The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda.

Inadequate T-cell control of Kaposi sarcoma-associated herpesvirus (KSHV) infection predisposes to development of Kaposi sarcoma (KS), but little is known about the T-cell response to KSHV. Postulating that KS tumors contain abundant KSHV-specific T-cells, we performed transcriptional profiling and T-cell receptor (TCR) repertoire analysis of tumor biopsies from 144 Ugandan adults with KS. We show that CD8+ T-cells and M2-polarized macrophages dominate the tumor micro-environment (TME). The TCR repertoire of KS tumor infiltrating lymphocytes (TIL) is shared across non-contiguous tumors and persists across time. Clusters of T-cells with predicted shared specificity for uncharacterized antigens, potentially encoded by KSHV, comprise ~25% of KS TIL, and are shared across tumors from different time points and individuals. Single-cell RNA-sequencing of blood identifies a non-proliferating effector memory phenotype and captured the TCRs in 14,698 putative KSHV-specific T-cells. These results suggest that a polyspecific KSHV-specific T-cell response inhibited by M2 macrophages exists within the KS TME, and provide a foundation for studies to define its specificity at a large scale.

Direct Observation of Group-V Dopant Substitutional Defects in CdTe Single Crystals.

Point defect chemistry strongly affects the fundamental properties of materials and has a decisive impact on device performance. The Group-V dopant is prominent acceptor species with high hole concentration in CdTe; however, its local atomic structure is still not clear owing to difficulties in definitive measurements and discrepancies between experimental observations and theoretical models. Herein, we report on direct observation of the local structure for the As dopant in CdTe single crystals by the X-ray fluorescence holography (XFH) technique, which is a powerful tool to visualize three-dimensional atomic configurations around a specific element. The XFH result shows the As substituting on both Cd (AsCd) and Te (AsTe) sites. Although AsTe has been well known as a shallow acceptor, AsCd has not attracted much attention and been discussed so far. Our results provide new insights into point defects by expanding the experimental XFH study in combination with theoretical first-principles studies in II-VI semiconductors.

Research to Translation: The Healthy Schools Toolkit and New Approaches to the Whole School, Whole Community, Whole Child Model.

BACKGROUND: The Whole School, Whole Community, Whole Child (WSCC) model is an evidence-based comprehensive framework to address health in schools. WSCC model use improves health and educational outcomes, but implementation remains a challenge. METHODS: Working with 6 schools in 2 districts in the Midwest, we used a mixed-methods approach to determine the people, systems, and messages needed to activate WSCC implementation. We report on social network analysis and message testing findings and research translation to develop the Healthy Schools Toolkit. RESULTS: Social networks for both districts included more than 150 individuals. Both demonstrated network densities less than half of the desirable threshold, with evidence of clustering by role and minimal cross-school relationships, posing challenges for WSCC implementation. Across stakeholder groups, messages that emphasize empathy, teamwork, and action were well-received, especially when shared by trusted individuals through communication channels that align with stakeholder needs. CONCLUSIONS: The Healthy Schools Toolkit provides an example of a translational product that helps to bridge research with practice. With features that highlight 6 design principles, the toolkit provides complementary activities that schools and districts can use as they plan for integration of the WSCC model.

Calorie restriction during gestation affects ovarian reserve in offspring in the mouse.

The aim of this study was to investigate the effect of calorie restriction (CR) during pregnancy in mice on metabolism and ovarian function in the offspring. Pregnant female mice were divided into two groups, a control group and a CR group (n=7 in each). Mice in the CR group were fed 50% of the amount consumed by control females from Day 10 of gestation until delivery. After weaning, the offspring received diet ad libitum until 3 months of age, when ovaries were collected. Ovaries were serially cut and every sixth section was used for follicle counting. Female offspring from CR dams tended to have increased bodyweight compared with offspring from control females (P=0.08). Interestingly, fewer primordial follicles (60% reduction; P=0.001), transitional follicles (P=0.0006) and total follicles (P=0.006) were observed in offspring from CR mothers. The number of primary, secondary and tertiary follicles did not differ between the groups (P>0.05). The CR offspring had fewer DNA double-strand breaks in primary follicle oocytes (P=0.03). In summary, CR during the second half of gestation decreased primordial ovarian follicle reserve in female offspring. These findings suggest that undernutrition during the second half of gestation may decrease the reproductive lifespan of female offspring.

