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Lancet  2014;385(9962):55-71.
Female sex workers (FSWs) bear a disproportionately large burden of HIV infection worldwide. Despite decades of research and programme activity, the epidemiology of HIV and the role that structural determinants have in mitigating or potentiating HIV epidemics and access to care for FSWs is poorly understood. We reviewed available published data for HIV prevalence and incidence, condom use, and structural determinants among this group. Only 87 (43%) of 204 unique studies reviewed explicitly examined structural determinants of HIV. Most studies were from Asia, with few from areas with a heavy burden of HIV such as sub-Saharan Africa, Russia, and eastern Europe. To further explore the potential effect of structural determinants on the course of epidemics, we used a deterministic transmission model to simulate potential HIV infections averted through structural changes in regions with concentrated and generalised epidemics, and high HIV prevalence among FSWs. This modelling suggested that elimination of sexual violence alone could avert 17% of HIV infections in Kenya (95% uncertainty interval [UI] 1–31) and 20% in Canada (95% UI 3–39) through its immediate and sustained effect on non-condom use) among FSWs and their clients in the next decade. In Kenya, scaling up of access to antiretroviral therapy among FSWs and their clients to meet WHO eligibility of a CD4 cell count of less than 500 cells per μL could avert 34% (95% UI 25–42) of infections and even modest coverage of sex worker-led outreach could avert 20% (95% UI 8–36) of infections in the next decade. Decriminalisation of sex work would have the greatest effect on the course of HIV epidemics across all settings, averting 33–46% of HIV infections in the next decade. Multipronged structural and community-led interventions are crucial to increase access to prevention and treatment and to promote human rights for FSWs worldwide.
PMCID: PMC4297548  PMID: 25059947
2.  New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures 
Autism Research  2015;8(5):522-533.
Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach's alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach's alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP. Autism Res 2015, 8: 522–533. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
PMCID: PMC4690162  PMID: 25959701
broader autism phenotype; informant interview; self-report interview; interrater reliability; retest reliability
3.  Cost-effectiveness analysis of a communication-focused therapy for pre-school children with autism: results from a randomised controlled trial 
BMC Psychiatry  2015;15:316.
Autism is associated with impairments that have life-time consequences for diagnosed individuals and a substantial impact on families. There is growing interest in early interventions for children with autism, yet despite the substantial economic burden, there is little evidence of the cost-effectiveness of such interventions with which to support resource allocation decisions. This study reports an economic evaluation of a parent-mediated, communication-focused therapy carried out within the Pre-School Autism Communication Trial (PACT).
152 pre-school children with autism were randomly assigned to treatment as usual (TAU) or PACT + TAU. Primary outcome was severity of autism symptoms at 13-month follow-up. Economic data included health, education and social services, childcare, parental productivity losses and informal care.
Clinically meaningful symptom improvement was evident for 53 % of PACT + TAU versus 41 % of TAU (odds ratio 1.91, p = 0.074). Service costs were significantly higher for PACT + TAU (mean difference £4,489, p < 0.001), but the difference in societal costs was smaller and non-significant (mean difference £1,385, p = 0.788) due to lower informal care rates for PACT + TAU.
Improvements in outcome generated by PACT come at a cost. Although this cost is lower when burden on parents is included, the cost and effectiveness results presented do not support the cost-effectiveness of PACT + TAU compared to TAU alone.
Trial registration
Current Controlled Trials ISRCTN58133827
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-015-0700-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4685630  PMID: 26691535
Autism; Economic evaluation; Cost-effectiveness; Pre-school; Communication
4.  Psychometric Properties of the Parent-Infant Caregiving Touch Scale 
Frontiers in Psychology  2015;6:1887.
