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Purpose: The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence. Methods: We used longitudinal data (baseline ages 9–10 and Year 2 [Y2] ages 11–12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation. Results: We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes. Conclusion: During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology.

Background: Tuberculous meningitis (TBM) causes high mortality and morbidity, in part due to raised intracranial pressure (ICP). Automated pupillometry (NPi) and optic nerve sheath diameter (ONSD) are both low-cost, easy-to-use and non-invasive techniques that correlate with ICP and neurological status. However, it is uncertain how to apply these techniques in the management of TBM., Methods: We conducted a pilot study enrolling 20 adults with TBM in the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. Our objective was to investigate the relationships between baseline and serial measurements of NPi and ONSD and disease severity and outcome. Serial NPi and ONSD were performed for 30 days, at discharge, and at 3-months, with measurements correlated with clinical progression and outcomes., Results: ONSD and NPi measurements had an inverse relationship. Higher ONSD and lower NPi values were associated with lower Glasgow coma score. Baseline NPi was a strong predictor 3-month outcome (median NPi 4.55, interquartile range 4.35-4.65 for good outcomes versus 2.60, IQR 0.65-3.95 for poor outcomes, p = 0.002). Pupil inequality (NPi ≥0.7) was also strongly associated with poor 3-month outcomes (p = 0.006). Individual participants' serial NPi and ONSD were variable during initial treatment and correlated with clinical condition and outcome., Conclusion: Pupillometry and ONSD may be used to predict clinical deterioration and outcome from TBM. Future, larger studies are need explore the optimal timing of measurements and to define how they might be used to optimise treatments and improve outcomes from TBM., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The childhood-to-adolescence transition is a notable period of change including pubertal development, neurodevelopment, and psychopathology onset, that occurs in divergent patterns between sexes. This study examined the effects of sex and puberty on cortical thickness (CT) in children and explored whether CT changes over time related to emergence of psychopathology in early adolescence., Methods: We used longitudinal data (baseline ages 9-10 and Year 2 [Y2] ages 11-12) from the ABCD Study (n = 9985). Linear and penalized function-on-function regressions modeled the impact of puberty, as it interacts with sex, on CT. Focusing on regions that showed sex differences, linear and logistic regressions modeled associations between change in CT and internalizing problems and suicide ideation., Results: We identified significant sex differences in the inverse relation between puberty and CT in fifteen primarily posterior brain regions. Nonlinear pubertal effects across age were identified in the fusiform, isthmus cingulate, paracentral, and precuneus. All effects were stronger for females relative to males during this developmental window. We did not identify associations between CT change and early adolescent clinical outcomes., Conclusion: During this age range, puberty is most strongly associated with regional changes in CT in females, which may have implications for the later emergence of psychopathology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF)., Research Question: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function?, Study Design and Methods: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI., Results: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H 2 O and peak cough flows < 270 L/min., Interpretation: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures., (Copyright © 2021 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Raised lipoprotein(a) [Lp(a)] is a cardiovascular risk factor common in patients with refractory angina. The apolipoprotein(a) component of Lp(a) exhibits structural homology with plasminogen and can enhance thrombosis and impair fibrinolysis., Objectives: The objective of the study was to assess the effect of lipoprotein apheresis on markers of thrombosis and fibrinolysis in patients with high Lp(a)., Methods: In a prospective, single-blind, crossover trial, 20 patients with refractory angina and raised Lp(a) > 50 mg/dL were randomized to three months of weekly lipoprotein apheresis or sham. Blood taken before and after apheresis/sham was assessed using the Global Thrombosis Test, to assess time taken for in vitro thrombus formation (occlusion time) and endogenous fibrinolysis (lysis time), as well as von Willebrand Factor, fibrinogen, D-dimer, thrombin/anti-thrombin III complex, prothrombin fragments 1 + 2, and thrombin generation assays., Results: Lp(a) was significantly reduced by apheresis (100.2 [interquartile range {IQR}, 69.6143.0] vs 24.8 [17.2,34.0] mg/dL, P = .0001) but not by sham (P = .0001 between treatment arms). Apheresis prolonged occlusion time (576 ± 116 s vs 723 ± 142 s, P < .0001) reflecting reduced platelet reactivity and reduced lysis time (1340 [1128, 1682] s vs 847 [685,1302] s, P = .0006) reflecting enhanced fibrinolysis, without corresponding changes with sham. Apheresis, but not sham, reduced von Willebrand Factor (149 [89.0, 164] vs 64.2 [48.5, 89.8] IU/dL, P = .0001), and fibrinogen (3.12 ± 0.68 vs 2.20 ± 0.53 g/L, P < .0001), and increased prothrombin fragments 1 + 2 (158.16 [128.77, 232.09] vs 795.12 [272.55, 1201.00] pmol/L, P = .0006). There was no change in D-dimer, thrombin/anti-thrombin III complex, or thrombin generation assay with apheresis or sham., Conclusion: Lipoprotein apheresis reduces Lp(a) and improves some thrombotic and fibrinolytic parameters in patients with refractory angina., (Copyright © 2019 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

