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1.  Estimating the Cost-Effectiveness of Pre-Exposure Prophylaxis to Reduce HIV-1 and HSV-2 Incidence in HIV-Serodiscordant Couples in South Africa 
PLoS ONE  2015;10(1):e0115511.
Objective
To estimate the cost-effectiveness of daily oral tenofovir-based PrEP, with a protective effect against HSV-2 as well as HIV-1, among HIV-1 serodiscordant couples in South Africa.
Methods
We incorporated HSV-2 acquisition, transmission, and interaction with HIV-1 into a microsimulation model of heterosexual HIV-1 serodiscordant couples in South Africa, with use of PrEP for the HIV-1 uninfected partner prior to ART initiation for the HIV-1 1infected partner, and for one year thereafter.
Results
We estimate the cost per disability-adjusted life-year (DALY) averted for two scenarios, one in which PrEP has no effect on reducing HSV-2 acquisition, and one in which there is a 33% reduction. After a twenty-year intervention, the cost per DALY averted is estimated to be $10,383 and $9,757, respectively – a 6% reduction, given the additional benefit of reduced HSV-2 acquisition. If all couples are discordant for both HIV-1 and HSV-2, the cost per DALY averted falls to $1,445, which shows that the impact is limited by HSV-2 concordance in couples.
Conclusion
After a 20-year PrEP intervention, the cost per DALY averted with a reduction in HSV-2 is estimated to be modestly lower than without any effect, providing an increase of health benefits in addition to HIV-1 prevention at no extra cost. The small degree of the effect is in part due to a high prevalence of HSV-2 infection in HIV-1 serodiscordant couples in South Africa.
doi:10.1371/journal.pone.0115511
PMCID: PMC4304839  PMID: 25616135
2.  The relationship between separation anxiety and impairment 
Journal of anxiety disorders  2007;22(4):635-641.
The goal of this study was to characterize the contemporaneous and prognostic relationship between symptoms of separation anxiety disorder (SAD) and associated functional impairment. The sample comprised n=2067 8–16 year-old twins from a community-based registry. Juvenile subjects and their parents completed a personal interview on two occasions, separated by an average follow-up period of 18 months, about the subject’s current history of SAD and associated functional impairment. Results showed that SAD symptoms typically caused very little impairment but demonstrated significant continuity over time. Older youth had significantly more persistent symptoms than younger children. Prior symptom level independently predicted future symptom level and diagnostic symptom threshold, with and without impairment. Neither diagnostic threshold nor severity of impairment independently predicted outcomes after taking account of prior symptom levels. The results indicate that impairment may index current treatment need but symptom levels provide the best information about severity and prognosis.
doi:10.1016/j.janxdis.2007.06.002
PMCID: PMC4286259  PMID: 17658718
separation anxiety; disorders; anxiety; DSM-IV; impairment; clinical significance criterion
3.  Point of care testing for urinary tract infection in primary care (POETIC): protocol for a randomised controlled trial of the clinical and cost effectiveness of FLEXICULT™ informed management of uncomplicated UTI in primary care 
BMC Family Practice  2014;15(1):187.
Background
Urinary tract infections (UTI) are the most frequent bacterial infection affecting women and account for about 15% of antibiotics prescribed in primary care. However, some women with a UTI are not prescribed antibiotics or are prescribed the wrong antibiotics, while many women who do not have a microbiologically confirmed UTI are prescribed antibiotics. Inappropriate antibiotic prescribing unnecessarily increases the risk of side effects and the development of antibiotic resistance, and wastes resources.
POETIC is a randomised controlled trial of a Point Of Care Test (POCT) (Flexicult™) guided UTI management strategy for use in primary care, which may help General Practitioners more effectively decide both whether or not to prescribe antibiotics, and if so, to select the most appropriate antibiotic.
Methods/design
614 adult female patients will be recruited from four primary care research networks (Wales, England, Spain, the Netherlands) and individually randomised to either POCT guided care or the guideline-informed ‘standard care’ arm. Urine and stool samples (where possible) will be obtained at presentation (day 1) and two weeks later for microbiological analysis. All participants will be followed up on the course of their illness and their quality of life, using a 2 week self-completed symptom diary. At 3 months, a primary care notes review will be conducted for evidence of further evidence of treatment failures, recurrence, complications, hospitalisations and health service costs.
The primary objective is to compare appropriate antibiotic use on day 3 between the POCT and standard care arms using multi-level logistic regression to produce an odds ratio and associated 95% confidence interval. Costs of the two management approaches will be assessed in terms of the primary outcome.
