Optical projection tomography implemented for accessibility and low cost (OPTImAL).

Optical projection tomography (OPT) is a three-dimensional mesoscopic imaging modality that can use absorption or fluorescence contrast, and is widely applied to fixed and live samples in the mm-cm scale. For fluorescence OPT, we present OPT implemented for accessibility and low cost, an open-source research-grade implementation of modular OPT hardware and software that has been designed to be widely accessible by using low-cost components, including light-emitting diode (LED) excitation and cooled complementary metal-oxide-semiconductor (CMOS) cameras. Both the hardware and software are modular and flexible in their implementation, enabling rapid switching between sample size scales and supporting compressive sensing to reconstruct images from undersampled sparse OPT data, e.g. to facilitate rapid imaging with low photobleaching/phototoxicity. We also explore a simple implementation of focal scanning OPT to achieve higher resolution, which entails the use of a fan-beam geometry reconstruction method to account for variation in magnification. This article is part of the Theo Murphy meeting issue 'Open, reproducible hardware for microscopy'.

Effect of monensin on milk production efficiency and milk composition in lactating dairy cows fed modern diets.

Since the US Food and Drug Administration's approval of monensin in 2004, significant nutritional advances have been made to increase feed efficiency and milk fat production. Recent evidence suggests monensin's adverse effect on milk fat percentage may be absent when diets are formulated to address known diet-induced milk fat depression risk factors. Thus, study objectives were to evaluate effects of monensin level on dry matter intake (DMI), milk production and composition, and efficiency of high-producing cows fed diets formulated to optimize milk fat. Ninety-six lactating Holstein cows (36 primiparous, 60 multiparous; 106 ± 17 d in milk [DIM]) were balanced by parity, DIM, and milk production and were randomly assigned to 1 of 12 pens with 8 cows per pen. All cows received 11 g/t monensin for 5 wk after which pens received 1 of 4 dietary treatments (n = 3) formulated to provide 0 (CON), 11 (R11), 14.5 (R14.5), or 18 (R18) g/t monensin for 9 wk. The basal diet was 54% forage, 27% NDF, 29% starch, and 2.3% rumen unsaturated fatty acid load. Pen was the experimental unit and data were analyzed using the Fit Model Procedure of JMP. Effects of treatment, time, and treatment × time interaction were included as fixed effects and pen as a random effect. Least squares means were determined and linear and quadratic contrasts were tested. Dry matter intake tended to decrease linearly with increasing monensin dose. Milk yield, fat percentage, and protein percentage and yield were unaffected by treatment while fat yield was quadratically increased. Milk de novo and mixed fatty acid (FA) yields (g/d) increased quadratically with monensin whereas preformed FA linearly decreased during the experimental period. Energy-corrected milk (ECM) was quadratically increased by monensin. Milk urea nitrogen concentrations increased linearly with increasing monensin dose. Monensin linearly increased feed efficiency (ECM/DMI, 3.5% fat-corrected milk/DMI, and solids-corrected milk/DMI). Body weight gain did not differ between treatments. Estimated dietary energy tended to increase linearly with increasing monensin level. These data suggest monensin improves component-corrected milk production efficiency, estimated dietary energy, and does not negatively affect milk fat percentage or FA profile.

openFrame: A modular, sustainable, open microscopy platform with single-shot, dual-axis optical autofocus module providing high precision and long range of operation.

'openFrame' is a modular, low-cost, open-hardware microscopy platform that can be configured or adapted to most light microscopy techniques and is easily upgradeable or expandable to multiple modalities. The ability to freely mix and interchange both open-source and proprietary hardware components or software enables low-cost, yet research-grade instruments to be assembled and maintained. It also enables rapid prototyping of advanced or novel microscope systems. For long-term time-lapse image data acquisition, slide-scanning or high content analysis, we have developed a novel optical autofocus incorporating orthogonal cylindrical optics to provide robust single-shot closed-loop focus lock, which we have demonstrated to accommodate defocus up to ±37 µm with <200 nm accuracy, and a two-step autofocus mode which we have shown can operate with defocus up to ±68 µm. We have used this to implement automated single molecule localisation microscopy (SMLM) in a relatively low-cost openFrame-based instrument using multimode diode lasers for excitation and cooled CMOS cameras.

Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Accelerating single molecule localization microscopy through parallel processing on a high-performance computing cluster.

Super-resolved microscopy techniques have revolutionized the ability to study biological structures below the diffraction limit. Single molecule localization microscopy (SMLM) techniques are widely used because they are relatively straightforward to implement and can be realized at relatively low cost, e.g. compared to laser scanning microscopy techniques. However, while the data analysis can be readily undertaken using open source or other software tools, large SMLM data volumes and the complexity of the algorithms used often lead to long image data processing times that can hinder the iterative optimization of experiments. There is increasing interest in high throughput SMLM, but its further development and application is inhibited by the data processing challenges. We present here a widely applicable approach to accelerating SMLM data processing via a parallelized implementation of ThunderSTORM on a high-performance computing (HPC) cluster and quantify the speed advantage for a four-node cluster (with 24 cores and 128 GB RAM per node) compared to a high specification (28 cores, 128 GB RAM, SSD-enabled) desktop workstation. This data processing speed can be readily scaled by accessing more HPC resources. Our approach is not specific to ThunderSTORM and can be adapted for a wide range of SMLM software. LAY DESCRIPTION: Optical microscopy is now able to provide images with a resolution far beyond the diffraction limit thanks to relatively new super-resolved microscopy (SRM) techniques, which have revolutionized the ability to study biological structures. One approach to SRM is to randomly switch on and off the emission of fluorescent molecules in an otherwise conventional fluorescence microscope. If only a sparse subset of the fluorescent molecules labelling a sample can be switched on at a time, then each emitter will be, on average, spaced further apart than the diffraction-limited resolution of the conventional microscope and the separate bright spots in the image corresponding to each emitter can be localised to high precision by finding the centre of each feature using a computer program. Thus, a precise map of the emitter positions can be recorded by sequentially mapping the localisation of different subsets of emitters as they are switched on and others switched off. Typically, this approach, described as single molecule localisation microscopy (SMLM), results in large image data sets that can take many minutes to hours to process, depending on the size of the field of view and whether the SMLM analysis employs a computationally-intensive iterative algorithm. Such a slow workflow makes it difficult to optimise experiments and to analyse large numbers of samples. Faster SMLM experiments would be generally useful and automated high throughput SMLM studies of arrays of samples, such as cells, could be applied to drug discovery and other applications. However, the time required to process the resulting data would be prohibitive on a normal computer. To address this, we have developed a method to run standard SMLM data analysis software tools in parallel on a high-performance computing cluster (HPC). This can be used to accelerate the analysis of individual SMLM experiments or it can be scaled to analyse high throughput SMLM data by extending it to run on an arbitrary number of HPC processors in parallel. In this paper we outline the design of our parallelised SMLM software for HPC and quantify the speed advantage when implementing it on four HPC nodes compared to a powerful desktop computer.

A systematic review and meta-analysis of exercise interventions in schizophrenia patients.

BACKGROUND: The typically poor outcomes of schizophrenia could be improved through interventions that reduce cardiometabolic risk, negative symptoms and cognitive deficits; aspects of the illness which often go untreated. The present review and meta-analysis aimed to establish the effectiveness of exercise for improving both physical and mental health outcomes in schizophrenia patients. METHOD: We conducted a systematic literature search to identify all studies that examined the physical or mental effects of exercise interventions in non-affective psychotic disorders. Of 1581 references, 20 eligible studies were identified. Data on study design, sample characteristics, outcomes and feasibility were extracted from all studies and systematically reviewed. Meta-analyses were also conducted on the physical and mental health outcomes of randomized controlled trials. RESULTS: Exercise interventions had no significant effect on body mass index, but can improve physical fitness and other cardiometabolic risk factors. Psychiatric symptoms were significantly reduced by interventions using around 90 min of moderate-to-vigorous exercise per week (standardized mean difference: 0.72, 95% confidence interval -1.14 to -0.29). This amount of exercise was also reported to significantly improve functioning, co-morbid disorders and neurocognition. CONCLUSIONS: Interventions that implement a sufficient dose of exercise, in supervised or group settings, can be feasible and effective interventions for schizophrenia.

