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1.  Modeling the interaction between danoprevir and mericitabine in the treatment of chronic HCV infection 
Antiviral therapy  2015;21(4):297-306.
Modeling HCV RNA decline kinetics under therapy has proven useful for characterizing treatment effectiveness. Here we model HCV viral kinetics (VK) in 72 patients given a combination of danoprevir, a protease inhibitor and mericitabine, a nucleoside polymerase inhibitor for 14 days in the INFORM-1 trial. A biphasic VK model with time-varying danoprevir and mericitabine effectiveness and Bliss independence for characterizing the interaction between both drugs provided the best fit to the VK data. The average final antiviral effectiveness of the drug combination varied between 0.998 for 100 mg tid of danoprevir and 500 mg bid of mericitabine and 0.9998 for 600 mg bid of danoprevir and 1000 mg bid of mericitabine. Using the individual parameters estimated from the VK data collected over 2 weeks, we were not able to reproduce the low SVR rates obtained in more recent study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir for 24 weeks. This suggests that drug-resistant viruses emerge after 2 weeks of treatment and that longer studies are necessary to provide accurate predictions of longer treatment outcomes.
PMCID: PMC4862948  PMID: 26555159
2.  Psychological and social resources relate to biomarkers of allostasis in newly admitted nursing home residents 
Aging & mental health  2015;20(1):88-99.
This paper presents preliminary baseline data from a prospective study of nursing home adaptation that attempts to capture the complexity of residents’ adaptive resources by examining psychological, social, and biological variables from a longitudinal conceptual framework. Our emphasis was on validating an index of allostasis.
In a sample of 26 long-term care patients, we measured 6 hormone and protein biomarkers to capture the concept of allostasis as an index of physiological resilience, related to other baseline resources, including frailty, hope and optimism, social support, and mental health history, collected via interview with the resident and collaterals. We also examined the performance of self-report measures reflecting psychosocial and well-being constructs, given the prevalence of cognitive impairment in nursing homes.
Our results supported both the psychometric stability of our self-report measures, and the preliminary validity of our index of allostasis. Each biomarker was associated with at least one other resilience resource, suggesting that our choice of biomarkers was appropriate. As a group, the biomarkers showed good correspondence with the majority of other resource variables, and our standardized summation score was also associated with physical, social, and psychological resilience resources, including those reflecting physical and mental health vulnerability as well as positive resources of social support, optimism, and hope.
Although these results are based on a small sample, the effect sizes were large enough to confer some confidence in the value of pursuing further research relating biomarkers of allostasis to psychological and physical resources and well-being.
PMCID: PMC4628586  PMID: 26237175
nursing homes; allostasis; biomarkers; well-being; resilience
3.  Clergy Views on a Good Versus a Poor Death: Ministry to the Terminally Ill 
Journal of Palliative Medicine  2015;18(12):1000-1007.
Background: Clergy are often important sources of guidance for patients and family members making medical decisions at the end-of-life (EOL). Previous research revealed spiritual support by religious communities led to more aggressive care at the EOL, particularly among minority patients. Understanding this phenomenon is important to help address disparities in EOL care.
Objective: The study objective was to explore and describe clergy perspectives regarding “good” versus “poor” death within the participant's spiritual tradition.
Methods: This was a qualitative, descriptive study. Community clergy from various spiritual backgrounds, geographical locations within the United States, and races/ethnicities were recruited. Participants included 35 clergy who participated in one-on-one interviews (N = 14) and two focus groups (N = 21). Semistructured interviews explored clergy viewpoints on factors related to a “good death.” Principles of grounded theory were used to identify a final set of themes and subthemes.
Results: A good death was characterized by wholeness and certainty and emphasized being in relationship with God. Conversely, a “poor death” was characterized by separation, doubt, and isolation. Clergy identified four primary determinants of good versus poor death: dignity, preparedness, physical suffering, and community. Participants expressed appreciation for contextual factors that affect the death experience; some described a “middle death,” or one that integrates both positive and negative elements. Location of death was not viewed as a significant contributing factor.
Conclusions: Understanding clergy perspectives regarding quality of death can provide important insights to help improve EOL care, particularly for patients highly engaged with faith communities. These findings can inform initiatives to foster productive relationships between clergy, clinicians, and congregants and reduce health disparities.
PMCID: PMC4842946  PMID: 26317801
4.  The latent structure of Acute Stress Disorder symptoms in trauma‐exposed children and adolescents 
The revision of Acute Stress Disorder (ASD) in the DSM‐5 (DSM‐5, 2013) proposes a cluster‐free model of ASD symptoms in both adults and youth. Published evaluations of competing models of ASD clustering in youth have rarely been examined.
