PSGL-1 decorated with sialyl Lewisa/x promotes high affinity binding of myeloma cells to P-selectin but is dispensable for E-selectin engagement.

Dissemination of multiple myeloma into the bone marrow proceeds through sequential steps mediated by a variety of adhesion molecules and chemokines that eventually results in the extravasation of malignant plasma cells into this protective niche. Selectins are a class of C-type lectins that recognize carbohydrate structures exposed on blood borne cells and participate in the first step of the extravasation cascade, serving as brakes to slow down circulating cells enabling them to establish firm adhesion onto the endothelium. Myeloma cells enriched for the expression of selectin ligands present an aggressive disease in vivo that is refractory to bortezomib treatment and can be reverted by small molecules targeting E-selectin. In this study, we have defined the molecular determinants of the selectin ligands expressed on myeloma cells. We show that PSGL-1 is the main protein carrier of sialyl Lewisa/x-related structures in myeloma. PSGL-1 decorated with sialyl Lewisa/x is essential for P-selectin binding but dispensable for E-selectin binding. Moreover, sialylation is required for E-selectin engagement whereas high affinity binding to P-selectin occurs even in the absence of sialic acid. This study provides further knowledge on the biology of selectin ligands in myeloma, opening the way to their clinical application as diagnostic tools and therapeutic targets.

Sialofucosylation Enables Platelet Binding to Myeloma Cells via P-Selectin and Suppresses NK Cell-Mediated Cytotoxicity.

Multiple myeloma (MM) is a plasma cell disorder that develops in the bone marrow (BM) and is characterized by uncontrolled proliferation and the ability to disseminate to different sites of the skeleton. Sialofucosylated structures, particularly Sialyl Lewis a/x (SLea/x), facilitate the homing of MM cells into the BM, leading to resistance to bortezomib in vivo. Platelets have been shown to play an important role in tumor metastasis. Platelets can bind to the surface of cancer cells, forming a "cloak" that protects them from the shear stress of the bloodstream and natural killer (NK) cell-mediated cytotoxicity. In this study, we showed that the presence of SLea/x induced a strong binding of MM cells to P-selectin, leading to specific and direct interactions with platelets, which could be inhibited by a P-selectin-blocking antibody. Importantly, platelets surrounded SLea/x-enriched MM cells, protecting them from NK cell-mediated cytotoxicity. The interactions between the platelets and MM cells were also detected in BM samples obtained from MM patients. Platelet binding to SLea/x-enriched MM cells was increased in patients with symptomatic disease and at relapse. These data suggest an important role of SLea/x and platelets in MM disease progression and resistance to therapy.

CD38 knockout natural killer cells expressing an affinity optimized CD38 chimeric antigen receptor successfully target acute myeloid leukemia with reduced effector cell fratricide.

There is a strong biological rationale for the augmentation of allogeneic natural killer (NK) cell therapies with a chimeric antigen receptor (CAR) to enhance acute myeloid leukemia (AML) targeting. CD38 is an established immunotherapeutic target in multiple myeloma and under investigation as a target antigen in AML. CD38 expression on NK cells and its further induction during ex vivo NK cell expansion represents a barrier to the development of a CD38 CAR-NK cell therapy. We set out to develop a CD38 CAR-NK cell therapy for AML, first by using an NK cell line which has low baseline CD38 expression and subsequently healthy donor expanded NK cells. To overcome anticipated fratricide due to NK cell CD38 expression when using primary expanded NK cells, we applied CRISPR/Cas9 genome editing to disrupt the CD38 gene during expansion achieving a mean knockdown efficiency of 84%. The resulting CD38 KD expanded NK cells, after expression of an affinity optimized CD38 CAR, showed reduced NK cell fratricide and an enhanced ability to target primary AML blasts. Furthermore, the cytotoxic potential of CD38 CAR-NK cells was augmented by pre-treatment of the AML cells with all-trans retinoic acid which drove enhanced CD38 expression offering a rational combination therapy. These findings support the further investigation of CD38 KD - CD38 CAR-NK cells as a viable immunotherapeutic approach to the treatment of AML.

