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Background Violence perpetrated by psychiatric inpatients is associated with modifiable factors. Current structured approaches to assess inpatient violence risk lack predictive validity and linkage to interventions. Methods Adult psychiatric inpatients on forensic and general wards in three psychiatric hospitals were recruited and followed up prospectively for 6 months. Information on modifiable (dynamic) risk factors were collected every 1-4 weeks, and baseline background factors. Data were transferred to a web-based monitoring system (FOxWeb) to calculate a total dynamic risk score. Outcomes were extracted from an incident-reporting system recording aggression and interpersonal violence. The association between total dynamic score and violent incidents was assessed by multilevel logistic regression and compared with dynamic score excluded. Results We recruited 89 patients and conducted 624 separate assessments (median 5/patient). Mean age was 39 (s.d. 12.5) years with 20% (n = 18) female. Common diagnoses were schizophrenia-spectrum disorders (70%, n = 62) and personality disorders (20%, n = 18). There were 93 violent incidents. Factors contributing to violence risk were a total dynamic score of \u22651 (OR 3.39, 95% CI 1.25-9.20), 10-year increase in age (OR 0.67, 0.47-0.96), and female sex (OR 2.78, 1.04-7.40). Non-significant associations with schizophrenia-spectrum disorder were found (OR 0.50, 0.20-1.21). In a fixed-effect model using all covariates, AUC was 0.77 (0.72-0.82) and 0.75 (0.70-0.80) when the dynamic score was excluded. Conclusions In predicting violence risk in individuals with psychiatric disorders, modifiable factors added little incremental value beyond static ones in a psychiatric inpatient setting. Future work should make a clear distinction between risk factors that assist in prediction and those linked to needs.
\n \n\n \n \nBackground: Colorectal cancer (CRC) is a common and important disease. There are different tests for diagnosis, one of which is computed tomographic colonography (CTC). No test is perfect, and patients with normal CTC may subsequently develop CRC (either because it was overlooked originally, or because it has developed in the interim). This is termed post-investigation colorectal cancer (PICRC) or \"interval cancer\". How frequently this occurs after CTC is not known. The purpose of this systematic review and meta-analysis is to use the primary literature to estimate the PICRC rate after CTC, and explore associated factors. Methods: Primary studies reporting post-investigation colorectal cancer (PICRC) rates after CTC will be identified from PubMed, Embase and Cochrane Register of Controlled Trials databases. Peer-reviewed studies published after 1994 (the year CTC was introduced) will be included and the rate of PICRC within 36months of CTC recorded. Data will be extracted from selected studies for a random effects meta-analysis. Heterogeneity, risk of bias and publication bias will be assessed, and exploratory analysis will examine factors associated with higher PICRC rates in the literature. Conclusion: PICRC rates are the ultimate benchmark of diagnostic quality for colonic investigations. This systematic review and meta-analysis will identify and synthesise evidence to determine PICRC rates after CTC and explore factors that may contribute to higher rates. Systematic review registration: PROSPERO (registration number CRD42016042437 ).
