A., Smith, E. V., Kahn, R., Chiang, N., Vocci, F., Ciraulo, D., Dackis, C., Roache, J. D., Salloum, I. M., Somoza, E., Urschel, H. C., Elkashef, A. M. 2009; 104 (1-2): 133-139


    Modafinil was tested for efficacy in facilitating abstinence in cocaine-dependent patients, compared to placebo.This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 4-week follow-up. Six outpatient substance abuse treatment clinics participated in the study. There were 210 treatment-seekers randomized, having a diagnosis of cocaine dependence; 72 participants were randomized to placebo, 69 to modafinil 200mg, and 69 to modafinil 400mg, taken once daily on awakening. Participants came to the clinic three times per week for assessments and urine drug screens, and had one hour of individual psychotherapy weekly. The primary outcome measure was the weekly percentage of cocaine non-use days.The GEE regression analysis showed that for the total sample, there was no significant difference between either modafinil group and placebo in the change in average weekly percent of cocaine non-use days over the 12-week treatment period (p>0.79). However, two secondary outcomes showed significant effects by modafinil 200mg: the maximum number of consecutive non-use days for cocaine (p=0.02), and a reduction in craving (p=0.04). Also, a post hoc analysis showed a significant effect of modafinil that increased the weekly percentage of non-use days in the subgroup of those cocaine patients who did not have a history of alcohol dependence (p<0.02).These data suggest that modafinil, in combination with individual behavioral therapy, was effective for increasing cocaine non-use days in participants without co-morbid alcohol dependence, and in reducing cocaine craving.

    View details for DOI 10.1016/j.drugalcdep.2009.04.015

    View details for Web of Science ID 000268611000019

    View details for PubMedID 19560290

  • Simple counts of ADL dependencies do not adequately reflect older adults' preferences toward states of functional impairment JOURNAL OF CLINICAL EPIDEMIOLOGY Sims, T., Holmes, T. H., Bravata, D. M., Garber, A. M., Nelson, L. M., Goldstein, M. K. 2008; 61 (12): 1261-1270


    To use unweighted counts of dependencies in activities of daily living (ADLs) to assess the impact of functional impairment requires an assumption of equal preferences for each ADL dependency. To test this assumption, we analyzed standard gamble (SG) utilities of single and combination ADL dependencies among older adults.Four hundred older adults used multimedia software (FLAIR1) to report SG utilities for their current health and hypothetical health states of dependency in each of 7 ADLs and 8 of 30 combinations of ADL dependencies.Utilities for health states of multiple ADL dependencies were often greater than for states of single ADL dependencies. Dependence in eating, which is the ADL dependency with the lowest utility rating of the single ADL dependencies, ranked lower than 7 combination states. Similarly, some combination states with fewer ADL dependencies had lower utilities than those with more ADL dependencies. These findings were consistent across groups by gender, age, and education.Our results suggest that the count of ADL dependencies does not adequately represent the utility for a health state. Cost-effectiveness analyses and other evaluations of programs that prevent or treat functional dependency should apply utility weights rather than relying on simple ADL counts.

    View details for DOI 10.1016/j.jclinepi.2008.05.001

    View details for Web of Science ID 000261219700010

    View details for PubMedID 18722749

  • Differential effects of insulin sensitivity on androgens in obese women with polycystic ovary syndrome or normal ovulation METABOLISM-CLINICAL AND EXPERIMENTAL Asagami, T., Holmes, T. H., Reaven, G. 2008; 57 (10): 1355-1360


    The differential effects of insulin sensitivity and adiposity on androgen concentrations in women with polycystic ovary syndrome (PCOS) are unclear. To address this issue, we divided 43 overweight women into 4 groups based on both their clinical classification (PCOS or normal) and whether they were insulin resistant (IR) or insulin sensitive (IS) by their steady-state plasma glucose concentrations. Total testosterone concentrations were significantly increased as a function of both clinical classification (PCOS vs normal, P < .0001) and steady-state plasma glucose concentration (IR vs IS, P = .002). Mean testosterone concentrations were higher in PCOS-IR compared with PCOS-IS, normal-IR, or normal-IS women (P < .005). In addition, there was a statistically significant interaction (P = .03) between clinical classification (PCOS vs normal) and insulin sensitivity (IR vs IS) for testosterone concentrations. In contrast, androstenedione concentrations were higher in women with PCOS (P = .001), irrespective of whether they were IR or IS (P = .31); and no interaction between clinical classification and insulin sensitivity was discerned (P = .34). These results indicate that both PCOS and insulin resistance independently contributed to increased total testosterone concentrations within a group of overweight/obese women. These findings are consistent with the hypothesis that the ovaries of women with PCOS are hypersensitive to the ability of insulin to increase testosterone production and that the more insulin resistant the patient, the higher the testosterone concentration. In contrast, androstenedione concentrations seem to be independent of differences in insulin resistance. Our findings emphasize the need to increase understanding of the factors that modulate ovarian androgen secretion.

    View details for DOI 10.1016/j.metabol.2008.05.002

    View details for Web of Science ID 000260240500007

    View details for PubMedID 18803938

  • Influence of Prior Influenza Vaccination on Antibody and B-Cell Responses PLOS ONE Sasaki, S., He, X., Holmes, T. H., Dekker, C. L., Kemble, G. W., Arvin, A. M., Greenberg, H. B. 2008; 3 (8)


    Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7-9 and 21-35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.