Negative cognition, affect, metacognition and dimensions of paranoia in people at ultra-high risk of psychosis: a multi-level modelling analysis.

BACKGROUND: Paranoia is one of the commonest symptoms of psychosis but has rarely been studied in a population at risk of developing psychosis. Based on existing theoretical models, including the proposed distinction between 'poor me' and 'bad me' paranoia, we aimed to test specific predictions about associations between negative cognition, metacognitive beliefs and negative emotions and paranoid ideation and the belief that persecution is deserved (deservedness). METHOD: We used data from 117 participants from the Early Detection and Intervention Evaluation for people at risk of psychosis (EDIE-2) trial of cognitive­behaviour therapy, comparing them with samples of psychiatric in-patients and healthy students from a previous study. Multi-level modelling was utilized to examine predictors of both paranoia and deservedness, with post-hoc planned comparisons conducted to test whether person-level predictor variables were associated differentially with paranoia or with deservedness. RESULTS: Our sample of at-risk mental state participants was not as paranoid, but reported higher levels of 'bad-me' deservedness, compared with psychiatric in-patients. We found several predictors of paranoia and deservedness. Negative beliefs about self were related to deservedness but not paranoia, whereas negative beliefs about others were positively related to paranoia but negatively with deservedness. Both depression and negative metacognitive beliefs about paranoid thinking were specifically related to paranoia but not deservedness. CONCLUSIONS: This study provides evidence for the role of negative cognition, metacognition and negative affect in the development of paranoid beliefs, which has implications for psychological interventions and our understanding of psychosis.

Risk factors for rectal lymphogranuloma venereum in gay men: results of a multicentre case-control study in the U.K.

OBJECTIVE: To identify risk factors for rectal lymphogranuloma venereum (rLGV) in men who have sex with men (MSM). DESIGN: A case-control study at 6 U.K. hospitals compared MSM with rLGV (cases) with rLGV-negative controls: MSM without potential rLGV symptoms (CGa) and separately, MSM with such symptoms (CGs). METHODS: Between 2008 and 2010, there were 90 rLGV cases, 74 CGa and 69 CGs recruited. Lifestyles and sexual behaviours in the previous 3 months were reported using internet-based computer-assisted self-interviews. Logistic regression was used to investigate factors associated with rLGV. RESULTS: Cases were significantly more likely to be HIV-positive (89%) compared with CGa (46%) and CGs (64%). Independent behavioural risks for rLGV were: unprotected receptive anal intercourse (adjusted OR (AOR)10.7, 95% CI 3.5 to 32.8), fisting another (AOR=6.7, CI 1.8 to 25.3), sex under the influence of gamma-hydroxybutyrate (AOR=3.1, CI 1.3 to 7.4) and anonymous sexual contacts (AOR=2.7, CI 1.2 to 6.3), compared with CGa; unprotected insertive anal intercourse (AOR=4.7, CI 2.0 to 10.9) and rectal douching (AOR=2.9 CI 1.3 to 6.6), compared with CGs. An incubation period from exposure to symptoms of 30 days was indicated. CONCLUSIONS: Unprotected receptive anal intercourse is a key risk factor for rectal LGV with the likelihood that rectal-to-rectal transmission is facilitated where insertive anal sex also occurs. The association between HIV and rLGV appears linked to HIV-positive men seeking unprotected sex with others with the same HIV status, sexual and drug interests. Such men should be targeted for frequent STI screening and interventions to minimise associated risks.

Clinical predictors of rectal lymphogranuloma venereum infection: results from a multicentre case-control study in the U.K.

