Selenium and Vitamin E for Prevention of Non-Muscle-Invasive Bladder Cancer Recurrence and Progression: A Randomized Clinical Trial.

Importance: Selenium and vitamin E have been identified as promising agents for the chemoprevention of recurrence and progression of non-muscle-invasive bladder cancer. Objective: To determine whether selenium and/or vitamin E may prevent disease recurrence in patients with newly diagnosed NMIBC. Design, Setting, and Participants: This multicenter, prospective, double-blinded, placebo-controlled, 2 × 2 factorial randomized clinical trial included patients with newly diagnosed NMIBC recruited from 10 secondary or tertiary care hospitals in the UK. A total of 755 patients were screened for inclusion; 484 did not meet the inclusion criteria, and 1 declined to participate. A total of 270 patients were randomly assigned to 4 groups (selenium plus placebo, vitamin E plus placebo, selenium plus vitamin E, and placebo plus placebo) in a double-blind fashion between July 17, 2007, and October 10, 2011. Eligibility included initial diagnosis of NMIBC (stages Ta, T1, or Tis); randomization within 12 months of first transurethral resection was required. Interventions: Oral selenium (200 µg/d of high-selenium yeast) and matched vitamin E placebo, vitamin E (200 IU/d of d-alfa-tocopherol) and matched selenium placebo, selenium and vitamin E, or placebo and placebo. Main Outcome and Measures: Recurrence-free interval (RFI) on an intention-to-treat basis (analyses completed on November 28, 2022). Results: The study randomized 270 patients (mean [SD] age, 68.9 [10.4] years; median [IQR] age, 69 [63-77] years; 202 male [75%]), with 65 receiving selenium and vitamin E placebo, 71 receiving vitamin E and selenium placebo, 69 receiving selenium and vitamin E, and 65 receiving both placebos. Median overall follow-up was 5.5 years (IQR, 5.1-6.1 years); 228 patients (84%) were followed up for more than 5 years. Median treatment duration was 1.5 years (IQR, 0.9-2.5 years). The study was halted because of slow accrual. For selenium (n = 134) vs no selenium (n = 136), there was no difference in RFI (hazard ratio, 0.92; 95% CI, 0.65-1.31; P = .65). For vitamin E (n = 140) vs no vitamin E (n = 130), there was a statistically significant detriment to RFI (hazard ratio, 1.46; 95% CI, 1.02-2.09; P = .04). No significant differences were observed for progression-free interval or overall survival time with either supplement. Results were unchanged after Cox proportional hazards regression modeling to adjust for known prognostic factors. In total, 1957 adverse events were reported; 85 were serious adverse events, and all were considered unrelated to trial treatment. Conclusions and Relevance: In this randomized clinical trial of selenium and vitamin E, selenium supplementation did not reduce the risk of recurrence in patients with NMIBC, but vitamin E supplementation was associated with an increased risk of recurrence. Neither selenium nor vitamin E influenced progression or overall survival. Vitamin E supplementation may be harmful to patients with NMIBC, and elucidation of the underlying biology is required. Trial Registration: isrctn.org Identifier: ISRCTN13889738.

Infant domestic adoption: outcomes at mid-life.

BACKGROUND: Adoption studies can cast light on environmental influences on development, but heterogeneity in preplacement experiences often complicates interpretation of findings. METHODS: We studied infant-adopted samples drawn from the 1958 and 1970 British birth cohorts and examined mental health, well-being, physical health and externalizing outcomes at mid-life. Outcomes for adopted cohort members were compared with those of (a) individuals raised in two biological parent families ('general population' comparisons) and (b) birth comparison groups of other nonadopted children from similar circumstances at birth. RESULTS: In both cohorts, to-be-adopted children shared early characteristics in common with birth comparison children, but were placed in more socially advantaged adoptive homes. Followed to mid-life, there were few group differences on indicators of physical health or psychological well-being. Levels of psychological distress were comparable in the adopted and general population samples in both cohorts, and more favourable than in the birth comparison groups among women in the 1958 cohort; more beneficial childhood family circumstances contributed to these differences. Rates of adult externalizing outcomes were comparable in the adopted and birth comparison groups in both cohorts, and higher than in the general population samples; indicators of maternal and prenatal exposures contributed to these differences. CONCLUSIONS: Rearing in adoptive homes may provide protective effects in relation to internalizing problems but may not be as protective in relation to externalizing outcomes.

Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial).

INTRODUCTION: Liver cirrhosis is the fifth largest cause of adult deaths, and a major complication, variceal bleeding is associated with a 1-year mortality of 40%. There is uncertainty on the first-line therapy for prevention of variceal bleeding owing to a lack of adequately powered trials comparing non-selective beta blockers, in particular carvedilol, with variceal band ligation. METHODS AND ANALYSIS: CALIBRE is a multicentre, pragmatic, randomised controlled, open-label trial with an internal pilot. The two interventions are carvedilol 12.5 mg od or variceal band ligation (VBL). Patients with liver cirrhosis and medium to large oesophageal varices that have never bled are eligible for inclusion. The primary outcome is any variceal bleeding within 1 year of randomisation. Secondary endpoints include time to variceal bleed, mortality, transplant-free survival, adverse events, complications of cirrhosis, health-related quality of life, use of healthcare resources, patient preference and use of alternative or crossover therapies. The sample size is 2630 patients over a 4-year recruitment period, across 66 hospitals in the UK. ETHICS AND DISSEMINATION: The study has been approved by a National Health Service (NHS) Research Ethics Committee (REC) (reference number 18/NE/0296). The results of this trial will be submitted for publication in a peer reviewed journal. Participants will be informed via a link to a preview of the publication. A lay summary will also be provided via email or posted to participants prior to publication (ISRCTN reference number: 73887615).

Pressure garment to prevent abnormal scarring after burn injury in adults and children: the PEGASUS feasibility RCT and mixed-methods study.

BACKGROUND: Eleven million people suffer a fire-related injury worldwide every year, and 71% have significant scarring. Pressure garment therapy (PGT) is a standard part of burn scar management, but there is little evidence of its clinical effectiveness or cost-effectiveness. OBJECTIVE: To identify the barriers to, and the facilitators of, conducting a randomised controlled trial (RCT) of burn scar management with and without PGT and test whether or not such a trial is feasible. DESIGN: Web-based surveys, semistructured individual interviews, a pilot RCT including a health economic evaluation and embedded process evaluation. SETTING: UK NHS burns services. Interviews and the pilot trial were run in seven burns services. PARTICIPANTS: Thirty NHS burns services and 245 staff provided survey responses and 15 staff participated in individual interviews. Face-to-face interviews were held with 24 adult patients and 16 parents of paediatric patients who had undergone PGT. The pilot trial recruited 88 participants (57 adults and 31 children) who were at risk of hypertrophic scarring and were considered suitable for scar management therapy. Interviews were held with 34 participants soon after recruitment, with 23 participants at 12 months and with eight staff from six sites at the end of the trial. INTERVENTIONS: The intervention was standard care with pressure garments. The control was standard care comprising scar management techniques involving demonstration and recommendations to undertake massage three or four times per day with moisturiser, silicone treatment, stretching and other exercises. MAIN OUTCOME MEASURES: Feasibility was assessed by eligibility rates, consent rates, retention in allocated arms, adherence with treatment and follow-up and completion of outcome assessments. The outcomes from interview-based studies were core outcome domains and barriers to, and facilitators of, trial participation and delivery. RESULTS: NHS burns services treat 2845 patients per annum (1476 paediatric and 1369 adult) and use pressure garments for 6-18 months, costing £2,171,184. The majority of staff perceived a need for a RCT of PGT, but often lacked equipoise around the research question and PGT as a treatment. Strong views about the use of PGT have the potential to influence the conduct of a full-scale RCT. A range of outcome domains was identified as important via the qualitative research: perceptions of appearance, specific scar characteristics, function, pain and itch, broader psychosocial outcomes and treatment burden. The outcome tools evaluated in the pilot trial did not cover all of these domains. The planned 88 participants were recruited: the eligibility rate was 88% [95% confidence interval (CI) 83% to 92%], the consent rate was 47% (95% CI 40% to 55%). Five (6%) participants withdrew, 14 (16%) were lost to follow-up and 8 (9%) crossed over. Adherence was as in clinical practice. Completion of outcomes was high for adult patients but poorer from parents of paediatric patients, particularly for quality of life. Sections on range of movement and willingness to pay were found to be challenging and poorly completed. LIMITATIONS: The Brisbane Burn Scar Impact Profile appears more suitable in terms of conceptual coverage than the outcome scales that were used in the trial but was not available at the time of the study. CONCLUSIONS: A definitive RCT of PGT in burn scar management appears feasible. However, staff attitudes to the use of pressure garments may lead to biases, and the provision of training and support to sites and an ongoing assessment of trial processes are required. FUTURE WORK: We recommend that any future trial include an in-depth mixed-methods recruitment investigation and a process evaluation to account for this. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34483199. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 36. See the NIHR Journals Library website for further project information.