    View details for DOI 10.1371/journal.pone.0002975

    View details for Web of Science ID 000264420900002

    View details for PubMedID 18714352

  • Baseline Levels of Influenza-Specific CD4 Memory T-Cells Affect T-Cell Responses to Influenza Vaccines PLOS ONE He, X., Holmes, T. H., Sasaki, S., Jaimes, M. C., Kemble, G. W., Dekker, C. L., Arvin, A. M., Greenberg, H. B. 2008; 3 (7)


    Factors affecting immune responses to influenza vaccines have not been studied systematically. We hypothesized that T-cell and antibody responses to the vaccines are functions of pre-existing host immunity against influenza antigens.During the 2004 and 2005 influenza seasons, we have collected data on cellular and humoral immune reactivity to influenza virus in blood samples collected before and after immunization with inactivated or live attenuated influenza vaccines in healthy children and adults. We first used cross-validated lasso regression on the 2004 dataset to identify a group of candidate baseline correlates with T-cell and antibody responses to vaccines, defined as fold-increase in influenza-specific T-cells and serum HAI titer after vaccination. The following baseline parameters were examined: percentages of influenza-reactive IFN-gamma(+) cells in T and NK cell subsets, percentages of influenza-specific memory B-cells, HAI titer, age, and type of vaccine. The candidate baseline correlates were then tested with the independent 2005 dataset. Baseline percentage of influenza-specific IFN-gamma(+) CD4 T-cells was identified as a significant correlate of CD4 and CD8 T-cell responses, with lower baseline levels associated with larger T-cell responses. Baseline HAI titer and vaccine type were identified as significant correlates for HAI response, with lower baseline levels and the inactivated vaccine associated with larger HAI responses. Previously we reported that baseline levels of CD56(dim) NK reactivity against influenza virus inversely correlated with the immediate T-cell response to vaccination, and that NK reactivity induced by influenza virus depended on IL-2 produced by influenza-specific memory T-cells. Taken together these results suggest a novel mechanism for the homeostasis of virus-specific T-cells, which involves interaction between memory helper T-cells, CD56(dim) NK and DC.These results demonstrate that assessment of baseline biomarkers may predict immunologic outcome of influenza vaccination and may reveal some of the mechanisms responsible for variable immune responses following vaccination and natural infection.

    View details for DOI 10.1371/journal.pone.0002574

    View details for Web of Science ID 000263288200039

    View details for PubMedID 18596908

  • Bupropion for the treatment of methamphetamine dependence NEUROPSYCHOPHARMACOLOGY Elkashef, A. M., Rawson, R. A., Anderson, A. L., Li, S., Holmes, T., Smith, E. V., Chiang, N., Kahn, R., Vocci, F., Ling, W., Pearce, V. J., McCann, M., Campbell, J., Gorodetzky, C., Haning, W., Carlton, B., Mawhinney, J., Weis, D. 2008; 33 (5): 1162-1170


    Bupropion was tested for efficacy in increasing weeks of abstinence in methamphetamine-dependent patients, compared to placebo. This was a double-blind placebo-controlled study, with 12 weeks of treatment and a 30-day follow-up. Five outpatient substance abuse treatment clinics located west of the Mississippi participated in the study. One hundred and fifty-one treatment-seekers with DSM-IV diagnosis of methamphetamine dependence were consented and enrolled. Seventy-two participants were randomized to placebo and 79 to sustained-release bupropion 150 mg twice daily. Patients were asked to come to the clinic three times per week for assessments, urine drug screens, and 90-min group psychotherapy. The primary outcome was the change in proportion of participants having a methamphetamine-free week. Secondary outcomes included: urine for quantitative methamphetamine, self-report of methamphetamine use, subgroup analyses of balancing factors and comorbid conditions, addiction severity, craving, risk behaviors for HIV, and use of other substances. The generalized estimating equation regression analysis showed that, overall, the difference between bupropion and placebo groups in the probability of a non-use week over the 12-week treatment period was not statistically significant (p=0.09). Mixed model regression was used to allow adjustment for baseline factors in addition to those measured (site, gender, level of baseline use, and level of symptoms of depression). This subgroup analysis showed that bupropion had a significant effect compared to placebo, among male patients who had a lower level of methamphetamine use at baseline (p<0.0001). Comorbid depression and attention-deficit/hyperactivity disorder did not change the outcome. These data suggest that bupropion, in combination with behavioral group therapy, was effective for increasing the number of weeks of abstinence in participants with low-to-moderate methamphetamine dependence, mainly male patients, regardless of their comorbid condition.

    View details for DOI 10.1038/sj.npp.1301481

    View details for Web of Science ID 000253957600019

    View details for PubMedID 17581531

  • Phenotypic changes in influenza-specific CD8(+) T cells after immunization of children and adults with influenza vaccines JOURNAL OF INFECTIOUS DISEASES He, X., Holmes, T. H., Mahmood, K., Kemble, G. W., Dekker, C. L., Arvin, A. M., Greenberg, H. B. 2008; 197 (6): 803-811


    The effect of trivalent inactivated influenza vaccine (TIV) or live attenuated influenza vaccine (LAIV) on the phenotypes of circulating influenza-specific CD8+ T cells was analyzed by interferon (IFN)-gamma flow cytometry and tetramer staining. In adults, the expression of the T cell differentiation marker CD27 on virus-specific CD8+ T cells decreased after LAIV but increased after TIV. In children, expression of the cytotoxicity molecule perforin in influenza-specific CD8+ T cells increased after TIV but not after LAIV. Among children aged 6 months to 4 years who had not been vaccinated previously and who received 2 doses of TIV, CD27 expression decreased after each dose, whereas perforin expression increased after the second dose. These findings indicate that the phenotypic changes of influenza-specific CD8+ T cells differ depending on the type of vaccine and the age of the vaccinee. These differences are potentially affected by the different routes of vaccination and pathways of antigen presentation for TIV and LAIV.