OBJECTIVE: Since 2003, over 2000 cases of lymphogranuloma venereum (LGV) have been diagnosed in the U.K. in men who have sex with men (MSM). Most cases present with proctitis, but there are limited data on how to differentiate clinically between LGV and other pathology. We analysed the clinical presentations of rectal LGV in MSM to identify clinical characteristics predictive of LGV proctitis and produced a clinical prediction model. DESIGN: A prospective multicentre case-control study was conducted at six U.K. hospitals from 2008 to 2010. Cases of rectal LGV were compared with controls with rectal symptoms but without LGV. METHODS: Data from 98 LGV cases and 81 controls were collected from patients and clinicians using computer-assisted self-interviews and clinical report forms. Univariate and multivariate logistic regression was used to compare symptoms and signs. Clinical prediction models for LGV were compared using receiver operating curves. RESULTS: Tenesmus, constipation, anal discharge and weight loss were significantly more common in cases than controls. In multivariate analysis, tenesmus and constipation alone were suggestive of LGV (OR 2.98, 95% CI 0.99 to 8.98 and 2.87, 95% CI 1.01 to 8.15, respectively) and that tenesmus alone or in combination with constipation was a significant predictor of LGV (OR 6.97, 95% CI 2.71 to 17.92). The best clinical prediction was having one or more of tenesmus, constipation and exudate on proctoscopy, with a sensitivity of 77% and specificity of 65%. CONCLUSIONS: This study indicates that tenesmus alone or in combination with constipation makes a diagnosis of LGV in MSM presenting with rectal symptoms more likely.

2014 European guideline on the management of syphilis.

BACKGROUND: Syphilis remains a major public health problem in Europe (both in Eastern Europe since the 1990's and in Western Europe since the re-emergence of the disease in the late 1990's-early 2000's). METHODS: This guideline is an update of the IUSTI: 2008 European guideline on the management of syphilis and is produced by the European Guideline Editorial Board (http://www.iusti.org/regions/Europe/pdf/2013/Editorial_Board.pdf) and EDF Guideline Committee. RESULTS: It provides recommendations concerning the diagnosis and management of syphilis in Europe. Major advances include (1) broader use of PCR, immunohistochemistry, subtyping of the etiological agent Treponema pallidum subspecies pallidum, new treponemal tests, and rapid-point-of-care (POC) tests detecting both treponemal and non-treponemal antibodies, (2) more flexible options for screening (TT-treponemal test- first or NTT -non treponemal test- first or both TT and NTT), and (3) procaine penicillin is no longer the first line therapy option in any phase of the disease, i.e. long acting penicillin G (i.e. benzathine penicillin G-BPG) is the only first line therapy regimen in early syphilis and in late latent syphilis. CONCLUSIONS: Syphilis is a disease that is relatively easy to detect by appropriate serological tests, however, all laboratory results should be considered together with clinical data and sexual risk anamnesis. Syphilis is also easy to treat with BPG. A major concern about the supply of BPG in many European countries could threaten the efficacy of the policies of eradication of the disease in Europe.

Comparison of modelling techniques for milk-production forecasting.

The objective of this study was to assess the suitability of 3 different modeling techniques for the prediction of total daily herd milk yield from a herd of 140 lactating pasture-based dairy cows over varying forecast horizons. A nonlinear auto-regressive model with exogenous input, a static artificial neural network, and a multiple linear regression model were developed using 3 yr of historical milk-production data. The models predicted the total daily herd milk yield over a full season using a 305-d forecast horizon and 50-, 30-, and 10-d moving piecewise horizons to test the accuracy of the models over long- and short-term periods. All 3 models predicted the daily production levels for a full lactation of 305 d with a percentage root mean square error (RMSE) of ≤ 12.03%. However, the nonlinear auto-regressive model with exogenous input was capable of increasing its prediction accuracy as the horizon was shortened from 305 to 50, 30, and 10 d [RMSE (%)=8.59, 8.1, 6.77, 5.84], whereas the static artificial neural network [RMSE (%)=12.03, 12.15, 11.74, 10.7] and the multiple linear regression model [RMSE (%)=10.62, 10.68, 10.62, 10.54] were not able to reduce their forecast error over the same horizons to the same extent. For this particular application the nonlinear auto-regressive model with exogenous input can be presented as a more accurate alternative to conventional regression modeling techniques, especially for short-term milk-yield predictions.