The quality of clinical research in surgery has long attracted criticism. High-quality randomised trials have proved difficult to undertake in surgery, and many surgical treatments have therefore been adopted without adequate supporting evidence of efficacy and safety. This evidence deficit can adversely affect research funding and reimbursement decisions, lead to slow adoption of innovations, and permit widespread adoption of procedures that offer no benefit, or cause harm. Improvement in the quality of surgical evidence would therefore be valuable. The Idea, Development, Exploration, Assessment, and Long-term Follow-up (IDEAL) Framework and Recommendations specify desirable qualities for surgical studies, and outline an integrated evaluation pathway for surgery, and similar complex interventions. We used the IDEAL Recommendations to assess methodological progress in surgical research over time, assessed the uptake and influence of IDEAL, and identified the challenges to further methodological progress. Comparing studies from the periods 2000-04 and 2010-14, we noted apparent improvement in the use of standard outcome measures, adoption of Consolidated Standards of Reporting Trials (CONSORT) standards, and assessment of the quality of surgery and of learning curves, but no progress in the use of qualitative research or reporting of modifications during procedure development. Better education about research, integration of rigorous evaluation into routine practice and training, and linkage of such work to awards systems could foster further improvements in surgical evidence. IDEAL has probably contributed only slightly to the improvements described to date, but its uptake is accelerating rapidly. The need for the integrated evaluation template IDEAL offers for surgery and other complex treatments is becoming more widely accepted., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: Policy decisions about prostate cancer screening require data on the natural history of histological cancers and the resulting impact of screening. However, the gold standard procedure required to identify true positive histological cancer is a full autopsy of the gland which is not possible in screening studies, leading to verification bias. We aim to estimate the sensitivity of a prostate cancer screening round (PSA result to diagnosis) relative to histological cancer., Methods: We developed a framework combining data on UK screened and non-screened prostate cancer populations originating from a single round of population-based PSA testing among UK men aged 50-69 years, prostate cancer incidence data, and needle biopsy data from the published literature., Results: Sensitivity of a screening round was highest at age 65-69 years at 33% (95% CI: 30%-37%) and 24% (95% CI: 21%-28%) for PSA cut-off levels of 3 ng/ml and 4 ng/ml, respectively. Sensitivity was lowest at age 50-54 at 15% (95% CI: 12%-17%) and 9% (95% CI: 8%-11%) for PSA cut-off levels of 3 ng/ml and 4 ng/ml, respectively. In contrast, the clinical detection rate in the absence of mass screening, relative to histological cancer, varied between 0.2%-0.7% at age 50-54 and 1.2%-2.7% at age 65-69 from 1995 to 2012., Conclusions: The framework enabled the sensitivity of a prostate cancer screening round relative to histological cancer diagnosis to be estimated and provides a basis to determine the impact and cost-effectiveness of prostate cancer screening. The approach could be adapted to inform the sensitivity of other biomarkers, cancers and screening programmes., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Lung delivery of plasmid DNA encoding the CFTR gene complexed with a cationic liposome is a potential treatment option for patients with cystic fibrosis. We aimed to assess the efficacy of non-viral CFTR gene therapy in patients with cystic fibrosis., Methods: We did this randomised, double-blind, placebo-controlled, phase 2b trial in two cystic fibrosis centres with patients recruited from 18 sites in the UK. Patients (aged ≥12 years) with a forced expiratory volume in 1 s (FEV1) of 50-90% predicted and any combination of CFTR mutations, were randomly assigned, via a computer-based randomisation system, to receive 5 mL of either nebulised pGM169/GL67A gene-liposome complex or 0.9% saline (placebo) every 28 days (plus or minus 5 days) for 1 year. Randomisation was stratified by % predicted FEV1 (<70 vs ≥70%), age (<18 vs ≥18 years), inclusion in the mechanistic substudy, and dosing site (London or Edinburgh). Participants and investigators were masked to treatment allocation. The primary endpoint was the relative change in % predicted FEV1. The primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01621867., Findings: Between June 12, 2012, and June 24, 2013, we randomly assigned 140 patients to receive placebo (n=62) or pGM169/GL67A (n=78), of whom 116 (83%) patients comprised the per-protocol population. We noted a significant, albeit modest, treatment effect in the pGM169/GL67A group versus placebo at 12 months' follow-up (3.7%, 95% CI 0.1-7.3; p=0.046). This outcome was associated with a stabilisation of lung function in the pGM169/GL67A group compared with a decline in the placebo group. We recorded no significant difference in treatment-attributable adverse events between groups., Interpretation: Monthly application of the pGM169/GL67A gene therapy formulation was associated with a significant, albeit modest, benefit in FEV1 compared with placebo at 1 year, indicating a stabilisation of lung function in the treatment group. Further improvements in efficacy and consistency of response to the current formulation are needed before gene therapy is suitable for clinical care; however, our findings should also encourage the rapid introduction of more potent gene transfer vectors into early phase trials., Funding: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Programme., (Copyright © 2015 Alton et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Background: There is considerable evidence that the use of tidal volumes <6 ml kg(-1) predicted body weight (PBW) reduces mortality in mechanically ventilated patients. We evaluated the effectiveness of using a large screen displaying delivered tidal volume in ml kg(-1) (PBW) for reducing tidal volumes., Methods: We assessed the intervention in two 6-month periods. A qualitative study was undertaken after the intervention period to examine staff interaction with the intervention. The study was conducted in a mixed medical and surgical intensive care unit at University Hospitals Bristol, UK. Consecutive patients requiring controlled mechanical ventilation for more than 1 h were included. Alerts were triggered when tidal volume breached predetermined targets and these alerts were visible to ICU clinicians in real time., Results: A total of 199 patients with 7640 h of data were observed during the control time period and 249 patients with 10 656 h of data were observed in the intervention period. Time spent with tidal volumes <6 ml kg(-1) PBW increased from 17.5 to 28.6% of the period of controlled mechanical ventilation. Time spent with a tidal volume <8 ml kg(-1) PBW increased from 60.6 to 73.9%. The screens were acceptable to staff and stimulated an increase in attendance of clinicians at the bedside to adjust ventilators., Conclusions: Changing the format of data and displaying it with real-time alerts reduced delivered tidal volumes. Configuring information in a format more likely to result in desired outcomes has the potential to improve the translation of evidence into practice., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: A rare recurrent missense variant in HOXB13 (rs138213197/G84E) was recently reported to be associated with hereditary prostate cancer. Population-based studies have established that, since the frequency of this single-nucleotide polymorphism (SNP) varies between geographic regions, the associated proportion of prostate cancer (PrCa) risk contribution is also highly variable by country., Patients and Methods: This is the largest comprehensive case-control study assessing the prevalence of the HOXB13 G84E variant to date and is the first in the UK population. We genotyped 8652 men diagnosed with PrCa within the UK Genetic Prostate Cancer Study (UKGPCS) and 5252 healthy men from the UK ProtecT study., Results: HOXB13 G84E was identified in 0.5% of the healthy controls and 1.5% of the PrCa cases, and it was associated with a 2.93-fold increased risk of PrCa [95% confidence interval (CI) 1.94-4.59; P = 6.27 × 10(-8)]. The risk was even higher among men with family history of PrCa [odds ratio (OR) = 4.53, 95% CI 2.86-7.34; P = 3.1 × 10(-8)] and in young-onset PrCa (diagnosed up to the age of 55 years; OR = 3.11, 95% CI 1.98-5.00; P = 6.1 × 10(-7)). There was no significant association between Gleason Score, presenting prostate specific antigen, tumour-node-metastasis (TNM) stage or NCCN risk group and carrier status. HOXB13 G84E was not associated with overall or cancer-specific survival. We found that the polygenic PrCa risk score (PR score), calculated using the 71 known single-nucleotide polymorphisms (SNPs) associated with PrCa and the HOXB13 G84E variant act multiplicatively on PrCa risk. Based on the estimated prevalence and risk, this rare variant explains ∼1% of the familial risk of PrCa in the UK population., Conclusions: The clinical importance of HOXB13 G84E in PrCa management has not been established. This variant was found to have no effect on prognostic implications but could be used for stratifying screening, by identifying men at high risk., Clinical Trials Numbers: Prostate Testing for Cancer and Treatment (ProtecT): NCT02044172., Uk Genetic Prostate Cancer Study: Epidemiology and Molecular Genetics Studies (UKGPCS): NCT01737242., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background/objectives: Antipsychotic use is common in US nursing homes, despite evidence of increased risk of morbidity and mortality, and limited efficacy in older adults with dementia. Knowledge, attitudes, and beliefs regarding antipsychotic use among nursing home staff are unclear. The study aim was to describe nursing home leadership and direct care staff members' knowledge of antipsychotic risks, beliefs and attitudes about the effectiveness of antipsychotics and nonpharmacologic management of dementia-related behaviors, and perceived need for evidence-based training about antipsychotic medication safety., Design, Setting, Participants, and Measurements: Survey of leadership and direct care staff of nursing homes in Connecticut was conducted in June 2011. Questionnaire domains included knowledge of antipsychotic risks, attitudes about caring for residents with dementia, satisfaction with current behavior management training, beliefs about antipsychotic effectiveness, and need for staff training about antipsychotics and behavior management., Results: A total of 138 nursing home leaders and 779 direct care staff provided useable questionnaires. Only 24% of nursing home leaders identified at least 1 severe adverse effect of antipsychotics; 13% of LPNs and 12% of RNs listed at least 1 severe adverse effect. Fifty-six percent of direct care staff believed that medications worked well to manage resident behavior. Leaders were satisfied with the training that staff received to manage residents with challenging behaviors (62%). Fifty-five percent of direct care staff felt that they had enough training on how to handle difficult residents; only 37% felt they could do so without using medications., Conclusions: Findings suggest that a comprehensive multifaceted intervention designed for nursing homes should aim to improve knowledge of antipsychotic medication risks, change beliefs about appropriateness and effectiveness of antipsychotics for behavior management, and impart strategies and approaches for nonpharmacologic behavior management., (Copyright © 2013 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aims to validate a biostatistical approach to predict the likely effectiveness of screening in reducing advanced disease in the absence of data on incident screen and interval cancers., Methods: We derived the predicted relative reduction in advanced stage disease following screening from the expected proportion of advanced disease following screening and the observed proportion of advanced disease detected clinically among the controls. We compared the predicted estimates to those observed in a randomised trial., Results: Using our method, the predicted estimates of relative reduction in node positive breast cancer following screening were comparable to the observed estimates for the age groups 50-59 and 60-69 in the screening study (predicted 32% vs. observed 40% (p=0.274) and predicted 34% vs. observed 45% (p=0.068), respectively). However, for the age groups 40-49 and 70-74 the predicted values were overestimates of the likely effectiveness of screening compared to the observed values (predicted 38% vs. observed 16% (p=0.014) and predicted 34% vs. observed 0% (p=0.001), respectively)., Conclusion: When the number of cancer cases is more than hundred, the method of prediction using only prevalence screen data may be accurate. Where cancers are less common, for example in small populations or young age groups, further data from interval cancers or incidence screens may be necessary., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Selenocysteine (Sec) incorporation is an essential process required for the production of at least 25 human selenoproteins. This unique amino acid is co-translationally incorporated at specific UGA codons that normally serve as termination signals. Recoding from stop to Sec involves a cis-acting Sec insertion sequence element in the 3' untranslated region of selenoprotein mRNAs as well as Sec insertion sequence binding protein 2, Sec-tRNA(Sec), and the Sec-specific elongation factor, eEFSec. The interplay between recoding and termination at Sec codons has served as a focal point in researching the mechanism of Sec insertion, but the role of translation initiation has not been addressed. In this report, we show that the cricket paralysis virus intergenic internal ribosome entry site is able to support Sec incorporation, thus providing evidence that the canonical functions of translation initiation factors are not required. Additionally, we show that neither a 5' cap nor a 3' poly(A) tail enhances Sec incorporation. Interestingly, however, the presence of the internal ribosome entry site significantly decreases Sec incorporation efficiency, suggesting a role for translation initiation in regulating the efficiency of UGA recoding., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Fentanyl is frequently used for analgesia during emergency procedures. We present the cases of 2 patients who developed agitation and delirium after intravenous fentanyl administration. These patients were chronically taking selective serotonin reuptake inhibitors (SSRIs). Both developed neuromuscular examinations consistent with serotonin syndrome, a diagnosis that must be established on the basis of clinical criteria. Although they required aggressive supportive care, including mechanical ventilation, both patients made a full recovery. Use of fentanyl for procedural sedation may precipitate serotonin syndrome in patients taking SSRIs or other serotonergic drugs., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

