Test of cure and beyond: superiority of thermal ablation over LLETZ in the treatment of high-grade CIN.

PURPOSE: Among the treatment modalities for high-grade cervical intraepithelial neoplasia (CIN), large-loop excision of the transformation zone (LLETZ) is the commonest offered in the UK, whereas thermal ablation (TA) has not been common in several decades, despite several notable advantages. TA and LLETZ are both routinely undertaken in our colposcopy unit, and extensive follow-up data have been used to interrogate outcomes between the two modalities and determine whether one modality may be preferred over the other. METHODS: Up to 8 years of follow-up data (cytology and histology) were collected for patients who have undergone LLETZ or TA and failed post-treatment test of cure (ToC). These data were analysed and used to plot Kaplan-Meier survival curves, in order to compare outcomes: negative cytology, dyskaryosis, low- and high-grade CIN and invasive squamous cell carcinoma. RESULTS: i) Very few women treated with TA developed recurrent high-grade CIN in the follow-up period; (ii) LLETZ-treated women had a significantly higher rate of recurrence than those treated by TA; (iii) women who failed both virology and cytology components of post-treatment ToC had higher recurrence than those who failed only one, and the rate of recurrence was highest in those treated by LLETZ (> 65%). CONCLUSION: TA is an effective treatment of high-grade CIN, with a high chance of achieving double-negative ToC and low recurrence relative to LLETZ. We recommend the wider adoption of TA, so that young women of reproductive age have a choice of treatment with no reported adverse effects on pregnancy outcomes.

Manipulating twisted electrons in strong-field ionization.

We investigate the discrete orbital angular momentum (OAM) of photoelectrons freed in strong-field ionization. We use these 'twisted' electrons to provide an alternative interpretation on existing experimental work of vortex interferences caused by strong field ionization mediated by two counter-rotating circularly polarized pulses separated by a delay. Using the strong field approximation, we derive an interference condition for the vortices. In computations for a neon target we find very good agreement of the vortex condition with photoelectron momentum distributions computed with the strong field approximation, as well as with the time-dependent methods Qprop and R-Matrix. For each of these approaches we examine the OAM of the photoelectrons, finding a small number of vortex states localized in separate energy regions. We demonstrate that the vortices arise from the interference of pairs of twisted electron states. The OAM of each twisted electron state can be directly related to the number of arms of the spiral in that region. We gain further understanding by recreating the vortices with pairs of twisted electrons and use this to determine a semiclassical relation for the OAM. A discussion is included on measuring the OAM in strong field ionization directly or by employing specific laser pulse schemes as well as utilizing the OAM in time-resolved imaging of photo-induced dynamics.

Testing for causality between systematically identified risk factors and glioma: a Mendelian randomization study.

BACKGROUND: Whilst epidemiological studies have provided evidence of associations between certain risk factors and glioma onset, inferring causality has proven challenging. Using Mendelian randomization (MR), we assessed whether associations of 36 reported glioma risk factors showed evidence of a causal relationship. METHODS: We performed a systematic search of MEDLINE from inception to October 2018 to identify candidate risk factors and conducted a meta-analysis of two glioma genome-wide association studies (5739 cases and 5501 controls) to form our exposure and outcome datasets. MR analyses were performed using genetic variants to proxy for candidate risk factors. We investigated whether risk factors differed by subtype diagnosis (either glioblastoma (n = 3112) or non-glioblastoma (n = 2411)). MR estimates for each risk factor were determined using multiplicative random effects inverse-variance weighting (IVW). Sensitivity analyses investigated potential pleiotropy using MR-Egger regression, the weighted median estimator, and the mode-based estimator. To increase power, trait-specific polygenic risk scores were used to test the association of a genetically predicated increase in each risk factor with glioma onset. RESULTS: Our systematic search identified 36 risk factors that could be proxied using genetic variants. Using MR, we found evidence that four genetically predicted traits increased risk of glioma, glioblastoma or non-glioblastoma: longer leukocyte telomere length, liability to allergic disease, increased alcohol consumption and liability to childhood extreme obesity (> 3 standard deviations from the mean). Two traits decreased risk of non-glioblastoma cancers: increased low-density lipoprotein cholesterol (LDLc) and triglyceride levels. Our findings were similar across sensitivity analyses that made allowance for pleiotropy (genetic confounding). CONCLUSIONS: Our comprehensive investigation provides evidence of a causal link between both genetically predicted leukocyte telomere length, allergic disease, alcohol consumption, childhood extreme obesity, and LDLc and triglyceride levels, and glioma. The findings from our study warrant further research to uncover mechanisms that implicate these traits in glioma onset.