Uptake of COVID-19 vaccination in a medium secure psychiatric hospital population.

Patients in medium secure hospitals may be at particularly increased risk of coronavirus disease 2019 (COVID-19) infection and complications. We undertook a service evaluation involving all current in-patients within a single, English medium secure hospital to describe the uptake of the COVID-19 vaccine among this population. Data regarding capacity to consent to the vaccine, acceptance/refusal of this (and reasons for refusal) and demographics was retrospectively collected from the patients' clinical records and analysed. In total, 85 patients (92.4% of eligible patients) had capacity to decide if they wanted the COVID-19 vaccine. Of these 68 (80.0%) consented and 17 (20.0%) declined to consent. A similar proportion of patients aged under and over 40 years old consented to have the vaccine. Those from a Black Asian minority ethnic background were more likely to decline the vaccine than White British patients. The reasons for capacitous refusal appeared similar to those seen in the general population.

Psychological interventions for antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (AsPD) is associated with poor mental health, criminality, substance use and relationship difficulties. This review updates Gibbon 2010 (previous version of the review). OBJECTIVES: To evaluate the potential benefits and adverse effects of psychological interventions for adults with AsPD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also searched reference lists and contacted study authors to identify studies. SELECTION CRITERIA: Randomised controlled trials of adults, where participants with an AsPD or dissocial personality disorder diagnosis comprised at least 75% of the sample randomly allocated to receive a psychological intervention, treatment-as-usual (TAU), waiting list or no treatment. The primary outcomes were aggression, reconviction, global state/functioning, social functioning and adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: This review includes 19 studies (eight new to this update), comparing a psychological intervention against TAU (also called 'standard Maintenance'(SM) in some studies). Eight of the 18 psychological interventions reported data on our primary outcomes. Four studies focussed exclusively on participants with AsPD, and 15 on subgroups of participants with AsPD. Data were available from only 10 studies involving 605 participants. Eight studies were conducted in the UK and North America, and one each in Iran, Denmark and the Netherlands. Study duration ranged from 4 to 156 weeks (median = 26 weeks). Most participants (75%) were male; the mean age was 35.5 years. Eleven studies (58%) were funded by research councils. Risk of bias was high for 13% of criteria, unclear for 54% and low for 33%. Cognitive behaviour therapy (CBT) + TAU versus TAU One study (52 participants) found no evidence of a difference between CBT + TAU and TAU for physical aggression (odds ratio (OR) 0.92, 95% CI 0.28 to 3.07; low-certainty evidence) for outpatients at 12 months post-intervention. One study (39 participants) found no evidence of a difference between CBT + TAU and TAU for social functioning (mean difference (MD) -1.60 points, 95% CI -5.21 to 2.01; very low-certainty evidence), measured by the Social Functioning Questionnaire (SFQ; range = 0-24), for outpatients at 12 months post-intervention. Impulsive lifestyle counselling (ILC) + TAU versus TAU One study (118 participants) found no evidence of a difference between ILC + TAU and TAU for trait aggression (assessed with Buss-Perry Aggression Questionnaire-Short Form) for outpatients at nine months (MD 0.07, CI -0.35 to 