PTEN deficiency exposes a requirement for an ARF GTPase module for integrin-dependent invasion in ovarian cancer.

Dysregulation of the PI3K/AKT pathway is a common occurrence in high-grade serous ovarian carcinoma (HGSOC), with the loss of the tumour suppressor PTEN in HGSOC being associated with poor prognosis. The cellular mechanisms of how PTEN loss contributes to HGSOC are largely unknown. We here utilise time-lapse imaging of HGSOC spheroids coupled to a machine learning approach to classify the phenotype of PTEN loss. PTEN deficiency induces PI(3,4,5)P3 -rich and -dependent membrane protrusions into the extracellular matrix (ECM), resulting in a collective invasion phenotype. We identify the small GTPase ARF6 as a crucial vulnerability of HGSOC cells upon PTEN loss. Through a functional proteomic CRISPR screen of ARF6 interactors, we identify the ARF GTPase-activating protein (GAP) AGAP1 and the ECM receptor ß1-integrin (ITGB1) as key ARF6 interactors in HGSOC regulating PTEN loss-associated invasion. ARF6 functions to promote invasion by controlling the recycling of internalised, active ß1-integrin to maintain invasive activity into the ECM. The expression of the CYTH2-ARF6-AGAP1 complex in HGSOC patients is inversely associated with outcome, allowing the identification of patient groups with improved versus poor outcome. ARF6 may represent a therapeutic vulnerability in PTEN-depleted HGSOC.

Phase II proof-of-concept study of atorvastatin in castration-resistant prostate cancer.

OBJECTIVES: To test for evidence of statin-mediated effects in patients with castration-resistant prostate cancer (CRPC) as post-diagnosis use of statins in patients with prostate cancer is associated with favourable survival outcome. PATIENTS AND METHODS: The SPECTRE trial was a 6-weeks-long proof-of-concept single-arm Phase II treatment trial, combining atorvastatin and androgen deprivation therapy in patients with CRPC (regardless of metastatic status), designed to test for evidence of statin-mediated effects in patients with CRPC. The primary study endpoint was the proportion of patients achieving a ≥50% drop from baseline in prostate-specific antigen (PSA) levels at any time over the 6-week period of atorvastatin medication (PSA response). Exploratory endpoints include PSA velocity and serum metabolites identified by mass spectrometry . RESULTS: At the scheduled interim analysis, one of 12 patients experienced a ≥50% drop in PSA levels (primary endpoint), with ≥2 patients satisfying the primary endpoint required for further recruitment. All 12 patients experienced substantial falls in serum cholesterol levels following statin treatment. While all patients had comparable pre-study PSA velocities, six of 12 patients showed decreased PSA velocities after statin treatment, suggestive of disease stabilization. Unbiased metabolomics analysis on serial weekly blood samples identified tryptophan to be the dominant metabolite associated with patient response to statin. CONCLUSIONS: Data from the SPECTRE study provide the first evidence of statin-mediated effects on CRPC and early sign of disease stabilization. Our data also highlight the possibility of altered tryptophan metabolism being associated with tumour response.

Preliminary investigation of a significant national Cryptosporidium exceedance in the United Kingdom, August 2023 and ongoing.

Routine laboratory surveillance has identified an unprecedented and ongoing exceedance of Cryptosporidium spp. across the United Kingdom, notably driven by C. hominis transmission, since 14 August 2023. Information from 477 reported cases in England and Wales, followed up with a standardised exposure questionnaire as of 25 September 2023, identified foreign travel in 250 (54%) of 463 respondents and swimming in 234 (66%) of 353 cases. A significant, common exposure has not yet been identified in first analyses.

When are environmental DNA early detections of invasive species actionable?