Transition Metal-Substituted Krebs-Type Polyoxometalate-Doped PEDOT Films.

The transition metal-substituted Krebs-type polyoxometalates (POMs) [Sb2W20M2O70(H2O)6]n-, M = Fe(III), Co(II), or Cu(II), were surface immobilized within the conducting polymer 3,4-ethylenedioxythiophene (PEDOT) on glassy carbon electrode surfaces. The immobilized films of different thicknesses were characterized by electrochemical and surface-based techniques. The inherent redox activity for the Krebs-type POMs, [Sb2W20M2O70(H2O)6]n-, M = Fe(III), Co(II), or Cu(II), that were observed in the solution phase were maintained in the polymeric PEDOT matrix. The resulting films were found to be extremely stable toward redox switching between the various POM-based redox states. The films exhibited pH-dependent redox activity and thin layer behavior up to 100 mV s-1. The films were found to be highly conductive through the employment of electrochemical impedance spectroscopy. Surface characterization of the films was carried out by X-ray photoelectron spectroscopy, atomic force microscopy, and scanning electron microscopy graph.

IntAct: intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial.

AIM: Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near-infrared laparoscopy can minimize the rate of AL leak compared with conventional white-light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. METHOD: IntAct is a prospective, unblinded, parallel-group, multicentre, European, randomized controlled trial comparing surgery with intra-operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical AL at 90 days following surgery. Secondary end-points include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost-effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. DISCUSSION: IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning.

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine.

Is community treatment best? a randomised trial comparing delivery of cancer treatment in the hospital, home and GP surgery.

BACKGROUND: Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings. METHODS: Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient-perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics. RESULTS: There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19·5 to +5·2, P=0.25). There was a significant difference between the two community locations in favour of home (+15·2, 1·3 to 29·1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews. INTERPRETATION: Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs.

Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.

BACKGROUND: Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma. METHODS: To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls. RESULTS: The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ~0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown. CONCLUSION: Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.

Melanoma as a subsequent neoplasm in adult survivors of childhood cancer: a report from the childhood cancer survivor study.

BACKGROUND: Childhood cancer survivors have a sixfold increased risk of developing subsequent neoplasms when compared to the general population. We sought to describe the occurrence of melanoma as a subsequent neoplasm among adult survivors of childhood cancer. PATIENTS AND METHODS: Among 14,358 5-year survivors of childhood cancer diagnosed between 1970 and 1986, we calculated the cumulative incidence, standardized incidence ratio (SIR), and absolute excess risk (AER) of subsequent melanoma. Potential risk factors were assessed using a cause-specific hazards model. RESULTS: Fifty-seven melanomas (46 invasive, 2 ocular, and 9 in situ) occurred in 51 survivors. The median time to the development of melanoma was 21.0 years (range: 5.6-35.4 years) and the median age at melanoma was 32.3 years (range: 10.9-49.0 years). Initial cancer diagnoses included soft tissue and bone sarcoma (n = 15), leukemia (13), lymphoma (14), central nervous system malignancy (5), Wilms tumor (3), and neuroblastoma (1). The cumulative incidence of first subsequent melanoma at 35 years from initial cancer diagnosis was 0.55% [95% confidence interval (CI): 0.37-0.73]. The SIR of subsequent invasive malignant melanoma of the skin was 2.42 (95% CI: 1.77-3.23), and the AER was 0.10 (95% CI: 0.05-0.15) per 1,000 person-years. No statistically significant associations were found between melanoma risk and family history of cancer, demographic, or treatment-related factors. CONCLUSION: Survivors of childhood cancer have an approximate 2.5-fold increased risk of melanoma. Early screening and prevention strategies are warranted.

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.