    View details for DOI 10.1086/528804

    View details for Web of Science ID 000253773900005

    View details for PubMedID 18279048

  • Posttranslational regulation of I-E-d by affinity for CLIP JOURNAL OF IMMUNOLOGY Rinderknecht, C. H., Belmares, M. P., Catanzarite, T. L., Bankovich, A. J., Holmes, T. H., Garcia, K. C., Nanda, N. K., Busch, R., Kovats, S., Mellins, E. D. 2007; 179 (9): 5907-5915


    Several MHC class II alleles linked with autoimmune diseases form unusually low stability complexes with CLIP, leading us to hypothesize that this is an important feature contributing to autoimmune pathogenesis. To investigate cellular consequences of altering class II/CLIP affinity, we evaluated invariant chain (Ii) mutants with varying CLIP affinity for a mouse class II allele, I-E(d), which has low affinity for wild-type CLIP and is associated with a mouse model of spontaneous, autoimmune joint inflammation. Increasing CLIP affinity for I-E(d) resulted in increased cell surface and total cellular abundance and half-life of I-E(d). This reveals a post-endoplasmic reticulum chaperoning capacity of Ii via its CLIP peptides. Quantitative effects on I-E(d) were less pronounced in DM-expressing cells, suggesting complementary chaperoning effects mediated by Ii and DM, and implying that the impact of allelic variation in CLIP affinity on immune responses will be highest in cells with limited DM activity. Differences in the ability of cell lines expressing wild-type or high-CLIP-affinity mutant Ii to present Ag to T cells suggest a model in which increased CLIP affinity for class II serves to restrict peptide loading to DM-containing compartments, ensuring proper editing of antigenic peptides.

    View details for Web of Science ID 000250388000035

    View details for PubMedID 17947664

  • Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine PEDIATRIC INFECTIOUS DISEASE JOURNAL Zeman, A. M., Holmes, T. H., Stamatis, S., Tu, W., He, X., Bouvier, N., Kemble, G., Greenberg, H. B., Lewis, D. B., Arvin, A. M., Dekker, C. L. 2007; 26 (2): 107-115


    There have been no prior reports of the frequency of circulating influenza-specific, interferon gamma-producing memory CD4+ and CD8+ T-cells in healthy children who have received multiple influenza immunizations.We evaluated 21 previously immunized children, ages 3 to 9 years, before and 1 month after administration of trivalent inactivated influenza vaccine. Frequencies of influenza-specific CD4+ and CD8+ T-cells stimulated with trivalent inactivated influenza vaccine or A/Panama (H3N2) virus were determined by flow cytometry, and antibody responses to vaccine strains and a drifted H3N2 strain were measured by hemagglutination inhibition assay and neutralizing antibody assays.Mean change in CD4+ and in CD8+ T-cell frequencies after immunization was 0.01% (P > 0.39) with postimmunization CD4+ frequencies higher than CD8+ frequencies. Children with more previous vaccinations had a higher baseline frequency of CD4+ T-cells (P = 0.0002) but a smaller increase or even a decline from baseline after immunization (P = 0.003). An association between age and change in frequency was not detected. Baseline geometric mean titers (GMTs) and seroprotection rates were significantly higher in older children against A/Panama (neutralizing baseline GMT, P = 0.0488) and A/New Caledonia (hemagglutination inhibition baseline GMT and seroprotection, P < 0.0297). Baseline GMTs against B/Hong Kong were not associated with age or quantity of prior vaccinations.These findings suggest that children may plateau in CD4+ T-cell responses to influenza antigens with repeated exposures and that the number of exposures may play a large role in building a memory CD4+ T-cell response to influenza A, perhaps independently from age.

    View details for DOI 10.1097/01.inf.0000253251.03785.9b

    View details for Web of Science ID 000243985700002

    View details for PubMedID 17259871

  • Comparison of the influenza virus-specific effector and memory C-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines JOURNAL OF VIROLOGY Sasaki, S., Jaimes, M. C., Holmes, T. H., Dekker, C. L., Mahmood, K., Kemble, G. W., Arvin, A. M., Greenberg, H. B. 2007; 81 (1): 215-228