We used Confirmatory Factor Analysis (combined with multigroup invariance tests) to explore the latent structure of ASD symptoms in a trauma‐exposed sample of children and young people (N = 594). The DSM‐5 structure was compared with the previous DSM‐IV conceptualization (4‐factor), and two alternative models proposed in the literature (3‐factor; 5‐factor). Model fit was examined using goodness‐of‐fit indices. We also established DSM‐5 ASD prevalence rates relative to DSM‐IV ASD, and the ability of these models to classify children impaired by their symptoms.
Based on both the Bayesian Information Criterion, the interfactor correlations and invariance testing, the 3‐factor model best accounted for the profile of ASD symptoms. DSM‐5 ASD led to slightly higher prevalence rates than DSM‐IV ASD and performed similarly to DSM‐IV with respect to categorising children impaired by their symptoms. Modifying the DSM‐5 ASD algorithm to a 3+ or 4+ symptom requirement was the strongest predictor of impairment.
These findings suggest that a uni‐factorial general‐distress model is not the optimal model of capturing the latent structure of ASD symptom profiles in youth and that modifying the current DSM‐5 9+ symptom algorithm could potentially lead to a more developmentally sensitive conceptualization.
PMCID: PMC5091623  PMID: 27472990
Acute Stress Disorder; DSM‐5; factor analysis; children; post‐traumatic stress disorder
5.  Lifestyle Modification for Resistant Hypertension: The TRIUMPH Randomized Clinical Trial 
American heart journal  2015;170(5):986-994.e5.
Resistant hypertension (RH) is a growing health burden in this country affecting as many as one in five adults being treated for hypertension. RH is associated with increased risk of adverse cardiovascular disease (CVD) events and all-cause mortality. Strategies to reduce blood pressure in this high risk population are a national priority.
TRIUMPH is a single site, prospective, randomized clinical trial (RCT) to evaluate the efficacy of a center-based lifestyle intervention consisting of exercise training, reduced sodium and calorie DASH eating plan, and weight management compared to standardized education and physician advice in treating patients with RH. Patients (N=150) will be randomized in a 2:1 ratio to receive either a 4-month supervised lifestyle intervention delivered in the setting of a cardiac rehabilitation center or to a standardized behavioral counseling session to simulate real-world medical practice. The primary end point is clinic blood pressure; secondary endpoints include ambulatory blood pressure and an array of CVD biomarkers including left ventricular hypertrophy, arterial stiffness, baroreceptor reflex sensitivity, insulin resistance, lipids, sympathetic nervous system activity, and inflammatory markers. Lifestyle habits, blood pressure and CVD risk factors also will be measured at one year follow-up.
The TRIUMPH randomized clinical trial ( NCT02342808) is designed to test the efficacy of an intensive, center-based lifestyle intervention compared to a standardized education and physician advice counseling session on blood presssure and CVD biomarkers in patients with RH after 4 months of treatment, and will determine whether lifestyle changes can be maintained for a year.
PMCID: PMC4636732  PMID: 26542509
Resistant hypertension; DASH diet; exercise; obesity; cardiac rehabilitation
7.  Exercise as Treatment for Anxiety: Systematic Review and Analysis 
Exercise has been shown to reduce symptoms of anxiety, but few studies have studied exercise in individuals pre-selected because of their high anxiety.
To review and critically evaluate studies of exercise training in adults with either high levels of anxiety or an anxiety disorder.
We conducted a systematic review of randomized clinical trials (RCTs) in which anxious adults were randomized to an exercise or non-exercise control condition. Data were extracted concerning anxiety outcomes and study design. Existing meta-analyses were also reviewed.
Evidence from 12 RCTs suggested benefits of exercise, for select groups, similar to established treatments and greater than placebo. However, most studies had significant methodological limitations, including small sample sizes, concurrent therapies, and inadequate assessment of adherence and fitness levels.
Exercise may be a useful treatment for anxiety, but lack of data from rigorous, methodologically sound RCTs precludes any definitive conclusions about its effectiveness.
PMCID: PMC4498975  PMID: 25697132
Exercise; Physical activity; Anxiety; Anxiety disorders; Systematic review
8.  Minor genomic differences between related B6 and B10 mice affect severity of schistosome infection by governing the mode of dendritic cell activation 
European journal of immunology  2015;45(8):2312-2323.