Discussion
Although the Flexicult™ POCT is used in some countries in routine primary care, it’s clinical and cost effectiveness has never been evaluated in a randomised clinical trial. If shown to be effective, the use of this POCT could benefit individual sufferers and provide evidence for health care authorities to develop evidence based policies to combat the spread and impact of the unprecedented rise of infections caused by antibiotic resistant bacteria in Europe.
Trial registration number
ISRCTN65200697 (Registered 10 September 2013).
doi:10.1186/s12875-014-0187-4
PMCID: PMC4251943  PMID: 25425162
Urinary Tract Infection; Primary care; Adult women; Point-of-care-test; Near-patient testing; Antibiotic resistance; Cost effectiveness
4.  Community Mobilisation and Empowerment Interventions as Part of HIV Prevention for Female Sex Workers in Southern India: A Cost-Effectiveness Analysis 
PLoS ONE  2014;9(10):e110562.
Background
Most HIV prevention for female sex workers (FSWs) focuses on individual behaviour change involving peer educators, condom promotion and the provision of sexual health services. However, there is a growing recognition of the need to address broader societal, contextual and structural factors contributing to FSW risk behaviour. We assess the cost-effectiveness of adding community mobilisation (CM) and empowerment interventions (eg. community mobilisation, community involvement in programme management and services, violence reduction, and addressing legal policies and police practices), to core HIV prevention services delivered as part of Avahan in two districts (Bellary and Belgaum) of Karnataka state, Southern India.
Methods
An ingredients approach was used to estimate economic costs in US$ 2011 from an HIV programme perspective of CM and empowerment interventions over a seven year period (2004–2011). Incremental impact, in terms of HIV infections averted, was estimated using a two-stage process. An ‘exposure analysis’ explored whether exposure to CM was associated with FSW’s empowerment, risk behaviours and HIV/STI prevalence. Pathway analyses were then used to estimate the extent to which behaviour change may be attributable to CM and to inform a dynamic HIV transmission model.
Findings
The incremental costs of CM and empowerment were US$ 307,711 in Belgaum and US$ 592,903 in Bellary over seven years (2004–2011). Over a 7-year period (2004–2011) the mean (standard deviation, sd.) number of HIV infections averted through CM and empowerment is estimated to be 1257 (308) in Belgaum and 2775 (1260) in Bellary. This translates in a mean (sd.) incremental cost per disability adjusted life year (DALY) averted of US$ 14.12 (3.68) in Belgaum and US$ 13.48 (6.80) for Bellary - well below the World Health Organisation recommended willingness to pay threshold for India. When savings from ART are taken into account, investments in CM and empowerment are cost saving.
Conclusions
Our findings suggest that CM and empowerment is, at worst, highly cost-effective and, at best, a cost-saving investment from an HIV programme perspective. CM and empowerment interventions should therefore be considered as core components of HIV prevention programmes for FSWs.
doi:10.1371/journal.pone.0110562
PMCID: PMC4204894  PMID: 25333501
5.  Antiretroviral Therapy Uptake, Attrition, Adherence and Outcomes among HIV-Infected Female Sex Workers: A Systematic Review and Meta-Analysis 
PLoS ONE  2014;9(9):e105645.
Purpose
We aimed to characterize the antiretroviral therapy (ART) cascade among female sex workers (FSWs) globally.
Methods
We systematically searched PubMed, Embase and MEDLINE in March 2014 to identify studies reporting on ART uptake, attrition, adherence, and outcomes (viral suppression or CD4 count improvements) among HIV-infected FSWs globally. When possible, available estimates were pooled using random effects meta-analyses (with heterogeneity assessed using Cochran's Q test and I2 statistic).
Results
39 studies, reporting on 21 different FSW study populations in Asia, Africa, North America, South America, and Central America and the Caribbean, were included. Current ART use among HIV-infected FSWs was 38% (95% CI: 29%–48%, I2 = 96%, 15 studies), and estimates were similar between high-, and low- and middle-income countries. Ever ART use among HIV-infected FSWs was greater in high-income countries (80%; 95% CI: 48%–94%, I2 = 70%, 2 studies) compared to low- and middle-income countries (36%; 95% CI: 7%–81%, I2 = 99%, 3 studies). Loss to follow-up after ART initiation was 6% (95% CI: 3%–11%, I2 = 0%, 3 studies) and death after ART initiation was 6% (95% CI: 3%–11%, I2 = 0%, 3 studies). The fraction adherent to ≥95% of prescribed pills was 76% (95% CI: 68%–83%, I2 = 36%, 4 studies), and 57% (95% CI: 46%–68%, I2 = 82%, 4 studies) of FSWs on ART were virally suppressed. Median gains in CD4 count after 6 to 36 months on ART, ranged between 103 and 241 cells/mm3 (4 studies).