0.49; very low-certainty evidence). One study (142 participants) found no evidence of a difference between ILC + TAU and TAU alone for the adverse event of death (OR 0.40, 95% CI 0.04 to 4.54; very low-certainty evidence) or incarceration (OR 0.70, 95% CI 0.27 to 1.86; very low-certainty evidence) for outpatients between three and nine months follow-up. Contingency management (CM) + SM versus SM One study (83 participants) found evidence that, compared to SM alone, CM + SM may improve social functioning measured by family/social scores on the Addiction Severity Index (ASI; range = 0 (no problems) to 1 (severe problems); MD -0.08, 95% CI -0.14 to -0.02; low-certainty evidence) for outpatients at six months. 'Driving whilst intoxicated' programme (DWI) + incarceration versus incarceration One study (52 participants) found no evidence of a difference between DWI + incarceration and incarceration alone on reconviction rates (hazard ratio 0.56, CI -0.19 to 1.31; very low-certainty evidence) for prisoner participants at 24 months. Schema therapy (ST) versus TAU One study (30 participants in a secure psychiatric hospital, 87% had AsPD diagnosis) found no evidence of a difference between ST and TAU for the number of participants who were reconvicted (OR 2.81, 95% CI 0.11 to 74.56, P = 0.54) at three years. The same study found that ST may be more likely to improve social functioning (assessed by the mean number of days until patients gain unsupervised leave (MD -137.33, 95% CI -271.31 to -3.35) compared to TAU, and no evidence of a difference between the groups for overall adverse events, classified as the number of people experiencing a global negative outcome over a three-year period (OR 0.42, 95% CI 0.08 to 2.19). The certainty of the evidence for all outcomes was very low. Social problem-solving (SPS) + psychoeducation (PE) versus TAU One study (17 participants) found no evidence of a difference between SPS + PE and TAU for participants' level of social functioning (MD -1.60 points, 95% CI -5.43 to 2.23; very low-certainty evidence) assessed with the SFQ at six months post-intervention. Dialectical behaviour therapy versus TAU One study (skewed data, 14 participants) provided very low-certainty, narrative evidence that DBT may reduce the number of self-harm days for outpatients at two months post-intervention compared to TAU. Psychosocial risk management (PSRM; 'Resettle') versus TAU One study (skewed data, 35 participants) found no evidence of a difference between PSRM and TAU for a number of officially recorded offences at one year after release from prison. It also found no evidence of difference between the PSRM and TAU for the adverse event of death during the study period (OR 0.89, 95% CI 0.05 to 14.83, P = 0.94, 72 participants (90% had AsPD), 1 study, very low-certainty evidence). AUTHORS' CONCLUSIONS: There is very limited evidence available on psychological interventions for adults with AsPD. Few interventions addressed the primary outcomes of this review and, of the eight that did, only three (CM + SM, ST and DBT) showed evidence that the intervention may be more effective than the control condition. No intervention reported compelling evidence of change in antisocial behaviour. Overall, the certainty of the evidence was low or very low, meaning that we have little confidence in the effect estimates reported. The conclusions of this update have not changed from those of the original review, despite the addition of eight new studies. This highlights the ongoing need for further methodologically rigorous studies to yield further data to guide the development and application of psychological interventions for AsPD and may suggest that a new approach is required.

