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Depression and anxiety are major causes of absence from work and underperformance in the workplace. Cognitive behavioural therapy (CBT) can be effective in treating such problems and online versions offer many practical advantages. The aim of the study was to investigate the effectiveness of a computerized CBT intervention (MoodGYM) in a workplace context. The study was a phase III two-arm, parallel randomized controlled trial whose main outcome was total score on the Work and Social Adjustment Scale (WSAS). Depression, anxiety, psychological functioning, costs and acceptability of the online process were also measured. Most data were collected online for 637 participants at baseline, 359 at 6 weeks marking the end of the intervention and 251 participants at 12 weeks post-baseline. In both experimental and control groups depression scores improved over 6 weeks but attrition was high. There was no evidence for a difference in the average treatment effect of MoodGYM on the WSAS, nor for a difference in any of the secondary outcomes. This study found no evidence that MoodGYM was superior to informational websites in terms of psychological outcomes or service use, although improvement to subthreshold levels of depression was seen in nearly half the patients in both groups.

Background: Class III β -tubulin overexpression is a marker of resistance to microtubule disruptors in vitro , in vivo and in the clinic for many cancers, including breast cancer. The aims of this study were to develop a new model of class III β -tubulin expression, avoiding the toxicity associated with chronic overexpression of class III β -tubulin, and study the efficacy of a panel of clinical and pre-clinical drugs in this model. Methods: MCF-7 (ER+ve) and MDA-MB-231 (ER−ve) were either transfected with pALTER-TUBB3 or siRNA-tubb3 and 24 h later exposed to test compounds for a further 96 h for proliferation studies. RT–PCR and immunoblotting were used to monitor the changes in class III β -tubulin mRNA and protein expression. Results: The model allowed for subtle changes in class III β -tubulin expression to be achieved, which had no direct effect on the viability of the cells. Class III β -tubulin overexpression conferred resistance to paclitaxel and vinorelbine, whereas downregulation of class III β -tubulin rendered cells more sensitive to these two drugs. The efficacy of the colchicine-site binding agents, 2-MeOE2, colchicine, STX140, ENMD1198 and STX243 was unaffected by the changes in class III β -tubulin expression. Conclusion: These data indicate that the effect of class III β -tubulin overexpression may depend on where the drug’s binding site is located on the tubulin. Therefore, this study highlights for the first time the potential key role of targeting the colchicine-binding site, to develop new treatment modalities for taxane-refractory breast cancer.

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14-18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms.

Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three \"first wave\" proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501), as well as subdominant responses through common class I alleles (e.g. B7 and C*0304). Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that \"first wave\" antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design.

On the basis of previous ground-based and fly-by information, we knew that Titan's atmosphere was mainly nitrogen, with some methane, but its temperature and pressure profiles were poorly constrained because of uncertainties in the detailed composition. The extent of atmospheric electricity (‘lightning’) was also hitherto unknown. Here we report the temperature and density profiles, as determined by the Huygens Atmospheric Structure Instrument (HASI), from an altitude of 1,400 km down to the surface. In the upper part of the atmosphere, the temperature and density were both higher than expected. There is a lower ionospheric layer between 140 km and 40 km, with electrical conductivity peaking near 60 km. We may also have seen the signature of lightning. At the surface, the temperature was 93.65 ± 0.25 K, and the pressure was 1,467 ± 1 hPa. New views of Titan The Huygens probe landed on Titan on 14 January this year, and seven papers published in this issue record the encounter. They describe a world that resembles a primitive Earth, complete with weather systems and geological activity. The ‘Huygens on Titan’ section opens with an overview of the descent and landing and a News and Views piece. Tomasko et al . describe the dry riverbed and drainage channels seen during Huygens' descent, evidence that liquid methane falls as rain or erupts from cryovolcanoes, periodically flooding the surface. This paper includes the images used on the cover to the Huygens section. Niemann et al . measured the abundances of isotopes of argon, nitrogen and carbon in the atmosphere, and conclude that there is no evidence that Titan's methane comes from biological activity. Fulchignoni et al . obtained precise measurements of temperature and pressure from the upper atmosphere right down to the surface. On the way down Huygens recorded evidence for lightning. Zarnecki et al . report that the probe landed on a relatively smooth surface of icy grains with the consistency of wet clay or sand. Isräl et al . report that the aerosols in Titan's clouds have solid cores made from complex organic molecules containing carbon and nitrogen. And Bird et al . found that on average Titan's winds blow in the same direction as the moon rotates, and that close to the surface these winds are very weak, travelling at around walking speed.