Environmental DNA (eDNA) sampling provides sensitive early detection capabilities for recently introduced taxa. However, natural resource managers struggle with how to integrate eDNA results into an early detection rapid response program because positive eDNA detections are not always indicative of an eventual infestation. We used a structured decision making (SDM) framework to evaluate appropriate response actions to hypothetical eDNA early detections of an introduced aquatic plant in Sebago Lake (Maine, USA). The results were juxtaposed to a recent study that used a similar SDM approach to evaluate response actions to hypothetical eDNA early detections of introduced mussels in Jordanelle Reservoir (Utah, USA). We found that eDNA early detections were not actionable in Sebago Lake because the plant's invasion potential was spatially constrained and the current management activities provided acceptable levels of mitigation. In Jordanelle Reservoir, eDNA detections were actionable due to high invasion potential and analyses supported management actions to contain the invasion. The divergent outcomes of the two case studies are related to the unique attributes of the habitats and species, highlighting the utility of the SDM approach when considering an eDNA monitoring program. We use these two case studies to present a general SDM framework and a set of heuristics that can be efficiently applied to eDNA early detection rapid response scenarios and other instances associated with indeterminant eDNA detections, especially when there is an imperative to make decisions as quickly as possible.

Migration through physical constraints is enabled by MAPK-induced cell softening via actin cytoskeleton re-organization.

Cancer cells are softer than the normal cells, and metastatic cells are even softer. These changes in biomechanical properties contribute to cancer progression by facilitating cell movement through physically constraining environments. To identify properties that enabled passage through physical constraints, cells that were more efficient at moving through narrow membrane micropores were selected from established cell lines. By examining micropore-selected human MDA MB 231 breast cancer and MDA MB 435 melanoma cancer cells, membrane fluidity and nuclear elasticity were excluded as primary contributors. Instead, reduced actin cytoskeleton anisotropy, focal adhesion density and cell stiffness were characteristics associated with efficient passage through constraints. By comparing transcriptomic profiles between the parental and selected populations, increased Ras/MAPK signalling was linked with cytoskeleton rearrangements and cell softening. MEK inhibitor treatment reversed the transcriptional, cytoskeleton, focal adhesion and elasticity changes. Conversely, expression of oncogenic KRas in parental MDA MB 231 cells, or oncogenic BRaf in parental MDA MB 435 cells, significantly reduced cell stiffness. These results reveal that MAPK signalling, in addition to tumour cell proliferation, has a significant role in regulating cell biomechanics.This article has an associated First Person interview with the first author of the paper.

A G-protein-coupled chemoattractant receptor recognizes lipopolysaccharide for bacterial phagocytosis.

Phagocytes locate microorganisms via chemotaxis and then consume them using phagocytosis. Dictyostelium amoebas are stereotypical phagocytes that prey on diverse bacteria using both processes. However, as typical phagocytic receptors, such as complement receptors or Fcγ receptors, have not been found in Dictyostelium, it remains mysterious how these cells recognize bacteria. Here, we show that a single G-protein-coupled receptor (GPCR), folic acid receptor 1 (fAR1), simultaneously recognizes the chemoattractant folate and the phagocytic cue lipopolysaccharide (LPS), a major component of bacterial surfaces. Cells lacking fAR1 or its cognate G-proteins are defective in chemotaxis toward folate and phagocytosis of Klebsiella aerogenes. Computational simulations combined with experiments show that responses associated with chemotaxis can also promote engulfment of particles coated with chemoattractants. Finally, the extracellular Venus-Flytrap (VFT) domain of fAR1 acts as the binding site for both folate and LPS. Thus, fAR1 represents a new member of the pattern recognition receptors (PRRs) and mediates signaling from both bacterial surfaces and diffusible chemoattractants to reorganize actin for chemotaxis and phagocytosis.

Quality healthcare in extreme adversity: Developing a framework for action.

Quality issue: Improving quality of care has become a global health priority to improve health outcomes and strengthen health systems, particularly in the context of achieving universal health coverage. Initial assessment: The delivery of quality essential health services in settings of extreme adversity, such as fragile, conflict-affected, vulnerable or disaster contexts, has been identified as a high priority globally to address the massive level of need. Choice of solution: This paper provides an action framework to systematically address the quality of health services for state and non-state actors working in such settings. The framework is designed to be practical, comprehensible and simple in adoption and implementation. It describes challenges, a set of medical needs and population priorities, a menu of quality-related interventions, and a hierarchy of health system levels defining the roles and responsibilities of key actors. Conclusion: Optimizing the use of limited resources in delivering the best quality possible in 'the hardest of the hard settings' is imperative.