In the United States, infections related to influenza result in a huge burden to the health care system and emergency departments (EDs). Influenza vaccinations are a safe, cost-effective means to prevent morbidity and mortality. We sought to understand the factors that contribute to the professional and personal influenza vaccination practices of health care workers in the ED setting by assessing their knowledge, attitudes, and practices with regards to the influenza vaccine. A cross-sectional study of all full-time ED staff (nurses, emergency medicine residents, and emergency medicine faculty) at an urban academic medical center in Boston treating > 90,000 ED patients annually, was performed. We examined knowledge, attitudes, and practices regarding personal influenza vaccination and support of an ED-based influenza vaccination program using an anonymous, self-administered questionnaire. Of 130 ED staff, 126 individuals completed the survey (97% response rate). Overall, 69% of respondents reported that they were very or extremely likely to be vaccinated before the coming influenza season. Residents (94%) and attending physicians (82%) were significantly more likely than nurses (42%) to be vaccinated (p < 0.001). Respondents likely to be vaccinated this year were more likely to support a vaccination program for ED patients (80% vs. 55% of those not vaccinated,p < 0.001). Providing regular education on the efficacy of preventive vaccination therapy and dispelling misconceptions regarding adverse effects may reduce barriers to vaccination programs. An educational initiative may result in acceptance of influenza vaccination by ED providers themselves, which could result in increased support for an influenza vaccination program for ED patients.