Conclusions
Despite global increases in ART coverage, there is a concerning lack of published data on HIV treatment for FSWs. Available data suggest that FSWs can achieve levels of ART uptake, retention, adherence, and treatment response comparable to that seen among women in the general population, but these data are from only a few research settings. More routine programme data on HIV treatment among FSWs across settings should be collected and disseminated.
doi:10.1371/journal.pone.0105645
PMCID: PMC4179256  PMID: 25265158
6.  The Costs of Scaling Up HIV Prevention for High Risk Groups: Lessons Learned from the Avahan Programme in India 
PLoS ONE  2014;9(9):e106582.
Objective
The study objective is to measure, analyse costs of scaling up HIV prevention for high-risk groups in India, in order to assist the design of future HIV prevention programmes in South Asia and beyond.
Design
Prospective costing study.
Methods
This study is one of the most comprehensive studies of the costs of HIV prevention for high-risk groups to date in both its scope and size. HIV prevention included outreach, sexually transmitted infections (STI) services, condom provision, expertise enhancement, community mobilisation and enabling environment activities. Economic costs were collected from 138 non-government organisations (NGOs) in 64 districts, four state level lead implementing partners (SLPs), and the national programme level (Bill and Melinda Gates Foundation (BMGF)) office over four years using a top down costing approach, presented in US$ 2011.
Results
Mean total unit costs (2004–08) per person reached at least once a year and per monthly contact were US$ 235(56–1864) and US$ 82(12–969) respectively. 35% of the cost was incurred by NGOs, 30% at the state level SLP and 35% at the national programme level. The proportion of total costs by activity were 34% for expertise enhancement, 37% for programme management (including support and supervision), 22% for core HIV prevention activities (outreach and STI services) and 7% for community mobilisation and enabling environment activities. Total unit cost per person reached fell sharply as the programme expanded due to declining unit costs above the service level (from US$ 477 per person reached in 2004 to US$ 145 per person reached in 2008). At the service level also unit costs decreased slightly over time from US$ 68 to US$ 64 per person reached.
Conclusions
Scaling up HIV prevention for high risk groups requires significant investment in expertise enhancement and programme administration. However, unit costs decreased with programme expansion in spite of an increase in the scope of activities.
doi:10.1371/journal.pone.0106582
PMCID: PMC4159262  PMID: 25203052
7.  Who mixes with whom among men who have sex with men? Implications for modelling the HIV epidemic in southern India 
Journal of Theoretical Biology  2014;355(100):140-150.
In India, the identity of men who have sex with men (MSM) is closely related to the role taken in anal sex (insertive, receptive or both), but little is known about sexual mixing between identity groups. Both role segregation (taking only the insertive or receptive role) and the extent of assortative (within-group) mixing are known to affect HIV epidemic size in other settings and populations. This study explores how different possible mixing scenarios, consistent with behavioural data collected in Bangalore, south India, affect both the HIV epidemic, and the impact of a targeted intervention. Deterministic models describing HIV transmission between three MSM identity groups (mostly insertive Panthis/Bisexuals, mostly receptive Kothis/Hijras and versatile Double Deckers), were parameterised with behavioural data from Bangalore. We extended previous models of MSM role segregation to allow each of the identity groups to have both insertive and receptive acts, in differing ratios, in line with field data. The models were used to explore four different mixing scenarios ranging from assortative (maximising within-group mixing) to disassortative (minimising within-group mixing). A simple model was used to obtain insights into the relationship between the degree of within-group mixing, R0 and equilibrium HIV prevalence under different mixing scenarios. A more complex, extended version of the model was used to compare the predicted HIV prevalence trends and impact of an HIV intervention when fitted to data from Bangalore. With the simple model, mixing scenarios with increased amounts of assortative (within-group) mixing tended to give rise to a higher R0 and increased the likelihood that an epidemic would occur. When the complex model was fit to HIV prevalence data, large differences in the level of assortative mixing were seen between the fits identified using different mixing scenarios, but little difference was projected in future HIV prevalence trends. An oral pre-exposure prophylaxis (PrEP) intervention was modelled, targeted at the different identity groups. For intervention strategies targeting the receptive or receptive and versatile MSM together, the overall impact was very similar for different mixing patterns. However, for PrEP scenarios targeting insertive or versatile MSM alone, the overall impact varied considerably for different mixing scenarios; more impact was achieved with greater levels of disassortative mixing.