Recent work in animals suggests that the extent of early tactile stimulation by parents of offspring is an important element in early caregiving. We evaluate the psychometric properties of a new parent-report measure designed to assess frequency of tactile stimulation across multiple caregiving domains in infancy. We describe the full item set of the Parent-Infant Caregiving Touch Scale (PICTS) and, using data from a UK longitudinal Child Health and Development Study, the response frequencies and factor structure and whether it was invariant over two time points in early development (5 and 9 weeks). When their infant was 9 weeks old, 838 mothers responded on the PICTS while a stratified subsample of 268 mothers completed PICTS at an earlier 5 week old assessment (229 responded on both occasions). Three PICTS factors were identified reflecting stroking, holding and affective communication. These were moderately to strongly correlated at each of the two time points of interest and were unrelated to, and therefore distinct from, a traditional measure of maternal sensitivity at 7-months. A wholly stable psychometry over 5 and 9-week assessments was not identified which suggests that behavior profiles differ slightly for younger and older infants. Tests of measurement invariance demonstrated that all three factors are characterized by full configural and metric invariance, as well as a moderate degree of evidence of scalar invariance for the stroking factor. We propose the PICTS as a valuable new measure of important aspects of caregiving in infancy.
PMCID: PMC4678235  PMID: 26696945
mothers; infants; Parent-Infant Caregiving Touch Scale; stroking; early programming
5.  The Specific Role of Relationship Life Events in the Onset of Depression during Pregnancy and the Postpartum 
PLoS ONE  2015;10(12):e0144131.
The precipitating role of life events in the onset of depression is well-established. The present study sought to examine whether life events hypothesised to be personally salient would be more strongly associated with depression than other life events. In a sample of women making the first transition to parenthood, we hypothesised that negative events related to the partner relationship would be particularly salient and thus more strongly predictive of depression than other events.
A community-based sample of 316 first-time mothers stratified by psychosocial risk completed interviews at 32 weeks gestation and 29 weeks postpartum to assess dated occurrence of life events and depression onsets from conception to 29 weeks postpartum. Complete data was available from 273 (86.4%). Cox proportional hazards regression was used to examine risk for onset of depression in the 6 months following a relationship event versus other events, after accounting for past history of depression and other potential confounders.
52 women (19.0%) experienced an onset of depression between conception and 6 months postpartum. Both relationship events (Hazard Ratio = 2.1, p = .001) and other life events (Hazard Ratio = 1.3, p = .020) were associated with increased risk for depression onset; however, relationship events showed a significantly greater risk for depression than did other life events (p = .044).
The results are consistent with the hypothesis that personally salient events are more predictive of depression onset than other events. Further, they indicate the clinical significance of events related to the partner relationship during pregnancy and the postpartum.
PMCID: PMC4672906  PMID: 26645963
6.  The economic impact of epilepsy: a systematic review 
BMC Neurology  2015;15:245.
In this review we aimed to determine the economic impact of epilepsy and factors associated with costs to individuals and health systems.
A narrative systematic review of incidence and case series studies with prospective consecutive patient recruitment and economic outcomes published before July 2014 were retrieved from Medline, Embase and PsycInfo.
Of 322 studies reviewed, 22 studies met the inclusion criteria and 14 were from high income country settings. The total costs associated with epilepsy varied significantly in relation to the duration and severity of the condition, response to treatment, and health care setting. Where assessed, ‘out of pocket’ costs and productivity losses were found to create substantial burden on households which may be offset by health insurance. However, populations covered ostensibly for the upfront costs of care can still bear a significant economic burden.
Epilepsy poses a substantial economic burden for health systems and individuals and their families. There is uncertainty over the degree to which private health insurance or social health insurance coverage provides adequate protection from the costs of epilepsy. Future research is required to examine the role of different models of care and insurance programs in protecting against economic hardship for this condition, particularly in low and middle income settings.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-015-0494-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4660784  PMID: 26607561
Epilepsy; Direct costs; Indirect costs
7.  CD4+ cell dynamics in untreated HIV-1 infection: overall rates, and effects of age, viral load, sex and calendar time 
AIDS (London, England)  2015;29(18):2435-2446.