Superresolution microscopy reveals structural mechanisms driving the nanoarchitecture of a viral chromatin tether.

By tethering their circular genomes (episomes) to host chromatin, DNA tumor viruses ensure retention and segregation of their genetic material during cell divisions. Despite functional genetic and crystallographic studies, there is little information addressing the 3D structure of these tethers in cells, issues critical for understanding persistent infection by these viruses. Here, we have applied direct stochastic optical reconstruction microscopy (dSTORM) to establish the nanoarchitecture of tethers within cells latently infected with the oncogenic human pathogen, Kaposi's sarcoma-associated herpesvirus (KSHV). Each KSHV tether comprises a series of homodimers of the latency-associated nuclear antigen (LANA) that bind with their C termini to the tandem array of episomal terminal repeats (TRs) and with their N termini to host chromatin. Superresolution imaging revealed that individual KSHV tethers possess similar overall dimensions and, in aggregate, fold to occupy the volume of a prolate ellipsoid. Using plasmids with increasing numbers of TRs, we found that tethers display polymer power law scaling behavior with a scaling exponent characteristic of active chromatin. For plasmids containing a two-TR tether, we determined the size, separation, and relative orientation of two distinct clusters of bound LANA, each corresponding to a single TR. From these data, we have generated a 3D model of the episomal half of the tether that integrates and extends previously established findings from epifluorescent, crystallographic, and epigenetic approaches. Our findings also validate the use of dSTORM in establishing novel structural insights into the physical basis of molecular connections linking host and pathogen genomes.

A randomised feasibility study to investigate the impact of education and the addition of prompts on the sedentary behaviour of office workers.

BACKGROUND: Office workers have been identified as being at risk of accumulating high amounts of sedentary time in prolonged events during work hours, which has been associated with increased risk of a number of long-term health conditions.There is some evidence that providing advice to stand at regular intervals during the working day, and using computer-based prompts, can reduce sedentary behaviour in office workers. However, evidence of effectiveness, feasibility and acceptability for these types of intervention is currently limited. METHODS: A 2-arm, parallel group, cluster-randomised feasibility trial to assess the acceptability of prompts to break up sedentary behaviour was conducted with office workers in a commercial bank (n = 21). Participants were assigned to an education only group (EG) or prompt and education group (PG). Both groups received education on reducing and breaking up sitting at work, and the PG also received hourly prompts, delivered by Microsoft Outlook over 10 weeks, reminding them to stand. Objective measurements of sedentary behaviour were made using activPAL monitors worn at three time points: baseline, in the last 2 weeks of the intervention period and 12 weeks after the intervention. Focus groups were conducted to explore the acceptability of the intervention and the motivations and barriers to changing sedentary behaviour. RESULTS: Randomly generated, customised prompts, delivered by Microsoft Outlook, with messages about breaking up sitting, proved to be a feasible and acceptable way of delivering prompts to office workers. Participants in both groups reduced their sitting, but changes were not maintained at follow-up. The education session seemed to increase outcome expectations of the benefits of changing sedentary behaviour and promote self-regulation of behaviour in some participants. However, low self-efficacy and a desire to conform to cultural norms were barriers to changing behaviour. CONCLUSIONS: Prompts delivered by Microsoft Outlook were a feasible, low-cost way of prompting office workers to break up their sedentary behaviour, although further research is needed to determine whether this has an additional impact on sedentary behaviour, to education alone. The role of cultural norms, and promoting self-efficacy, should be considered in the design of future interventions. TRIAL REGISTRATION: This study was registered retrospectively as a clinical trial on ClinicalTrials.gov (ID no. NCT02609282) on 23 March 2015.