Histone chaperone HIRA deposits histone H3.3 onto foreign viral DNA and contributes to anti-viral intrinsic immunity.

The HIRA histone chaperone complex deposits histone H3.3 into nucleosomes in a DNA replication- and sequence-independent manner. As herpesvirus genomes enter the nucleus as naked DNA, we asked whether the HIRA chaperone complex affects herpesvirus infection. After infection of primary cells with HSV or CMV, or transient transfection with naked plasmid DNA, HIRA re-localizes to PML bodies, sites of cellular anti-viral activity. HIRA co-localizes with viral genomes, binds to incoming viral and plasmid DNAs and deposits histone H3.3 onto these. Anti-viral interferons (IFN) specifically induce HIRA/PML co-localization at PML nuclear bodies and HIRA recruitment to IFN target genes, although HIRA is not required for IFN-inducible expression of these genes. HIRA is, however, required for suppression of viral gene expression, virus replication and lytic infection and restricts murine CMV replication in vivo. We propose that the HIRA chaperone complex represses incoming naked viral DNAs through chromatinization as part of intrinsic cellular immunity.

Quality health care in extreme adversity-an action framework.

QUALITY PROBLEM OR ISSUE: There are record-setting numbers of people living in settings of extreme adversity and they continue to increase each year. INITIAL ASSESSMENT: There is a paucity of validated data on quality and safety across settings of extreme adversity. CHOICE OF SOLUTION: This paper argues for an action framework to address the unique challenges of providing quality in extreme adversity. IMPLEMENTATION: We describe a preliminary Quality in Extreme Adversity framework which has been informed by-and will continue to be validated through-literature, data collection, WHO expert consultations and through working in settings of extreme adversity with national authorities and NGOs. LESSONS LEARNED: Poor quality care costs lives, livelihoods and trust in health services. The recommended framework, based on evidence and experiential lessons, intends to address the WHO goal for 2019-2023 of 'one billion people better protected from health emergencies' (9).

Radiation Exposure to the Sacroiliac Joint From Low-Dose CT Compared With Radiography.

OBJECTIVE: The primary objective of this study was to estimate the effective dose delivered to the sacroiliac joint (SIJ) from low-dose (LD) CT compared with that from radiography. Secondary objectives included evaluation of diagnostic quality of LD CT of the SIJ and development of a clinical protocol for LD CT of the SIJ. MATERIALS AND METHODS: Data from 36 patients (19 women, 17 men) undergoing LD CT for suspected renal colic were analyzed. Two effective dose estimates were calculated: one for the SIJ and another for an extended region from the iliac crest to 1 cm below the SIJ. Thirty-six anteroposterior pelvic and 36 SIJ view radiographs were age-, sex-, and body width-matched to CT scans. Effective dose from radiography was estimated using the method described in International Commission on Radiologic Protection Publication 60. RESULTS: Maximum effective dose to the SIJ from LD CT was less than 1 mSv in all cases, with a mean ± SD of 0.42 ± 0.18 mSv (range, 0.14-0.83 mSv), whereas mean dose to the extended region was 0.57 ± 0.24 mSv (range, 0.19-1.11 mSv). Mean dose from SIJ radiographs was 0.15 ± 0.10 mSv (range, 0.07-1.38 mSv), and mean dose from a single pelvic radiograph was 0.09 ± 0.06 mSv (range, 0.04-0.37 mSv). All CT studies were of diagnostic quality for assessment of the SIJ. CONCLUSION: LD CT of the SIJ can be consistently performed with an effective radiation dose of less than 1 mSv. Because reliability and sensitivity of radiography for sacroiliitis is poor, we recommend that LD CT replace radiography for dedicated evaluation of the SIJ.

Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model: A Web-based program designed to evaluate the cost-effectiveness of disease management programs in heart failure.