CD4+ cell count is a key measure of HIV disease progression, and the basis of successive international guidelines for treatment initiation. CD4+ cell dynamics are used in mathematical and econometric models for evaluating public health need and interventions. Here, we estimate rates of CD4+ decline, stratified by relevant covariates, in a form that is clinically transparent and can be directly used in such models.
We analyse the AIDS Therapy Evaluation in the Netherlands cohort, including individuals with date of seroconversion estimated to be within 1 year and with intensive clinical follow-up prior to treatment initiation. Owing to the fact that CD4+ cell counts are intrinsically noisy, we separate the analysis into long-term trends of smoothed CD4+ cell counts and an observation model relating actual CD4+ measurements to the underlying smoothed counts. We use a monotonic spline smoothing model to describe the decline of smoothed CD4+ cell counts through categories CD4+ above 500, 350–500, 200–350 and 200 cells/μl or less. We estimate the proportion of individuals starting in each category after seroconversion and the average time spent in each category. We examine individual-level cofactors which influence these parameters.
Among untreated individuals, the time spent in each compartment was 3.32, 2.70, 5.50 and 5.06 years. Only 76% started in the CD4+ cell count above 500 cells/μl compartment after seroconversion. Set-point viral load (SPVL) was an important factor: individuals with at least 5 log10 copies/ml took 5.37 years to reach CD4+ cell count less than 200 cells/μl compared with 15.76 years for SPVL less than 4 log10 copies/ml.
Many individuals already have CD4+ cell count below 500 cells/μl after seroconversion. SPVL strongly influences the rate of CD4+ decline. Treatment guidelines should consider measuring SPVL, whereas mathematical models should incorporate SPVL stratification.
PMCID: PMC4645962  PMID: 26558543
CD4+ cell count; HIV; mathematical model; set-point viral load; viral load
9.  Callous–unemotional traits in adolescents with autism spectrum disorder 
The British Journal of Psychiatry  2015;207(5):392-399.
People with callous–unemotional traits and also those with autism spectrum disorder (ASD) display sociocognitive difficulties. However, the frequency and neurocognitive correlates of callous–unemotional traits within individuals with ASD are unknown.
To determine the prevalence of callous–unemotional traits in individuals with ASD and test their association with behavioural and cognitive measures.
Parents of 92 adolescents with ASD completed the Antisocial Processes Screening Device (APSD) for callous–unemotional traits. Adolescents participated in tasks of emotion recognition, theory of mind and cognitive flexibility.
In total 51% (n = 47) scored above a cut-off expected to identify the top 6% on the APSD. Of these 17% (n = 8) had concurrent conduct problems. Regression analyses found callous–unemotional traits were associated with specific impairment in fear recognition but not with theory of mind or cognitive flexibility.
Adolescents with ASD show high rates of callous–unemotional traits but, unlike in the general population, these are not strongly associated with conduct problems. The relationship of callous–unemotional traits to impairments in fear recognition suggests similar affective difficulties as in individuals with callous–unemotional traits without ASD.
PMCID: PMC4629071  PMID: 26382954
10.  Population-based 10-year event-free survival after radical prostatectomy for patients with prostate cancer in British Columbia 
We determined (1) the 10-year survival outcomes after radical treatment of prostate cancer and (2) the 10-year event-free survival following radical prostatectomy (RP) at a population-level in British Columbia (BC), Canada.
We identified all men with a new diagnosis of prostate cancer in BC between 1999 and 2000. Those treated with RP, external beam radiotherapy (EBRT) or brachytherapy (BT) were identified. Overall survival, and prostate cancer specific survival (PCSS) were calculated from diagnosis using the Kaplan-Meier method. For those men treated with RP, we calculated the 10-year event-free survival (freedom from salvage EBRT or androgen ablation, or death from prostate cancer). Reasons for initiating androgen therapy were unknown and may include symptomatic metastatic disease or asymptomatic biochemical recurrence. An important limitation was the absence of prostate-specific antigen data for staging or follow-up.