Pharmacological interventions for antisocial personality disorder.

BACKGROUND: Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010. OBJECTIVES: To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies. SELECTION CRITERIA: Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition. DATA COLLECTION AND ANALYSIS: Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events. MAIN RESULTS: We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes.   Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes. AUTHORS' CONCLUSIONS: The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.

Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma mouse model.

Aberrant glycosylation resulting from altered expression of sialyltransferases, such as ST3 ß-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3Fax-Neu5Ac delivered as a per-acetylated methyl ester pro-drug. Specifically, we show in vivo that 3Fax-Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3Fax-Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone marrow (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interactions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggesting that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3Fax-Neu5Ac alters the post-translational modification of the α4 integrin, which may explain the reduced affinity of α4ß1/α4ß7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as bortezomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications.

Executive function, attention, and memory deficits in antisocial personality disorder and psychopathy.

Antisocial personality disorder (ASPD) and psychopathy attempt to represent individuals demonstrating callousness and disregard for others. ASPD has been criticized for capturing a heterogeneous population whilst missing the essence of the diagnosis by neglecting interpersonal/affective deficits which measures of psychopathy include. This heterogeneity in operationalizations has led to diverse findings without clear understanding of what characterizes this broader population. This study sought to clarify the neuropsychological profiles of ASPD and psychopathy. The Cambridge Neuropsychological Test Assessment Battery was administered to 85 adult male offenders in a personality disorder secure service and to 20 healthy controls. Of patients with ASPD, 46% met criteria for psychopathy. Of those with psychopathy, 89% met criteria for ASPD. There were two sets of comparisons: ASPD versus other personality disorders versus controls and psychopathy versus other personality disorders versus controls. ASPD showed deficits across executive functions, visual short-term and working memory, and attention (compared with controls). Psychopathy showed deficits limited to attention, complex planning, inhibitory control, and response reversal. Response reversal and visual search deficits appeared specific to ASPD and psychopathy versus other personality disorders and may underpin antisocial traits. Additional deficits in inhibitory control and working memory appeared to distinguish ASPD from other personality disorders.

A selective inhibitor of histone deacetylase 3 prevents cognitive deficits and suppresses striatal CAG repeat expansions in Huntington's disease mice.

Huntington's disease (HD) is a neurodegenerative disorder whose major symptoms include progressive motor and cognitive dysfunction. Cognitive decline is a critical quality of life concern for HD patients and families. The enzyme histone deacetylase 3 (HDAC3) appears to be important in HD pathology by negatively regulating genes involved in cognitive functions. Furthermore, HDAC3 has been implicated in the aberrant transcriptional patterns that help cause disease symptoms in HD mice. HDAC3 also helps fuel CAG repeat expansions in human cells, suggesting that HDAC3 may power striatal expansions in the HTT gene thought to drive disease progression. This multifaceted role suggests that early HDAC3 inhibition offers an attractive mechanism to prevent HD cognitive decline and to suppress striatal expansions. This hypothesis was investigated by treating HdhQ111 knock-in mice with the HDAC3-selective inhibitor RGFP966. Chronic early treatment prevented long-term memory impairments and normalized specific memory-related gene expression in hippocampus. Additionally, RGFP966 prevented corticostriatal-dependent motor learning deficits, significantly suppressed striatal CAG repeat expansions, partially rescued striatal protein marker expression and reduced accumulation of mutant huntingtin oligomeric forms. These novel results highlight RGFP966 as an appealing multiple-benefit therapy in HD that concurrently prevents cognitive decline and suppresses striatal CAG repeat expansions.

Antipsychotic prescribing of consultant forensic psychiatrists working in different levels of secure care with patients with schizophrenia.

Aims and method To detect any differences in the antipsychotic prescribing practices of consultant forensic psychiatrists working in different levels of secure care with patients diagnosed with schizophrenia, and to identify potential reasons for any differences. Prescribing data were collected from four secure hospitals within one National Health Service trust. A questionnaire was sent to consultant forensic psychiatrists working at those hospitals as well as those working in the trust's community forensic services. Results Consultants working in high security prescribed more oral antipsychotics than consultants working in medium and low security, who prescribed more depot antipsychotics, as established via the prescribing data. The questionnaire provided insight regarding the reasons for these preferences. Clinical implications There were differences in the antipsychotic prescribing practices of consultant forensic psychiatrists working in different levels of secure care, and, overall, the rate of depot antipsychotic prescribing was lower than might be expected. Although it was positive that the rate of polypharmacy was low when compared with earlier studies, the lower-than-expected rate of depot antipsychotic prescribing has clinical implications.

The Saccharomyces cerevisiae Mre11-Rad50-Xrs2 complex promotes trinucleotide repeat expansions independently of homologous recombination.