    Cellular immune responses to influenza virus infection and influenza virus vaccination have not been rigorously characterized. We quantified the effector and memory B-cell responses in children and adults after administration of either live attenuated (LAIV) or inactivated (TIV) influenza virus vaccines and compared these to antibody responses. Peripheral blood mononuclear cells were collected at days 0, 7 to 12, and 27 to 42 after immunization of younger children (6 months to 4 years old), older children (5 to 9 years old), and adults. Influenza virus-specific effector immunoglobulin A (IgA) and IgG circulating antibody-secreting cells (ASC) and stimulated memory B cells were detected using an enzyme-linked immunospot assay. Circulating influenza virus-specific IgG and IgA ASC were detected 7 to 12 days after TIV and after LAIV immunization. Seventy-nine percent or more of adults and older children had demonstrable IgG ASC responses, while IgA ASC responses were detected in 29 to 53% of the subjects. The IgG ASC response rate to LAIV immunization in adults was significantly higher than the response rate measured by standard serum antibody assays (26.3% and 15.8% by neutralization and hemagglutination inhibition assays, respectively). IgG ASC and serum antibody responses were relatively low in the younger children compared to older children and adults. TIV, but not LAIV, significantly increased the percentage of circulating influenza virus-specific memory B cells detected at 27 to 42 days after immunization in children and adults. In conclusion, although both influenza vaccines are effective, we found significant differences in the B-cell and antibody responses elicited after LAIV or TIV immunization in adults and older children and between young children and older age groups.

    View details for DOI 10.1128/JVI.01957-06

    View details for Web of Science ID 000242958600020

    View details for PubMedID 17050593

  • Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines JOURNAL OF VIROLOGY He, X., Holmes, T. H., Zhang, C., Mahmood, K., Kemble, G. W., Lewis, D. B., Dekker, C. L., Greenberg, H. B., Arvin, A. M. 2006; 80 (23): 11756-11766


    The patterns of cellular immune responses induced by live attenuated influenza vaccine (LAIV) versus those of the trivalent inactivated influenza vaccine (TIV) have not been studied extensively, especially in children. The goals of this study were to evaluate the effects of TIV and LAIV immunization on cellular immunity to live influenza A virus in children and adults and to explore factors associated with variations in responses to influenza vaccines among individuals. A gamma interferon (IFN-gamma) flow cytometry assay was used to measure IFN-gamma-producing (IFN-gamma+) NK and T cells in peripheral blood mononuclear cell cultures stimulated with a live influenza A virus strain before and after LAIV or TIV immunization of children and adults. The mean percentages of influenza A virus-specific IFN-gamma+ CD4 and CD8 T cells increased significantly after LAIV, but not TIV, immunization in children aged 5 to 9 years. No increases in the mean levels of influenza A virus-reactive IFN-gamma+ T cells and NK cells were observed in adults given LAIV or TIV. TIV induced a significant increase in influenza A virus-reactive T cells in 6-month- to 4-year-old children; LAIV was not evaluated in this age group. The postvaccination changes (n-fold) in the percentages of influenza A virus-reactive IFN-gamma+ T and NK cells in adults were highly variable and correlated inversely with the prevaccination percentages, in particular with that of the CD56(dim) NK cell subset. In conclusion, our findings identify age, type of vaccine, and prevaccination levels of immune reactivity to influenza A virus as factors significantly associated with the magnitude of cellular immune responses to influenza vaccines.

    View details for DOI 10.1128/JVI.01460-06

    View details for Web of Science ID 000242222200032

    View details for PubMedID 16971435

  • Candidate early predictors for progression to joint damage in systemic juvenile idiopathic arthritis JOURNAL OF RHEUMATOLOGY Sandborg, C., Holmes, T. H., Lee, T., Biederman, K., Bloch, D. A., Emery, H., McCurdy, D., Mellins, E. D. 2006; 33 (11): 2322-2329


    To assess if joint damage at 2 years after diagnosis in patients with systemic juvenile idiopathic arthritis (SJIA) can be predicted by clinical or laboratory features assessed up to 3 or 6 months after diagnosis.Medical records from 70 children were retrospectively reviewed. The primary outcome measure was presence of joint damage at 2 years after diagnosis (JD2) as defined by presence of erosions or fusion in one or more joints. Potential predictor variables for JD2 in the first 3 and 6 months after diagnosis consisted of the highest observed white blood cell count, platelet count, erythrocyte sedimentation rate, active joint count, and presence of symptomatic pulmonary or cardiac disease or macrophage activation syndrome, and treatment data.The outcome of interest, JD2, was identified in 15/70 patients. Classification-tree analysis identified a pair of variables (highest observed platelet count and number of active joints) measured within the first 3 months after diagnosis that together predicted progression to JD2 with an estimated sensitivity of 87%, specificity of 82%, and positive predictive value of 57%. Multivariate logistic regression analyses at 3 months found that higher quantities of joints with active arthritis and early use of methotrexate (MTX) were factors significantly associated with increased odds of progression to JD2 (active joints odds ratio = 1.08, 95% CI 1.00-1.16, p = 0.04; MTX OR = 11.85, 95% CI 1.89-74.26, p = 0.01). Unsupervised cluster analysis identified 2 major phenotypes of patients at 3 months characterized by different ages at onset, acute phase markers, active joint counts, and presence of serositis. These phenotypes differed 3-fold in proportion of subjects progressing to JD2 (p < 0.05).By 3 months after diagnosis, a clinical phenotype based on active joint count and platelet count may be prognostic of an increased risk of progression to JD2. Use of corticosteroids did not appear to change the risk of joint damage. In contrast, the presence of serositis appeared to be associated with decreased risk of joint damage.