A randomized, multicenter, open-label, blinded end point trial comparing the effects of spironolactone to chlorthalidone on left ventricular mass in patients with early-stage chronic kidney disease: Rationale and design of the SPIRO-CKD trial.

BACKGROUND: Chronic kidney disease (CKD) is associated with increased left ventricular (LV) mass and arterial stiffness. In a previous trial, spironolactone improved these end points compared with placebo in subjects with early-stage CKD, but it is not known whether these effects were specific to the drug or secondary to blood pressure lowering. AIM: The aim was to investigate the hypothesis that spironolactone is superior to chlorthalidone in the reduction of LV mass while exerting similar effects on blood pressure. DESIGN: This is a multicenter, prospective, randomized, open-label, blinded end point clinical trial initially designed to compare the effects of 40weeks of treatment with spironolactone 25mg once daily to chlorthalidone 25mg once daily on the co-primary end points of change in pulse wave velocity and change in LV mass in 350 patients with stages 2 and 3 CKD on established treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Because of slow recruitment rates, it became apparent that it would not be possible to recruit this sample size within the funded time period. The study design was therefore changed to one with a single primary end point of LV mass requiring 150 patients. Recruitment was completed on 31 December 2016, at which time 154 patients had been recruited. Investigations included cardiac magnetic resonance imaging, applanation tonometry, 24-hour ambulatory blood pressure monitoring, and laboratory tests. Subjects are assessed before and after 40weeks of randomly allocated drug therapy and at 46weeks after discontinuation of the study drug.

BAlloon versus Stenting in severe Ischaemia of the Leg-3 (BASIL-3): study protocol for a randomised controlled trial.

BACKGROUND: Severe limb ischaemia (SLI) is defined as the presence of rest pain and/or tissue loss secondary to lower extremity atherosclerotic peripheral arterial disease. The superficial femoral and popliteal arteries are the most commonly diseased vessels in such patients and are being increasingly treated using endovascular revascularisation techniques. However, it is currently unknown whether drug-eluting stents and drug-coated balloons confer additional clinical benefits over more established techniques using plain balloons and bare metal stents, or whether they represent a cost-effective use of NHS resources. METHODS: The BASIL-3 trial is a UK National Institute for Health Research, Health Technology Assessment Programme-funded, multicentre, randomised controlled trial (RCT) comparing the clinical and cost-effectiveness of plain balloon angioplasty with or without bail-out bare metal stenting, drug-coated balloon angioplasty with or without bail-out bare metal stenting, and primary stenting with drug-eluting stents for SLI secondary to femoro-popliteal disease. Patients with 'multilevel' disease may receive aorto-iliac and/or infrapopliteal treatments concurrently with their randomised femoro-popliteal intervention. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the index limb or death from any cause. The primary outcome for the economic analysis is cost per quality-adjusted life year. Secondary outcome measures include overall survival, major adverse limb events, major adverse cardiac events, relief of ischaemic pain, healing of tissue loss, and quality of life. The required sample size has been calculated at 861 participants (287 on each arm). These patients will be recruited over 3 years and followed-up for between 2 and 5 years. DISCUSSION: BASIL-3 is a pragmatic RCT designed to reflect current UK clinical practice. The results will inform decision-making regarding the appropriateness of funding the use of drug-coated balloons and drug-eluting stents, by the NHS, for the management of SLI due to femoro-popliteal disease. TRIAL REGISTRATION: ISRCTN Registry, identifier: ISRCTN14469736 . Registered on 22 October 2015.

Total Hip Arthroplasty Improves Pain and Function but Not Physical Activity.