There is evidence from North American trials that supported employment using the individual placement and support (IPS) model is effective in helping individuals with severe mental illness gain competitive employment. There have been few trials in other parts of the world. To investigate the effectiveness and cost-effectiveness of IPS in the UK. Individuals with severe mental illness in South London were randomised to IPS or local traditional vocational services (treatment as usual) (ISRCTN96677673). Two hundred and nineteen participants were randomised, and 90% assessed 1 year later. There were no significant differences between the treatment as usual and intervention groups in obtaining competitive employment (13% in the intervention group and 7% in controls; risk ratio 1.35, 95% CI 0.95-1.93, P = 0.15), nor in secondary outcomes. There was no evidence that IPS was of significant benefit in achieving competitive employment for individuals in South London at 1-year follow-up, which may reflect suboptimal implementation. Implementation of IPS can be challenging in the UK context where IPS is not structurally integrated with mental health services, and economic disincentives may lead to lower levels of motivation in individuals with severe mental illness and psychiatric professionals.

Risk assessment is now regarded as a necessary competence in psychiatry. The area under the curve (AUC) statistic of the receiver operating characteristic curve is increasingly offered as the main evidence for accuracy of risk assessment instruments. But, even a highly statistically significant AUC is of limited value in clinical practice.

Abstract Objective To investigate whether a form of advance agreement for people with severe mental illness can reduce the use of inpatient services and compulsory admission or treatment. Design Single blind randomised controlled trial, with randomisation of individual patients. The investigator was blind to allocation. Setting Eight community mental health teams in southern England. Participants 160 people with an operational diagnosis of psychotic illness or non-psychotic bipolar disorder who had experienced a hospital admission within the previous two years. Intervention The joint crisis plan was formulated by the patient, care coordinator, psychiatrist, and project worker and contained contact information, details of mental and physical illnesses, treatments, indicators for relapse, and advance statements of preferences for care in the event of future relapse. Main outcome measures Admission to hospital, bed days, and use of the Mental Health Act over 15 month follow up. Results Use of the Mental Health Act was significantly reduced for the intervention group, 13% (10/80) of whom experienced compulsory admission or treatment compared with 27% (21/80) of the control group (risk ratio 0.48, 95% confidence interval 0.24 to 0.95, P = 0.028). As a consequence, the mean number of days of detention (days spent as an inpatient while under a section of the Mental Health Act) for the whole intervention group was 14 compared with 31 for the control group (difference 16, 0 to 36, P = 0.04). For those admitted under a section of the Mental Health Act, the number of days of detention was similar in the two groups (means 114 and 117, difference 3, −61 to 67, P = 0.98). The intervention group had fewer admissions (risk ratio 0.69, 0.45 to 1.04, P = 0.07). There was no evidence for differences in bed days (total number of days spent as an inpatient) (means 32 and 36, difference 4, −18 to 26, P = 0.15 for the whole sample; means 107 and 83, difference −24, −72 to 24, P = 0.39 for those admitted). Conclusions Use of joint crisis plans reduced compulsory admissions and treatment in patients with severe mental illness. The reduction in overall admission was less. This is the first structured clinical intervention that seems to reduce compulsory admission and treatment in mental health services.

Wastewater treatment plant effluents contain a variety of endocrine disrupting chemicals (EDCs), including chemicals with estrogenic activity such as 17β-estradiol (E2), 17α-ethinyl estradiol (EE2), and nonylphenols. These substances can affect both behavior and physiology in vertebrate animals. To explore the presence and effects of these EDCs in a natural setting, juvenile and adult male fathead minnows, Pimephales promelas, were held in cages upstream and downstream of the effluent site of a wastewater treatment plant for 21 days and subsequently tested for changes in reproductive behaviors and production of vitellogenin. Additionally, estrogenic activity in the stream was measured using a yeast bioassay. Estrogenicity was found to be significantly higher downstream of the wastewater effluent when compared to levels upstream. Vitellogenin levels did not show a correlational pattern with levels of estrogenicity in the water, but two measures of reproductive behaviors occurred significantly less often in downstream males than upstream males. This suggests that a brief (three-week) exposure to stream water containing wastewater treatment plant effluent can bring about changes in reproductive behavior of fish and that behavior may be more sensitive to low levels of environmental endocrine disruptors than vitellogenin production.

There is little consistency in how severe mental illness (SMI) is defined in practice, and no operational definitions. To test two operationalized definitions, based on the National Institute of Mental Health (1987) definition: the first uses three criteria (diagnosis of psychosis; duration of service contact > or = 2 years; GAF score < or = 50), the second only the last two. Annual prevalence rates of SMI in two European catchment areas for each criterion and the criteria combined were calculated. The first definition produced rates of 2.55 and 1.34/1000 in London and Verona, respectively; the second permitted an additional 0.98/1000 non-psychotic disorders to be included in Verona. The three-dimensional definition selects a small group of patients with SMI who have psychotic disorders. The two-dimensional approach allows estimates of SMI prevalence rates which include all forms of mental disorder.