\n \n\n \n \nBackground: Most tobacco control programmes for adolescents are based around prevention of uptake, but teenage smoking is still common. It is unclear if interventions that are effective for adults can also help adolescents to quit. This is the update of a Cochrane Review first published in 2006. Objectives: To evaluate the effectiveness of strategies that help young people to stop smoking tobacco. Search methods: We searched the Cochrane Tobacco Addiction Group's Specialized Register in June 2017. This includes reports for trials identified in CENTRAL, MEDLINE, Embase and PsyclNFO. Selection criteria: We included individually and cluster-randomized controlled trials recruiting young people, aged under 20 years, who were regular tobacco smokers. We included any interventions for smoking cessation; these could include pharmacotherapy, psycho-social interventions and complex programmes targeting families, schools or communities. We excluded programmes primarily aimed at prevention of uptake. The primary outcome was smoking status after at least six months' follow-up among those who smoked at baseline. Data collection and analysis: Two review authors independently assessed the eligibility of candidate trials and extracted data. We evaluated included studies for risk of bias using standard Cochrane methodology and grouped them by intervention type and by the theoretical basis of the intervention. Where meta-analysis was appropriate, we estimated pooled risk ratios using a Mantel-Haenszel fixed-effect method, based on the quit rates at six months' follow-up. Main results: Forty-one trials involving more than 13,000 young people met our inclusion criteria (26 individually randomized controlled trials and 15 cluster-randomized trials). We judged the majority of studies to be at high or unclear risk of bias in at least one domain. Interventions were varied, with the majority adopting forms of individual or group counselling, with or without additional self-help materials to form complex interventions. Eight studies used primarily computer or messaging interventions, and four small studies used pharmacological interventions (nicotine patch or gum, or bupropion). There was evidence of an intervention effect for group counselling (9 studies, risk ratio (RR) 1.35, 95% confidence interval (CI) 1.03 to 1.77), but not for individual counselling (7 studies, RR 1.07, 95% CI 0.83 to 1.39), mixed delivery methods (8 studies, RR 1.26, 95% CI 0.95 to 1.66) or the computer or messaging interventions (pooled RRs between 0.79 and 1.18, 9 studies in total). There was no clear evidence for the effectiveness of pharmacological interventions, although confidence intervals were wide (nicotine replacement therapy 3 studies, RR 1.11, 95% CI 0.48 to 2.58; bupropion 1 study RR 1.49, 95% CI 0.55 to 4.02). No subgroup precluded the possibility of a clinically important effect. Studies of pharmacotherapies reported some adverse events considered related to study treatment, though most were mild, whereas no adverse events were reported in studies of behavioural interventions. Our certainty in the findings for all comparisons is low or very low, mainly because of the clinical heterogeneity of the interventions, imprecision in the effect size estimates, and issues with risk of bias. Authors' conclusions: There is limited evidence that either behavioural support or smoking cessation medication increases the proportion of young people that stop smoking in the long-term. Findings are most promising for group-based behavioural interventions, but evidence remains limited for all intervention types. There continues to be a need for well-designed, adequately powered, randomized controlled trials of interventions for this population of smokers.
\n \n\n \n \nBackground: Older adults with bacterial skin infections may present with atypical symptoms, making diagnosis difficult. There is limited authoritative guidance on how older adults in the community present with bacterial skin infections. To date there have been no systematic reviews assessing the diagnostic value of symptoms and signs in identifying bacterial skin infections in older adults in the community. Methods: We searched Medline and Medline in process, Embase and Web of Science, from inception to September 2017. We included cohort and cross-sectional studies assessing the diagnostic accuracy of symptoms and signs in predicting bacterial skin infections in adults in primary care aged over 65 years. The QUADAS-2 tool was used to assess study quality. Results: We identified two observational studies of low-moderate quality, with a total of 7991 participants, providing data to calculate the diagnostic accuracy of 5 unique symptoms in predicting bacterial skin infections. The presence of wounds [LR+: 7.93 (CI 4.81-13.1)], pressure sores [LR+: 4.85 (CI 2.18-10.8)] and skin ulcers [LR+: 6.26 (CI 5.49-7.13)] help to diagnose bacterial skin infections. The presence of urinary incontinence does not help to predict bacterial skin infections (LR + 's of 0.99 and 1.04; LR-'s of 0.96 and 1.04). Conclusions: Currently, there is insufficient evidence to inform the diagnosis of bacterial skin infections in older adults in the community; clinicians should therefore rely upon their clinical judgement and experience. Evidence from high quality primary care studies in older adults, including studies assessing symptoms traditionally associated with bacterial skin infections (e.g. erythema and warmth), is urgently needed to guide practice.