Trinucleotide repeats (TNRs) are tandem arrays of three nucleotides that can expand in length to cause at least 17 inherited human diseases. Somatic expansions in patients can occur in differentiated tissues where DNA replication is limited and cannot be a primary source of somatic mutation. Instead, mouse models of TNR diseases have shown that both inherited and somatic expansions can be suppressed by the loss of certain DNA repair factors. It is generally believed that these repair factors cause misprocessing of TNRs, leading to expansions. Here we extend this idea to show that the Mre11-Rad50-Xrs2 (MRX) complex of Saccharomyces cerevisiae is a causative factor in expansions of short TNRs. Mutations that eliminate MRX subunits led to significant suppression of expansions whereas mutations that inactivate Rad51 had only a minor effect. Coupled with previous evidence, this suggests that MRX drives expansions of short TNRs through a process distinct from homologous recombination. The nuclease function of Mre11 was dispensable for expansions, suggesting that expansions do not occur by Mre11-dependent nucleolytic processing of the TNR. Epistasis between MRX and post-replication repair (PRR) was tested. PRR protects against expansions, so a rad5 mutant gave a high expansion rate. In contrast, the mre11 rad5 double mutant gave a suppressed expansion rate, indistinguishable from the mre11 single mutant. This suggests that MRX creates a TNR substrate for PRR. Protein acetylation was also tested as a mechanism regulating MRX activity in expansions. Six acetylation sites were identified in Rad50. Mutation of all six lysine residues to arginine gave partial bypass of a sin3 HDAC mutant, suggesting that Rad50 acetylation is functionally important for Sin3-mediated expansions. Overall we conclude that yeast MRX helps drive expansions of short TNRs by a mechanism distinct from its role in homologous recombination and independent of the nuclease function of Mre11.

Development and validation of a treatment progress scale for personality disordered offenders.

BACKGROUND: There is a need for a measure to evaluate change in treatment for offenders with a personality disorder, and the Progress Rating Scale (PRS) was developed to meet this need taking account of multiprofessional input. METHOD: The PRS comprises six process and five non-process items developed via thematic analysis of routine CPA patient treatment reports at a forensic Personality Disorder Service. Rating for items was fully standardized and operationalized with revisions aiming to maximize inter-rater agreement reflecting good face and content validity. Psychometric properties were examined using PRS ratings for 147 patients at three different time points in conjunction with relevant psychometrics. RESULTS: Following refinement, the instrument demonstrated good content validity. Intra-class correlations suggested moderate to substantial inter-rater agreement (intraclass correlations: 0.63-0.92). Item analyses indicated good internal consistency for process items (Cronbach's alpha: 0.82-0.88). Correlations with relevant psychometrics revealed meaningful relationships between PRS scores, defence styles and social problem solving. PRS score trajectories were in line with previously known treatment outcomes supporting predictive validity. CONCLUSION: The PRS shows promise as process measure in clinical settings but requires further testing on other samples to confirm initial findings and demonstrate its utility.

Payment by results in forensic mental health.

Forensic mental health services are low-volume, high-cost services. Payment by results (PbR) is the UK s latest attempt to improve efficiency and controls pending behaviours within the secure services. This article discusses the utility of the PbR mechanic in forensic mental health. It explores PbR implementation in non-forensic mental health settings, similar funding processes internationally, and early PbR implementation work in the UK's secure services. Finally, the article discusses the challenges faced when implementing PbR in forensic mental health services and puts forward possible next steps in determining the utility of PbR in forensic mental health.

Defence styles in a sample of forensic patients with personality disorder.

BACKGROUND: Ego defences, often considered central to clinical work, have received surprisingly little attention in the forensic literature. METHOD: In this exploratory study, 114 male inpatients completed the Defence Style Questionnaire (DSQ) following their admission to a specialist personality disorder (PD) service. Change in DSQ scores over time was examined using mixed effects models for those (n = 48) remaining in treatment for at least 18 months. RESULTS: Defensive functioning at baseline was less mature in comparison with non-clinical norms, with two other non-forensic PD samples, and with a male paedophile sample, but was unrelated to criminal history. Axis II severity was negatively associated with overall defensive functioning (ODF). Antisocial PD was positively associated with a maladaptive defence style. Borderline PD was negatively associated with self-sacrificing defences. Avoidant PD was negatively associated with both self-sacrificing and adaptive styles. Non-completion of treatment was predicted by low ODF scores and high maladaptive defence style scores at baseline. ODF improved significantly over time in treatment and was predicted by strong antisocial and weak schizotypal PD pathologies. CONCLUSIONS: Defence style, as measured by the DSQ, appears to have the potential to inform assessment and measure change in this group of offenders.