Highlights
•Different mixing scenarios are explored for 3 groups of role-segregated MSM.•Models show that the mixing scenario affects both R0 and endemic HIV prevalence.•When models are fit to data, predicted HIV trends are unaffected by mixing.•Impact of targeted (but not non-targeted) interventions can be affected by mixing.
doi:10.1016/j.jtbi.2014.04.005
PMCID: PMC4064301  PMID: 24727187
Mathematical model; Mixing matrix; Sexually transmitted infection; Disassortative mixing; Pre-exposure prophylaxis
8.  Diurnal variation of gait in patients with rheumatoid arthritis: The DIVIGN study☆ 
Background
Circadian variation of joint stiffness (morning stiffness) and its impact on functional ability are widely recognised in rheumatoid arthritis. Subsequent within-day variation of walking ability is important due to the increased availability of instrumented gait analysis. This study aimed to quantify diurnal variation of gait in patients with rheumatoid arthritis, and explore associations with disease characteristics.
Methods
Thirty one inpatients with rheumatoid arthritis walked at a self-selected speed along a GAITRite instrumented walkway 5 times during a single day.
Findings
Participants showed marked diurnal variation in gait, leading to a systematic variation throughout the day (F = 19.56, P = < 0.001). Gait velocity and stride length both increased, whereas the proportion of each gait cycle spent in stance phase or double support decreased, consistent with improving function throughout the day. Although absolute gait velocity correlated with disease characteristics, the magnitude of diurnal variation appeared to be independent of disease activity (rho = 0.26, P = 0.15), disease duration (rho = − 0.19, P = 0.324), and underlying functional ability (rho = 0.09, P = 0.65).
Interpretation
Although morning stiffness is well recognised in rheumatoid arthritis, this is the first time that its effect on gait has been quantified. Patients with rheumatoid arthritis exhibited a systematic change in walking ability throughout the day, which was independent of disease characteristics. These findings have important implications for the interpretation of existing data and the design of future studies. Repeat measures should be conducted at the same time of day to exclude the effects of diurnal variation.
Highlights
•Patients with rheumatoid arthritis exhibited a systematic change in walking ability throughout the day.•The magnitude of within day change appeared independent of disease characteristics.•In future, repeat measures should be conducted at the same time of day to exclude the effects of diurnal variation.
doi:10.1016/j.clinbiomech.2014.05.009
PMCID: PMC4166456  PMID: 24954102
Rheumatoid arthritis; Gait analysis; Diurnal variation
9.  Health benefits, costs, and cost-effectiveness of earlier eligibility for adult antiretroviral therapy and expanded treatment coverage: a combined analysis of 12 mathematical models 
The lancet global health  2013;2(1):23-34.
Background
New WHO guidelines recommend ART initiation for HIV-positive persons with CD4 cell counts ≤500 cells/µL, a higher threshold than was previously recommended. Country decision makers must consider whether to further expand ART eligibility accordingly.
Methods
We used multiple independent mathematical models in four settings—South Africa, Zambia, India, and Vietnam—to evaluate the potential health impact, costs, and cost-effectiveness of different adult ART eligibility criteria under scenarios of current and expanded treatment coverage, with results projected over 20 years. Analyses considered extending eligibility to include individuals with CD4 ≤500 cells/µL or all HIV-positive adults, compared to the previous recommendation of initiation with CD4 ≤350 cells/µL. We assessed costs from a health system perspective, and calculated the incremental cost per DALY averted ($/DALY) to compare competing strategies. Strategies were considered ‘very cost-effective’ if the $/DALY was less than the country’s per capita gross domestic product (GDP; South Africa: $8040, Zambia: $1425, India: $1489, Vietnam: $1407) and ‘cost-effective’ if $/DALY was less than three times per capita GDP.
Findings
In South Africa, the cost per DALY averted of extending ART eligibility to CD4 ≤500 cells/µL ranged from $237 to $1691/DALY compared to 2010 guidelines; in Zambia, expanded eligibility ranged from improving health outcomes while reducing costs (i.e. dominating current guidelines) to $749/DALY. Results were similar in scenarios with substantially expanded treatment access and for expanding eligibility to all HIV-positive adults. Expanding treatment coverage in the general population was therefore found to be cost-effective. In India, eligibility for all HIV-positive persons ranged from $131 to $241/DALY and in Vietnam eligibility for CD4 ≤500 cells/µL cost $290/DALY. In concentrated epidemics, expanded access among key populations was also cost-effective.
Interpretation
Earlier ART eligibility is estimated to be very cost-effective in low- and middle-income settings, although these questions should be revisited as further information becomes available. Scaling-up ART should be considered among other high-priority health interventions competing for health budgets.