\n \n\n \n \nBackground: The increasing prevalence of type 2 diabetes poses both clinical and public health challenges. Cost-effective approaches to prevent progression of the disease in primary care are needed. Evidence suggests that intensive multifactorial interventions including medication and behaviour change can significantly reduce cardiovascular morbidity and mortality among patients with established type 2 diabetes, and that patient education in self-management can improve short-term outcomes. However, existing studies cannot isolate the effects of behavioural interventions promoting self-care from other aspects of intensive primary care management. The ADDITION-Plus trial was designed to address these issues among recently diagnosed patients in primary care over one year. Methods/Design. ADDITION-Plus is an explanatory randomised controlled trial of a facilitator-led, theory-based behaviour change intervention tailored to individuals with recently diagnosed type 2 diabetes. 34 practices in the East Anglia region participated. 478 patients with diabetes were individually randomised to receive (i) intensive treatment alone (n = 239), or (ii) intensive treatment plus the facilitator-led individual behaviour change intervention (n = 239). Facilitators taught patients key skills to facilitate change and maintenance of key behaviours (physical activity, dietary change, medication adherence and smoking), including goal setting, action planning, self-monitoring and building habits. The intervention was delivered over one year at the participant's surgery and included a one-hour introductory meeting followed by six 30-minute meetings and four brief telephone calls. Primary endpoints are physical activity energy expenditure (assessed by individually calibrated heart rate monitoring and movement sensing), change in objectively measured dietary intake (plasma vitamin C), medication adherence (plasma drug levels), and smoking status (plasma cotinine levels) at one year. We will undertake an intention-to-treat analysis of the effect of the intervention on these measures, an assessment of cost-effectiveness, and analyse predictors of behaviour change in the cohort. Discussion. The ADDITION-Plus trial will establish the medium-term effectiveness and cost-effectiveness of adding an externally facilitated intervention tailored to support change in multiple behaviours among intensively-treated individuals with recently diagnosed type 2 diabetes in primary care. Results will inform policy recommendations concerning the management of patients early in the course of diabetes. Findings will also improve understanding of the factors influencing change in multiple behaviours, and their association with health outcomes. Trial registration. ISRCTN: ISRCTN99175498. \u00a9 2011 Griffin et al; licensee BioMed Central Ltd.
\n \n\n \n \nMcm2-7 (MCM) proteins are part of the origin licensing machinery that regulates initiation of DNA replication. Geminin is a licensing repressor and prevents reinitiation of DNA replication during S-G2-M phase by blocking reloading of Mcm2-7 at replication origins. Here, we have analysed these replication licensing factors (RLFs) to determine whether the pathway becomes deregulated during mammary carcinogenesis, and have assessed their potential value as prognostic markers. Protein expression profiles were generated for Ki67, Mcm2, geminin, HER-2, ER and PR in a series of reduction mammoplasty (n=18) and breast cancer specimens (n=120), and compared to clinicopathological parameters. A large proportion of epithelial cells of the terminal duct lobular unit reside in a primed 'replication licensed' but not proliferating state. This state is characterised by Mcm2 expression and absence of Ki67 and the S/G2/M marker geminin. In breast cancers, increasing tumour grade is associated with increased Ki67, Mcm2 and geminin expression. The Mcm2/Ki67 ratio decreases through the grades, indicating a shift from a predominantly licensed state to an actively proliferating state. This shift is associated with an increase in the geminin/Ki67 ratio, signifying a shortening of G1 phase in breast cancer cells. Ki67, Mcm2 and the Mcm2/Ki67 ratio are statistically significantly associated with the Nottingham Prognostic Index (NPI), but geminin and the geminin/Ki67 ratio are not. Ki67, Mcm2 and Mcm2/Ki67 are highly correlated with one another, with Mcm2 being the single most important predictor of NPI score (P<0.001). However, only 12% of variation in NPI is explained by Mcm2, as the labelling index for this marker is approaching 100% for many of the high-grade tumours. The origin licensing phenotypes of normal breast and breast cancers therefore relate to their cellular differentiation status, and high-level MCM expression in more poorly differentiated tumours severely constrains their use as prognostic markers in breast cancer. \u00a9 2005 Cancer Research UK.