Background: Under-recruitment to randomised controlled trials (RCTs) is often problematic and there may be particular difficulties in recruiting patients with severe mental illness., Aim: To evaluate reasons for under-recruitment in an RCT of patients with severe mental illness, Methods: Qualitative study during the recruitment phase of an RCT of supported employment. Trial staff and recruiting clinicians were interviewed. Data were analyzed thematically using constant comparative techniques., Results: Recruitment rates were low. Five main reasons for recruitment difficulties were found. These included: (i) misconceptions about trials, (ii) lack of equipoise, (iii) misunderstanding of the trial arms, (iv) variable interpretations of eligibility criteria, (v) paternalism., Conclusion: Reasons for recruitment difficulties in trials involving patients with severe mental illness include issues that occur in trials in general, but others are more specific to these patients. Clinician and patient involvement in the study design may improve recruitment in future similar trials.

Introduction: Strategies to improve recruitment to RCTs (randomised controlled trials) are limited. The ProtecT (Prostate testing for cancer and Treatment) study successfully developed a complex intervention based on qualitative research methods to increase recruitment rates. The Quartet study (Qualitative Research to Improve Recruitment to RCTs) was established to evaluate whether the ProtecT qualitative methods could be transferred into other RCTs. This paper reports on the barriers and facilitators in setting up these collaborations., Methods: The Quartet study collaborated with five RCTs. Qualitative methods used were: interviews and focus groups with RCT staff; audio-recording recruitment interactions; and feedback sessions for RCT staff based on qualitative findings. Data were audio-recorded, transcribed and analysed using content and thematic analyses. Issues arising during establishment of collaborations were recorded and analysed., Results: Establishing collaborations proved challenging and not always surmountable. Difficulties were encountered in gaining agreement of RCT staff to participate because of central RCT staff's lack of authority over recruitment staff, poor communication within RCTs and recruiters' reluctance to have their practice scrutinised. The complexity of the recruitment process also hindered translation of ProtecT methods. Although Quartet enabled significant recruitment issues to surface, the bureaucratic tasks involved in securing governance approval delayed onset of collaborations, reducing the time to address issues and evaluate Quartet's impact., Discussion: The Quartet study established collaborations with a range of RCTs and gained valuable insights for future collaborations between qualitative researchers and RCTs. Qualitative research methods need to be included at the feasibility stage of a RCT or fully integrated into the RCT, as in the ProtecT study, with routine audio-recording for monitoring and training purposes. Quartet-like collaborations could then be established without delay, and recruitment processes of RCTs could become transparent, monitored and improved.