BACKGROUND: People with hip osteoarthritis are likely to limit physical activity (PA) engagement due to pain and lack of function. Total hip arthroplasty (THA) reduces pain and improves function, potentially allowing increased PA. PA of THA patients was quantified to 12 months postoperation. The hypothesis was that postoperatively levels of PA would increase. METHODS: PA of 30 THA patients (67 ± 7 years) was objectively measured preoperatively and 3 and 12 months postoperation. Harris Hip Score (HHS), Oxford Hip Score (OHS), and 6-minute walk test (6MWT) were recorded. Mixed linear modelling was used to examine relationships of outcomes with time, baseline body mass index (BMI), age, gender, and baseline HHS. RESULTS: Time was not a significant factor in predicting volume measures of PA, including sit-to-stand transitions, upright time, and steps. Notably, baseline BMI was a significant predictor of upright time, steps, largest number of steps in an upright bout, HHS, and 6MWT. Baseline HHS helped predict longest upright bout, cadence of walking bouts longer than 60 seconds, and OHS. The significant effect of participant as a random intercept in the model for PA outcomes suggested habituation from presurgery to postsurgery. CONCLUSION: Volume measures of PA did not change from presurgery to 12 months postsurgery despite improvement in HHS, OHS, and 6MWT. Baseline BMI was a more important predictor of upright activity and stepping than time. Preoperative and postoperative PA promotion could be used to modify apparently habitual low levels of PA to enable full health benefits of THA to be gained.

Is Early Experience Destiny? Review of Research on Long-Term Outcomes following International Adoption with Special Reference to the British Chinese Adoption Study.

The pathway from adverse early experience to adulthood for internationally adopted children is complex in identifying key influences, impacts, and outcomes. This review arose from the authors' involvement in the British Chinese Adoption Study, a recent outcomes study that explored the links between early orphanage care, adoptive experiences, and midadulthood. It differs from previous reviews in focusing on a greater length of time since adoption. Both quantitative and qualitative studies were included to allow for examination of a fuller range of adult-related outcomes rather than mental health scores alone. The sampling, methods, and results of reviewed articles are summarised and a critical commentary is provided. Despite methodological differences and identified strengths and weaknesses, conclusions are drawn on the basis of the evidence available. Special attention is paid to the interpretation of negative outcomes. Findings identify areas that should be explored further in order to gain a fuller understanding of midlife outcomes of people who experienced a poor start in life followed by international adoption. Such studies help in refining lifespan developmental theories.

Agreement of the activPAL3 and activPAL for characterising posture and stepping in adults and children.

Characterisation of physical activity and sedentary behaviour under free-living conditions is becoming increasingly important in light of growing evidence for the health implications of these behaviours. The integrity of long-term follow-up and the ability to compare outcomes between studies is critically dependent on the agreement of outcomes from successive generations of monitors. This study evaluated the agreement of the activPAL and second generation activPAL3 devices. Agreement was assessed in both adults (median 27.6y IQR 22.6) (n=20) and young people (median 12.0y IQR 4.1) (n=8) during standardised and daily living (ADL) test activities. During standardised activities; sedentary duration, upright duration, stepping duration and overall number of steps were all detected within small limits of agreement (≤5%). However, the activPAL characterised more steps during jogging than the activPAL3 (adults +8.36%, young people +6.80%). Also during ADL differences arose due to different posture characterisation in young people and lower step detection in the activPAL than the activPAL3 (adults -20.58%, young people -11.43%). Second-by-second posture analysis demonstrated high levels (>90%) of agreement for all activities between monitors. However, sensitivity (68.7%) and positive predictive value (78.8%) for adult stepping demonstrated disagreement between monitor interpretation of movement patterns during ADL. Agreement between monitor outcomes for standardised activities provides confidence that these outcomes can be considered almost equivalent. However, for characterisation of jogging and smaller movements during ADL, it is likely that significant differences between monitor outcomes will arise.

Bypass versus angio plasty in severe ischaemia of the leg - 2 (BASIL-2) trial: study protocol for a randomised controlled trial.