\n \n\n \n \nThe DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.
\n \n\n \n \nPurpose: DNA replication licensing factors and Aurora kinases play critical roles in maintaining genomic integrity. We used multiparameter analyses of these cell cycle regulatory proteins to investigate their role in the progression of epithelial ovarian carcinoma (EOC). Experimental Design: In a cohort of 143 patients, we linked the protein expression profiles of the proliferation marker Ki67, the replication licensing factors Mcm2 and geminin, and the Aurora A and B kinases to tumor DNA ploidy status and clinical outcome. Results: Ki67, Mcm2, geminin, and Aurora A and B are significantly associated with tumor grade and ploidy status (P < 0.0001). Aurora A and its substrate H3S10ph are also significantly associated with Federation of International Obstetricians and Gynecologists tumor stage (P = 0.006 and P = 0.002, respectively). Aurora A and tumor ploidy status are predictive of disease-free survival in this cohort [hazard ratio (HR), 1.29; 95% confidence intervals (95% CI), 1.06-1.58, P = 0.01 and HR, 1.80 (1.05-3.08), P = 0.03, respectively], with Aurora A of particular prognostic importance in early stage disease [HR, 1.72 (1.19-2.48), P = 0.004 for disease-free survival and HR, 1.81 (1.14-2.87), P = 0.01 for overall survival]. Conclusions: Our data show that Ki67, Mcm2, geminin and Aurora A and B can be used as an adjunct to conventional prognostic indicators and as an aid to develop a tumor progression model for EOC. Dysregulation of Aurora A seems to be an early event in EOC with a key role in tumor progression. In view of present drug development programs for specific Aurora kinase inhibitors, our findings have important implications for the use of Aurora A as a biomarker and as a potential therapeutic target. \u00a92007 American Association for Cancer Research.
\n \n\n \n \nThe DNA replication (or origin) licensing system ensures precise duplication of the genome in each cell cycle and is a powerful regulator of cell proliferation in metazoa. Studies in yeast, Drosophila melanogaster and Xenopus laevis have characterised the molecular machinery that constitutes the licensing system, but it remains to be determined how this important evolutionary conserved pathway is regulated in Homo sapiens. We have investigated regulation of the origin licensing factors Cdc6, Cdt1, Mcm2 and Geminin in human somatic and germ cells. Cdc6 and Cdt1 play an essential role in DNA replication initiation by loading the Mcm2-7 complex, which is required for unwinding the DNA helix, onto chromosomal origins. Geminin is a repressor of origin licensing that blocks Mcm2-7 loading onto origins. Our studies demonstrate that Cdc6, Cdt1 and Mcm2 play a central role in coordinating growth during the proliferation-differentiation switch in somatic self-renewing systems and that Cdc6 expression is rate-limiting for acquisition of replication competence in primary oocytes. In striking contrast, we show that proliferation control during male gametogenesis is not linked to Cdc6 or Mcm2, but appears to be coordinated by the negative regulator Geminin with Cdt1 becoming rate-limiting in late prophase. Our data demonstrate a striking sexual dimorphism in the mechanisms repressing origin licensing and preventing untimely DNA synthesis during meiosis I, implicating a pivotal role for Geminin in maintaining integrity of the male germline genome.