Cognitive behavioral therapy may have a rehabilitative, not normalizing, effect on functional connectivity in adolescent depression.

BACKGROUND: Whether the differences in brain structure and function, characteristic of adult major depressive disorder (MDD1), are present in adolescent MDD is still unclear, but it has been shown that cognitive behavioral therapy (CBT2) affects resting-state functional connectivity in both adult and adolescent MDD patients, with the claim that CBT has a normalizing effect on MDD-related functional disruption, but this has not been directly tested. METHODS: 128 adolescent MDD patients and 40 adolescent controls were enrolled in the study. We investigated pre-treatment differences in cortical thickness, white matter volume, and resting-state functional connectivity. We also investigated the longitudinal effects of CBT on resting-state functional connectivity, and the relationship between pre-treatment functional disruption and CBT-related changes to resting-state functional connectivity was assessed by the correlation of pre-treatment cross-sectional effects and longitudinal CBT-related effects across multiple brain regions. RESULTS: Patients had greater cortical thickness and white matter volume within fronto-limbic regions of the brain. Patients had greater pre-treatment resting-state functional connectivity within the default-mode, fronto-limbic, central-executive, and salience networks. CBT increased resting-state functional connectivity of the subgenual anterior cingulate and amygdala seeds with predominantly frontal regions. Regions showing the greatest pre-treatment functional disruption showed the weakest CBT-related changes. LIMITATIONS: For ethical reasons, there was no placebo group. CONCLUSIONS: Adolescent MDD is associated with structural and functional differences also seen in adult patients. CBT-related changes in resting-state functional connectivity do not appear to show a normalizing effect, but instead indicate rehabilitative effects on resting-state functional connectivity.

Effect of caloric restriction and rapamycin on ovarian aging in mice.

Caloric restriction (CR) increases the preservation of the ovarian primordial follicular reserve, which can potentially delay menopause. Rapamycin also increases preservation on the ovarian reserve, with similar mechanism to CR. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on metabolism, ovarian reserve, and gene expression in mice. Thirty-six female mice were allocated into three groups: control, rapamycin-treated (4 mg/kg body weight every other day), and 30% CR. Caloric restricted females had lower body weight (P < 0.05) and increased insulin sensitivity (P = 0.003), while rapamycin injection did not change body weight (P > 0.05) and induced insulin resistance (P < 0.05). Both CR and rapamycin females displayed a higher number of primordial follicles (P = 0.02 and 0.04, respectively), fewer primary, secondary, and tertiary follicles (P < 0.05) and displayed increased ovarian Foxo3a gene expression (P < 0.05). Despite the divergent metabolic effects of the CR and rapamycin treatments, females from both groups displayed a similar increase in ovarian reserve, which was associated with higher expression of ovarian Foxo3a.

The utility of serology for elimination surveillance of trachoma.

Robust surveillance methods are needed for trachoma control and recrudescence monitoring, but existing methods have limitations. Here, we analyse data from nine trachoma-endemic populations and provide operational thresholds for interpretation of serological data in low-transmission and post-elimination settings. Analyses with sero-catalytic and antibody acquisition models provide insights into transmission history within each population. To accurately estimate sero-conversion rates (SCR) for trachoma in populations with high-seroprevalence in adults, the model accounts for secondary exposure to Chlamydia trachomatis due to urogenital infection. We estimate the population half-life of sero-reversion for anti-Pgp3 antibodies to be 26 (95% credible interval (CrI): 21-34) years. We show SCRs below 0.015 (95% confidence interval (CI): 0.0-0.049) per year correspond to a prevalence of trachomatous inflammation-follicular below 5%, the current threshold for elimination of active trachoma as a public health problem. As global trachoma prevalence declines, we may need cross-sectional serological survey data to inform programmatic decisions.

Restrictive versus liberal blood transfusion for acute upper gastrointestinal bleeding (TRIGGER): a pragmatic, open-label, cluster randomised feasibility trial.