X-linked hydrocephalus, spastic paraplegia type I and MASA syndrome are related disorders with loci in subchromosomal region Xq28. We have previously shown that X-linked hydrocephalus is caused by mutations in the gene for neural cell adhesion molecule L1 (L1CAM), an axonal glycoprotein involved in neuronal migration and differentiation. Here we report mutations of the L1 gene in MASA syndrome and SPG1, in addition to HSAS families. Two of the HSAS mutations would abolish cell surface expression of L1 and represent the first functional null mutations in this disorder. Our results indicate that these three syndromes from part of a clinical spectrum resulting from a heterogeneous group of mutations in the L1 gene.

Transition to a first suicide attempt among young and middle-aged males with a history of suicidal thoughts: A two-year cohort study.

INTRODUCTION: Although many studies have examined the risk and protective factors associated with suicidal behavior, little is known about the probability of transition from suicidal thoughts to suicidal attempts and the factors that distinguish those who have suicidal thoughts from those who progress to a suicide attempt. OBJECTIVES: To determine the probability and predictors of transition to a suicide attempt among young and middle-aged males with a history of suicidal thoughts but no prior history of attempting suicide. METHODS: We used data from the first two waves of the Australian Longitudinal Study on Male Health, approximately two years apart. We followed the cohort of males aged 18-55 years who, at wave 1, reported a lifetime history of suicidal ideation but no history of a prior suicide attempt. We report transition probabilities to a first suicide attempt at Wave 2 and used logistic regression models to examine baseline predictors of transition to a first suicide attempt over the two-year period among males aged 18 years and older. RESULTS: From the 1,564 males with suicidal thoughts at wave 1,140 participants (8.9%; 95% CI:7.6,10.5) reported to have had their first suicide attempt in the two-year period. In multivariate analyses, males aged 30-39 (OR=0.31; 95% CI: 0.16,0.60), 40-49 (OR=0.47; 95% CI:0.24,0.91) and 50-55 (OR=0.31; 95% CI: 0.13,0.73) all had lower odds of a first suicide attempt compared to males aged 18-29 years. The odds of a first suicide attempt were significantly higher for males who were: living in inner regional areas (ref: major cities) (OR=2.32; 95% CI: 1.33,4.04); homosexual or bisexual (OR=2.51; 95% CI: 1.17,5.36); working night shift as their main job (OR=1.75; 95% CI: 1.05,2.91); and, living with a disability (OR=1.99; 95% CI: 1.07,3.65). Clinical indicators such as symptoms of depression and illicit substance use were not significant predictors of transition to a first suicide attempt in multivariate models, nor were indicators of social connection. CONCLUSION: We estimated that 8.9% of Australian males aged 15-55 years with a history of suicidal thoughts and no prior history of suicide attempts will progress to a first suicide attempt within two-years. Neither psychological distress, illicit substance use nor social connection indicators were correlated with transition to a first suicide attempt. Rather, it was socio-demographic indicators that were associated with transition to a first suicide attempt.

A randomised study evaluating the use of pyridoxine to avoid capecitabine dose modifications.

BACKGROUND: Pyridoxine is frequently used to treat capecitabine-induced hand-foot syndrome (HFS), although the evidence of benefit is lacking. We performed a randomised placebo-controlled trial to determine whether pyridoxine could avoid the need for capecitabine dose modifications and improve outcomes. METHODS: A total of 106 patients planned for palliative single-agent capecitabine (53 in each arm, 65%/35% colorectal/breast cancer) were randomised to receive either concomitant pyridoxine (50 mg po) or matching placebo three times daily. RESULTS: Compared with placebo, pyridoxine use was associated with an increased rate of avoiding capecitabine dose modifications (37% vs 23%, relative risk 0.59, 95% CI 0.29, 1.20, P=0.15) and fewer grade 3/4 HFS-related adverse events (9% vs 17%, odds ratio 0.51, 95% CI 0.15-1.6, P=0.26). Use of pyridoxine did not improve response rate or progression-free survival. CONCLUSION: Pyridoxine may reduce the need for capecitabine dose modifications and the incidence of severe HFS, but does not impact on antitumour effect.

Value of subtraction MRI in assessing treatment response following image-guided loco-regional therapies for hepatocellular carcinoma.