Energy demand on dairy farms in Ireland.

Reducing electricity consumption in Irish milk production is a topical issue for 2 reasons. First, the introduction of a dynamic electricity pricing system, with peak and off-peak prices, will be a reality for 80% of electricity consumers by 2020. The proposed pricing schedule intends to discourage energy consumption during peak periods (i.e., when electricity demand on the national grid is high) and to incentivize energy consumption during off-peak periods. If farmers, for example, carry out their evening milking during the peak period, energy costs may increase, which would affect farm profitability. Second, electricity consumption is identified in contributing to about 25% of energy use along the life cycle of pasture-based milk. The objectives of this study, therefore, were to document electricity use per kilogram of milk sold and to identify strategies that reduce its overall use while maximizing its use in off-peak periods (currently from 0000 to 0900 h). We assessed, therefore, average daily and seasonal trends in electricity consumption on 22 Irish dairy farms, through detailed auditing of electricity-consuming processes. To determine the potential of identified strategies to save energy, we also assessed total energy use of Irish milk, which is the sum of the direct (i.e., energy use on farm) and indirect energy use (i.e., energy needed to produce farm inputs). On average, a total of 31.73 MJ was required to produce 1 kg of milk solids, of which 20% was direct and 80% was indirect energy use. Electricity accounted for 60% of the direct energy use, and mainly resulted from milk cooling (31%), water heating (23%), and milking (20%). Analysis of trends in electricity consumption revealed that 62% of daily electricity was used at peak periods. Electricity use on Irish dairy farms, therefore, is substantial and centered around milk harvesting. To improve the competitiveness of milk production in a dynamic electricity pricing environment, therefore, management changes and technologies are required that decouple energy use during milking processes from peak periods.

Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice.

AIMS/HYPOTHESIS: Individuals carrying type 2 diabetes risk alleles in TCF7L2 display decreased beta cell levels of T cell factor 7 like-2 (TCF7L2) immunoreactivity, and impaired insulin secretion and beta cell sensitivity to glucagon-like peptide 1 (GLP-1). Here, we sought to determine whether selective deletion of Tcf7l2 in mouse pancreas impairs insulin release and glucose homeostasis. METHODS: Pancreas-specific Tcf7l2-null (pTcf7l2) mice were generated by crossing mice carrying conditional knockout alleles of Tcf7l2 (Tcf7l2-flox) with mice expressing Cre recombinase under the control of the Pdx1 promoter (Pdx1.Cre). Gene expression was assessed by real-time quantitative PCR and beta cell mass by optical projection tomography. Glucose tolerance, insulin secretion from isolated islets, and plasma insulin, glucagon and GLP-1 content were assessed by standard protocols. RESULTS: From 12 weeks of age, pTcf7l2 mice displayed decreased oral glucose tolerance vs control littermates; from 20 weeks they had glucose intolerance upon administration of glucose by the intraperitoneal route. pTcf7l2 islets displayed impaired insulin secretion in response to 17 (vs 3.0) mmol/l glucose (54.6 ± 4.6%, p < 0.01) or to 17 mmol/l glucose plus 100 nmol/l GLP-1 (44.3 ± 4.9%, p < 0.01) compared with control islets. Glp1r (42 ± 0.08%, p < 0.01) and Ins2 (15.4 ± 4.6%, p < 0.01) expression was significantly lower in pTcf7l2 islets than in controls. Maintained on a high-fat (but not on a normal) diet, pTcf7l2 mice displayed decreased expansion of pancreatic beta cell volume vs control littermates. No differences were observed in plasma insulin, proinsulin, glucagon or GLP-1 concentrations. CONCLUSIONS/INTERPRETATION: Selective deletion of Tcf7l2 in the pancreas replicates key aspects of the altered glucose homeostasis in human carriers of TCF7L2 risk alleles, indicating the direct role of this factor in controlling beta cell function.