BACKGROUND: Transfusion thresholds for acute upper gastrointestinal bleeding are controversial. So far, only three small, underpowered studies and one single-centre trial have been done. Findings from the single-centre trial showed reduced mortality with restrictive red blood cell (RBC) transfusion. We aimed to assess whether a multicentre, cluster randomised trial is a feasible method to substantiate or refute this finding. METHODS: In this pragmatic, open-label, cluster randomised feasibility trial, done in six university hospitals in the UK, we enrolled all patients aged 18 years or older with new presentations of acute upper gastrointestinal bleeding, irrespective of comorbidity, except for exsanguinating haemorrhage. We randomly assigned hospitals (1:1) with a computer-generated randomisation sequence (random permuted block size of 6, without stratification or matching) to either a restrictive (transfusion when haemoglobin concentration fell below 80 g/L) or liberal (transfusion when haemoglobin concentration fell below 100 g/L) RBC transfusion policy. Neither patients nor investigators were masked to treatment allocation. Feasibility outcomes were recruitment rate, protocol adherence, haemoglobin concentration, RBC exposure, selection bias, and information to guide design and economic evaluation of the phase 3 trial. Main exploratory clinical outcomes were further bleeding and mortality at day 28. We did analyses on all enrolled patients for whom an outcome was available. This trial is registered, ISRCTN85757829 and NCT02105532. FINDINGS: Between Sept 3, 2012, and March 1, 2013, we enrolled 936 patients across six hospitals (403 patients in three hospitals with a restrictive policy and 533 patients in three hospitals with a liberal policy). Recruitment rate was significantly higher for the liberal than for the restrictive policy (62% vs 55%; p=0·04). Despite some baseline imbalances, Rockall and Blatchford risk scores were identical between policies. Protocol adherence was 96% (SD 10) in the restrictive policy vs 83% (25) in the liberal policy (difference 14%; 95% CI 7-21; p=0·005). Mean last recorded haemoglobin concentration was 116 (SD 24) g/L for patients on the restrictive policy and 118 (20) g/L for those on the liberal policy (difference -2·0 [95% CI -12·0 to 7·0]; p=0·50). Fewer patients received RBCs on the restrictive policy than on the liberal policy (restrictive policy 133 [33%] vs liberal policy 247 [46%]; difference -12% [95% CI -35 to 11]; p=0·23), with fewer RBC units transfused (mean 1·2 [SD 2·1] vs 1·9 [2·8]; difference -0·7 [-1·6 to 0·3]; p=0·12), although these differences were not significant. We noted no significant difference in clinical outcomes. INTERPRETATION: A cluster randomised design led to rapid recruitment, high protocol adherence, separation in degree of anaemia between groups, and non-significant reduction in RBC transfusion in the restrictive policy. A large cluster randomised trial to assess the effectiveness of transfusion strategies for acute upper gastrointestinal bleeding is both feasible and essential before clinical practice guidelines change to recommend restrictive transfusion for all patients with acute upper gastrointestinal bleeding. FUNDING: NHS Blood and Transplant Research and Development.

Molecular variation in AVP and AVPR1a in New World monkeys (Primates, Platyrrhini): evolution and implications for social monogamy.

The neurohypophysial hormone arginine vasopressin (AVP) plays important roles in fluid regulation and vascular resistance. Differences in AVP receptor expression, particularly mediated through variation in the noncoding promoter region of the primary receptor for AVP (AVPR1a), may play a role in social phenotypes, particularly social monogamy, in rodents and humans. Among primates, social monogamy is rare, but is common among New World monkeys (NWM). AVP is a nonapeptide and generally conserved among eutherian mammals, although a recent paper demonstrated that some NWM species possess a novel form of the related neuropeptide hormone, oxytocin. We therefore characterized variation in the AVP and AVPR1a genes in 22 species representing every genus in the three major platyrrhine families (Cebidae, Atelidae and Pitheciidae). For AVP, a total of 16 synonymous substitutions were detected in 15 NWM species. No non-synonymous substitutions were noted, hence, AVP is conserved in NWM. By contrast, relative to the human AVPR1a, 66 predicted amino acids (AA) substitutions were identified in NWM. The AVPR1a N-terminus (ligand binding domain), third intracellular (G-protein binding domain), and C-terminus were variable among species. Complex evolution of AVPR1a is also apparent in NWM. A molecular phylogenetic tree inferred from AVPR1a coding sequences revealed some consensus taxonomic separation by families, but also a mixed group composed of genera from all three families. The overall dN/dS ratio of AVPR1a was 0.11, but signals of positive selection in distinct AVPR1a regions were observed, including the N-terminus, in which we identified six potential positive selection sites. AA substitutions at positions 241, 319, 399 and 409 occurred uniquely in marmosets and tamarins. Our results enhance the appreciation of genetic diversity in the mammalian AVP/AVPR1a system, and set the stage for molecular modeling of the neurohypophyseal hormones and social behavior in primates.