BACKGROUND: Heart failure disease management programs can influence medical resource use and quality-adjusted survival. Because projecting long-term costs and survival is challenging, a consistent and valid approach to extrapolating short-term outcomes would be valuable. METHODS: We developed the Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model, a Web-based simulation tool designed to integrate data on demographic, clinical, and laboratory characteristics; use of evidence-based medications; and costs to generate predicted outcomes. Survival projections are based on a modified Seattle Heart Failure Model. Projections of resource use and quality of life are modeled using relationships with time-varying Seattle Heart Failure Model scores. The model can be used to evaluate parallel-group and single-cohort study designs and hypothetical programs. Simulations consist of 10,000 pairs of virtual cohorts used to generate estimates of resource use, costs, survival, and incremental cost-effectiveness ratios from user inputs. RESULTS: The model demonstrated acceptable internal and external validity in replicating resource use, costs, and survival estimates from 3 clinical trials. Simulations to evaluate the cost-effectiveness of heart failure disease management programs across 3 scenarios demonstrate how the model can be used to design a program in which short-term improvements in functioning and use of evidence-based treatments are sufficient to demonstrate good long-term value to the health care system. CONCLUSION: The Tools for Economic Analysis of Patient Management Interventions in Heart Failure Cost-Effectiveness Model provides researchers and providers with a tool for conducting long-term cost-effectiveness analyses of disease management programs in heart failure.

Interventions for drug-using offenders with co-occurring mental illness.

BACKGROUND: This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases up to May 2014 and 5 Internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to reduce, eliminate, or prevent relapse of drug use and criminal activity, or both in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Eight trials with 2058 participants met the inclusion criteria. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most 'Risk of bias' items, we rated the majority of studies as unclear. Overall, we could not statistically combine the results due to the heterogenous nature of the different study interventions and comparison groups. A narrative summary of the findings identified that the interventions reported limited success with reducing self report drug use, but did have some impact on re-incarceration rates, but not re-arrest. In the single comparisons, we found moderate-quality evidence that therapeutic communities determine a reduction in re-incarceration but reported less success for outcomes of re-arrest, moderate quality of evidence and self report drug use. Three single studies evaluating case management via a mental health drug court (very low quality of evidence), motivational interviewing and cognitive skills (low and very low quality of evidence) and interpersonal psychotherapy (very low quality of evidence) did not report significant reductions in criminal activity and self report drug use respectively. Quality of evidence for these three types of interventions was low to very low. The trials reported some cost information, but it was not sufficient to be able to evaluate the cost-effectiveness of the interventions. AUTHORS' CONCLUSIONS: Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. Overall, the studies showed a high degree of variation, warranting a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.

Pharmacological interventions for drug-using offenders.

BACKGROUND: The review represents one in a family of four reviews focusing on a range of different interventions for drug-using offenders. This specific review considers pharmacological interventions aimed at reducing drug use or criminal activity, or both, for illicit drug-using offenders. OBJECTIVES: To assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched Fourteen electronic bibliographic databases up to May 2014 and five additional Web resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials assessing the efficacy of any pharmacological intervention a component of which is designed to reduce, eliminate or prevent relapse of drug use or criminal activity, or both, in drug-using offenders. We also report data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: Fourteen trials with 2647 participants met the inclusion criteria. The interventions included in this review report on agonistic pharmacological interventions (buprenorphine, methadone and naltrexone) compared to no intervention, other non-pharmacological treatments (e.g. counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). Studies could not be combined all together because the comparisons were too different. Only subgroup analysis for type of pharmacological treatment were done. When compared to non-pharmacological, we found low quality evidence that agonist treatments are not effective in reducing drug use or criminal activity, objective results (biological) (two studies, 237 participants (RR 0.72 (95% CI 0.51 to 1.00); subjective (self-report), (three studies, 317 participants (RR 0.61 95% CI 0.31 to 1.18); self-report drug use (three studies, 510 participants (SMD: -0.62 (95% CI -0.85 to -0.39). We found low quality of evidence that antagonist treatment was not effective in reducing drug use (one study, 63 participants (RR 0.69, 95% CI 0.28 to 1.70) but we found moderate quality of evidence that they significantly reduced criminal activity (two studies, 114 participants, (RR 0.40, 95% CI 0.21 to 0.74).Findings on the effects of individual pharmacological interventions on drug use and criminal activity showed mixed results. In the comparison of methadone to buprenorphine, diamorphine and naltrexone, no significant differences were displayed for either treatment for self report dichotomous drug use (two studies, 370 participants (RR 1.04, 95% CI 0.69 to 1.55), continuous measures of drug use (one study, 81 participants, (mean difference (MD) 0.70, 95% CI -5.33 to 6.73); or criminal activity (one study, 116 participants, (RR 1.25, 95% CI 0.83 to 1.88) between methadone and buprenorphine. Similar results were found for comparisons with diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants, (RR 1.25, 95% CI 1.03 to 1.51) or naltrexone for dichotomous measures of reincarceration (one study, 44 participants, (RR 1.10, 95% CI 0.37 to 3.26), and continuous outcome measure of crime, (MD -0.50, 95% CI -8.04 to 7.04) or self report drug use (MD 4.60, 95% CI -3.54 to 12.74). AUTHORS' CONCLUSIONS: When compared to non-pharmacological treatment, agonist treatments did not seem effective in reducing drug use or criminal activity. Antagonist treatments were not effective in reducing drug use but significantly reduced criminal activity. When comparing the drugs to one another we found no significant differences between the drug comparisons (methadone versus buprenorphine, diamorphine and naltrexone) on any of the outcome measures. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias.