Gene expression profiles of gliomas in formalin-fixed paraffin-embedded material.

BACKGROUND: We have recently demonstrated that expression profiling is a more accurate and objective method to classify gliomas than histology. Similar to most expression profiling studies, our experiments were performed using fresh frozen (FF) glioma samples whereas most archival samples are fixed in formalin and embedded in paraffin (FFPE). Identification of the same, expression-based intrinsic subtypes in FFPE-stored samples would enable validation of the prognostic value of these subtypes on these archival samples. In this study, we have therefore determined whether the intrinsic subtypes identified using FF material can be reproduced in FFPE-stored samples. METHODS: We have performed expression profiling on 55 paired FF-FFPE glioma samples using HU133 plus 2.0 arrays (FF) and Exon 1.0 ST arrays (FFPE). The median time in paraffin of the FFPE samples was 14.1 years (range 6.6-26.4 years). RESULTS: In general, the correlation between FF and FFPE expression in a single sample was poor. We then selected the most variable probe sets per gene (n=17,583), and of these, the 5000 most variable probe sets on FFPE expression profiles. This unsupervised selection resulted in a better concordance (R(2)=0.54) between expression of FF and FFPE samples. Importantly, this probe set selection resulted in a correct assignment of 87% of FFPE samples into one of seven intrinsic subtypes identified using FF samples. Assignment to the same molecular cluster as the paired FF tissue was not correlated to time in paraffin. CONCLUSION: We are the first to examine a large cohort of paired FF and FFPE samples. We show that expression data from FFPE material can be used to assign samples to intrinsic molecular subtypes identified using FF material. This assignment allows the use of archival material, including material derived from large-randomised clinical trials, to determine the predictive and/or prognostic value of 'intrinsic glioma subtypes' on Exon arrays. This would enable clinicians to provide patients with an objective and accurate diagnosis and prognosis, and a personalised treatment strategy.

Induction of alloimmune tolerance in heart transplantation through gene silencing of TLR adaptors.

Toll-like receptors (TLRs) activate biochemical pathways that evoke activation of innate immunity, which leads to dendritic cell (DC) maturation and initiation of adaptive immune responses that provoke allograft rejection. We aimed to prolong allograft survival by selectively inhibiting expression of the common adaptors of TLR signaling, namely MyD88 and TRIF, using siRNA. In vitro we demonstrated that blocking expression of MyD88 and TRIF led to reduced DC maturation. In vivo treatment of recipients with MyD88 and TRIF siRNA significantly prolonged allograft survival in the BALB/c > C57BL6 cardiac transplant model. Moreover, the combination of MyD88 and TRIF siRNA along with a low dose of rapamycin further extended the allograft survival (88.8 ± 7.1 days). Tissue histopathology demonstrated an overall reduction in lymphocyte interstitium infiltration, vascular obstruction and hemorrhage in mice treated with MyD88 and TRIF siRNA vector plus rapamycin. Furthermore, treatment was associated with an increase in the numbers of CD4(+) CD25(+) FoxP3(+) regulatory T cells and Th2 deviation. To our knowledge, this study is the first demonstration of prolonging the survival of allogeneic heart grafts through gene silencing of TLR signaling adaptors, highlighting the therapeutic potential of siRNA in clinical transplantation.

Cognitive therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medication: an exploratory trial.