Restrictive vs liberal blood transfusion for acute upper gastrointestinal bleeding: rationale and protocol for a cluster randomized feasibility trial.

Acute upper gastrointestinal bleeding (AUGIB) is the commonest reason for hospitalization with hemorrhage in the UK and the leading indication for transfusion of red blood cells (RBCs). Observational studies suggest an association between more liberal RBC transfusion and adverse patient outcomes, and a recent randomised trial reported increased further bleeding and mortality with a liberal transfusion policy. TRIGGER (Transfusion in Gastrointestinal Bleeding) is a pragmatic, cluster randomized trial which aims to evaluate the feasibility and safety of implementing a restrictive versus liberal RBC transfusion policy in adult patients admitted with AUGIB. The trial will take place in 6 UK hospitals, and each centre will be randomly allocated to a transfusion policy. Clinicians throughout each hospital will manage all eligible patients according to the transfusion policy for the 6-month trial recruitment period. In the restrictive centers, patients become eligible for RBC transfusion when their hemoglobin is <8 g/dL. In the liberal centers patients become eligible for transfusion once their hemoglobin is <10 g/dL. All clinicians will have the discretion to transfuse outside of the policy but will be asked to document the reasons for doing so. Feasibility outcome measures include protocol adherence, recruitment rate, and evidence of selection bias. Clinical outcome measures include further bleeding, mortality, thromboembolic events, and infections. Quality of life will be measured using the EuroQol EQ-5D at day 28, and the costs associated with hospitalization for AUGIB in the UK will be estimated. Consent will be sought from participants or their representatives according to patient capacity for use of routine hospital data and day 28 follow up. The study has ethical approval for conduct in England and Scotland. Results will be analysed according to a pre-defined statistical analysis plan and disseminated in peer reviewed publications to relevant stakeholders. The results of this study will inform the feasibility and design of a phase III randomized trial.

Prevalence, management, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding in the United Kingdom.

BACKGROUND: Coagulopathy after major hemorrhage has been found to be an independent risk factor for mortality after traumatic bleeding. It is unclear whether similar associations are present in other causes of major hemorrhage. We describe the prevalence, use of plasma, and outcomes of patients with coagulopathy after acute nonvariceal upper gastrointestinal bleeding (NVUGIB). STUDY DESIGN AND METHODS: This study was a multicenter UK national audit. Data were collected prospectively on consecutive admissions with upper gastrointestinal bleeding over a 2-month period to 212 UK hospitals. Coagulopathy was defined as an international normalized ratio (INR) of at least 1.5. Logistic regression was used to examine the relationship between coagulopathy and patient-related outcome measures of mortality, rebleeding, and need for surgery and/or radiologic intervention. RESULTS: A total of 4478 patients were included in the study. Coagulopathy was present in 16.4% (444/2709) of patients in whom an INR was recorded. Patients with coagulopathy were more likely to present with hemodynamic shock (45% vs. 36%), have a higher clinical Rockall score (4 vs. 2), receive red blood cell transfusion (79% vs. 48%) and have high-risk stigmata of hemorrhage at endoscopy (34% vs. 25%). After adjustment for confounders the presence of a coagulopathy was associated with a fivefold increased in the odds of mortality (odds ratio, 5.63; 95% confidence interval, 3.09-10.27; p < 0.001). Only 35% of patients with coagulopathy received fresh-frozen plasma transfusion. CONCLUSIONS: Coagulopathy was prevalent in 16% of patients after NVUGIB and independently associated with more than a fivefold increase in the odds of in-hospital mortality. Wide variation in plasma use exists indicates clinical uncertainty regarding optimal practice.