Due to increasing use of allografts from donation after cardiac death (DCD) donors, we evaluated DCD liver transplants and impact of recipient and donor factors on graft survival. Liver transplants from DCD donors reported to UNOS were analyzed against donation after brain death (DBD) donor liver transplants performed between 1996 and 2003. We defined a recipient cumulative relative risk (RCRR) using significant risk factors identified from a Cox regression analysis: age; medical condition at transplantation; regraft status; dialysis received and serum creatinine. Graft survival from DCD donors (71% at 1 year and 60% at 3 years) were significantly inferior to DBD donors (80% at 1 year and 72% at 3 years, p < 0.001). Low-risk recipients (RCRR < or = 1.5) with low-risk DCD livers (DWIT < 30 min and CIT < 10 h, n = 226) achieved graft survival rates (81% and 67% at 1 and 3 years, respectively) not significantly different from recipients with DBD allografts (80% and 72% at 1 and 3 years, respectively, log-rank p = 0.23). Liver allografts from DCD donors may be used to increase the cadaveric donor pool, with favorable graft survival rates achieved when low-risk grafts are transplanted in a low-risk setting. Whether transplantation of these organs in low-risk recipients provides a survival benefit compared to the waiting list is unknown.

Management decisions for patients with cancer are frequently taken within the context of a multi-disciplinary team (MDT). There is little known, however, about decision-making at team meetings and whether MDT decisions are all implemented. This study evaluated team decision-making in upper gastrointestinal cancer. Consecutive MDT treatment decisions were recorded for patients with oesophageal, gastric, pancreatic and peri-ampullary tumours. Implementation of MDT decisions was investigated by examining hospital records. Where decisions were implemented it was recorded as concordant and discordant if the decision changed. Reasons for changes in MDT decisions were identified. 273 decisions were studied and 41 (15.1%) were discordant (not implemented), (95% confidence interval 11.1-20.0%). Looking at the reasons for discordance, 18 (43.9%) were due to co-morbid health issues, 14 (34.2%) related to patient choice and 8 (19.5%) decisions changed when more clinical information was available. For one discordant decision, the reason was not apparent. Discordant decisions were more frequent for patients with pancreatic or gastric carcinoma as compared to oesophageal cancer (P = 0.001). Results show that monitoring concordance between MDT decisions and final treatment implementation is useful to inform team decision-making. For upper gastrointestinal cancer, MDTs require more information about co morbid disease and patient choice to truly optimize the implementation of multi-disciplinary expertise.

Epidemiologically, screening is justified by the importance of the disease and the lack of prospects for primary prevention, but evidence from natural history is unhelpful since men are more likely to die with, rather than from, prostate cancer. The available screening tests do not always detect men whose lesions could result in future morbidity or mortality. Evidence is limited for the benefits of treatment for localised cancers detected through screening, whereas the evidence for harm is clear. Observational evidence for the effect of population screening programmes is mixed, with no clear association between intensity of screening and reduced prostate cancer mortality. Screening for prostate cancer cannot be justified in low-risk populations, but the balance of benefit and harm will be more favourable after risk stratification. Prostate cancer screening can be justified only in research programmes designed to assess its effectiveness and help identify the groups who may benefit.

Complete rupture of the quadriceps femoris tendon is a well-described injury. There is a scarcity of literature relating to the outcome of patients with this injury after surgery. We undertook a retrospective analysis of patients who had surgical repair of their ruptured quadriceps tendon at our institution over a seven year period-totalling 27 patients. Males were more commonly affected with a M:F ratio of 8:1. The peak incidence was in the sixth decade of life. The non-dominant limb was twice as likely to be affected. Assessment consisted of completion of a functional knee questionnaire, clinical examination and isokinetic testing on a Biodex dynanometer. Symptomatic outcome following surgical repair was excellent with a mean symptom score generated of 22.7 out of a maximum of 25. 18/19 patients returned to their premorbid level of activity on average 18.1 weeks following injury. There was no difference in quadriceps girth comparing affected and unaffected limbs. Less than 5 degrees deficit in range of motion existed between affected and unaffected limbs. Approximately two-thirds of patients were the same or better when comparing peak torque/body weight, average power, maximum average peak torque and total work/body weight in affected and unaffected limbs.

Recent research suggests that many adolescents hold unrealistic and idealised beliefs about the likely consequences of pregnancy and parenthood. Such attitudes potentially play an important role in the aetiology of adolescent pregnancy. Disillusionment with reality may also contribute to postnatal depression, domestic violence and child abuse. This paper reports on the development of a scale to measure the prevalence of such beliefs. The scale was administered to a sample of 1546 Australian adolescents. Between one-quarter and one-third of the sample exhibited idealised beliefs, with males having higher levels of idealization. On factor analysis, the idealization construct comprised an overestimation of positive aspects and an underestimation of negative ones. Subjects reported that very few of their beliefs derived from formal educational input., (Copyright 2001 The Association for Professionals in Services for Adolescents.)