    View details for Web of Science ID 000242010700035

    View details for PubMedID 16960920

  • Phenotypic and functional status of intrahepatic T cells in chronic hepatitis C JOURNAL OF INFECTIOUS DISEASES Wang, J., Holmes, T. H., de Guevara, L. L., Cheung, R., Wright, T. L., He, X., Greenberg, H. B. 2006; 194 (8): 1068-1077


    Polychromatic flow-cytometric assays were used to analyze paired intrahepatic and peripheral lymphocyte samples from 37 patients with chronic hepatitis C. Compared with peripheral cells, intrahepatic T cells were selectively enriched with CD45RO+ memory T cells but had a lower percentage of CD4+ T cells expressing the differentiation markers CD27 and CD28. The percentage of intrahepatic CD45RO+ and CD28+ T cells correlated with the degree of liver inflammation, which suggests that memory T cells at relatively early stages of differentiation are directly involved in liver inflammation. Despite their memory phenotype, intrahepatic T cells were defective in proliferation capability, produced less interferon- gamma in response to stimulation by T cell receptor, and contained less perforin but expressed higher levels of Fas and Fas ligand, compared with their counterparts in peripheral blood. The distinct characteristics of intrahepatic T cells suggest that they play an important role in the immunopathogenesis of chronic hepatitis C.

    View details for Web of Science ID 000240548500007

    View details for PubMedID 16991081

  • T-cell immunity to subclinical cytomegalovirus infection reduces cardiac allograft disease CIRCULATION Tu, W., Potena, L., Stepick-Biek, P., Liu, L., Dionis, K. Y., Luikart, H., Fearon, W. F., Holmes, T. H., Chin, C., Cooke, J. P., Valantine, H. A., Mocarski, E. S., Lewis, D. B. 2006; 114 (15): 1608-1615


    Asymptomatic cytomegalovirus (CMV) replication is frequent after cardiac transplantation in recipients with pretransplantation CMV infection. How subclinical viral replication influences cardiac allograft disease remains poorly understood, as does the importance of T-cell immunity in controlling such replication.Thirty-nine cardiac recipients who were pretransplantation CMV antibody positive were longitudinally studied for circulating CMV-specific CD4 and CD8 T-cell responses, CMV viral load in blood neutrophils, and allograft rejection during the first posttransplantation year. Nineteen of these recipients were also analyzed for changes of coronary artery intimal, lumen, and whole-vessel area. All recipients received early prophylactic therapy with ganciclovir. No recipients developed overt CMV disease. Those with detectable levels of CMV-specific CD4 T cells in the first month after transplantation were significantly protected from high mean and peak posttransplantation viral load (P<0.05), acute rejection (P<0.005), and loss of allograft coronary artery lumen (P<0.05) and of whole-vessel area (P<0.05) compared with those who lacked this immune response. The losses of lumen and vessel area were both significantly correlated with the time after transplantation at which a CD4 T-cell response was first detected (P<0.05) and with the cumulative graft rejection score (P<0.05).The early control of subclinical CMV replication after transplantation by T-cell immunity may limit cardiac allograft rejection and vascular disease. Interventions to increase T-cell immunity might be clinically useful in limiting these adverse viral effects.

    View details for DOI 10.1161/CIRCULATIONAHA.105.607549

    View details for Web of Science ID 000241077600011

    View details for PubMedID 17015794

  • Variability and gender differences in memory T cell immunity to varicella-zoster virus in healthy adults VACCINE Klein, N. P., Holmes, T. H., Sharp, M. A., Heineman, T. C., Schleiss, M. R., Bernstein, D. I., Kemble, G., Arvin, A. M., Dekker, C. L. 2006; 24 (33-34): 5913-5918


    Latent varicella zoster virus (VZV) can reactivate and cause zoster, the prevention of which relies upon cellular immunity to VZV. To assess temporal variation of VZV cell-mediated immunity in healthy naturally immune adults, we evaluated VZV-specific responder cell frequencies (RCF) longitudinally over 1 year in each of 25 adults. VZV-specific CD4+ T cells were detected (p < 0.003) and showed minimal variability in RCF. Additional analysis of VZV T cell RCF revealed differences between genders, with only males (p < 0.005) having detectable VZV-specific memory CD4+ T cell responses by this method. Taken together, results suggest that further studies regarding immunization of younger adults and females with the modified, high-potency live attenuated VZV vaccine may be warranted.

    View details for DOI 10.1016/j.vaccine.2006.04.060

    View details for Web of Science ID 000239982300001

    View details for PubMedID 16759768

  • The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures. Journal of clinical sleep medicine Kushida, C. A., Nichols, D. A., Quan, S. F., Goodwin, J. L., White, D. P., Gottlieb, D. J., Walsh, J. K., Schweitzer, P. K., Guilleminault, C., Simon, R. D., Leary, E. B., Hyde, P. R., Holmes, T. H., Bloch, D. A., Green, S., McEvoy, L. K., Gevins, A., Dement, W. C. 2006; 2 (3): 288-300


    To assess the size, time course, and durability of the effects of long-term continuous positive airway pressure (CPAP) therapy on neurocognitive function, mood, sleepiness, and quality of life in patients with obstructive sleep apnea.Randomized, double-blinded, 2-arm, sham-controlled, multicenter, long-term, intention-to-treat trial of CPAP therapy.Sleep clinics and laboratories at 5 university medical centers and community-based hospitals. Patients or Participants: Target enrollment is 1100 randomly assigned subjects across 5 clinical centers.Active versus sham (subtherapeutic) CPAP. Measurements and Results: A battery of conventional and novel tests designed to evaluate neurocognitive function, mood, sleepiness, and quality of life.The Apnea Positive Pressure Long-term Efficacy Study (APPLES) is designed to study obstructive sleep apnea and test the effects of CPAP through a comprehensive, controlled, and long-term trial in a large sample of subjects with obstructive sleep apnea.