Major earthquakes occur regularly on an isolated plate boundary fault.

The scarcity of long geological records of major earthquakes, on different types of faults, makes testing hypotheses of regular versus random or clustered earthquake recurrence behavior difficult. We provide a fault-proximal major earthquake record spanning 8000 years on the strike-slip Alpine Fault in New Zealand. Cyclic stratigraphy at Hokuri Creek suggests that the fault ruptured to the surface 24 times, and event ages yield a 0.33 coefficient of variation in recurrence interval. We associate this near-regular earthquake recurrence with a geometrically simple strike-slip fault, with high slip rate, accommodating a high proportion of plate boundary motion that works in isolation from other faults. We propose that it is valid to apply time-dependent earthquake recurrence models for seismic hazard estimation to similar faults worldwide.

Red blood cell transfusion practice in patients presenting with acute upper gastrointestinal bleeding: a survey of 815 UK clinicians.

BACKGROUND: Acute upper gastrointestinal bleeding (AUGIB) accounts for 14% of all red blood cell (RBC) transfusions in the United Kingdom, despite little evidence to guide optimal blood transfusion strategies and few data on the variation in practice. We aimed to survey UK clinicians about their RBC transfusion practice in AUGIB. STUDY DESIGN AND METHODS: A survey describing six clinical vignettes of AUGIB was sent to practicing gastroenterologists, acute care physicians, and upper gastrointestinal surgeons. Respondents were asked to select a hemoglobin (Hb) trigger at which they would ordinarily transfuse RBCs. RESULTS: The response rate was 48% (815/1709). Transfusion triggers differed significantly between all six cases (p < 0.001). There was significant variation in the selected Hb trigger between different clinical specialties for five of the six scenarios. Surgeons were more likely to select a lower Hb transfusion trigger than physicians across all six scenarios (p < 0.005), as were clinicians who had graduated more recently (p < 0.05 for Scenarios 1-3). The responses suggested the belief that restrictive use of RBCs is appropriate, which is in part discordant with actual observed practice. Only 70% of respondents reported familiarity with national guidelines for AUGIB. CONCLUSIONS: There is significant variation in the reported approach to transfusion practice among clinicians caring for patients with AUGIB, with both patient- and clinician-related factors accounting for these differences. Further studies are needed to evaluate the safety and efficacy of differing blood transfusion strategies in patients presenting with AUGIB.

Acute upper gastrointestinal bleeding in the UK: patient characteristics, diagnoses and outcomes in the 2007 UK audit.

OBJECTIVE: To describe the patient characteristics, diagnoses and clinical outcomes of patients presenting with acute upper gastrointestinal bleeding (AUGIB) in the 2007 UK Audit. DESIGN: Multi-centre survey. SETTING: All UK hospitals admitting patients with AUGIB. PARTICIPANTS: All adults (>16 years) presenting in or to UK hospitals with AUGIB between 1 May and 30 June 2007. RESULTS: Data on 6750 patients (median age 68 years) was collected from 208 participating hospitals. New admissions (n=5550) were younger (median age 65 years) than inpatients (n=1107, median age 71 years), with less co-morbidity (any co-morbidity 46% vs 71%, respectively). At presentation 9% (599/6750) had known cirrhosis, 26% a history of alcohol excess, 11% were taking non-steroidal anti-inflammatory drugs and 28% aspirin. Peptic ulcer disease accounted for 36% of AUGIB and bleeding varices 11%. In 13% there was evidence of further bleeding after the first endoscopy. 1.9% underwent surgery and 1.2% interventional radiology for AUGIB. Median length of stay was 5 days. Overall mortality in hospital was 10% (675/6750, 95% CI 9.3 to 10.7), 7% in new admissions and 26% among inpatients. Mortality was highest in those with variceal bleeding (15%) and with malignancy (17%). CONCLUSIONS: AUGIB continues to result in substantial mortality although it appears to be lower than in 1993. Mortality is particularly high among inpatients and those bleeding from varices or upper gastrointestinal malignancy. Surgical or radiological interventions are little used currently.