Among 6028 incident cases, RP was the curative-intent treatment within 1 year in 1360 (22.6%) patients, EBRT in 1367 (22.7%), and BT in 357 (5.9%). The 10-year PCSS was 98% for RP, 95% for EBRT and 98% for BT (log rank p < 0.0001). The 10-year overall survival was 87%. The 10-year event-free survival for those treated with RP was 79% and varied with Gleason grade: 87%, 74%, and 52% for Gleason 2–6, 7, and 8–10, respectively (p < 0.0001).
This population-based study provides outcomes which can inform patient decision-making and provide a benchmark to which other therapies can be compared. Event-free rates for patients treated with RP vary with Gleason score. There is room for improvement in the outcomes of patients with high Gleason score treated with RP.
PMCID: PMC4707893  PMID: 26788230
11.  Eligibility for interventions, co-occurrence and risk factors for unhealthy behaviours in patients consulting for routine primary care: results from the Pre-Empt study 
BMC Family Practice  2015;16:133.
Smoking, excessive drinking, lack of exercise and a poor diet remain key causes of premature morbidity and mortality globally, yet it is not clear what proportion of patients attending for routine primary care are eligible for interventions about these behaviours, the extent to which they co-occur within individuals, and which individuals are at greatest risk for multiple unhealthy behaviours. The aim of the trial was to examine ‘intervention eligibility’ and co-occurrence of the ‘big four’ risky health behaviours – lack of exercise, smoking, an unhealthy diet and excessive drinking – in a primary care population.
Data were collected from adult patients consulting routinely in general practice across South Wales as part of the Pre-Empt study; a cluster randomised controlled trial.
After giving consent, participants completed screening instruments, which included the following to assess eligibility for an intervention based on set thresholds: AUDIT-C (for alcohol), HSI (for smoking), IPAQ (for exercise) and a subset of DINE (for diet). The intervention following screening was based on which combination of risky behaviours the patient had. Descriptive statistics, χ2 tests for association and ordinal regressions were undertaken.
Two thousand sixty seven patients were screened: mean age of 48.6 years, 61.9 % female and 42.8 % in a managerial or professional occupation. In terms of numbers of risky behaviours screened eligible for, two was the most common (43.6 %), with diet and exercise (27.2 %) being the most common combination. Insufficient exercise was the most common single risky behaviour (12.0 %). 21.8 % of patients would have been eligible for an intervention for three behaviours and 5.9 % for all four behaviours. Just 4.5 % of patients did not identify any risky behaviours. Women, older age groups and those in managerial or professional occupations were more likely to exhibit all four risky behaviours.
Very few patients consulting for routine primary care screen ineligible for interventions about common unhealthy behaviours, and most engage in more than one of the major common unhealthy behaviours. Clinicians should be particularly alert to opportunities to engaging younger, non professional men and those with multi-morbidity about risky health behaviour.
Trial registration
PMCID: PMC4600219  PMID: 26453044
Screening; Health behaviours; Primary care; Physical activity; Diet; Smoking
12.  The influence of snoring, mouth breathing and apnoea on facial morphology in late childhood: a three-dimensional study 
BMJ Open  2015;5(9):e009027.
To explore the relationship between the prevalence of sleep disordered breathing (SDB) and face shape morphology in a large cohort of 15-year-old children.
Observational longitudinal cohort study
Avon Longitudinal Study of Parents and Children (ALSPAC), South West of England.
Three-dimensional surface laser scans were taken for 4784 white British children from the ALSPAC during a follow-up clinic. A total of 1724 children with sleep disordered breathing (SDB) and 1862 healthy children were identified via parents’ report of sleep disordered symptoms for their children. We excluded from the original cohort all children identified as having congenital abnormalities, diagnoses associated with poor growth and children with adenoidectomy and/or tonsillectomy.
Main outcome measures
Parents in the ALSPAC reported sleep disordered symptoms (snoring, mouth breathing and apnoea) for their children at 6, 18, 30, 42, 57, 69 and 81 months. Average facial shells were created for children with and without SDB in order to explore surface differences.