    View details for PubMedID 17561541

  • Cocaine Rapid Efficacy Screening Trials (CREST): lessons learned ADDICTION Kampman, K. M., Leiderman, D., Holmes, T., LoCastro, J., Bloch, D. A., Reid, M. S., Shoptaw, S., Montgomery, M. A., Winhusen, T. M., Somoza, E. C., Ciraulo, D. A., Elkashef, A., Vocci, F. 2005; 100: 102-110


    The Cocaine Rapid Efficacy Screening Trials (CREST) were designed by the National Institute on Drug Abuse Division of Treatment Research and Development (NIDA, DT R&D) to rapidly screen a number of medications potentially useful for the treatment of cocaine dependence.Each CREST trial was designed to compare several medications in a single trial against an unmatched placebo. The placebo group was included in each trial to avoid the nearly universal positive response to medications seen in open-label trials. In addition, a common set of procedures and outcome measures were employed throughout to increase comparability of results obtained from different trials and from different times.In all, 18 medications were screened in seven different trials, conducted in four different sites throughout the United States involving 398 cocaine-dependent patients.Three medications were found to be promising enough to include in subsequent larger trials. Common statistical procedures for evaluating medications were developed to facilitate comparisons across sites and across time. A portion of the data were pooled and analyzed, which yielded some useful insights into cocaine dependence and its treatment. Finally, a review of individual trials together with the pooled analysis revealed several potential improvements for future screening trials.Overall, the CREST trials proved to be useful for rapidly screening medications for treatment of cocaine dependence, but several modifications in design should be made before this framework is applied further.

    View details for Web of Science ID 000227729200010

    View details for PubMedID 15730354

  • Retrospective analyses of pooled data from CREST I and CREST II trials for treatment of cocaine dependence ADDICTION Elkashef, A., Holmes, T. H., Bloch, D. A., Shoptaw, S., Kampman, K., Reid, M. S., Somoza, E. R., Ciraulo, D., Rotrosen, J., Leiderman, D., Montgomery, A., Vocci, F. 2005; 100: 91-101


    To analyze pooled data from the Cocaine Rapid Evaluation Screening Trial (CREST). Pooling data from these small pilot trials into four major drug classes permitted data exploration for treatment and covariate effects with increased sample size.Small pilot trials were conducted to screen fifteen medications as prospective treatments for cocaine dependence. Studies included a flexible 2-week to 4-week screening/baseline period followed by an 8-week randomized treatment condition. Participants were randomized equally to one of up to three active medications or placebo.Five Medications Development Research Units at the five academic centers of University of Cincinnati, New York University, University of Pennsylvania, University of California Los Angeles and Boston University.The pooled data set consisted of 357 total subjects. Standardized inclusion and exclusion criteria were employed in subject selection to enhance consistency of cocaine-dependent study participants across all sites (see reports on individual trials in this supplement for details). All participants provided at least two urine samples that were positive for cocaine metabolite during a two-week period prior to being randomized.All subjects in these trials, those randomized to placebo and active medications, received active treatment in the form of evidence-based cognitive behavioral therapy.Quantitative urine benzoylecgonine (BE), self-report of cocaine use, and total Brief Substance Craving Scale (BSCS) scores were compared between each class of medication and its matched-placebo group.Regression analysis of pooled data did not identify any statistically significant differences between treatment and matched-placebo for any of the four classes. Exploration of the effects of baseline covariates indicated that gender and African American status were associated significantly with outcome. Female gender was consistently associated with poorer outcomes for medication and placebo groups, while the direction of association between African American status and outcome differed by treatment groups. Retention was also examined: dropout rates may have been somewhat higher for placebo than treatment groups during the early active-treatment period. Classification trees were used to identify characteristics of subjects who were abstinent for at least two weeks during the eight-week trial; only 4.0% of females while 17.9% of males achieved this criterion.Results presented here may prove useful for planning future clinical trials for therapies targeting cocaine dependence.

    View details for Web of Science ID 000227729200009

    View details for PubMedID 15730353

  • T cell-dependent production of IFN-gamma by NK cells in response to influenza A virus JOURNAL OF CLINICAL INVESTIGATION He, X. S., Draghi, M., Mahmood, K., Holmes, T. H., Kemble, G. W., Dekker, C. L., Arvin, A. M., Parham, P., Greenberg, H. B. 2004; 114 (12): 1812-1819


    The role of human NK cells in viral infections is poorly understood. We used a cytokine flow-cytometry assay to simultaneously investigate the IFN-gamma response of NK and T lymphocytes to influenza A virus (fluA). When PBMCs from fluA-immune adult donors were incubated with fluA, IFN-gamma was produced by both CD56(dim) and CD56(bright) subsets of NK cells, as well as by fluA-specific T cells. Purified NK cells did not produce IFN-gamma in response to fluA, while depletion of T lymphocytes reduced to background levels the fluA-induced IFN-gamma production by NK cells, which indicates that T cells are required for the IFN-gamma response of NK cells. The fluA-induced IFN-gamma production of NK cells was suppressed by anti-IL-2 Ab, while recombinant IL-2 replaced the helper function of T cells for IFN-gamma production by NK cells. This indicates that IL-2 produced by fluA-specific T cells is involved in the T cell-dependent IFN-gamma response of NK cells to fluA. Taken together, these results suggest that at an early stage of recurrent viral infection, NK-mediated innate immunity to the virus is enhanced by preexisting virus-specific T cells.