Funding
The Bill and Melinda Gates Foundation and World Health Organization
doi:10.1016/S2214-109X(13)70172-4
PMCID: PMC4114402  PMID: 25083415
10.  Validation of the Modes of Transmission Model as a Tool to Prioritize HIV Prevention Targets: A Comparative Modelling Analysis 
PLoS ONE  2014;9(7):e101690.
Background
The static Modes of Transmission (MOT) model predicts the annual fraction of new HIV infections acquired across subgroups (MOT metric), and is used to focus HIV prevention. Using synthetic epidemics via a dynamical model, we assessed the validity of the MOT metric for identifying epidemic drivers (behaviours or subgroups that are sufficient and necessary for HIV to establish and persist), and the potential consequence of MOT-guided policies.
Methods and Findings
To generate benchmark MOT metrics for comparison, we simulated three synthetic epidemics (concentrated, mixed, and generalized) with different epidemic drivers using a dynamical model of heterosexual HIV transmission. MOT metrics from generic and complex MOT models were compared against the benchmark, and to the contribution of epidemic drivers to overall HIV transmission (cumulative population attributable fraction over t years, PAFt). The complex MOT metric was similar to the benchmark, but the generic MOT underestimated the fraction of infections in epidemic drivers. The benchmark MOT metric identified epidemic drivers early in the epidemics. Over time, the MOT metric did not identify epidemic drivers. This was not due to simplified MOT models or biased parameters but occurred because the MOT metric (irrespective of the model used to generate it) underestimates the contribution of epidemic drivers to HIV transmission over time (PAF5–30). MOT-directed policies that fail to reach epidemic drivers could undermine long-term impact on HIV incidence, and achieve a similar impact as random allocation of additional resources.
Conclusions
Irrespective of how it is obtained, the MOT metric is not a valid stand-alone tool to identify epidemic drivers, and has limited additional value in guiding the prioritization of HIV prevention targets. Policy-makers should use the MOT model judiciously, in combination with other approaches, to identify epidemic drivers.
doi:10.1371/journal.pone.0101690
PMCID: PMC4090151  PMID: 25014543
11.  Subcategories of restricted and repetitive behaviors in children with autism spectrum disorders 
Research suggests that restricted and repetitive behaviors (RRBs) can be subdivided into repetitive sensory motor (RSM) and insistence on Sameness (IS) behaviors. However, because the majority of previous studies have used the Autism Diagnostic Interview-Revised (ADI-R), it is not clear whether these subcategories reflect the actual organization of RRBs in ASD. Using data from the Simons Simplex Collection (n=1825), we examined the association between scores on the ADI-R and the Repetitive Behavior Scale-Revised (RBS-R). Analyses supported the construct validity of RSM and IS subcategories. As in previous studies, IS behaviors showed no relationship with IQ. These findings support the continued use of RRB subcategories, particularly IS behaviors, as a means of creating more behaviorally homogeneous subgroups of children with ASD.
doi:10.1007/s10803-012-1671-0
PMCID: PMC3579001  PMID: 23065116
Autism spectrum disorders; repetitive behaviors; subcategories; repetitive sensory motor; insistence on sameness
12.  RSV-encoded NS2 promotes epithelial cell shedding and distal airway obstruction 
The Journal of Clinical Investigation  2014;124(5):2219-2233.
Respiratory syncytial virus (RSV) infection is the major cause of bronchiolitis in young children. The factors that contribute to the increased propensity of RSV-induced distal airway disease compared with other commonly encountered respiratory viruses remain unclear. Here, we identified the RSV-encoded nonstructural 2 (NS2) protein as a viral genetic determinant for initiating RSV-induced distal airway obstruction. Infection of human cartilaginous airway epithelium (HAE) and a hamster model of disease with recombinant respiratory viruses revealed that NS2 promotes shedding of infected epithelial cells, resulting in two consequences of virus infection. First, epithelial cell shedding accelerated the reduction of virus titers, presumably by clearing virus-infected cells from airway mucosa. Second, epithelial cells shedding into the narrow-diameter bronchiolar airway lumens resulted in rapid accumulation of detached, pleomorphic epithelial cells, leading to acute distal airway obstruction. Together, these data indicate that RSV infection of the airway epithelium, via the action of NS2, promotes epithelial cell shedding, which not only accelerates viral clearance but also contributes to acute obstruction of the distal airways. Our results identify RSV NS2 as a contributing factor for the enhanced propensity of RSV to cause severe airway disease in young children and suggest NS2 as a potential therapeutic target for reducing the severity of distal airway disease.