Re-offending in forensic patients released from secure care: the role of antisocial/borderline personality disorder co-morbidity, substance dependence and severe childhood conduct disorder.

BACKGROUND: Research suggests that a particular externalising phenotype, manifested in a developmental trajectory from severe childhood conduct disorder through early-onset substance abuse to adult antisocial/borderline personality disorder co-morbidity, may increase risk of antisocial behaviour in general and criminal recidivism in particular. AIM: This study aims to test the hypothesis that antisocial/borderline co-morbidity together with the triad of substance dependence, severe conduct disorder and borderline pathology would result in an increased risk of criminal recidivism. METHODS: Fifty-three men who had been assessed and treated in a secure hospital unit were followed up after they had returned to the community. They were assessed for severity of the following: (i) antisocial personality disorder; (ii) borderline personality disorder; (iii) drug/alcohol dependence; and (iv) high Psychopathy Checklist Revised scores (factors 1 and 2). RESULTS: Patients with antisocial/borderline co-morbidity took significantly less time to re-offend compared with those without such co-morbidity. Both Psychopathy Checklist Revised factor 2 and the tripartite risk measure significantly predicted time to re-offence; the former largely accounted for the predictive accuracy of the latter. CONCLUSION: Risk of criminal recidivism can be adequately assessed without recourse to the pejorative term 'psychopath'. It is sufficient to assess the presence of the three elements of our risk measure: borderline and antisocial personality disorders in the context of drug/alcohol dependence and severe childhood conduct disorder. Practical implications of the study are as follows. (i) Sound assessment of personality, inclusive of a detailed history of childhood conduct disorder as well as adolescent and adult substance misuse, yields good enough information about risk of recidivism without recourse to the pejorative concept of 'psychopathy'. (ii) Given the high risk of alcohol-related violence in individuals with antisocial/borderline co-morbidity, there is a need for specific alcohol-directed interventions to help such men retain control of their substance use.

Patients with a history of arson admitted to medium security: characteristics on admission and follow-up postdischarge.

Patients who set fires are a perennial cause of concern with psychiatric services although perhaps rather neglected in the clinical research literature. The current study considered the characteristics on admission of 129 patients, 93 men and 36 women, with a known history of arson who had been admitted to a medium secure psychiatric hospital. The distinguishing characteristics of the sample were high numbers of patients with extensive criminal histories, most probably due to high levels of prison transfer and a higher occurrence of mental illness than psychopathic disorder. Aside from return to prison, most patients were discharged either to another psychiatric hospital or directly to the community. There was a high rate of re-conviction after discharge, mainly for minor offences, with about one in 10 of discharged patients committing arson. It was established, however, that not all incidents of arson led to a prosecution. It is concluded that there are weaknesses in the areas of both risk assessment and evidence-based treatment for arsonists.

Histone deacetylase complexes promote trinucleotide repeat expansions.