    View details for DOI 10.1172/JCI200422797

    View details for Web of Science ID 000225695800016

    View details for PubMedID 15599406

  • Selective developmental defects of cord blood antigen-presenting cell subsets HUMAN IMMUNOLOGY Drohan, L., Harding, J. J., Holm, B., Cordoba-Tongson, E., Dekker, C. L., Holmes, T., Maecker, H., Mellins, E. D. 2004; 65 (11): 1356-1369


    Defective antigen-presenting cell (APC) function has been hypothesized to contribute to increased infection susceptibility in newborns. We used multiparameter flow cytometry to characterize APC subsets in adult peripheral blood (APB) and cord blood (CB). APB had a higher proportion of CD11c+ dendritic cells (DC), whereas CB mainly contained CD123+ DC. APB was enriched in CD16+CD11c+ DC subset, whereas CD34+CD11c-CD123lo cells were prominent in CB. Lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production was dampened in myeloid DC and monocytes from CB, whereas IL-1alpha production was not different. The reduction in TNF-alpha response did not appear to result from reduced surface detection of LPS, because CD14, toll-like receptor (TLR)-4 and TLR-2 levels were not reduced in CB APC compared with APB cells. Also, there was no correlation between TLR-2 or TLR-4 levels and TNF-alpha production in myeloid DC and monocytes. CB monocytes had lower surface HLA-DR immediately ex vivo. Both APB and CB monocytes upregulated HLA-DR after incubation, but an additional LPS-induced increase in HLA-DR was suggested only in APB monocytes. APB monocytes also showed a greater LPS-induced increase in CD40 expression. Together, our data show significant, selective differences in circulating APC between neonates and adults.

    View details for DOI 10.1016/j.humimm.2004.09.011

    View details for Web of Science ID 000225728800010

    View details for PubMedID 15556686

  • Expression of chemokine receptors on intrahepatic and peripheral lymphocytes in chronic hepatitis C infection: Its relationship to liver inflammation JOURNAL OF INFECTIOUS DISEASES Wang, J. H., Holmes, T. H., Cheung, R., Greengberg, H. B., He, X. S. 2004; 190 (5): 989-997


    Intrahepatic lymphocytes are believed to be directly involved in the immunopathogenesis of chronic liver diseases. Little is known about the trafficking of lymphocytes into the liver and their role in chronic hepatitis C infection.The expression of 4 chemokine receptors and an activation marker on multiple lymphocyte subsets in paired liver biopsy and peripheral blood specimens from 23 patients with chronic hepatitis C infection were analyzed by a 6-color flow-cytometric assay.CCR5, CXCR3, and CXCR6 were expressed on intrahepatic CD4+ and CD8+ T cells, natural killer (NK) T cells, NK cells, and B cells at significantly higher frequencies than on peripheral lymphocyte subsets. The expression of these receptors and the activation marker CD38 tended to increase with the severity of liver inflammation. This increase was significant for several intrahepatic lymphocytes subsets. Correlations in expression differed among pairs of these extralymphoid homing receptors on the intrahepatic T cells.The homing program for intrahepatic lymphocytes involves multiple extralymphoid chemokine receptors that are regulated by >1 pathway. The expression of homing receptors on intrahepatic lymphocytes is associated with the immunopathogenesis of chronic hepatitis C disease. These preliminary results indicate that confirmational studies with larger sample sizes are warranted.

    View details for Web of Science ID 000223114800018

    View details for PubMedID 15295707

  • Antiviral CD8 T cells in the control of primary human cytomegalovirus infection in early childhood JOURNAL OF INFECTIOUS DISEASES Chen, S. F., Tu, W. W., Sharp, M. A., Tongson, E. C., He, X. S., Greenberg, H. B., Holmes, T. H., Wang, Z. T., Kemble, G., Manganello, A. M., Adler, S. P., Dekker, C. L., Levvis, D. B., Arvin, A. M. 2004; 189 (9): 1619-1627


    Human cytomegalovirus (CMV) establishes persistent infection, with control of replication thought to be mediated by CMV-specific CD8 T cells. Primary CMV infection commonly affects young children and causes prolonged viral shedding in saliva and urine. We investigated whether this virus-host interaction pattern reflects a developmental deficiency of antiviral CD8 T cell-mediated immunity during childhood. CMV-specific CD8 T cell responses in asymptomatic children with active infection were not different from adults with recent or long-term infection in frequency and functional analyses. High urine CMV concentrations were detected, despite these CMV-specific CD8 T cell responses. We conclude that delayed resolution of primary CMV infection in young children is not caused by a deficient CMV-specific CD8 T cell response. Because these healthy children continue to have local CMV replication, we suggest that CD8 T cells may function primarily to prevent symptomatic, disseminated disease.