Differences in facial measurements were found between the children with and without SDB throughout early childhood. The mean differences included an increase in face height in SDB children of 0.3 mm (95% CI −0.52 to −0.05); a decrease in mandibular prominence of 0.9° (95% CI −1.30 to −0.42) in SDB children; and a decrease in nose prominence and width of 0.12 mm (95% CI 0.00 to 0.24) and 0.72 mm (95% CI −0.10 to −0.25), respectively, in SDB children. The odds of children exhibiting symptoms of SDB increased significantly with respect to increased face height and mandible angle, but reduced with increased nose width and prominence.
The combination of a long face, reduced nose prominence and width, and a retrognathic mandible may be diagnostic facial features of SBD that may warrant a referral to specialists for the evaluation of other clinical symptoms of SDB.
PMCID: PMC4563226  PMID: 26351193
ALSPAC; sleep disordered breathing; snoring; apnoea; mouth-breathing; three-dimensional imaging
13.  The Prevalence of Cardiac Risk Factors in Men with Localized Prostate Cancer Undergoing Androgen Deprivation Therapy in British Columbia, Canada 
Journal of Oncology  2015;2015:820403.
Background. While androgen deprivation therapy (ADT) reduces the risk of prostate cancer-specific mortality in high-risk localized prostate cancer, it adversely affects cardiovascular (CV) risk factor profiles in treated men. Methods. We retrospectively reviewed the charts of 100 consecutive men with intermediate- or high-risk localized prostate cancer referred to the British Columbia Cancer Agency for ADT. Data on CV risk factors and disease were collected and Framingham risk scores were calculated. Results. The median age of the study cohort was 73 years. Established cardiovascular disease was present in 25% of patients. Among patients without established CV disease, calculated Framingham risk was high in 65%, intermediate in 33%, and low in 1%. Baseline hypertension was present in 58% of patients, dyslipidemia in 51%, and diabetes or impaired glucose tolerance in 24%. Hypertension was more prevalent in the study cohort than in an age- and sex-matched population sample (OR 1.74, P = 0.006); diabetes had a similar prevalence (OR 0.93, P = 0.8). Conclusions. Patients receiving ADT have a high prevalence of cardiovascular disease and risk factors and are more likely to be hypertensive than population controls. Low rates of CV risk screening suggest opportunities for improved primary and secondary prevention of CV disease in this population.
PMCID: PMC4537764  PMID: 26300918
14.  Reduced Face Preference in Infancy: A Developmental Precursor to Callous-Unemotional Traits? 
Biological Psychiatry  2015;78(2):144-150.
Children with callous-unemotional (CU) traits, a proposed precursor to adult psychopathy, are characterized by impaired emotion recognition, reduced responsiveness to others’ distress, and a lack of guilt or empathy. Reduced attention to faces, and more specifically to the eye region, has been proposed to underlie these difficulties, although this has never been tested longitudinally from infancy. Attention to faces occurs within the context of dyadic caregiver interactions, and early environment including parenting characteristics has been associated with CU traits. The present study tested whether infants’ preferential tracking of a face with direct gaze and levels of maternal sensitivity predict later CU traits.
Data were analyzed from a stratified random sample of 213 participants drawn from a population-based sample of 1233 first-time mothers. Infants’ preferential face tracking at 5 weeks and maternal sensitivity at 29 weeks were entered into a weighted linear regression as predictors of CU traits at 2.5 years.
Controlling for a range of confounders (e.g., deprivation), lower preferential face tracking predicted higher CU traits (p = .001). Higher maternal sensitivity predicted lower CU traits in girls (p = .009), but not boys. No significant interaction between face tracking and maternal sensitivity was found.
This is the first study to show that attention to social features during infancy as well as early sensitive parenting predict the subsequent development of CU traits. Identifying such early atypicalities offers the potential for developing parent-mediated interventions in children at risk for developing CU traits.