Expansions of DNA trinucleotide repeats cause at least 17 inherited neurodegenerative diseases, such as Huntington's disease. Expansions can occur at frequencies approaching 100% in affected families and in transgenic mice, suggesting that specific cellular proteins actively promote (favor) expansions. The inference is that expansions arise due to the presence of these promoting proteins, not their absence, and that interfering with these proteins can suppress expansions. The goal of this study was to identify novel factors that promote expansions. We discovered that specific histone deacetylase complexes (HDACs) promote CTG•CAG repeat expansions in budding yeast and human cells. Mutation or inhibition of yeast Rpd3L or Hda1 suppressed up to 90% of expansions. In cultured human astrocytes, expansions were suppressed by 75% upon inhibition or knockdown of HDAC3, whereas siRNA against the histone acetyltransferases CBP/p300 stimulated expansions. Genetic and molecular analysis both indicated that HDACs act at a distance from the triplet repeat to promote expansions. Expansion assays with nuclease mutants indicated that Sae2 is one of the relevant factors regulated by Rpd3L and Hda1. The causal relationship between HDACs and expansions indicates that HDACs can promote mutagenesis at some DNA sequences. This relationship further implies that HDAC3 inhibitors being tested for relief of expansion-associated gene silencing may also suppress somatic expansions that contribute to disease progression.

Engagement in a medium secure personality disorder service: a comparative study of psychological functioning and offending outcomes.

BACKGROUND: Specialist treatment programmes for personality disordered offenders suffer from high rates of non-completion. This has important consequences for service providers and individual patients. METHOD: Data from hospital records and the Offenders Index were compared for groups of treatment completers (n = 22) and non-completers (n = 59) discharged from a specialist treatment programme. RESULTS: Twenty-seven percent of patients completed treatment, 37% were expelled for rule breaking and 35% disengaged early from treatment. Psychometric assessments of anger expression and anxiety showed no differences between the groups, however, treatment completers showed lower levels of impulsivity and psychopathy than either of the non-completer groups. Rates of post-discharge offending for grave and standard list offences were 56.8 and 10.8%, respectively. CONCLUSIONS: Despite careful selection methods, a large proportion of personality-disordered patients admitted to specialist units failed to complete treatment. Psychometric assessments of anger expression, anxiety and impulsivity showed limited utility in differentiating treatment completers and non-completers. Sample size limitations in this naturalistic follow-up impacted on the interpretation of differences observed between the groups on the primary outcome measure of re-offending after discharge.

Characteristics of offenders referred to a medium secure NHS personality disorder service: the first five years.

BACKGROUND: As new services for offenders with personality disorder emerge in the UK, there is interest in the methods of assessments and characteristics of patients admitted. AIM: To evaluate use of selection criteria for admission to a dedicated personality disorder service within medium secure hospital provision in the UK, and to test for features that discriminate between those admitted and those rejected. METHOD: A structured multidisciplinary assessment was administered to offenders referred to a new personality disorder service in a medium secure psychiatric unit. The evaluation included self-report and observer ratings across a range of domains including categorical axis I disorders and axis II disorders, dimensional assessment of personality and ratings of intellect and risk. RESULTS: Sixty-eight male offenders were assessed, of whom 47 were offered admission. No differences were found between those accepted or rejected on demographic, offence and most clinical characteristics. Axis I comorbidity was high in both groups (over 90%). There was no indication of staff overriding exclusion criteria but men who were accepted had greater extraversion and conscientiousness on the NEO-FFI. CONCLUSION: Staff screening men for suitability for admission to this new specialist medium security hospital unit stayed true to given exclusion criteria in their decision not to offer a bed. Characteristics with face value as qualities necessary for engagement in treatments appeared to influence positive choices. Next steps will be to test the validity of choice with outcome studies.

Does treatment really make psychopaths worse? A review of the evidence.

We aimed to evaluate critically the evidence behind the perceived inverse association between the degree of psychopathy as reflected by a high score on the Hare Psychopathy Checklist-Revised (PCL-R) and treatment response. A literature search with the key identifiers of PCL-R (or its derivatives) and treatment response produced 24 studies that were then systematically evaluated. This showed that only three studies were of an appropriate research design to answer the question and of these, none met our standard for an acceptable study. We conclude therefore that the commonly held belief of an inverse relationship between high-scores on the PCL-R and treatment response has not been established.