Infection with the helminth Schistosoma mansoni results in hepato-intestinal granulomatous inflammation mediated by CD4 T cells directed against parasite eggs. The severity of disease varies greatly in humans and mice; however, the genetic basis of such a heterogenous immune response remains poorly understood. Here we show that, despite their close genetic relationship, C57BL/10SnJ (B10) mice developed significantly more pronounced immunopathology and higher Th17-cell responses than C57BL/6J (B6) mice. Similarly, live egg-stimulated B10-derived dendritic cells (DCs) produced significantly more IL-1β and IL-23, resulting in higher IL-17 production by CD4 T cells. Gene expression analysis disclosed a heightened proinflammatory cytokine profile together with a strikingly low expression of Ym1 in B10 vs. B6 mice, consistent with failure of B10 DCs to attain alternative activation. To genetically dissect the differential response, we developed and analyzed congenic mouse strains that capture major regions of allelic variation, and found that the level of inflammation was controlled by a relatively small number of genes in a locus mapping to chromosome 4 117-143 MB. Our study has thus identified novel genomic regions that regulate the severity of the schistosome infection by way of controlling the mode of DC activation and consequent CD4 T-cell subset development.
PMCID: PMC4597890  PMID: 25959828
Dendritic cell activation; Host/pathogen interactions; B6/B10 mice; Genetics; Th17; Schistosoma mansoni
9.  Open source approaches to establishing Roseobacter clade bacteria as synthetic biology chassis for biogeoengineering 
PeerJ  2016;4:e2031.
Aim. The nascent field of bio-geoengineering stands to benefit from synthetic biologists’ efforts to standardise, and in so doing democratise, biomolecular research methods. Roseobacter clade bacteria comprise 15–20% of oceanic bacterio-plankton communities, making them a prime candidate for establishment of synthetic biology chassis for bio-geoengineering activities such as bioremediation of oceanic waste plastic. Developments such as the increasing affordability of DNA synthesis and laboratory automation continue to foster the establishment of a global ‘do-it-yourself’ research community alongside the more traditional arenas of academe and industry. As a collaborative group of citizen, student and professional scientists we sought to test the following hypotheses: (i) that an incubator capable of cultivating bacterial cells can be constructed entirely from non-laboratory items, (ii) that marine bacteria from the Roseobacter clade can be established as a genetically tractable synthetic biology chassis using plasmids conforming to the BioBrickTM standard and finally, (iii) that identifying and subcloning genes from a Roseobacter clade species can readily by achieved by citizen scientists using open source cloning and bioinformatic tools.
Method. We cultivated three Roseobacter species, Roseobacter denitrificans, Oceanobulbus indolifexand Dinoroseobacter shibae. For each species we measured chloramphenicol sensitivity, viability over 11 weeks of glycerol-based cryopreservation and tested the effectiveness of a series of electroporation and heat shock protocols for transformation using a variety of plasmid types. We also attempted construction of an incubator-shaker device using only publicly available components. Finally, a subgroup comprising citizen scientists designed and attempted a procedure for isolating the cold resistance anf1 gene from Oceanobulbus indolifexcells and subcloning it into a BioBrickTM formatted plasmid.
Results. All species were stable over 11 weeks of glycerol cryopreservation, sensitive to 17 µg/mL chloramphenicol and resistant to transformation using the conditions and plasmids tested. An incubator-shaker device, ‘UCLHack-12’ was assembled and used to cultivate sufficient quantity of Oceanobulbus indolifexcells to enable isolation of the anf1 gene and its subcloning into a plasmid to generate the BioBrickTM BBa_K729016.
Conclusion.The process of ‘de-skilling’ biomolecular techniques, particularly for relatively under-investigated organisms, is still on-going. However, our successful cell growth and DNA manipulation experiments serve to indicate the types of capabilities that are now available to citizen scientists. Science democratised in this way can make a positive contribution to the debate around the use of bio-geoengineering to address oceanic pollution or climate change.
PMCID: PMC4941783  PMID: 27441104
Synthetic biology; Biogeoengineering; Open source; Molecular biology; Marine biology; Bioremediation; DIYbio
10.  Development and psychometric properties of the Pulmonary-specific Quality-of-Life Scale in lung transplant patients 
The Pulmonary-specific Quality-of-Life Scale (PQLS) was developed to measure quality of life (QoL) among patients awaiting lung transplant. The objective of this study was to determine the psychometric properties of the PQLS, identify empirically derived sub-scales, and examine ability to detect changes in pulmonary-specific QoL scores after lung transplantation.
Data were derived from the INSPIRE trial, a dual-site randomized controlled trial of coping skills training in 389 lung transplant candidates (obstructive [48.3%], restrictive [24.2%], cystic fibrosis [13.6%], and other [13.9%]). Cronbach alpha was calculated to assess the internal reliability of the PQLS (n = 388). Test-retest reliability was assessed with correlation coefficients between baseline and 12-week post-baseline scores for the usual care control condition (n = 140). Convergent validity was assessed with correlation coefficients between the PQLS and established measures of QoL and emotional distress, 6-minute walk test distance, forced expiratory volume in 1 second, and use of supplemental oxygen at rest (n = 388). Change from baseline to 6 months post-transplantation was assessed with repeated measures analysis of variance (n = 133).