Interventions for female drug-using offenders.

BACKGROUND: This is an updated version of a Cochrane review first published in Issue 3, 2006 (Perry 2006). The review represents one in a family of four reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders. This specific review considers interventions for female drug-using offenders. OBJECTIVES: To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity, or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases up to May 2014 and five additional Website resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials (RCTs) designed to reduce, eliminate or prevent relapse of drug use or criminal activity in female drug-using offenders. We also reported data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Nine trials with 1792 participants met the inclusion criteria. Trial quality and risks of bias varied across each study. We rated the majority of studies as being at 'unclear' risk of bias due to a lack of descriptive information. We divided the studies into different categories for the purpose of meta-analyses: for any psychosocial treatments in comparison to treatment as usual we found low quality evidence that there were no significant differences in arrest rates, (two studies; 489 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.45 to 1.52) or drug use (one study; 77 participants; RR 0.65, 95% CI 0.20 to 2.12), but we found moderate quality evidence that there was a significant reduction in reincarceration, (three studies; 630 participants; RR 0.46, 95% CI 0.34 to 0.64). Pharmacological intervention using buprenorphine in comparison to a placebo did not significantly reduce self reported drug use (one study; 36 participants; RR 0.58, 95% CI 0.25 to 1.35). No cost or cost-effectiveness evidence was reported in the studies. AUTHORS' CONCLUSIONS: Three of the nine trials show a positive trend towards the use of any psychosocial treatment in comparison to treatment as usual showing an overall significant reduction in subsequent reincarceration, but not arrest rates or drug use. Pharmacological interventions in comparison to a placebo did not significantly reduce drug use and did not measure criminal activity. Four different treatment comparisons showed varying results and were not combined due to differences in the intervention and comparison groups. The studies overall showed a high degree of heterogeneity for types of comparisons and outcome measures assessed, which limited the possibility to pool the data. Descriptions of treatment modalities are required to identify the important elements for treatment success in drug-using female offenders. More trials are required to increase the precision of confidence with which we can draw conclusions about the effectiveness of treatments for female drug-using offenders.

Associations between seattle heart failure model scores and medical resource use and costs: findings from HF-ACTION.

BACKGROUND: Prognostic models, such as the Seattle Heart Failure Model (SHFM), have been developed to predict patient survival. The extent to which they predict medical resource use and costs has not been explored. In this study, we evaluated relationships between baseline SHFM scores and 1-year resource use and costs using data from a clinical trial. METHODS AND RESULTS: We applied generalized linear models to examine the relative impact of a 1-unit increase in SHFM scores on counts of medical resource use and direct medical costs at 1 year of follow-up. Of 2331 randomized patients, 2288 (98%) had a rounded integer SHFM score between -1 and 2, consistent with predicted 1-year survival of 98% and 74%, respectively. At baseline, median age was 59 years, 28% of patients were women, and nearly two-thirds of the cohort had New York Heart Association class II heart failure and one-third had class III heart failure. Higher SHFM scores were associated with more hospitalizations (rate ratio per 1-unit increase, 1.86; P < .001), more inpatient days (2.30; P < .001), and higher inpatient costs (2.28; P < .001), outpatient costs (1.54; P < .001), and total medical costs (2.13; P < .001). CONCLUSION: Although developed to predict all-cause mortality, SHFM scores also predict medical resource use and costs.