Colesevelam hydrochloride is a novel, potent, non-absorbed lipid-lowering agent previously shown to reduce low density lipoprotein (LDL) cholesterol. To examine the efficacy and safety of coadministration of colesevelam and atorvastatin, administration of these agents alone or in combination was examined in a double-blind study of 94 hypercholesterolemic men and women (baseline LDL cholesterol > or =160 mg/dl). After 4 weeks on the American Heart Association Step I diet, patients were randomized among five groups: placebo; colesevelam 3.8 g/day; atorvastatin 10 mg/day; coadminstered colesevelam 3.8 g/day plus atorvastatin 10 mg/day; or atorvastatin 80 mg/day. Fasting lipids were measured at screening, baseline and 2 and 4 weeks of treatment. LDL cholesterol decreased by 12-53% in all active treatment groups (P<0.01). LDL cholesterol reductions with combination therapy (48%) were statistically superior to colesevelam (12%) or low-dose atorvastatin (38%) alone (P<0.01), but similar to those achieved with atorvastatin 80 mg/day (53%). Total cholesterol decreased 6-39% in all active treatment groups (P<0.05). High density lipoprotein cholesterol increased significantly for all groups including placebo (P<0.05). Triglycerides decreased in patients taking atorvastatin alone (P<0.05), but were unaffected by colesevelam alone or in combination. The frequency of side effects did not differ among groups. At recommended starting doses of each agent, coadministration of colesevelam and atorvastatin was well tolerated, efficacious and produced additive LDL cholesterol reductions comparable to those observed with the maximum atorvastatin dose.

Flavan-3-ols are the most abundant flavonoids in the human diet, but little is known about their absorption and metabolism. In this study, the absorption and metabolism of the monomeric flavan-3-ol, catechin, was investigated after the in situ perfusion of the jejunum + ileum in rats. Five concentrations of catechin were studied, ranging from 1 to 100 micromol/L. The absorption of catechin was directly proportional to the concentration, and 35 +/- 2% of the perfused catechin was absorbed during the 30-min period. Effluent samples contained only native catechin, indicating that intestinal excretion of metabolites is not a mechanism of catechin elimination. Catechin was absorbed into intestinal cells and metabolized extensively because no native catechin could be detected in plasma from the mesenteric vein. Mesenteric plasma contained glucuronide conjugates of catechin and 3'-O-methyl catechin (3'OMC), indicating the intestinal origin of these conjugates. Additional methylation and sulfation occurred in the liver, and glucuronide + sulfate conjugates of 3'OMC were excreted extensively in bile. Circulating forms were mainly glucuronide conjugates of catechin and 3'OMC. The data further demonstrate the role of the rat small intestine in the glucuronidation and methylation of flavonoids as well as the role of the liver in sulfation, methylation and biliary excretion.

Tumor-related immunoglobulin heavy-chain (IgH) rearrangements are markers for polymerase chain reaction (PCR) detection of minimal residual disease (MRD) in B-cell malignancies. Nested PCR with patient IgH allele-specific oligonucleotide primers can detect 1 tumor cell in 10(4) to 10(6) normal cells. In childhood acute lymphoblastic leukemia (ALL), persistence of PCR-detectable disease is associated with increased risk of relapse. The clinical significance of qualitative PCR data can be limited, however, because patients can harbor detectable MRD for prolonged periods without relapse. Recent studies indicate that a quantitative rise in tumor burden identifies patients who are at high risk for relapse. Therefore, an efficient and reliable PCR method for MRD quantification is needed for ALL patients. We have developed a real-time PCR method to quantify MRD with IgH V(H) gene family consensus fluorogenically labeled probes. With this method, a small number of probes can be used to quantify MRD in a large number of different patients. The assay was found to be both accurate and reproducible over a wide range and capable of detecting approximately 1 tumor cell in 5 x 10(4) normal cells. We demonstrate that this methodology can discriminate between patients with persistence of MRD who relapse and those who do not. This technique is generally applicable to B-cell malignancies and is currently being used to quantify MRD in a number of prospective clinical studies at our institution. (Blood. 2000;95:2651-2658)

Background: Red wine consumption may decrease the risk of coronary heart disease through the actions of its constituent flavonoids. (+)-Catechin is an abundant flavonoid in red wine., Objective: The objective was to determine changes in plasma (+)-catechin concentrations after ingestion of a single, moderate serving of dealcoholized red wine reconstituted with either water (DRW) or water and alcohol (ARW)., Design: Nine subjects (5 men, 4 women) ingested, in random order, 120 mL DRW on one day and 120 mL ARW on another day. Both the DRW and ARW contained 35 mg (121 micromol) free (+)-catechin. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, and 8 h. Plasma was analyzed by gas chromatography-mass spectrometry for (+)-catechin after enzymatic release of sulfate and glucuronide conjugates., Results: Calcium ions were needed to effectively hydrolyze (+)-catechin conjugates in plasma containing EDTA. Neither the ARW or DRW nor sex affected the area under the curve at 8 h, the maximum concentration (c(max)), or the time it took for plasma total (+)-catechin to reach maximum concentration (t(max)). Pooled mean (+/-SEM) values for the ARW and DRW were as follows: area under the curve, 306.1 +/- 29.5 nmol*h/L; c(max), 76.7 +/- 7.5 nmol/L; and t(max), 1.44 +/- 0.13 h. The half-life of (+)-catechin in plasma was significantly less (P = 0.038) after ingestion of the ARW (3.17 h) than after ingestion of the DRW (4.08 h)., Conclusions: Increases in plasma total (+)-catechin concentrations were not significantly different after single moderate servings of either the ARW or DRW. Alcohol in the ARW hastened the elimination of (+)-catechin from the plasma compartment. (+)-Catechin elimination may represent excretion or conversion to methylated derivatives.