The PQLS was internally reliable and stable across 12 weeks. The PQLS correlated strongly with QoL measures (e.g., Shortness of Breath Questionnaire, r = 0.78, p < 0.0001), moderately with mood and anxiety (e.g., Beck Depression Inventory-II, r = 0.59, p < 0.0001), and modestly with lung disease severity (e.g., 6-minute walk test, r = −0.41, p < 0.0001). PQLS scores improved by nearly 2 SDs after transplant.
These results demonstrated the reliability, validity, and sensitivity to change of the PQLS for measuring pulmonary QoL among patients with advanced lung disease and the responsiveness of the PQLS to changes in QoL after lung transplantation.
PMCID: PMC4784246  PMID: 25980570
lung transplant; quality of life; cystic fibrosis; pulmonary fibrosis; COPD
11.  Six-Minute-Walk Distance and Accelerometry Predict Outcomes in Chronic Obstructive Pulmonary Disease Independent of Global Initiative for Chronic Obstructive Lung Disease 2011 Group 
Rationale: The 2011 combined Global Initiative for Chronic Obstructive Lung Disease (GOLD) assessment incorporates symptoms, exacerbation history, and spirometry in discriminating risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Six-minute-walk distance (6MWD) and accelerometry also have been used to assess disease severity in COPD. The association between these measures and the risks of hospitalization and mortality in the context of GOLD 2011 is unknown.
Objectives: To describe changes in exercise tolerance and physical activity over time in patients with COPD and to test the hypothesis that lower baseline 6MWD or accelerometry step count is associated with increased risk of COPD-related hospitalization or all-cause mortality, independent of GOLD 2011 group.
Methods: Physical function and medical outcomes were prospectively assessed in 326 patients with moderate to severe COPD in INSPIRE-II, a randomized controlled trial of a coping skills training intervention. Cox models were used to determine if GOLD 2011 group, 6MWD, or accelerometry steps were associated with risk of COPD-related hospitalization or all-cause mortality.
Measurements and Main Results: Physical function declined over time in GOLD group D but remained stable in groups A, B, and C. GOLD classification was associated with time to death or first COPD-related hospitalization. Baseline 6MWD was more strongly associated with time to death or first COPD-related hospitalization (hazard ratio, 0.50 [95% confidence interval, 0.34, 0.73] per 150 m, P = 0.0003) than GOLD 2011 classification. A similar relationship was observed for accelerometry steps (hazard ratio, 0.80 [95% confidence interval, 0.70, 0.92] per 1,000 steps, P = 0.002).
Conclusions: Exercise tolerance and daily physical activity are important predictors of hospitalization and mortality in COPD, independent of GOLD 2011 classification. Physical function may represent a modifiable risk factor that warrants increased attention as a target for interventions to improve clinically meaningful outcomes in COPD.
PMCID: PMC4418313  PMID: 25568929
exercise; chronic obstructive pulmonary disease; accelerometry; mortality; hospitalization
12.  A Drug-Disease Model Describing the Effect of Oseltamivir Neuraminidase Inhibition on Influenza Virus Progression 
A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate β, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate δ, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (β) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation.
PMCID: PMC4538552  PMID: 26100715
13.  Safety and Upper Respiratory Pharmacokinetics of the Hemagglutinin Stalk-Binding Antibody VIS410 Support Treatment and Prophylaxis Based on Population Modeling of Seasonal Influenza A Outbreaks 
EBioMedicine  2016;5:147-155.
Seasonal influenza is a major public health concern in vulnerable populations. Here we investigated the safety, tolerability, and pharmacokinetics of a broadly neutralizing monoclonal antibody (VIS410) against Influenza A in a Phase 1 clinical trial. Based on these results and preclinical data, we implemented a mathematical modeling approach to investigate whether VIS410 could be used prophylactically to lessen the burden of a seasonal influenza epidemic and to protect at-risk groups from associated complications.
Using a single-ascending dose study (n = 41) at dose levels from 2 mg/kg–50 mg/kg we evaluated the safety as well as the serum and upper respiratory pharmacokinetics of a broadly-neutralizing antibody (VIS410) against influenza A ( identifier NCT02045472). Our primary endpoints were safety and tolerability of VIS410 compared to placebo. We developed an epidemic microsimulation model testing the ability of VIS410 to mitigate attack rates and severe disease in at risk-populations.