PMCID: PMC4510143  PMID: 25526972
Callous-unemotional traits; Face preference; Maternal sensitivity; Infant development; Precursor; Psychopathy
15.  Development of ProCaRS Clinical Nomograms for Biochemical Failure-free Survival Following Either Low-Dose Rate Brachytherapy or Conventionally Fractionated External Beam Radiation Therapy for Localized Prostate Cancer 
Cureus  null;7(6):e276.
Purpose: Although several clinical nomograms predictive of biochemical failure-free survival (BFFS) for localized prostate cancer exist in the medical literature, making valid comparisons can be challenging due to variable definitions of biochemical failure, the disparate distribution of prognostic factors, and received treatments in patient populations. The aim of this investigation was to develop and validate clinically-based nomograms for 5-year BFFS using the ASTRO II “Phoenix” definition for two patient cohorts receiving low-dose rate (LDR) brachytherapy or conventionally fractionated external beam radiation therapy (EBRT) from a large Canadian multi-institutional database.
Methods and Materials: Patients were selected from the GUROC (Genitourinary Radiation Oncologists of Canada) Prostate Cancer Risk Stratification (ProCaRS) database if they received (1) LDR brachytherapy ≥ 144 Gy (n=4208) or (2) EBRT ≥ 70 Gy  (n=822). Multivariable Cox regression analysis for BFFS was performed separately for each cohort and used to generate clinical nomograms predictive of 5-year BFFS. Nomograms were validated using calibration plots of nomogram predicted probability versus observed probability via Kaplan-Meier estimates.
Results: Patients receiving LDR brachytherapy had a mean age of 64 ± 7 years, a mean baseline PSA of 6.3 ± 3.0 ng/mL, 75% had a Gleason 6, and 15% had a Gleason 7, whereas patients receiving EBRT had a mean age of 70 ± 6 years, a mean baseline PSA of 11.6 ± 10.7 ng/mL, 30% had a Gleason 6, 55% had a Gleason 7, and 14% had a Gleason 8-10. Nomograms for 5-year BFFS included age, use and duration of androgen deprivation therapy (ADT), baseline PSA, T stage, and Gleason score for LDR brachytherapy and an ADT (months), baseline PSA, Gleason score, and biological effective dose (Gy) for EBRT.
Conclusions: Clinical nomograms examining 5-year BFFS were developed for patients receiving either LDR brachytherapy or conventionally fractionated EBRT and may assist clinicians in predicting an outcome. Future work should be directed at examining the role of additional prognostic factors, comorbidities, and toxicity in predicting survival outcomes.
PMCID: PMC4494461  PMID: 26180700
radiotherapy; prostate cancer; ldr brachytherapy; fractionated external beam radiation therapy; biochemical failure; nomogram
16.  Protocol for a multicentre randomiSed controlled TRial of IntraVEnous immunoglobulin versus standard therapy for the treatment of transverse myelitis in adults and children (STRIVE) 
BMJ Open  2015;5(5):e008312.
Transverse myelitis (TM) is an immune-mediated disorder of the spinal cord which causes motor and sensory disturbance and limited recovery in 50% of patients. Standard treatment is steroids, and patients with more severe disease appear to respond to plasma exchange (PLEX). Intravenous immunoglobulin (IVIG) has also been used as an adjunct to steroids, but evidence is lacking. We propose the first randomised control trial in adults and children, to determine the benefit of additional treatment with IVIG.
Methods and analysis
170 adults and children aged over 1 year with acute first episode TM or neuromyelitis optica (with myelitis) will be recruited over a 2.5-year period and followed up for 12 months. Participants randomised to the control arm will receive standard therapy of intravenous methylprednisolone (IVMP). The intervention arm will receive the above standard therapy, plus additional IVIG.