doi:10.1172/JCI72948
PMCID: PMC4001550  PMID: 24713657
13.  Option Grids to facilitate shared decision making for patients with Osteoarthritis of the knee: protocol for a single site, efficacy trial 
Background
Despite policy interest, an ethical imperative, and evidence of the benefits of patient decision support tools, the adoption of shared decision making (SDM) in day-to-day clinical practice remains slow and is inhibited by barriers that include culture and attitudes; resources and time pressures. Patient decision support tools often require high levels of health and computer literacy. Option Grids are one-page evidence-based summaries of the available condition-specific treatment options, listing patients’ frequently asked questions. They are designed to be sufficiently brief and accessible enough to support a better dialogue between patients and clinicians during routine consultations. This paper describes a study to assess whether an Option Grid for osteoarthritis of the knee (OA of the knee) facilitates SDM, and explores the use of Option Grids by patients disadvantaged by language or poor health literacy.
Methods/Design
This will be a stepped wedge exploratory trial involving 72 patients with OA of the knee referred from primary medical care to a specialist musculoskeletal service in Oldham. Six physiotherapists will sequentially join the trial and consult with six patients using usual care procedures. After a period of brief training in using the Option Grid, the same six physiotherapists will consult with six further patients using an Option Grid in the consultation. The primary outcome will be efficacy of the Option Grid in facilitating SDM as measured by observational scores using the OPTION scale. Comparisons will be made between patients who have received the Option Grid and those who received usual care. A Decision Quality Measure (DQM) will assess quality of decision making. The health literacy of patients will be measured using the REALM-R instrument. Consultations will be observed and audio-recorded. Interviews will be conducted with the physiotherapists, patients and any interpreters present to explore their views of using the Option Grid.
Discussion
Option Grids offer a potential solution to the barriers to implementing traditional decision aids into routine clinical practice. The study will assess whether Option Grids can facilitate SDM in day-to-day clinical practice and explore their use with patients disadvantaged by language or poor health literacy.
Trial registration
Current Controlled Trials ISRCTN94871417
doi:10.1186/1472-6963-14-160
PMCID: PMC3986464  PMID: 24708747
Shared decision making; Decision aids; Osteoarthritis of the knee; Arthritis; Health literacy; Patient communication
14.  Does Change in Cognitive Function Predict Change in Costs of Care for People With a Schizophrenia Diagnosis Following Cognitive Remediation Therapy? 
Schizophrenia Bulletin  2014;40(6):1472-1481.
Background and Aims: Schizophrenia leads to significant personal costs matched by high economic costs. Cognitive function is a strong predictor of disabilities in schizophrenia, which underpin these costs. This study of cognitive remediation therapy (CRT), which has been shown to improve cognition and reduce disability in schizophrenia, aims to investigate associations between improvements in cognition and cost changes. Methods: Eighty-five participants with schizophrenia were randomized to receive CRT or treatment as usual and were assessed at baseline, posttherapy, and 6 month follow-up. Four structural equation models investigated associations between changes in cognitive function and costs of care. Results: All 4 models provided a good fit. Improvement in 3 individual cognitive variables did not predict total cost changes (model 1). But improvement in a single latent cognition factor was associated with a reduction in depression, which in turn was associated with reduced subsequent total costs (model 2). No significant associations with constituent daycare and special accommodation cost changes were apparent with 3 individual cognitive change variables (model 3). But improvement in a single latent cognitive change variable was associated with subsequent reductions in both daycare and special accommodation costs (model 4). Conclusion: This study exemplifies a method of using cost changes to investigate the effects and mechanisms of CRT and suggests that executive function change may be an important target if we are to reduce disability and resultant health and social care costs.
doi:10.1093/schbul/sbu046
PMCID: PMC4193717  PMID: 24682210
cognition; functioning; executive function; working memory; cognitive predictors
15.  An examination of the demographic predictors of adolescent breakfast consumption, content, and context 
BMC Public Health  2014;14:264.
Background
Breakfast consumption is important to health; however, adolescents often skip breakfast, and an increased understanding of the breakfast consumption patterns of adolescents is needed. The purpose of this study was to identify the predictors of breakfast eating, including the content and context, in an adolescent sample from Australia and England.
Methods
Four-hundred and eighty-one students completed an online questionnaire measuring breakfast skipping, and breakfast content (what was eaten) and context (who they ate with, involvement in preparation). Logistic regression was conducted to investigate the predictors of skipping breakfast, breakfast context, and consumption of the ten most commonly consumed foods. Chi-square analyses were used to examine differences in breakfast content according to context.