VIS410 was found to be generally safe and well-tolerated at all dose levels, from 2–50 mg/kg. Overall, 27 of 41 subjects (65.9%) reported a total of 67 treatment emergent adverse events (TEAEs). TEAEs were reported by 20 of 30 subjects (66.7%) who received VIS410 and by 7 of 11 subjects (63.6%) who received placebo. 14 of 16 TEAEs related to study drug were considered mild (Grade 1) and 2 were moderate (Grade 2). Two subjects (1 subject who received 30 mg/kg VIS410 and 1 subject who received placebo) experienced serious AEs (Grade 3 or 4 TEAEs) that were not related to study drug. VIS410 exposure was approximately dose-proportional with a mean half-life of 12.9 days. Mean VIS410 Cmax levels in the upper respiratory tract were 20.0 and 25.3 μg/ml at the 30 mg/kg and 50 mg/kg doses, respectively, with corresponding serum Cmax levels of 980.5 and 1316 μg/mL. Using these pharmacokinetic data, a microsimulation model showed that median attack rate reductions ranged from 8.6% (interquartile range (IQR): 4.7%–11.0%) for 2% coverage to 22.6% (IQR: 12.7–30.0%) for 6% coverage. The overall benefits to the elderly, a vulnerable subgroup, are largest when VIS410 is distributed exclusively to elderly individuals, resulting in reductions in hospitalization rates between 11.4% (IQR: 8.2%–13.3%) for 2% coverage and 30.9% (IQR: 24.8%–35.1%) for 6% coverage among those more than 65 years of age.
VIS410 was generally safe and well tolerated and had good relative exposure in both serum and upper respiratory tract, supporting its use as either a single-dose therapeutic or prophylactic for influenza A. Including VIS410 prophylaxis among the public health interventions for seasonal influenza has the potential to lower attack rates and substantially reduce hospitalizations in individuals over the age of 65.
Visterra, Inc.
•VIS410, a broadly neutralizing monoclonal antibody, neutralizes seasonal strains of influenza A.•VIS410 was found to be safe and well tolerated in a phase 1 clinical study.•VIS410 drug levels in the upper respiratory tract support treatment and prophylaxis of influenza A.•Epidemic modeling of VIS410 as a prophylactic therapy demonstrated substantial reduction of hospitalizations.
Influenza infection results in significant morbidity and mortality especially in high risk groups such as the elderly. VIS410 is a broadly neutralizing antibody engineered to bind the influenza A virus. VIS410 was shown to be safe and well tolerated in a phase 1 clinical trial in healthy adult volunteers. Measurements of drug levels of VIS410 in the upper respiratory tract demonstrated that protective levels were achieved at the site of infection. Epidemic modeling indicate that for an antibody such as VIS410 prophylactic administration to 4–6% of the population would be sufficient to substantially suppress hospitalizations related to severe influenza.
PMCID: PMC4816807  PMID: 27077121
Influenza; Monoclonal antibody; Epidemic modeling; Prophylaxis
14.  Communication between office‐based primary care providers and nurses working within patients' homes: an analysis of process data from CAPABLE  
Journal of Clinical Nursing  2016;25(3-4):454-462.
Aims and Objectives
To examine themes of communication between office‐based primary care providers and nurses working in private residences; to assess which methods of communication elicit fruitful responses to nurses’ concerns.
Lack of effective communication between home health care nurses and primary care providers contributes to clinical errors, inefficient care delivery and decreased patient safety. Few studies have described best practices related to frequency, methods and reasons for communication between community‐based nurses and primary care providers.
Secondary analysis of process data from ‘Community Aging in Place: Advancing Better Living for Elders (CAPABLE)’.
Independent reviewers analysed nurse documentation of communication (phone calls, letters and client coaching) initiated for 70 patients and analysed 45 letters to primary care providers to identify common concerns and recommendations raised by CAPABLE nurses.
Primary care providers responded to 86% of phone calls, 56% of letters and 50% of client coaching efforts. Primary care providers addressed 86% of concerns communicated by phone, 34% of concerns communicated by letter and 41% of client‐raised concerns. Nurses’ letters addressed five key concerns: medication safety, pain, change in activities of daily living, fall safety and mental health. In letters, CAPABLE nurses recommended 58 interventions: medication change; referral to a specialist; patient education; and further diagnostic evaluation.
Effective communication between home‐based nurses and primary care providers enhances care coordination and improves outcomes for home‐dwelling elders. Various methods of contact show promise for addressing specific communication needs.
Relevance to clinical practice
Nurses practicing within patients’ homes can improve care coordination by using phone calls to address minor matters and written letters for detailed communication. Future research should explore implementation of Situation, Background, Assessment and Recommendation in home care to promote safe and efficient communication. Nurses should empower patients to address concerns directly with providers through use of devices including health passports.
PMCID: PMC4738578  PMID: 26818370
communication; elders; home health; nursing; primary care
15.  Non-replication of the association between 5HTTLPR and response to psychological therapy for child anxiety disorders 
The British Journal of Psychiatry  2016;208(2):182-188.