\n \n\n \n \nIntroduction: We examined the design, analysis and reporting in multi-reader multi-case (MRMC) research studies using the area under the receiver-operating curve (ROC AUC) as a measure of diagnostic performance. Methods: We performed a systematic literature review from 2005 to 2013 inclusive to identify a minimum 50 studies. Articles of diagnostic test accuracy in humans were identified via their citation of key methodological articles dealing with MRMC ROC AUC. Two researchers in consensus then extracted information from primary articles relating to study characteristics and design, methods for reporting study outcomes, model fitting, model assumptions, presentation of results, and interpretation of findings. Results were summarized and presented with a descriptive analysis. Results: Sixty-four full papers were retrieved from 475 identified citations and ultimately 49 articles describing 51 studies were reviewed and extracted. Radiological imaging was the index test in all. Most studies focused on lesion detection vs. characterization and used less than 10 readers. Only 6 (12%) studies trained readers in advance to use the confidence scale used to build the ROC curve. Overall, description of confidence scores, the ROC curve and its analysis was often incomplete. For example, 21 (41%) studies presented no ROC curve and only 3 (6%) described the distribution of confidence scores. Of 30 studies presenting curves, only 4 (13%) presented the data points underlying the curve, thereby allowing assessment of extrapolation. The mean change in AUC was 0.05 (20.05 to 0.28). Non-significant change in AUC was attributed to underpowering rather than the diagnostic test failing to improve diagnostic accuracy. Conclusions: Data reporting in MRMC studies using ROC AUC as an outcome measure is frequently incomplete, hampering understanding of methods and the reliability of results and study conclusions. Authors using this analysis should be encouraged to provide a full description of their methods and results.
\n \n\n \n \nPurpose: We aimed to externally validate the Oxford Risk of Recidivism (OxRec) tool to estimate 1- and 2-year risk of violent reoffending in people released from prison in England. Methods: We identified people released from prison using administrative data shared between official prison and police services. We extracted information on criminal history, clinical and sociodemographic risk predictors, and outcomes. The outcomes were violent reoffending at 1 and 2 years after release from prison, identified using official police data. Predictive ability was examined using measures of calibration (calibration statistics and plots) and discrimination (area under the receiver operating characteristic curve [AUC]; sensitivity, specificity, positive and negative predictive values [PPV; NPV]) for predetermined risk thresholds. Recalibration of the model was conducted when necessary. Results: In total, 1,770 individuals (median age = 33 [IQR 27\u201340]; 92% were male) were identified as recently released from prison. 31% (n = 550) and 43% (n = 765) reoffended within 1 and 2 years, respectively. Simple validation of the original model found a systematic underestimation of the probability of reoffending. However, after recalibration, OxRec was associated with AUCs of 0.71 (95% CI: 0.69-0.74) for 1-year and 0.71 (0.68-0.74) for 2-year follow-up. At a pre-specified threshold of 40% for 2-year violent reoffending risk, sensitivity was 77% (95% CI: 74%-80%), specificity 54% (51%-58%), PPV 56% (53%-59%) and NPV 76% (73%-79%). In addition, in the revised model, measures of calibration were good (calibration in the large was null for both time points). Conclusions: External validations of risk assessment tools for reoffending with adequate sample sizes can be conducted using linked data between prison and police services, and may require model recalibration before implementation. In this validation, OxRec had good performance on measures of discrimination and calibration. It can be considered as part of approaches to improve decision-making about risk of serious offending and the allocation of resources in the criminal justice system.