Results
Most students (88%) had consumed breakfast on the day of the survey; breakfast skipping was more common in England (18%) than in Australia (8%). Country, gender, socioeconomic status, and body mass index (BMI) were all predictors of breakfast content and context. Whether adolescents ate with others and/or were involved in breakfast preparation predicted the content of breakfast consumed.
Conclusions
This study provides a comprehensive examination of the factors underlying breakfast consumption (content and context) and has important implications for the development of evidence-based interventions to improve rates of breakfast consumption and the quality of food consumed amongst adolescents.
doi:10.1186/1471-2458-14-264
PMCID: PMC4000053  PMID: 24645936
Breakfast; Australia; England; Diet; Nutrition
16.  Does Statin or ASA Affect Survival When Prostate Cancer Is Treated with External Beam Radiation Therapy? 
Prostate Cancer  2014;2014:184297.
Background. Prior studies evaluating the effect of statins or acetylsalicylic acid (ASA) on the survival of men receiving prostate cancer were treatment have reported conflicting results, and have not adjusted for comorbidity. Our aim is to investigate the influence of statins and ASA on prostate cancer survival, when comorbidity is adjusted for, in men treated with external beam radiation therapy (EBRT) for prostate cancer. Methods. A cohort of 3851 patients with prostate cancer treated with curative EBRT ± androgen deprivation therapy (ADT) between 2000 and 2007. Stage, treatment, medication use, and Charlson comorbidity index (CCI) scores were analyzed. Results. Median followup was 8.4 years. Mean age was 70.3 years. Neoadjuvant ADT was used in 67%. Statins were used in 23%, ASA in 24%, and both in 11%. Comorbidity scores were 0 in 65%, 1 in 25%, and ≥2 in 10% of patients. Statin and ASA use were associated with increased age and comorbidity. Although statin and ASA use were significantly associated with improved prostate cancer specific survival (PCSS) on univariate analysis, neither were on multivariate analysis. Conclusion. Neither statin nor ASA use impacted PCSS on multivariate competing risks analysis. Survival was impacted by increased comorbidity as well as statin and ASA use.
doi:10.1155/2014/184297
PMCID: PMC3960556  PMID: 24729876
17.  Molecular Organization of the Mucins and Glycocalyx Underlying Mucus Transport Over Mucosal Surfaces of the Airways 
Mucosal immunology  2012;6(2):379-392.
Mucus, with its burden of inspired particulates, and pathogens, is cleared from mucosal surfaces of the airways by cilia beating within the periciliary layer (PCL). The PCL is held to be ‘watery’ and free of mucus by thixotropic-like forces arising from beating cilia. With radii of gyration ~250 nm, however, polymeric mucins should reptate readily into the PCL, so we assessed the glycocalyx for barrier functions. The PCL stained negative for MUC5AC and MUC5B, but it was positive for keratan sulfate, a glycosaminoglycan commonly associated with glycoconjugates. Shotgun proteomics showed keratan sulfate-rich fractions from mucus containing abundant tethered mucins, MUC1, MUC4, and MUC16, but no proteoglycans. Immuno-histology by light and electron microscopy localized MUC1 to microvilli, MUC4 and MUC20 to cilia, and MUC16 to goblet cells. Electron and atomic force microscopy revealed molecular lengths of 190–1,500 nm for tethered mucins, and a finely textured glycocalyx matrix filling interciliary spaces. Adenoviral particles were excluded from glycocalyx of the microvilli, while the smaller AAV penetrated, but were trapped within. Hence, tethered mucins organized as a space-filling glycocalyx function as a selective barrier for the PCL, broadening their role in innate lung defense and offering new molecular targets for conventional and gene therapies.
doi:10.1038/mi.2012.81
PMCID: PMC3637662  PMID: 22929560
lung; airways epithelium; mucosal innate immunity; mucus; mucin; mucociliary clearance
18.  Heterosexual Anal Intercourse: A Neglected Risk Factor for HIV? 
Heterosexual anal intercourse confers a much greater risk of HIV transmission than vaginal intercourse, yet its contribution to heterosexual HIV epidemics has been under researched. In this article we review the current state of knowledge of heterosexual anal intercourse practice worldwide and identify the information required to assess its role in HIV transmission within heterosexual populations, including input measures required to inform mathematical models. We then discuss the evidence relating anal intercourse and HIV with sexual violence.
doi:10.1111/aji.12064
PMCID: PMC3938911  PMID: 23279040
Anal intercourse; HIV; infectiousness; sexual violence
19.  Image Registration for Quantitative Parametric Response Mapping of Cancer Treatment Response1 
Translational Oncology  2014;7(1):101-110.