We previously reported an association between 5HTTLPR genotype and outcome following cognitive–behavioural therapy (CBT) in child anxiety (Cohort 1). Children homozygous for the low-expression short-allele showed more positive outcomes. Other similar studies have produced mixed results, with most reporting no association between genotype and CBT outcome.
To replicate the association between 5HTTLPR and CBT outcome in child anxiety from the Genes for Treatment study (GxT Cohort 2, n = 829).
Logistic and linear mixed effects models were used to examine the relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both cohorts were performed.
There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2. Mega-analyses identified a significant association between 5HTTLPR and remission from all anxiety disorders at follow-up (odds ratio 0.45, P = 0.014), but not primary anxiety disorder outcomes.
The association between 5HTTLPR genotype and CBT outcome did not replicate. Short-allele homozygotes showed more positive treatment outcomes, but with small, non-significant effects. Future studies would benefit from utilising whole genome approaches and large, homogenous samples.
PMCID: PMC4837384  PMID: 26294368
16.  A pharmacokinetic/viral kinetic model to evaluate the treatment effectiveness of danoprevir against chronic HCV 
Antiviral therapy  2014;20(5):469-477.
Viral kinetic models have proven useful to characterize treatment effectiveness during HCV therapy with interferon (IFN) or with direct acting antivirals (DAAs).
We use a pharmacokinetic/viral kinetic (PK/VK) model to describe HCV RNA kinetics during treatment with danoprevir, a protease inhibitor. In a phase 1 study, danoprevir monotherapy was administered for 14 days in ascending doses ranging from 200 to 600 mg per day to 40 patients of whom 32 were treatment-naïve and 8 were non-responders to prior PEG-IFN-α/ribavirin treatment.
In most patients, a biphasic decline of HCV RNA during therapy was observed. A two-compartment PK model and a VK model that considered treatment effectiveness to vary with the predicted danoprevir concentration inside the second compartment provided a good fit to the viral load data. A time-varying effectiveness model was also used to fit the viral load data. The antiviral effectiveness increased in a dose-dependent manner, with a 14-day time-averaged effectiveness of 0.95 at the lowest dose (100 mg bid) and 0.99 at the highest dose (200 mg tid). Prior IFN non-responders exhibited a 14-day time-averaged effectiveness of 0.98 (300 mg bid). The second phase decline showed two different behaviors, with 30% of patients exhibiting a rapid decline of HCV RNA, comparable to that seen with other protease inhibitors (>0.3 d−1), whereas the viral decline was slower in the other patients.
Our results are consistent with the modest SVR rates from the INFORM-SVR study where patients were treated with a combination of mericitabine and ritonavir-boosted danoprevir.
PMCID: PMC4400215  PMID: 25321394
17.  Neurocognitive Changes after Lung Transplantation 
Rationale: Neurocognitive impairments are associated with reduced quality of life and may adversely affect medical compliance, but their prevalence after lung transplantation has not been extensively studied.
Objectives: To examine the frequency of neurocognitive impairment after lung transplantation and to examine perioperative factors affecting post-transplant neurocognitive function.
Measurements and Main Results: We performed serial assessments of neurocognitive function in a consecutive series of 47 subjects who received transplants between March 2013 and November 2013 (45% women; mean age, 53.5 ± 17.2 yr). Neurocognitive function was assessed using a composite measure including the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score and Trail Making Test parts A and B obtained before transplant, at hospital discharge, and 3 months after discharge. The presence of neurocognitive impairment was assessed using the Montreal Cognitive Assessment Battery (MoCA), and in-hospital delirium was assessed using the Confusion Assessment Method. Results demonstrated that neurocognitive performance initially worsened among non–cystic fibrosis patients and improved over follow-up (P = 0.002). Time effects were strongest on Trail Making Test part B (P < 0.001) and the RBANS (P = 0.054). Participants who exhibited delirium during their hospitalization showed poorer performance during follow-up assessments (P = 0.006). Examination of cognitive impairment rates demonstrated that 21 participants (45%) exhibited neurocognitive impairment (MoCA < 26) before lung transplant, whereas 27 (57%) participants exhibited impairment after transplantation, and 19 (57%) participants continued to neurocognitive impairment during a 3-month follow-up.
Conclusions: Neurocognitive impairments are prevalent among lung transplant candidates and appear to worsen in some patients after transplant. Delirium during hospitalization is associated with worse neurocognitive function after transplant among patients without cystic fibrosis.
PMCID: PMC4298983  PMID: 25375275
lung transplantation; neurocognitive performance; delirium
18.  Does a Syrinx Matter for Return to Play in Contact Sports? A Case Report and Evidence-Based Review of Return-to-Play Criteria After Transient Quadriplegia 
Sports Health  2014;6(5):440-445.