Chemotaxis: a feedback-based computational model robustly predicts multiple aspects of real cell behaviour.

The mechanism of eukaryotic chemotaxis remains unclear despite intensive study. The most frequently described mechanism acts through attractants causing actin polymerization, in turn leading to pseudopod formation and cell movement. We recently proposed an alternative mechanism, supported by several lines of data, in which pseudopods are made by a self-generated cycle. If chemoattractants are present, they modulate the cycle rather than directly causing actin polymerization. The aim of this work is to test the explanatory and predictive powers of such pseudopod-based models to predict the complex behaviour of cells in chemotaxis. We have now tested the effectiveness of this mechanism using a computational model of cell movement and chemotaxis based on pseudopod autocatalysis. The model reproduces a surprisingly wide range of existing data about cell movement and chemotaxis. It simulates cell polarization and persistence without stimuli and selection of accurate pseudopods when chemoattractant gradients are present. It predicts both bias of pseudopod position in low chemoattractant gradients and--unexpectedly--lateral pseudopod initiation in high gradients. To test the predictive ability of the model, we looked for untested and novel predictions. One prediction from the model is that the angle between successive pseudopods at the front of the cell will increase in proportion to the difference between the cell's direction and the direction of the gradient. We measured the angles between pseudopods in chemotaxing Dictyostelium cells under different conditions and found the results agreed with the model extremely well. Our model and data together suggest that in rapidly moving cells like Dictyostelium and neutrophils an intrinsic pseudopod cycle lies at the heart of cell motility. This implies that the mechanism behind chemotaxis relies on modification of intrinsic pseudopod behaviour, more than generation of new pseudopods or actin polymerization by chemoattractants.

Interventions for drug-using offenders with co-occurring mental illness.

BACKGROUND: This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases (searched between 2004 and 21 March 2013) and five internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to reduce, eliminate or prevent relapse in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified 76 trials across the four reviews. Following a process of pre-screening, we judged eight trials to meet the inclusion criteria for this specific review (three of the five trials are awaiting classification). The five included 1502 participants. The interventions reported on case management via a mental health drugs court, a therapeutic community, and an evaluation of a motivational interviewing technique and cognitive skills in comparison to relaxation training. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most risk of bias items, we rated the majority of studies as unclear. Overall, the combined interventions did not show a statistically significant reduction in self reported drug use (2 studies, 715 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.44 to 1.55). A statistically significantly reduction was shown for re-incarceration (4 studies, 627 participants; RR 0.40, 95% CI 0.24 to 0.67 and mean difference (MD) 28.72, 95% CI 5.89 to 51.54) but not re-arrest (2 studies, 518 participants; RR 1.00, 95% CI 0.90 to 1.12). A specific subgroup analysis combining studies using therapeutic community interventions showed a statistically significant reduction in re-incarceration (2 studies, 266 participants; RR 0.29, 95% CI 0.16 to 0.54) but not re-arrest (1 study, 428 participants; RR 0.90, 95% CI 0.61 to 1.33). Case management via a mental health court and motivational interviewing with cognitive skills did not show a statistically significant reduction in criminal activity (1 study, 235 participants; RR 1.05, 95% CI 0.90 to 1.22) or self reported drug misuse (1 study, 162 participants; MD -7.42, 95% CI -20.12 to 5.28). Due to the small number of studies, we were unable to analyse the impact of setting on outcome. Some cost information was provided in the trials but not sufficient to be able to evaluate the cost effectiveness of the interventions. AUTHORS' CONCLUSIONS: This review highlights the paucity of evidence for drug misusing offenders with co-occurring mental health problems. Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. The studies overall, showed a high degree of statistical variation demonstrating a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.