Imaging biomarkers capable of early quantification of tumor response to therapy would provide an opportunity to individualize patient care. Image registration of longitudinal scans provides a method of detecting treatment associated changes within heterogeneous tumors by monitoring alterations in the quantitative value of individual voxels over time, which is unattainable by traditional volumetric-based histogram methods. The concepts involved in the use of image registration for tracking and quantifying breast cancer treatment response using parametric response mapping (PRM), a voxel-based analysis of diffusion-weighted magnetic resonance imaging (DW-MRI) scans, are presented. Application of PRM to breast tumor response detection is described, wherein robust registration solutions for tracking small changes in water diffusivity in breast tumors during therapy are required. Methodologies that employ simulations are presented for measuring expected statistical accuracy of PRM for response assessment. Test-retest clinical scans are used to yield estimates of system noise to indicate significant changes in voxel-based changes in water diffusivity. Overall, registration-based PRM image analysis provides significant opportunities for voxel-based image analysis to provide the required accuracy for early assessment of response to treatment in breast cancer patients receiving neoadjuvant chemotherapy.
PMCID: PMC3998680  PMID: 24772213
20.  Effects of Vitamin D on Airway Epithelial Cell Morphology and Rhinovirus Replication 
PLoS ONE  2014;9(1):e86755.
Vitamin D has been linked to reduced risk of viral respiratory illness. We hypothesized that vitamin D could directly reduce rhinovirus (RV) replication in airway epithelium. Primary human bronchial epithelial cells (hBEC) were treated with vitamin D, and RV replication and gene expression were evaluated by quantitative PCR. Cytokine/chemokine secretion was measured by ELISA, and transepithelial resistance (TER) was determined using a voltohmmeter. Morphology was examined using immunohistochemistry. Vitamin D supplementation had no significant effects on RV replication, but potentiated secretion of CXCL8 and CXCL10 from infected or uninfected cells. Treatment with vitamin D in the form of 1,25(OH)2D caused significant changes in cell morphology, including thickening of the cell layers (median of 46.5 µm [35.0–69.0] vs. 30 µm [24.5–34.2], p<0.01) and proliferation of cytokeratin-5-expressing cells, as demonstrated by immunohistochemical analysis. Similar effects were seen for 25(OH)D. In addition to altering morphology, higher concentrations of vitamin D significantly upregulated small proline-rich protein (SPRR1β) expression (6.3 fold-induction, p<0.01), suggestive of squamous metaplasia. Vitamin D treatment of hBECs did not alter repair of mechanically induced wounds. Collectively, these findings indicate that vitamin D does not directly affect RV replication in airway epithelial cells, but can influence chemokine synthesis and alters the growth and differentiation of airway epithelial cells.
doi:10.1371/journal.pone.0086755
PMCID: PMC3901706  PMID: 24475177
21.  KCTU randomisation and IMP management system 
Trials  2013;14(Suppl 1):P63.
doi:10.1186/1745-6215-14-S1-P63
PMCID: PMC3980242
22.  Rasch analysis of the PedsQL 3.0 diabetes module 
Trials  2013;14(Suppl 1):O40.
doi:10.1186/1745-6215-14-S1-O40
PMCID: PMC3981023
25.  Human Parainfluenza Virus Serotypes Differ in Their Kinetics of Replication and Cytokine Secretion in Human Tracheobronchial Airway Epithelium 
Virology  2012;433(2):320-328.
Human parainfluenza viruses (PIVs) cause acute respiratory illness in children, the elderly, and immunocompromised patients. PIV3 is a common cause of bronchiolitis and pneumonia, whereas PIV1 and 2 are frequent causes of upper respiratory tract illness and croup. To assess how PIV1, 2, and 3 differ with regard to replication and induction of type I interferons, interleukin-6, and relevant chemokines, we infected primary human airway epithelium (HAE) cultures from the same tissue donors and examined replication kinetics and cytokine secretion. PIV1 replicated to high titer yet did not induce cytokine secretion until late in infection, while PIV2 replicated less efficiently but induced an early cytokine peak. PIV3 replicated to high titer but induced a slower rise in cytokine secretion. The T cell chemoattractants CXCL10 and CXCL11 were the most abundant chemokines induced. Differences in replication and cytokine secretion might explain some of the differences in PIV serotype-specific pathogenesis and epidemiology.
doi:10.1016/j.virol.2012.08.027
PMCID: PMC3469718  PMID: 22959894
Human parainfluenza virus; Human airway epithelium; cytokines; chemokines; interferon; pathogenesis

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