Flavonoids are components of fruits, vegetables and wines. An abundance of flavonoids in the diet is correlated with reduced heart disease mortality, suggesting that they act as protective nutrients. However, little is known about the absorption and metabolism of flavonoids after normal foods are consumed. This study measured the levels of one abundant flavonoid, (+)-catechin, and its metabolites in plasma after five male and four female volunteers consumed 120 mL of red wine (RW) one day and de-alcoholized red wine (DRW) on a separate day. Each wine sample contained 35 +/- 1 mg catechin (mean +/- SEM). Plasma levels of catechin and its metabolite 3'-O-methylcatechin (3'MC) were determined by gas chromatography-mass spectrometry (GC-MS) of the trimethylsilylated (TMS) derivatives. Glucuronide and sulfate conjugates were determined after enzymatic hydrolysis. Before RW or DRW consumption, plasma levels of catechin, 3'MC and all conjugates were <2 nmol/L. After 1 h, average levels of catechin, 3'MC and all conjugates increased to 91 +/- 14 nmol/L (RW) and 81 +/- 11 nmol/L (DRW). At 1 h, 21 +/- 1% of the metabolites were methylated and <2% of catechin and 3'MC were unconjugated. Catechin was present as both a sulfate conjugate and a conjugate containing both glucuronide and sulfate residues. 3'MC was present primarily as a glucuronide conjugate. At every time point, catechin was present almost exclusively as metabolites, and these levels were independent of ethanol. Therefore, if flavonoids are protective nutrients, the active forms are likely to be metabolites, which are far more abundant in plasma than the forms that exist in foods.

We have compared bispectral index (BIS), 95% spectral edge frequency (SEF) and approximate entropy (ApEn) in 37 patients during induction and recovery from a short general anaesthetic. Heart rate variability (HRV) was also compared during induction only. These indices were noted at the start of induction, when a syringe held between the thumb and fingertips was dropped, at insertion of a laryngeal mask or tracheal tube (tube insertion), at incision, at the end of surgery, on return of the gag reflex and when the patient could follow a verbal command. When indices at the start of induction were compared with those at tube insertion, all four decreased significantly. BIS decreased from a mean of 95.38 (SEM 1.02) to 44.22 (1.05), mean SEF from 20.91 (1.19) to 14.14 (0.70) Hz, mean HRV from 37.1 (7.75) to 17.9 (3.6) bpm2 and ApEn from 0.90 (0.06) to 0.65 (0.04). Using logistic regression, the indices were compared both individually and in combination as to the power of distinguishing awake (at pre-induction) from asleep (at tube insertion) states. BIS had the best predictive power, with a sensitivity of 97.3%, specificity 94.4%, positive predictive value 94.7% and negative predictive value 97.1%. A combination of the indices conferred no additional predictive advantage.

Background: There has been a long-standing failure in many countries to satisfy the demand for several elective surgical treatments, including total hip replacement. We set out to estimate the population requirement for primary total hip replacement in England., Methods: We undertook a cross-sectional study of a stratified random sample of 28,080 individuals aged 35 and over from 40 general practices in inner-city, urban, and rural areas of Avon and Somerset, UK. Prevalent disease was identified through a two-stage process: a self-report screening questionnaire (22,978 of 26,046 responded) and subsequent clinical examination. Incident disease was estimated from the point prevalence by statistical modelling. The requirement for total hip replacement surgery was estimated on the basis of pain and loss of functional ability, with adjustment for evidence of comorbidity and patients' treatment preferences., Findings: 3169 people reported hip pain on the screening questionnaire. 2018 were invited for clinical examination, and 1405 attended. The prevalence of self-reported hip pain was 107 per 1000 (95% CI 101-113) for men and 173 per 1000 (166-180) for women. The prevalence of hip disease severe enough to require surgery was 15.2 (12.7-17.8) per 1000 aged 35-85 years. The corresponding annual incidence of hip disease requiring surgery was estimated as 2.23 (1.56-2.90), which suggests an overall requirement in England of 46,600 operations per year for patients who expressed a preference for, and were suitable for, surgery; the recent actual provision in England was about 43,500., Interpretation: This research suggests that the satisfaction of demand for total hip replacement, given agreed criteria for surgery, is a realistic objective.

(+)-Catechin and (-)-epicatechin are found in many foods and may have important effects on human health. These compounds, like many other catechols, are thought to be converted to methylated metabolites after ingestion. This paper describes the synthesis of the 3'- and 4'-methyl ethers and their unambiguous identification. These products, along with catechin, epicatechin and an internal standard, (+)-taxifolin, were separated using RP-HPLC with ultraviolet, electrochemical and fluorescence detection. The trimethylsilylated derivatives of the seven compounds were also separated by GC with mass spectrometric detection. The limits of detection and selectivity of the analytical methods were compared with respect to their application in complex matrices such as human plasma.