AIM: To compare contrast-enhanced subtraction magnetic resonance imaging (MRI) with contrast-enhanced standard MRI in assessing treatment response following loco-regional therapies for hepatocellular carcinoma (HCC). METHOD AND MATERIALS: Institutional review board approval was obtained and informed consent was waived for this retrospective study. All patients were analysed from our institution's liver tumour database that had loco-regional HCC therapy and the following: (1) a contrast-enhanced MRI ≤6 weeks post-treatment, (2) an unenhanced T1-weighted high-signal treatment zone (TZ) ≥1 cm, (3) follow-up contrast-enhanced MRI performed ≥6 months post-treatment. Randomized standard and subtraction TZ datasets were independently assessed by three blinded radiology readers for either complete treatment necrosis or residual disease. The standard of reference (SOR) comprised a consensus read by two radiologists with knowledge of the follow-up MRI and all available clinical data. Statistical analyses were performed using receiver operating characteristics (ROC), t-test, and kappa statistic. RESULTS: Twenty-six patients (19 male and seven female patients; mean age 60 years, standard deviation 10.9 years, range 46-88 years) had a total of 45 corresponding HCCs and TZs. For ROC, the area under the curve (AUC) was 0.93 (subtraction protocol) versus 0.90 (standard protocol; p = 0.49). For the t-test, the mean reader confidence level was 4.4, 3.6, and 4.4 (subtraction protocol) versus 3, 3, and 3.7 (standard protocol; p ≤ 0.011). The kappa statistic for reader-to-SOR agreement was 0.83, 0.63, and 0.71 (subtraction protocol) versus 0.51, 0.36, and 0.64 (standard protocol). CONCLUSION: Subtraction MRI significantly improves the reader confidence level in the assessment of treatment response following loco-regional therapies for HCC.

Discrimination experienced by sexual minority males in Australia: Associations with suicidal ideation and depressive symptoms.

INTRODUCTION: Discrimination has been under-examined as a social determinant of the higher rates of poor mental health experienced by sexual minorities. The objectives of our study were to: 1) assess whether discrimination was independently associated with poor mental health among sexual minority males, and 2) assess the potential mediation role of discrimination in the associations between sexual minority status and poor mental health. METHODS: We used cross-sectional data on 13,230 males aged 18-55 years from the Australian Longitudinal Study on Male Health; bisexual and homosexual males comprised 1.5% and 1.6% of the sample, respectively. We fit Poisson regression and zero-inflated negative binomial regression models to examine suicidality, depressive symptoms and perceived discrimination in the past two years as correlates of suicidality and depressive symptoms. RESULTS: Statistically significant differences were observed in the prevalence of perceived discrimination by sexual orientation (p < 0.001), with the highest prevalence among bisexual (29.3%) and homosexual (40.4%) males, and the lowest prevalence among heterosexual males (18.6%). After adjusting for confounding, bisexual/homosexual males had higher rates of perceived discrimination (IRR = 1.88, p < 0.001), recent suicidal ideation (IRR = 1.51, p = 0.008), lifetime suicide attempt (IRR = 2.09, p < 0.001) and recent depressive symptoms (IRR = 1.34, p < 0.001) than heterosexual males. Analysis of ß-coefficients suggested that discrimination may mediate a small to moderate proportion of the association between sexual minority status and poor mental health. LIMITATIONS: Use of cross-sectional data. CONCLUSION: Poor mental health is more common among sexual minority males, and discrimination may be a contributor to these mental health disparities. Reducing discrimination should be considered as part of a strategy to improve the mental wellbeing of sexual minority males.

The chance of transition: strategies for multidisciplinary collaboration.

Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.

Accelerated BEP: a phase I trial of dose-dense BEP for intermediate and poor prognosis metastatic germ cell tumour.

BACKGROUND: We used bleomycin, etoposide, cisplatin (BEP), the most effective regimen in the treatment of germ cell tumours (GCTs) and increased dose-density by using pegfilgrastim to shorten cycle length. Our aim was to assess safety and tolerability. METHODS: Sixteen male patients with intermediate or poor prognosis metastatic GCT were treated with four cycles of 3-day BEP with G-CSF on a 14-day cycle for a planned relative dose-density of 1.5 compared with standard BEP. RESULTS: Eleven intermediate and five poor prognosis patients were treated. In all, 14 of 16 patients completed the study treatment. Toxicities were comparable to previous studies using standard BEP, except for mucositis and haematological toxicity that were more severe. The overall relative dose-density for all 16 patients was mean 1.38 (range 0.72-1.5; median 1.46). Complete response was achieved after chemotherapy alone in two patients (13%) and following chemotherapy plus surgery in nine additional patients (56%). Four patients (25%) had a partial response and normalised their marker levels. At a median follow-up of 4.4 years (range 2.1-6.8) the estimated 5-year progression-free survival probability is 81% (95% CI 64-100%). CONCLUSION: Accelerated BEP is tolerable without major additional toxicity. A randomised controlled trial will be required to obtain comparative efficacy data.