Primary outcome will be a 2-point improvement on the American Spinal Injury Association (ASIA) Impairment scale at 6 months postrandomisation by blinded assessors. Additional secondary and tertiary outcome measures will be collected: ASIA motor and sensory scales, Kurtzke expanded disability status scale, International Spinal Cord Injury (SCI) Bladder/Bowel Data Set, Client Services Receipt Index, Pediatric Quality of Life Inventory, EQ-5D, SCI Pain and SCI Quality of Life Data Sets. Biological samples will be biobanked for future studies. After 6-months' follow-up of the first 52 recruited patients futility analysis will be carried out. Health economics analysis will be performed to calculate cost-effectiveness. After 6 months’ recruitment futility analysis will be performed.
Ethics and dissemination
Research Ethics Committee Approval was obtained: 14/SC/1329. Current protocol: v3.0 (15/01/2015). Study findings will be published in peer-reviewed journals.
Trial registration numbers
This study is registered with EudraCT (REF: 2014-002335-34), (REF: NCT02398994) and ISRCTN (REF: 12127581).
PMCID: PMC4452744  PMID: 26009577
17.  Effects of prenatal and postnatal depression, and maternal stroking, at the glucocorticoid receptor gene 
Translational Psychiatry  2015;5(5):e560-.
In animal models, prenatal and postnatal stress is associated with elevated hypothalamic–pituitary axis (HPA) reactivity mediated via altered glucocorticoid receptor (GR) gene expression. Postnatal tactile stimulation is associated with reduced HPA reactivity mediated via increased GR gene expression. In this first study in humans to examine the joint effects of prenatal and postnatal environmental exposures, we report that GR gene (NR3C1) 1-F promoter methylation in infants is elevated in the presence of increased maternal postnatal depression following low prenatal depression, and that this effect is reversed by self-reported stroking of the infants by their mothers over the first weeks of life.
PMCID: PMC4471282  PMID: 25942041
18.  Multi-Site Clinical Evaluation of DW-MRI as a Treatment Response Metric for Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy 
PLoS ONE  2015;10(3):e0122151.
To evaluate diffusion weighted MRI (DW-MR) as a response metric for assessment of neoadjuvant chemotherapy (NAC) in patients with primary breast cancer using prospective multi-center trials which provided MR scans along with clinical outcome information.
Materials and Methods
A total of 39 patients with locally advanced breast cancer accrued from three different prospective clinical trials underwent DW-MR examination prior to and at 3–7 days (Hull University), 8–11 days (University of Michigan) and 35 days (NeoCOMICE) post-treatment initiation. Thirteen patients, 12 of which participated in treatment response study, from UM underwent short interval (<1hr) MRI examinations, referred to as “test-retest” for examination of repeatability. To further evaluate stability in ADC measurements, a thermally controlled diffusion phantom was used to assess repeatability of diffusion measurements. MRI sequences included contrast-enhanced T1-weighted, when appropriate, and DW images acquired at b-values of 0 and 800 s/mm2. Histogram analysis and a voxel-based analytical technique, the Parametric Response Map (PRM), were used to derive diffusion response metrics for assessment of treatment response prediction.
Mean tumor apparent diffusion coefficient (ADC) values generated from patient test-retest examinations were found to be very reproducible (|ΔADC|<0.1x10-3mm2/s). This data was used to calculate the 95% CI from the linear fit of tumor voxel ADC pairs of co-registered examinations (±0.45x10-3mm2/s) for PRM analysis of treatment response. Receiver operating characteristic analysis identified the PRM metric to be predictive of outcome at the 8–11 (AUC = 0.964, p = 0.01) and 35 day (AUC = 0.770, p = 0.05) time points (p<.05) while whole-tumor ADC changes where significant at the later 35 day time interval (AUC = 0.825, p = 0.02).
This study demonstrates the feasibility of performing a prospective analysis of DW-MRI as a predictive biomarker of NAC in breast cancer patients. In addition, we provide experimental evidence supporting the use of sensitive analytical tools, such as PRM, for evaluating ADC measurements.
PMCID: PMC4376686  PMID: 25816249
19.  Doctors’ approaches to PSA testing and overdiagnosis in primary healthcare: a qualitative study 
BMJ Open  2015;5(3):e006367.