Use of endoscopy for management of acute upper gastrointestinal bleeding in the UK: results of a nationwide audit.

OBJECTIVES: To examine the use of endoscopy in the UK for acute upper gastrointestinal bleeding (AUGIB) and compare with published standards. To assess the organisation of endoscopy services for AUGIB in the UK. To examine the relationship between outcomes and out of hours (OOH) service provision. DESIGN: Multi-centre cross sectional clinical audit. SETTING: All UK hospitals accepting admissions with AUGIB. PATIENTS: All adults (>or=16 yrs) presenting with AUGIB between 1st May and 30th June 2007. DATA: Collection A custom designed web-based reporting tool was used to collect data on patient characteristics, comorbidity and haemodynamic status at presentation to calculate the Rockall score, use and timing of endoscopy, treatment including endoscopic, rebleeding and in-hospital mortality. A mailed questionnaire was used to collect data on facilities and service organisation. RESULTS: Data on 6750 patients (median age 68 years) were analysed from 208 hospitals. 74% underwent inpatient endoscopy; of these 50% took place within 24 h of presentation, 82% during normal working hours and 3% between midnight and 8 am. Of patients deemed high-risk (pre-endoscopy Rockall score >or=5) only 55% were endoscoped within 24 h and 14% waited >or=72 h for endoscopy. Lesions with a high risk of rebleeding were present in 28% of patients of whom 74% received endoscopic therapy. Further bleeding was evident in 13% and mortality in those endoscoped was 7.4% (95% CI 6.7% to 8.1%). In 52% of hospitals a consultant led out of hours (OOH) endoscopy rota existed; in these hospitals 20% of first endoscopies were performed OOH compared with 13% in those with no OOH rota and endoscopic therapy was more likely to be administered (25% vs 21% in hospitals with no OOH rota). The risk adjusted mortality ratio was higher (1.21, p=0.10, (95%CI 0.96 to 1.51)) in hospitals without such rotas. CONCLUSIONS: This audit has found continuing delays in performing endoscopy after AUGIB and underutilisation of standard endoscopic therapy particularly for variceal bleeding. In hospitals with a formal OOH endoscopy rota patients received earlier endoscopy, were more likely to receive endoscopic therapy and may have a lower mortality.

3D Topology Preserving Flows for Viewpoint-Based Cortical Unfolding.

We present a variational method for unfolding of the cortex based on a user-chosen point of view as an alternative to more traditional global flattening methods, which incur more distortion around the region of interest. Our approach involves three novel contributions. The first is an energy function and its corresponding gradient flow to measure the average visibility of a region of interest of a surface with respect to a given viewpoint. The second is an additional energy function and flow designed to preserve the 3D topology of the evolving surface. The third is a method that dramatically improves the computational speed of the 3D topology preservation approach by creating a tree structure of the 3D surface and using a recursion technique. Experiments results show that the proposed approach can successfully unfold highly convoluted surfaces such as the cortex while preserving their topology.

A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

OBJECTIVES: To determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with selective serotonin reuptake inhibitors (SSRIs) plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. DESIGN: A pragmatic randomised controlled trial (RCT) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation. SETTING: Six English CAMHS participated in the study. PARTICIPANTS: A total of 208 patients aged between 11 and 17 years were recruited and randomised. INTERVENTIONS: All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT. MAIN OUTCOME MEASURES: The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS). RESULTS: Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on a severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at any time point. This lack of difference held when baseline and treatment characteristics where taken into account (age, sex, severity, co-morbid characteristics, quality and quantity of CBT treatment, number of clinic attendances). The SSRI + CBT group was somewhat more expensive over the 28 weeks than the SSRI-only group (p=0.057) and no more cost-effective. Over the trial period there was on average a decrease in suicidal thoughts and self-harm compared with levels recorded at baseline. There was no significant increase in disinhibition, irritability and violence compared with levels at baseline. Around 20% (n=40) of patients in the trial were non-responders. Of these, 17 (43%) showed no improvement by 28 weeks and 23 (57%) were considered minimally (n=10) or moderately to severely worse (n=13). CONCLUSIONS: For moderately to severely depressed adolescents who are non-responsive to a BII, the addition of CBT to fluoxetine plus routine clinical care does not improve outcome or confer protective effects against adverse events and is not cost-effective. SSRIs (mostly fluoxetine) are not likely to result in harmful adverse effects. The findings are broadly consistent with existing guidelines on the treatment of moderate to severe depression. Modification is advised for those presenting with moderate (6-8 symptoms) to severe depressions (>8 symptoms) and in those with either overt suicidal risk and/or high levels of personal impairment. In such cases, the time allowed for response to psychosocial interventions should be no more than 2-4 weeks, after which fluoxetine should be prescribed. Further research should focus on evaluating the efficacy of specific psychological treatments against brief psychological intervention, determining the characteristics of patients with severe depression who are non-responsive to fluoxetine, relapse prevention in severe depression and improving tools for determining treatment responders and non-responders.