Evidence for the equal resilience of Triodia spp. (Poaceae), from different functional groups, to frequent fire dating back to the late Pleistocene.

Species with different regenerative responses to fire are hypothesised to coexist by utilising the different temporal and spatial niche opportunities created by the stochasticity of the fire regime. This is strongly supported by observations of instability of species' presence and abundance at the local scale while these are stable at the community scale. However, observations of species coexistence in fire-prone communities are limited to several decades only. To improve the robustness of this hypothesis, coalescent analysis, using chloroplast microsatellites, was undertaken on three sympatric species of Triodia from different functional groups in the fire-prone Kimberley region of Western Australia. The results inferred that T. bitextura, an obligate resprouter, Triodia sp., an obligate seeder, and T. epactia, a facultative resprouter, had mean T(mrca) values of 65k, 40k and 111k generations, respectively. Using a mutation rate of 3.2 × 10(-5) and a generation time of 5 years gave T(mrca) values of 436k, 203k and 556 k years, respectively. These results provide evidence for the coexistence of these species to the same fire regime dating back to the late Pleistocene. It also demonstrates the long-term resilience of an obligate seeder, Triodia sp., in a frequently burnt environment at the community scale.

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)).

OBJECTIVES: This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. METHODS: Patients with active disease on stable MTX (10-25 mg/week) were randomised to rituximab 2 x 500 mg (n=168), rituximab 2 x 1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) > or =2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2 x 500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. RESULTS: At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2 x 500 mg) + MTX, rituximab (2 x 1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. CONCLUSIONS: Rituximab (at 2 x 500 mg and 2 x 1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

An evaluation of the effect of an educational intervention for Australian social workers on competence in delivering brief cognitive behavioural strategies: a randomised controlled trial.

BACKGROUND: Broad community access to high quality evidence-based primary mental health care is an ongoing challenge around the world. In Australia one approach has been to broaden access to care by funding psychologists and other allied health care professionals to deliver brief psychological treatments to general practitioners' patients. To date, there has been a scarcity of studies assessing the efficacy of social worker delivered psychological strategies. This study aims to build the evidence base by evaluating the impact of a brief educational intervention on social workers' competence in delivering cognitive behavioural strategies (strategies derived from cognitive behavioural therapy). METHODS: A randomised controlled trial design was undertaken with baseline and one-week follow-up measurement of both objective and self-perceived competence. Simulated consultations with standardised depressed patients were recorded on videotape and objective competence was assessed by blinded reviewers using the Cognitive Therapy Scale. Questionnaires completed by participants were used to measure self-perceived competence. The training intervention was a 15 hour face-to-face course involving presentations, video example consultations, written materials and rehearsal of skills in pairs. RESULTS: 40 Melbourne-based (Australia) social workers enrolled and were randomised and 9 of these withdrew from the study before the pre training simulated consultation. 30 of the remaining 31 social workers (97%) completed all phases of the intervention and evaluation protocol (16 from intervention and 14 from control group). The intervention group showed significantly greater improvements than the control group in objective competence (mean improvement of 14.2 (7.38-21.02) on the 66 point Cognitive Therapy Scale) and in subjective confidence (mean improvement of 1.28 (0.84-1.72) on a 5 point Likert scale). On average, the intervention group improved from below to above the base competency threshold on the Cognitive Therapy Scale whilst the control group remained below. CONCLUSIONS: Social workers can attain significant improvements in competency in delivering cognitive behavioural strategies from undertaking brief face to face training. This is relevant in the context of health reforms that involve social worker delivery of evidence based psychological care. Further research is required to assess how these improvements in competence translate into performance in practice and clinical outcomes for patients.