Transient quadriplegia is a rare injury that can change the course of an athlete’s career if misdiagnosed or managed inappropriately. The clinician should be well versed in the return-to-play criteria for this type of injury. Unfortunately, when an unknown preexisting syrinx is present in the athlete, there is less guidance on their ability to return to play. This case report and review of the current literature illustrates a National Collegiate Athletic Association (NCAA) Division I football player who suffered a transient quadriplegic event during a kickoff return that subsequently was found to have an incidental cervical syrinx on magnetic resonance imaging. The player was able to have a full neurologic recovery, but ultimately he was withheld from football.
PMCID: PMC4137682  PMID: 25177422
transient quadriplegia; syrinx; return to play
19.  Understanding the effect of the HCV polymerase inhibitor mericitabine on early viral kinetics in the phase 2 JUMP-C and PROPEL studies 
The aim was to evaluate early viral kinetics in patients receiving mericitabine [hepatitis C virus (HCV) nucleoside polymerase inhibitor] with peginterferon alfa-2a (40KD) and ribavirin in two clinical trials (PROPEL and JUMP-C).
We examined rapid virological responses (RVRs; week 4 HCV RNA <15 IU ml−1) and complete early virological responses (cEVR; week 12 HCV RNA <15 IU ml−1) in HCV genotype 1/4-infected patients receiving mericitabine (500 or 1000 mg) or placebo twice daily plus peginterferon alfa-2a and ribavirin.
Among IL28B rs12979860 CC genotype patients receiving 500 or 1000 mg mericitabine or placebo, respectively, RVR rates were 64.3% (95% confidence interval: 38.8–83.7%), 95.1% (83.9–98.7%) and 33.3% (20.2–49.7%), and cEVR rates were 100% (78.5–100%), 100% (91.4–100%) and 80.6% (65.0–90.3%). Among non-CC genotype patients, RVR rates were 26.5% (14.6–43.1%), 52.3% (43.0–61.3%) and 5.7% (2.2–13.8%), and cEVR rates were 76.5% (60.0–87.6%), 84.6% (76.6–90.1%) and 28.6% (19.3–40.1%), respectively. In multiple regression analysis, IL28B genotype (P < 0.0001), mericitabine dose (P < 0.0001) and bodyweight (P = 0.0009) were associated with first-phase (α) slope (change in log10 HCV RNA from baseline to week 1).
Mericitabine-containing triple therapy reduces the impact of IL28B genotype on RVR and cEVR compared with peginterferon alfa-2a and ribavirin dual therapy. The IL28B genotype, mericitabine dose and bodyweight are the most important factors associated with the α slope, and there is no evidence of a pharmacokinetic drug–drug interaction between mericitabine and ribavirin.
PMCID: PMC4243904  PMID: 24602156
hepatitis C virus polymerase inhibitor; mericitabine; pharmacodynamics; pharmacokinetics; ribavirin
20.  Mass Spectrometry Imaging for Dissecting Steroid Intracrinology within Target Tissues 
Analytical chemistry  2013;85(23):11576-11584.
Steroid concentrations within tissues are modulated by intracellular enzymes. Such ‘steroid intracrinology’ influences hormone-dependent cancers and obesity, and provides targets for pharmacological inhibition. However, no high resolution methods exist to quantify steroids within target tissues. We developed mass spectrometry imaging (MSI), combining matrix assisted laser desorption ionization with on-tissue derivatization with Girard T and Fourier Transform Ion Cyclotron Resonance Mass Spectrometry, to quantify substrate and product (11-dehydrocorticosterone and corticosterone) of the glucocorticoid-amplifying enzyme 11β-HSD1. Regional steroid distribution was imaged at 150-200μm resolution in rat adrenal gland and mouse brain sections, and confirmed with collision induced dissociation/liquid extraction surface analysis. In brains of mice with 11β-HSD1 deficiency or inhibition, MSI quantified changes in sub-regional corticosterone/11-dehydrocorticosterone ratio, distribution of inhibitor, and accumulation of the alternative 11β-HSD1 substrate, 7-ketocholesterol. MSI data correlated well with LC-MS/MS in whole brain homogenates. MSI with derivatization is a powerful new tool to investigate steroid biology within tissues.