Background: The effectiveness of cataract surgery on one eye is well established, but concerns over health-care expenditure have called into question the value of cataract surgery on the second eye. We examined the effects of second eye surgery in terms of patient perceptions as well as through visual acuity, contrast sensitivity, and stereoacuity tests., Methods: 208 otherwise healthy patients awaiting second eye cataract surgery were recruited into our randomised trial. At randomisation participants were allocated expedited surgery (planned to take place within 6 weeks) or routine surgery (routine waiting time, 7-12 months). Assessments were made at randomisation and again at review after about 6 months. Eight primary trial outcomes consisted of four questionnaire items and four visual function tests, done with both eyes open., Findings: Traditional clinical tests of success in cataract surgery (visual acuity and contrast sensitivity) showed only slight differences in binocular vision in favour of the expedited-surgery group. There were major benefits for the expedited-surgery group in terms of reported visual symptoms and effects on quality of life. At review, differences in self-reported vision related difficulties between the two groups ranged from 11% (95% CI 4.4-17%, activities) to 30% (19-41%, reading). Stereoacuity was better in the expedited surgery group, the difference between the groups for the proportions with stereoacuity of 3000 s of arc or worse was 58% (47-69%)., Interpretation: This trial has shown that there is a clear benefit from second eye cataract surgery.

The conventional view that sexual function is not adversely affected by lower urinary tract symptoms (LUTS), assumed to be caused by enlargement secondary to benign prostatic hyperplasia (BPH), was investigated in this study of 423 men aged 40 years and over in a community population in the UK and 1271 urology clinic attenders aged 45 years and over in 12 countries, using the ICSmale and ICSsex questionnaires. Sexual dysfunction was found to be common: in the community, age standardized prevalences of reduced rigidity of erections were 53%, reduced ejaculation 47%, and pain on ejaculation 5%; in clinic men, age standardized prevalences of reduced rigidity of erections were 60%, reduced ejaculation 62%, and pain on ejaculation 17%. Sex lives were reported to be spoiled by LUTS in 8% of community men and 46% in the clinic. There were negative trends for age in the extent to which clinic men were bothered by these symptoms, although older men were still very concerned. Significantly raised odds ratios of sexual dysfunction were found in those with LUTS, especially storage symptoms associated with incontinence. Urinary flow rates were not associated with sexual symptoms. Sexual dysfunction is, therefore, strongly associated with LUTS, is a matter of concern to the men affected, and should be taken into account when managing patients with LUTS.

Background: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease., Methods: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible., Findings: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done., Interpretation: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.

To assess the clinical significance of minimal residual disease (MRD) detection by polymerase chain reaction (PCR) we analyzed samples from 26 patients with mantle cell lymphoma (MCL) who had undergone bone marrow transplantation (BMT) at the Dana-Farber Cancer Institute. The BCL-1/IgH translocation and clonally rearranged Ig heavy chain genes (IgH) provided molecular markers for detection and follow-up of MRD by polymerase chain reaction (PCR) amplification in 19 of the 26 (73%) MCL patients studied. IgH gene sequencing analysis showed somatic mutations in MCL that are characteristic of an antigen driven process suggesting that, in MCL, the final malignant transformation occurs in a mature B cell. Of the 19 patients with a PCR amplifiable marker, 17 underwent autologous, 1 an allogeneic, and 1 a syngeneic bone marrow transplantation (BMT). All patients had PCR-detectable MRD in the bone marrow (BM) at the time of BMT, irrespective of any history of histological BM involvement. In contrast to other B-cell malignancies, we found that immunological purging with complement-mediated lysis eradicated PCR-detectable MCL in only two patients. Moreover reinfusion of MRD was associated with a poor outcome. More than half of the patients undergoing autologous BMT had relapsed by the time of restaging at 2 years after autologous BMT. In four MCL patients in whom no residual lymphoma was reinfused, including the allogeneic and the syngeneic BMT, only one patient relapsed. Persistence of MRD detection after BMT was also associated with a high probability of relapse, although one patient did not have PCR-detectable MRD in peripheral blood or BM before relapse at nodal sites. We conclude that PCR amplification of disease-specific markers is a feasible and sensitive method to assess MRD and its clinical significance in patients with MCL. Moreover, PCR amplification provides a tool to evaluate modifications of purging and stem cell collection procedures that may be required for the management of this otherwise incurable disease.

Objective: Although several mental disorders have been shown to be common in adolescents with substance use disorders, prior studies have not specifically focused on alcohol dependence and have not had sufficient sample sizes to examine gender effects. This study contrasts mental disorder diagnoses and symptoms between a sample of adolescents with alcohol dependence and a community control sample of adolescents and incorporates gender analyses., Method: Adolescents (aged 14 years 0 months to 18 years 0 months) with alcohol dependence (females: n = 55; males: n = 78) and community-dwelling control adolescents without substance use disorders (females: n = 44; males: n = 42) were assessed by means of a semistructured interview for DSM-III-R., Results: While cannabis and hallucinogen use disorders were common in the alcohol dependence group, females and males had similar rates. Conduct disorder (CD), oppositional defiant disorder, attention-deficit hyperactivity disorder, major depression (MD), and posttraumatic stress disorder (PTSD) had significantly higher rates in the alcohol dependence than in the community control group. Depression and PTSD symptoms were more strongly associated with alcohol dependence in females than in males. A configural frequency analysis showed that CD and MD tended to occur together in both female and male adolescents with alcohol dependence., Conclusions: While alcohol-dependent females and males similarly exhibited more comorbid disorders than control adolescents, gender affects the relationship of alcohol dependence to MD and PTSD. Rather than reflecting distinct types, the comorbid disorders of CD and MD jointly characterize many adolescents with alcohol dependence.