(1) To explain general practitioners’ (GPs’) approaches to prostate-specific antigen (PSA) testing and overdiagnosis; (2) to explain how GPs reason about their PSA testing routines and (3) to explain how these routines influence GPs’ personal experience as clinicians.
Primary care practices in Australia including men's health clinics and rural practices with variable access to urology services.
32 urban and rural GPs within Australia. We included GPs of varying ages, gender (11 female), clinical experience and patient populations. All GPs interested in participating in the study were included.
Primary and secondary outcome measure(s)
Data were analysed using grounded theory methods to determine how and why GPs provide (or do not provide) PSA testing to their asymptomatic male patients.
We observed patterned variation in GP practice, and identified four heuristics to describe GP preference for, and approaches to, PSA testing and overdiagnosis: (1) GPs who prioritised avoiding underdiagnosis, (2) GPs who weighed underdiagnosis and overdiagnosis case by case, (3) GPs who prioritised avoiding overdiagnosis and (4) GPs who did not engage with overdiagnosis at all. The heuristics guided GPs’ Routine Practice (usual testing, communication and responses to patient request). The heuristics also reflected GPs’ different Practice Rationales (drawing on experience, medicolegal obligations, guidelines and evidence) and produced different Practice Outcomes (GPs’ experiences of the consequences of their PSA testing decisions). Some of these heuristics were more responsive to patient preferences than others.
Variation in GPs’ PSA testing practices is strongly related to their approach to overdiagnosis and underdiagnosis of prostate cancer. Men receive very different care depending on their GP's reasoning and practice preferences. Future policy to address overdiagnosis will be more likely to succeed if it responds to these patterned variations.
PMCID: PMC4368999  PMID: 25783420
20.  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.
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.
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.
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.
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.
PMCID: PMC4304839  PMID: 25616135
21.  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.
PMCID: PMC4286259  PMID: 17658718
separation anxiety; disorders; anxiety; DSM-IV; impairment; clinical significance criterion
22.  Inter-plant communication through mycorrhizal networks mediates complex adaptive behaviour in plant communities 
AoB Plants  2015;7:plv050.
Trees can communicate with each other through networks in soil. Much like social networks or neural networks, the fungal mycelia of mycorrhizas allow signals to be sent between trees in a forest. These mycorrhizal networks are effectively an information highway, with recent studies demonstrating the exchange of nutritional resources, defence signals and allelochemicals. Sensing and responding to networked signals elicits complex behavioural responses in plants. This ability to communicate ('tree talk') is a foundational process in forest ecosystems.
Adaptive behaviour of plants, including rapid changes in physiology, gene regulation and defence response, can be altered when linked to neighbouring plants by a mycorrhizal network (MN). Mechanisms underlying the behavioural changes include mycorrhizal fungal colonization by the MN or interplant communication via transfer of nutrients, defence signals or allelochemicals. We focus this review on our new findings in ectomycorrhizal ecosystems, and also review recent advances in arbuscular mycorrhizal systems. We have found that the behavioural changes in ectomycorrhizal plants depend on environmental cues, the identity of the plant neighbour and the characteristics of the MN. The hierarchical integration of this phenomenon with other biological networks at broader scales in forest ecosystems, and the consequences we have observed when it is interrupted, indicate that underground ‘tree talk’ is a foundational process in the complex adaptive nature of forest ecosystems.
PMCID: PMC4497361  PMID: 25979966
Complex adaptive systems; ectomycorrhiza; forests; mycorrhizal networks; plant behaviour; plant communication
23.  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;15:187.
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.
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.
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).
PMCID: PMC4251943  PMID: 25425162
Urinary Tract Infection; Primary care; Adult women; Point-of-care-test; Near-patient testing; Antibiotic resistance; Cost effectiveness
24.  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.
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.
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.
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.
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.
PMCID: PMC4204894  PMID: 25333501
25.  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.
We aimed to characterize the antiretroviral therapy (ART) cascade among female sex workers (FSWs) globally.
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).
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).
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.
PMCID: PMC4179256  PMID: 25265158

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