PMCID: PMC4392804  PMID: 24134553
Mass Spectrometry Imaging; Intracrinology; Glucocorticoids; 11β-HSD1
21.  Inhibitory Fcγ receptor is required for the maintenance of tolerance through distinct mechanisms1 
The inhibitory Fcγ receptor, FcγRIIB, is widely expressed on B cells, dendritic cells and myeloid effector cells and modulates a variety of antibody-driven in vivo functions. While it has been established that FcγRIIB plays an important role in the maintenance of peripheral tolerance, the responsible cell-specific FcγRIIB expression remains to be determined. In this study, we generated mice with selective deletion of FcγRIIB in B cells, dendritic cells and myeloid effector cells and evaluated these novel strains in models of tolerance and autoimmune diseases. Our results demonstrate that mice with selective deletion of FcγRIIB expression in B cells and dendritic cells have increased antibody and T cell responses, respectively, and display enhanced susceptibility to disease in distinct models, suggesting that FcγRIIB expression in distinct cellular populations contributes to the maintenance of peripheral tolerance through different mechanisms.
PMCID: PMC3967505  PMID: 24563255
Inhibitory Fcγ receptor; conditional knockout; tolerance; anti-nuclear antibodies; collagen induced arthritis
22.  Trauma-focused cognitive behaviour therapy versus treatment as usual for post traumatic stress disorder (PTSD) in young children aged 3 to 8 years: study protocol for a randomised controlled trial 
Trials  2015;16:116.
Following horrific or life-threatening events approximately 10 to 15% of young children develop post traumatic stress disorder (PTSD). The symptoms of this disorder are distressing - nightmares, flashbacks, anger outbursts and disturbed play. These symptoms cause major disruption to a child’s functioning and, if left untreated, can persist for many years. As yet, there are no established empirically-validated treatments for PTSD in young children. Trauma-focused cognitive behaviour therapy (TF-CBT) is a psychological intervention that is effective in treating the disorder in older children (8 to 12 years), adolescents and adults. This study examines TF-CBT adapted for children aged between 3 and 8 years.
This protocol describes a two-arm exploratory randomised controlled trial comparing TF-CBT to treatment as usual (TAU) in children aged 3 to 8 years with a principal diagnosis of PTSD following a single-event discrete trauma. Using a half-crossover design, 44 participants will be randomly allocated to receive the intervention or to receive TAU. Those allocated to TAU will be offered TF-CBT at the end of the ‘treatment’ period (approximately 12 weeks) if still indicated. The primary outcome is PTSD diagnosis according to DSM-5 criteria for children 6 years and younger at post-treatment. Secondary outcomes include effects on co-morbid diagnoses and changes in emotion and trauma symptoms at each of the follow-up points (post-treatment, 3-months, 12-months). Additionally, broader efficacy will be considered with regard to treatment feasibility, acceptability and service utilisation. The key targets of the intervention are trauma memory, the interpretation of the meaning of the event, and the management of symptoms.
This is the first European trial to examine the efficacy of TF-CBT in alleviating PTSD in very young children. As well as providing much-needed data on the utility of the intervention, this exploratory trial will also allow us to gather important information about the feasibility of delivering the treatment in UK National Health Service (NHS) settings, and its acceptability to the children and their families. This study will highlight aspects of the intervention that need improvement or modification in preparation for a full-scale evaluation in a larger sample.
Trial registration
ISRCTN35018680, registered on 18 November 2013.
PMCID: PMC4417274  PMID: 25872653
Post traumatic stress disorder; Anxiety; Children; Trauma-focused cognitive behaviour therapy; PTSD
23.  Impact of aerobic exercise on neurobehavioral outcomes 
Numerous studies have examined the relationship between physical activity and cognitive function, demonstrating that greater physical activity is associated with lower incidence of cognitive impairment in later life. Due to an increasingly large number of older adults at risk for cognitive impairment, the relationship between physical activity and cognition has garnered increasing public health relevance and multiple randomized trials have demonstrated that exercise interventions among sedentary adults improve cognitive performance in multiple domains of function. This article will examine the relationship between physical activity and cognitive function by reviewing several different areas of literature, including the prevalence of cognitive impairment, assessment methods, observational studies examining physical activity and cognition, and intervention studies. The present review is intended to provide a historical tutorial of existing literature linking physical activity, exercise, and cognitive function among both healthy and clinical populations.
PMCID: PMC4321747  PMID: 25674157
Physical activity; Neurocognition; Aerobic exercise
24.  Managing and recognizing complications after treatment of acromioclavicular joint repair or reconstruction 
Complications of the acromioclavicular joint injuries can occur as a result of the injury itself, conservative management, or surgical treatment. Fortunately, the majority of acromioclavicular surgeries utilizing modern techniques and instrumentation result in successful outcomes. However, clinical failures do occur with frequency. The ability to identify the causative factor of failures makes revision surgery more likely to be successful. The purposes of this review are to highlight common problems that can occur following acromioclavicular joint surgery and discuss techniques that can be utilized in revision surgery.
PMCID: PMC4596186  PMID: 25663435
Acromioclavicular joint injuries; Coracoclavicular reconstruction; Shoulder separation; Shoulder surgery complication

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