BACKGROUND: Severe limb ischaemia is defined by ischaemic rest/night pain, tissue loss, or both, secondary to arterial insufficiency and is increasingly caused by infra-popliteal (below the knee) disease, mainly as a result of the increasing worldwide prevalence of diabetes. Currently, it is unknown whether vein bypass surgery or the best endovascular treatment (angioplasty or stenting) represents the optimal revascularisation strategy in terms of amputation-free survival, overall survival, relief of symptoms, quality of life and cost-effective use of health care resources. METHODS/DESIGN: The Bypass vs. Angioplasty in Severe Ischaemia of the Leg - 2 Trial is a UK National Institute of Health Research, Health Technology Assessment funded, multi-centre randomised controlled trial that compares, at the point of clinical equipoise, the clinical and cost-effectiveness of a 'vein bypass first' and a 'best endovascular treatment first' revascularisation strategy for severe limb ischaemia due to infra-popliteal disease. The primary clinical outcome is amputation-free survival defined as the time to major (above the ankle) amputation of the trial limb or death from any cause. The primary outcome for the cost-effectiveness analysis is cost per quality-adjusted life year. Secondary outcomes include overall survival, quality of life, in-hospital mortality and morbidity, repeat and crossover interventions, healing of tissue loss and haemodynamic changes following revascularisation. Sample size is estimated at 600 patients. An economic evaluation will be conducted from the perspective of the National Health Service and comprise a 'within-study' analysis, based on prospectively collected trial data and a 'model-based' analysis, which will extrapolate and compare costs and effects beyond the study follow-up period. DISCUSSION: The BASIL-2 trial is designed to be pragmatic and represent current practice within the United Kingdom. Patients with severe limb ischaemia can only be randomised into the trial where clinical equipose exists. The advent of hybrid operating procedures should not be a barrier to randomisation, should a patient require inflow correction prior to tibial revascularisation. ISRCTN: 27728689 Date of registration: 12 May 2014.

Upright Time and Sit-To-Stand Transition Progression After Total Hip Arthroplasty: An Inhospital Longitudinal Study.

BACKGROUND: Although early mobilization in hospital is a key element of post-total hip arthroplasty rehabilitation, it is poorly documented. METHODS: To gain quantitative insight into inhospital mobilization, upright times and sit-to-stand transitions (STS) were measured using a thigh-mounted movement sensor in 44 participants (13 males and 31 females), age 50 to 82 years, in an observational, postsurgery, inhospital, longitudinal study. RESULTS: Some participants performed no activity in the first 24 hours after surgery. However, in the last 24 hours before discharge, participants performed a median of 40 (interquartile range [IQR], 15) STS and spent 134 minutes (IQR, 74 minutes) upright. Activity in rehabilitation constituted 19.4% (IQR, 15.8%) of STS and 13.3% (IQR, 5.5%) of upright time. Females spent longer in hospital (80 hours; IQR, 24) compared to males (54 hours; IQR, 26). CONCLUSION: Although there was considerable activity within rehabilitation periods, a large majority of STS and upright time occurred outside rehabilitation. Within the last 24 hours in hospital, all participants were upright for prolonged periods and completed numerous STS.

Validity and reliability of the activPAL3 for measuring posture and stepping in adults and young people.

Characterisation of free-living physical activity requires the use of validated and reliable monitors. This study reports an evaluation of the validity and reliability of the activPAL3 monitor for the detection of posture and stepping in both adults and young people. Twenty adults (median 27.6y; IQR22.6y) and 8 young people (12.0y; IQR4.1y) performed standardised activities and activities of daily living (ADL) incorporating sedentary, upright and stepping activity. Agreement, specificity and positive predictive value were calculated between activPAL3 outcomes and the gold-standard of video observation. Inter-device reliability was calculated between 4 monitors. Sedentary and upright times for standardised activities were within ±5% of video observation as was step count (excluding jogging) for both adults and young people. Jogging step detection accuracy reduced with increasing cadence >150stepsmin(-1). For ADLs, sensitivity to stepping was very low for adults (40.4%) but higher for young people (76.1%). Inter-device reliability was either good (ICC(1,1)>0.75) or excellent (ICC(1,1)>0.90) for all outcomes. An excellent level of detection of standardised postures was demonstrated by the activPAL3. Postures such as seat-perching, kneeling and crouching were misclassified when compared to video observation. The activPAL3 appeared to accurately detect 'purposeful' stepping during ADL, but detection of smaller stepping movements was poor. Small variations in outcomes between monitors indicated that differences in monitor placement or hardware may affect outcomes. In general, the detection of posture and purposeful stepping with the activPAL3 was excellent indicating that it is a suitable monitor for characterising free-living posture and purposeful stepping activity in healthy adults and young people.