    View details for Web of Science ID 000220951300010

    View details for PubMedID 15116298

  • Ten categories of statistical errors: a guide for research in endocrinology and metabolism AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM Holmes, T. H. 2004; 286 (4): E495-E501


    A simple framework is introduced that defines ten categories of statistical errors on the basis of type of error, bias or imprecision, and source: sampling, measurement, estimation, hypothesis testing, and reporting. Each of these ten categories is illustrated with examples pertinent to research and publication in the disciplines of endocrinology and metabolism. Some suggested remedies are discussed, where appropriate. A review of recent issues of American Journal of Physiology: Endocrinology and Metabolism and of Endocrinology finds that very small sample sizes may be the most prevalent cause of statistical error in this literature.

    View details for DOI 10.1152/ajpendo.00484.2003

    View details for Web of Science ID 000220095300001

    View details for PubMedID 15010353

  • Cord blood antigen presenting cells show selective deficits in inflammatory responses Drohan, L., Holm, B., Holmes, T., Tongson, E. C., Dekker, C., Maecker, H., Mellins, E. NATURE PUBLISHING GROUP. 2004: 390A-390A
  • Persistent and selective deficiency of CD4(+) T cell immunity to cytomegalovirus in immunocompetent young children JOURNAL OF IMMUNOLOGY Tu, W. W., Chen, S., Sharp, M., Dekker, C., Manganello, A. M., Tongson, E. C., Maecker, H. T., Holmes, T. H., Wang, Z. T., Kemble, G., Adler, S., Arvin, A., Lewis, D. B. 2004; 172 (5): 3260-3267


    Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4(+) T cells that produced IFN-gamma than did adults. These differences in CD4(+) T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-gamma production by CD8(+) T cells. The IFN-gamma-producing CD4(+) T cells of children or adults that were reactive with CMV Ags were mainly the CCR7(low) cell subset of memory (CD45R0(high)CD45RA(low)) cells. The decreased IFN-gamma response to CMV in children was selective, because their CCR7(low) memory CD4(+) T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4(+) T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4(+) T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4(+) T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.

    View details for Web of Science ID 000189186000069

    View details for PubMedID 14978134

  • Composite spirometric-computed tomography outcome measure in early cystic fibrosis lung disease AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Robinson, T. E., Leung, A. N., Northway, W. H., Blankenberg, F. G., Chan, F. P., Bloch, D. A., Holmes, T. H., Moss, R. B. 2003; 168 (5): 588-593


    With the advent of therapies aimed at young patients with cystic fibrosis, who have mildly reduced pulmonary function, the need for improved outcome measures that discriminate treatment effects has become important. Pulmonary function measurements or chest high-resolution computed tomography (HRCT) scores have been separately used to assess interventions. We evaluated these modalities separately and together during a treatment study to develop a more sensitive outcome measure. In a 1-year trial, 25 children randomized either to daily Pulmozyme or to normal saline aerosol were evaluated at randomization and at 3 and 12 months. Outcome variables were pulmonary function test (PFT) results, a global HRCT score, and a composite score incorporating PFTs and HRCT scoring. Regression analyses with generalized estimating equations permitted estimation of the difference in treatment effect between groups over time for each outcome. The largest difference in treatment effects observed at 12 months, measured by the percentage change from baseline, were with the composite total and maximal CT/PFT scores (35.4 and 30.4%), compared with mean forced expiratory flow during the middle half of the FVC (FEF25-75%) (13.0%) and total and maximal global HRCT scores (6.2%, 7.2%). The composite total and maximal CT/PFT scores were the most sensitive outcome measures for discriminating a treatment effect in children with cystic fibrosis with normal or mildly reduced pulmonary function during a 1-year trial of Pulmozyme.

    View details for DOI 10.1164/rccm.200209-1093OC

    View details for Web of Science ID 000185039000015

    View details for PubMedID 12746252

  • Deficient cytomegalovirus-specific Th1 responses in young children with urine virus shedding Tu, W. W., Chen, S. R., Sharp, M., Dekker, C., Manganello, A. M., Maecker, H., Holmes, T. H., Kemble, G., Adler, S., Arvin, A., Lewis, D. B. FEDERATION AMER SOC EXP BIOL. 2003: C301-C301
  • Analysis of the frequencies and of the memory T cell phenotypes of human CD8(+) T cells specific for influenza A viruses JOURNAL OF INFECTIOUS DISEASES He, X. S., Mahmood, K., Maecker, H. T., Holmes, T. H., Kemble, G. W., Arvin, A. M., Greenberg, H. B. 2003; 187 (7): 1075-1084


    We characterized the human CD8+ T cell response against influenza A viruses by a flow cytometry-based assay. Peripheral blood mononuclear cells (PBMCs) were incubated with inactivated influenza virus preparation, for 17 h, and were stained for intracellular interferon-gamma. Major histocompatibility complex class I-restricted memory CD8+ T cells specific for influenza antigens were detected in PBMCs from all 19 adult donors, at an average frequency of 0.39%. On average, 83% of influenza virus-specific CD8+ T cells expressed the differentiation-associated marker CD27, a percentage that is significantly higher than that of CD8+ T cells specific for pp65 of human cytomegalovirus (53%). These observations indicate that class I-restricted immunity against influenza A viruses is characterized by the persistence, after clearance of infection, of circulating antigen-specific CD8+ T cells. The different patterns of CD27 expression in influenza virus- and cytomegalovirus-specific CD8+ T cells suggest that influenza virus-specific memory and effector CD8+ T cells can be differentiated by phenotypic analysis.

    View details for Web of Science ID 000181713000007

    View details for PubMedID 12660922

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