Cost-effectiveness of selective serotonin reuptake inhibitors and routine specialist care with and without cognitive behavioural therapy in adolescents with major depression.

BACKGROUND: Major depression is an important and costly problem among adolescents, yet evidence to support the provision of cost-effective treatments is lacking. AIMS: To assess the short-term cost-effectiveness of combined selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) together with clinical care compared with SSRIs and clinical care alone in adolescents with major depression. METHOD: Pragmatic randomised controlled trial in the UK. Outcomes and costs were assessed at baseline, 12 and 28 weeks. RESULTS: The trial comprised 208 adolescents, aged 11-17 years, with major or probable major depression who had not responded to a brief initial psychosocial intervention. There were no significant differences in outcome between the groups with and without CBT. Costs were higher in the group with CBT, although not significantly so (P=0.057). Cost-effectiveness analysis and exploration of the associated uncertainty suggest there is less than a 30% probability that CBT plus SSRIs is more cost-effective than SSRIs alone. CONCLUSIONS: A combination of CBT plus SSRIs is not more cost-effective in the short-term than SSRIs alone for treating adolescents with major depression in receipt of routine specialist clinical care.

A hybrid Eulerian-Lagrangian approach for thickness, correspondence, and gridding of annular tissues.

We present a novel approach to efficiently compute thickness, correspondence, and gridding of tissues between two simply connected boundaries. The solution of Laplace's equation within the tissue region provides a harmonic function whose gradient flow determines the correspondence trajectories going from one boundary to the other. The proposed method uses and expands upon two recently introduced techniques in order to compute thickness and correspondences based on these trajectories. Pairs of partial differential equations are efficiently computed within an Eulerian framework and combined with a Lagrangian approach so that correspondences trajectories are partially constructed when necessary. Examples are presented in order to compare the performance of this method with those of the pure Lagrangian and pure Eulerian approaches. Results show that the proposed technique takes advantage of both the speed of the Eulerian approach and the accuracy of the Lagrangian approach.

Validity of the Rockall scoring system after endoscopic therapy for bleeding peptic ulcer: a prospective cohort study.

BACKGROUND: The Rockall scoring system was developed in unselected patients, the majority of whom did not receive endoscopic therapy. The aim of this study was to assess the validity of the Rockall system in high-risk patients who undergo endoscopic therapy for peptic ulcer hemorrhage. METHODS: Rockall scores were calculated in 247 patients with major peptic ulcer bleeding entered into a randomized trial of endoscopic therapy. The observed rates of recurrent bleeding and mortality after endoscopic therapy were compared with predicted rates derived from Rockall's study group. The validity of the Rockall system was assessed in terms of calibration and discrimination. RESULTS: Rates of recurrent bleeding and mortality after endoscopic therapy increased with an increasing Rockall score. Observed rates of recurrent bleeding and mortality were below predicted rates, and calibration of the Rockall system was poor (Mantel-Haenszel chi square = 25.8, p < 0.0001 for recurrent bleeding; Mantel-Haenszel chi square = 15.1, p < 0.0001 for death). For the prediction of recurrent bleeding, the area under the receiver operating characteristic curve was low (63.4%), but the system was satisfactory when predicting mortality (area under the resulting curve, 84.3%). CONCLUSIONS: After endoscopic therapy for a bleeding peptic ulcer, the Rockall scoring system can identify patients at high risk of death, but it is inadequate for the prediction of recurrent bleeding.