The British Chinese Adoption Study: orphanage care, adoption and mid-life outcomes.

BACKGROUND: While studies of ex-orphanage care show adverse effects on development, the longer-term impact on mid-life psychosocial functioning and physical health has not been established. METHODS: Orphanage records provided baseline data on a sample of 100 Hong Kong Chinese girls who were subsequently adopted into the UK. A mid-life follow-up using standardised questionnaires and face-to-face interviews assessed current circumstances, life satisfaction and mental and physical health outcomes. Comparisons were made with age-matched UK-born adopted and nonadopted women. RESULTS: Half the group spent between 1 and 2 years in orphanages, average age at adoptive placement was 23 months and 72% participated in the follow-up. Despite this poor early start, mid-life outcomes were commensurate with the comparison groups in terms of mental and physical health measures. Serious psychiatric and social difficulties were largely absent. Although the timing and extent of exposure to orphanage care did not influence outcome, participants' reports of poorer quality adoptive family experience and a negative view of their adoption were significantly associated with poorer mental health outcomes (difference in means = 0.76, 95% CI 1.33-0.19, p = .01; difference in means = 1.2, 95% CI 0.68-1.73, p = .01, respectively). CONCLUSIONS: Moderately depriving orphanage care did not predict enduring adverse consequences in mid-life but subsequent poor adoption experience was associated with outcome.

A comparison of patient and tumour characteristics in two UK bladder cancer cohorts separated by 20 years.

OBJECTIVES: To compare patient and tumour characteristics at presentation from two large bladder cancer cohorts, with recruitment separated by 15-20 years To identify significant differences in the West Midlands' urothelial cancer of the bladder (UCB) population during this period. PATIENTS AND METHODS: Data were collected prospectively from 1478 patients newly diagnosed with UCB in the West Midlands from January 1991 to June 1992 (Cohort 1), and from 1168 patients newly diagnosed with UBC within the same region from December 2005 to April 2011 (Cohort 2). Gender, age, smoking history, and tumour grade, stage, type, multiplicity and size at presentation were compared using a Pearson chi-square test or Cochran-Armitage trend test, as appropriate. RESULT: Cohort 2 had a higher proportion of male patients (P = 0.021), elderly patients (P < 0.001), grade 3 tumours (P < 0.001), Ta/T1 tumours (P = 0.008), multiple tumours (P < 0.001), and tumours of ≤2 cm in diameter (P < 0.001). CONCLUSIONS: There were significant differences between the cohorts. These differences are potentially explained by an ageing population, changes in grading practices, improved awareness of important symptoms, improved cystoscopic technology, and reductions in treatment delays. Regional cohorts remain important for identifying changes in tumour and patient characteristics that may influence disease management in the UK and beyond.

The Role of Non-Actuality Implicatures in Processing Elided Constituents.

When an elided constituent and its antecedent do not match syntactically, the presence of a word implying the non-actuality of the state of affairs described in the antecedent seems to improve the example (This information should be released but Gorbachev didn't. vs This information was released but Gorbachev didn't.) We model this effect in terms of Non-Actuality Implicatures (NAIs) conveyed by non-epistemic modals like should and other words such as want to and be eager to that imply non-actuality. We report three studies. A rating and interpretation study showed that such implicatures are drawn and that they improve the acceptability of mismatch ellipsis examples. An interpretation study showed that adding a NAI trigger to ambiguous examples increases the likelihood of choosing an antecedent from the NAI clause. An eye movement study shows that a NAI trigger also speeds online reading of the ellipsis clause. By introducing alternatives (the desired state of affairs vs. the actual state of affairs), the NAI trigger introduces a potential Question Under Discussion (QUD). Processing an ellipsis clause is easier, the processor is more confident of its analysis, when the ellipsis clause comments on the QUD.

Still no phonological typicality effect on word reading time (and no good explanation of one, either): a rejoinder to Farmer, Monaghan, Misyak, and Christiansen.