BACKGROUND: Although antipsychotic medication is the first line of treatment for schizophrenia, many service users choose to refuse or discontinue their pharmacological treatment. Cognitive therapy (CT) has been shown to be effective when delivered in combination with antipsychotic medication, but has yet to be formally evaluated in its absence. This study evaluates CT for people with psychotic disorders who have not been taking antipsychotic medication for at least 6 months. METHOD: Twenty participants with schizophrenia spectrum disorders received CT in an open trial. Our primary outcome was psychiatric symptoms measured using the Positive and Negative Syndromes Scale (PANSS), which was administered at baseline, 9 months (end of treatment) and 15 months (follow-up). Secondary outcomes were dimensions of hallucinations and delusions, self-rated recovery and social functioning. RESULTS: T tests and Wilcoxon's signed ranks tests revealed significant beneficial effects on all primary and secondary outcomes at end of treatment and follow-up, with the exception of self-rated recovery at end of treatment. Cohen's d effect sizes were moderate to large [for PANSS total, d=0.85, 95% confidence interval (CI) 0.32-1.35 at end of treatment; d=1.26, 95% CI 0.66-1.84 at follow-up]. A response rate analysis found that 35% and 50% of participants achieved at least a 50% reduction in PANSS total scores by end of therapy and follow-up respectively. No patients deteriorated significantly. CONCLUSIONS: This study provides preliminary evidence that CT is an acceptable and effective treatment for people with psychosis who choose not to take antipsychotic medication. An adequately powered randomized controlled trial is warranted.

Effects of drop-out on efficacy estimates in five Cochrane reviews of popular antipsychotics for schizophrenia.

OBJECTIVE: Our aim was to find out how Cochrane reviews of five popular or frequently prescribed second-generation antipsychotics in the UK (olanzapine, risperidone, quetiapine, amisulpride and aripiprazole) approached the problem of high drop-out in placebo-controlled trials. METHOD: We examined the following: (i) whether reviews included data from studies with a level of drop-out exceeding their stated exclusion criterion; (ii) the level of missing data each efficacy outcome in each review relied upon; and (iii) impact of excluding studies with high drop-out. RESULTS: All reviews included data they stated they would exclude because of unacceptable levels of attrition, four (risperidone, olanzapine, amisulpride, aripiprazole) without clear acknowledgement or justification. Several reviews also excluded data from a number of relatively low-attrition studies because of missing standard deviations. CONCLUSION: Cochrane reviews of five popular antipsychotics for schizophrenia misrepresented the available evidence on their efficacy. The impact of including high-attrition studies was difficult to quantify because of the exclusion of relevant low-attrition studies. Further analysis of the efficacy of these drugs in studies with acceptable rates of attrition is required. To reduce the problem of high attrition, trialists should gather follow-up data from people who leave the double-blind process early.

Cannabis use and age at onset of symptoms in subjects at clinical high risk for psychosis.

OBJECTIVE: Numerous studies have found a robust association between cannabis use and the onset of psychosis. Nevertheless, the relationship between cannabis use and the onset of early (or, in retrospect, prodromal) symptoms of psychosis remains unclear. The study focused on investigating the relationship between cannabis use and early and high-risk symptoms in subjects at clinical high risk for psychosis. METHOD: Prospective multicenter, naturalistic field study with an 18-month follow-up period in 245 help-seeking individuals clinically at high risk. The Composite International Diagnostic Interview was used to assess their cannabis use. Age at onset of high risk or certain early symptoms was assessed retrospectively with the Interview for the Retrospective Assessment of the Onset of Schizophrenia. RESULTS: Younger age at onset of cannabis use or a cannabis use disorder was significantly related to younger age at onset of six symptoms (0.33 < r(s) < 0.83, 0.004 < P < 0.001). Onset of cannabis use preceded symptoms in most participants. CONCLUSION: Our results provide support that cannabis use plays an important role in the development of psychosis in vulnerable individuals. Cannabis use in early adolescence should be discouraged.

Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations.

BACKGROUND: The number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer. PATIENTS AND METHODS: Using commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria. RESULTS: A total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: -0.78 (P = 0.0007) for the ORR difference model; -0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: -0.67 (P = 0.013) for the ORR difference model and -0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation. CONCLUSIONS: These analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.