\n \n\n \n \nBACKGROUND: There has been a rapid growth in the publication of new prediction models relevant to child and adolescent mental health. However, before their implementation into clinical services, it is necessary to appraise the quality of their methods and reporting. We conducted a systematic review of new prediction models in child and adolescent mental health, and examined their development and validation. METHOD: We searched five databases for studies developing or validating multivariable prediction models for individuals aged 18\u00a0years old or younger from 1 January 2018 to 18 February 2021. Quality of reporting was assessed using the Transparent Reporting of a multivariable prediction models for Individual Prognosis Or Diagnosis checklist, and quality of methodology using items based on expert guidance and the PROBAST tool. RESULTS: We identified 100 eligible studies: 41 developing a new prediction model, 48 validating an existing model and 11 that included both development and validation. Most publications (k\u00a0=\u00a075) reported a model discrimination measure, while 26 investigations reported calibration. Of 52 new prediction models, six (12%) were for suicidal outcomes, 18 (35%) for future diagnosis, five (10%) for child maltreatment. Other outcomes included violence, crime, and functional outcomes. Eleven new models (21%) were developed for use in high-risk populations. Of development studies, around a third were sufficiently statistically powered (k\u00a0=\u00a016%, 31%), while this was lower for validation investigations (k\u00a0=\u00a012, 25%). In terms of performance, the discrimination (as measured by the C-statistic) for new models ranged from 0.57 for a tool predicting ADHD diagnosis in an external validation sample to 0.99 for a machine learning model predicting foster care permanency. CONCLUSIONS: Although some tools have recently been developed for child and adolescent mental health for prognosis and child maltreatment, none can be currently recommended for clinical practice due to a combination of methodological limitations and poor model performance. New work needs to use ensure sufficient sample sizes, representative samples, and testing of model calibration.
\n \n\n \n \nOxford Mental Illness and Suicide tool (OxMIS) is a standardised, scalable, and transparent instrument for suicide risk assessment in people with severe mental illness (SMI) based on 17 sociodemographic, criminal history, familial, and clinical risk factors. However, alongside most prediction models in psychiatry, external validations are currently lacking. We utilised a Finnish population sample of all persons diagnosed by mental health services with SMI (schizophrenia-spectrum and bipolar disorders) between 1996 and 2017 (n\u2009=\u2009137,112). To evaluate the performance of OxMIS, we initially calculated the predicted 12-month suicide risk for each individual by weighting risk factors by effect sizes reported in the original OxMIS prediction model and converted to a probability. This probability was then used to assess the discrimination and calibration of the OxMIS model in this external sample. Within a year of assessment, 1.1% of people with SMI (n\u2009=\u20091475) had died by suicide. The overall discrimination of the tool was good, with an area under the curve of 0.70 (95% confidence interval: 0.69\u20130.71). The model initially overestimated suicide risks in those with elevated predicted risks of >5% over 12 months (Harrell\u2019s Emax\u2009=\u20090.114), which applied to 1.3% (n\u2009=\u20091780) of the cohort. However, when we used a 5% maximum predicted suicide risk threshold as is recommended clinically, the calibration was excellent (ICI\u2009=\u20090.002; Emax\u2009=\u20090.005). Validating clinical prediction tools using routinely collected data can address research gaps in prediction psychiatry and is a necessary step to translating such models into clinical practice.
\n \n\n \n \nBackground Physical health outcomes in severe mental illness are worse than in the general population. Routine physical health check completion in this group is poor. Aims To quantitatively and qualitatively evaluate the impact of point of care (POC) blood testing on physical health check completion in community mental health services. Method In a prospective cohort design, we equipped an early intervention service (EIS) and a community mental health team (CMHT) with a POC blood testing device for 6 months. We compared rates of blood test and full physical health check completion in the intervention teams with a matched EIS and CMHT, historically and during the intervention. We explored attitudes to POC testing using thematic analysis of semi-structured interviews with patients and clinicians. Results Although the CMHT scarcely used the POC device and saw no change in outcomes, direct comparison of testing rates in the intervention period showed increased physical health check completion in the EIS with the device (rate ratio RR = 5.18; 95% CI 2.54-12.44; P < 0.001) compared with usual care. The rate was consistent with the EIS's increasing rate of testing over time (RR = 0.45; 95% 0.09-2.08; P = 0.32). Similar trends were seen in blood test completion. POC testing was acceptable to patients but clinicians reported usability, provision and impact on the therapeutic relationship as barriers to uptake. Conclusions POC testing was beneficial and acceptable to patients and may increase physical health check uptake. Further research, accounting for clinician barriers, is needed to evaluate its clinical and cost-effectiveness.
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