In this brief rejoinder, we respond to Farmer, Monaghan, Misyak, and Christiansen (2011). We argue that the data still do not support the claim that reading time is affected by the phonological typicality of a word for its part of speech. We also question Farmer et al.'s claim that interleaving syntactic structures in an experiment modifies grammatically based syntactic expectations.

WITHDRAWN: Exercise for treating anterior cruciate ligament injuries in combination with collateral ligament and meniscal damage of the knee in adults.

BACKGROUND: The anterior cruciate ligament (ACL) is the most frequently injured ligament of the knee. The ACL may be damaged in isolation but often other ligaments and menisci are implicated. The injury may be managed surgically or conservatively. Injury causes pain, effusion and inflammation leading to alteration in muscle function. Regaining muscular control is essential if the individual wishes to return to pre-injury level of function and patients will invariably be referred for rehabilitation. OBJECTIVES: To present the best evidence for effectiveness of exercise used in the treatment of ACL injuries in combination with collateral ligament and meniscal damage to the knee in adults, on return to work and pre-injury levels of activity. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (October 2006), Cochrane Central Register of Controlled Trials (The Cochrane Library 2006, Issue 3), MEDLINE (1996 to October 2006), EMBASE (1980 to October 2006), other databases and reference lists of articles. SELECTION CRITERIA: We included randomised controlled trials and quasi-randomised trials testing exercise programmes designed to treat adults with ACL injuries in combination with collateral ligament and meniscal damage. Included trials randomised participants to receive any combination of the following: no care, usual care, a single-exercise intervention, and multiple-exercise interventions. The primary outcome measures of interest were returning to work and return to pre-injury level of activity post treatment, at six months and one year. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Five trials (243 participants) evaluated different exercise programmes following ACL reconstruction and one trial (100 participants) compared supervised with self-monitored exercises as part of conservative treatment. No study compared the effect of exercise versus no exercise. Methodological quality scores varied considerably across the trials; participant and assessor blinding were poorly reported. Pooling of data was rarely possible due to the wide variety of comparisons, outcome measures and time points reported, and lack of appropriate data. Insufficient evidence was found to support the efficacy of one exercise intervention over another. AUTHORS' CONCLUSIONS: This review has demonstrated an absence of evidence to support one form of exercise intervention over another. Further research should be considered in the form of large scale well-designed and well-reported randomised controlled trials with suitable outcome measures and surveillance periods. Suitable outcome measures should include a measure of functional outcome relevant to the individual.

Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial.

PURPOSE: The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial included a prospectively planned pathology substudy testing the predictive value of progesterone receptor (PgR) expression for outcome of estrogen receptor-positive (ER-positive) early breast cancer treated with exemestane versus tamoxifen. PATIENTS AND METHODS: Pathology blocks from 4,781 TEAM patients randomly assigned to exemestane versus tamoxifen followed by exemestane for 5 years of total therapy were collected centrally, and tissue microarrays were constructed from samples from 4,598 patients. Quantitative analysis of hormone receptors (ER and PgR) was performed by using image analysis and immunohistochemistry, and the results were linked to outcome data from the main TEAM trial and analyzed relative to disease-free survival and treatment. RESULTS: Of 4,325 eligible ER-positive patients, 23% were PgR-poor (Allred < 4) and 77% were PgR- rich (Allred ≥ 5). No treatment-by-marker effect for PgR was observed for exemestane versus tamoxifen (PgR-rich hazard ratio [HR], 0.83; 95% CI, 0.65 to 1.05; PgR-poor HR, 0.85; 95% CI, 0.61 to 1.19; P = .88 for interaction). Both PgR and ER expression were associated with patient prognosis in univariate (PgR HR, 0.53; 95% CI, 0.43 to 0.65; P < .001; ER HR, 0.66; 95% CI, 0.51 to 0.86; P = .002), and multivariate analyses (P < .001 and P = .001, respectively). A trend toward a treatment-by-marker effect for ER-rich patients was observed. CONCLUSION: Preferential exemestane versus tamoxifen treatment benefit was not predicted by PgR expression; conversely, patients with ER-rich tumors may derive additional benefit from exemestane. Quantitative analysis of ER and PgR expression provides highly significant information on risk of early relapse (within 1 to 3 years) during treatment.