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Background: Mindfulness and acceptance-based approaches have been trialled in professional sport. The present pilot study was a randomized controlled trial with professional ballet dancers investigating the effectiveness of the Mindfulness-Acceptance-Commitment (MAC) approach, developed for athletes, compared to an education program which included topics relevant to ballet and performance. Methods: Participants included 16 professional ballet dancers (2 men and 14 women) who were randomly assigned into either the MAC or education group for 1 session per week, for 6 weeks. Participants were assessed pre-and post-intervention using the Mindfulness Inventory for Sport (MIS) and the Acceptance Action Questionnaire (AAQ-II). Within 2 weeks of the final mindfulness session, all participants completed a semi-structured interview. Results: No differences were found when comparing the questionnaire responses between pre- and post- intervention, nor between the MAC group and the control group at post intervention for all subscales. Although dancers reported in the interviews that the sessions were valuable, they advised their ability to dedicate time to mindfulness ongoing would be challenging. Conclusions: Mindfulness interventions, as explored in this study, show promise to promote the well-being of professional ballet dancers. For consistent and ongoing mindfulness practice, future designs should seek to embed mindfulness practice into dancer and company schedules., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: There remains an unmet need for safe and cost-effective adjunctive treatment of advanced colorectal cancer (CRC). The omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and has anti-inflammatory as well as antineoplastic properties. A phase 2 randomised trial of preoperative EPA free fatty acid 2 g daily in patients undergoing surgery for CRC liver metastasis showed no difference in the primary endpoint (histological tumour proliferation index) compared with placebo. However, the trial demonstrated possible benefit for the prespecified exploratory endpoint of postoperative disease-free survival. Therefore, we tested the hypothesis that EPA treatment, started before liver resection surgery (and continued postoperatively), improves CRC outcomes in patients with CRC liver metastasis., Methods and Analysis: The EPA for Metastasis Trial 2 trial is a randomised, double-blind, placebo-controlled, phase 3 trial of 4 g EPA ethyl ester (icosapent ethyl (IPE; Vascepa)) daily in patients undergoing liver resection surgery for CRC liver metastasis with curative intent. Trial treatment continues for a minimum of 2 years and maximum of 4 years, with 6 monthly assessments, including quality of life outcomes, as well as annual clinical record review after the trial intervention. The primary endpoint is CRC progression-free survival. Key secondary endpoints are overall survival, as well as the safety and tolerability of IPE. A minimum 388 participants are estimated to provide 247 CRC progression events during minimum 2-year follow-up, allowing detection of an HR of 0.7 in favour of IPE, with a power of 80% at the 5% (two sided) level of significance, assuming drop-out of 15%., Ethics and Dissemination: Ethical and health research authority approval was obtained in January 2018. All data will be collected by 2025. Full trial results will be published in 2026. Secondary analyses of health economic data, biomarker studies and other translational work will be published subsequently., Trial Registration Number: NCT03428477., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

This longitudinal study modeled children's complex executive function (EF) development using the Groton Maze Learning Task (GMLT). Using a cohort-sequential design, 147 children (61 males, 5.5-11 years) were recruited from six multicultural primary schools in Melbourne and Perth, Australia. Race/ethnicity data were not available. Children were assessed on the GMLT at 6-month intervals over 2-years between 2010 and 2012. Growth curve models describe age-related change from 5.5 to 12.5 years old. Results showed a quadratic growth trajectory on each measure of error-that is, those that reflect visuospatial memory, executive control (or the ability to apply rules for action), and complex EF. The ability to apply rules for action, while a rate-limiting factor in complex EF, develops rapidly over early-to-mid childhood., (© 2023 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.)

Self-report wellness measures are used extensively in elite sport as valid indicators of the adaptive responses to training and performance of an athlete. Wellness parameters such as quality and quantity of sleep, muscle soreness, fatigue, and stress are monitored in professional sport via Athlete Management Systems (AMS) and self-report monitoring applications (App). However, the use of a monitoring App specifically for professional classical ballet dancers has not been tested. This study piloted a self-report App to measure wellness constructs in a professional ballet company. Three male and two female dancers volunteered to take part in the mixed-method study, entering daily wellness data, frequency of work-related activities, and injury status into an App on their smart phones. Via a focus group interview session, perceptions of wellness and experiences using the App were found to be favorable, with dancers reporting that the App enhanced awareness of their well-being. To further develop monitoring tools in professional ballet companies, it is recommended that the App be made specific to the wellness needs of dancers.

Importance: Older and/or frail patients are underrepresented in landmark cancer trials. Tailored research is needed to address this evidence gap., Objective: The GO2 randomized clinical trial sought to optimize chemotherapy dosing in older and/or frail patients with advanced gastroesophageal cancer, and explored baseline geriatric assessment (GA) as a tool for treatment decision-making., Design, Setting, and Participants: This multicenter, noninferiority, open-label randomized trial took place at oncology clinics in the United Kingdom with nurse-led geriatric health assessment. Patients were recruited for whom full-dose combination chemotherapy was considered unsuitable because of advanced age and/or frailty., Interventions: There were 2 randomizations that were performed: CHEMO-INTENSITY compared oxaliplatin/capecitabine at Level A (oxaliplatin 130 mg/m2 on day 1, capecitabine 625 mg/m2 twice daily on days 1-21, on a 21-day cycle), Level B (doses 0.8 times A), or Level C (doses 0.6 times A). Alternatively, if the patient and clinician agreed the indication for chemotherapy was uncertain, the patient could instead enter CHEMO-BSC, comparing Level C vs best supportive care., Main Outcomes and Measures: First, broad noninferiority of the lower doses vs reference (Level A) was assessed using a permissive boundary of 34 days reduction in progression-free survival (PFS) (hazard ratio, HR = 1.34), selected as acceptable by a forum of patients and clinicians. Then, the patient experience was compared using Overall Treatment Utility (OTU), which combines efficacy, toxic effects, quality of life, and patient value/acceptability. For CHEMO-BSC, the main outcome measure was overall survival., Results: A total of 514 patients entered CHEMO-INTENSITY, of whom 385 (75%) were men and 299 (58%) were severely frail, with median age 76 years. Noninferior PFS was confirmed for Levels B vs A (HR = 1.09 [95% CI, 0.89-1.32]) and C vs A (HR = 1.10 [95% CI, 0.90-1.33]). Level C produced less toxic effects and better OTU than A or B. No subgroup benefited from higher doses: Level C produced better OTU even in younger or less frail patients. A total of 45 patients entered the CHEMO-BSC randomization: overall survival was nonsignificantly longer with chemotherapy: median 6.1 vs 3.0 months (HR = 0.69 [95% CI, 0.32-1.48], P = .34). In multivariate analysis in 522 patients with all variables available, baseline frailty, quality of life, and neutrophil to lymphocyte ratio were independently associated with OTU, and can be combined in a model to estimate the probability of different outcomes., Conclusions and Relevance: This phase 3 randomized clinical trial found that reduced-intensity chemotherapy provided a better patient experience without significantly compromising cancer control and should be considered for older and/or frail patients. Baseline geriatric assessment can help predict the utility of chemotherapy but did not identify a group benefiting from higher-dose treatment., Trial Registration: isrctn.org Identifier: ISRCTN44687907.

Objective: In high-performance sport, the use of self-report measures is expanding. The exploration of wellness states in response to training and performance requires further investigation for professional ballet dancers and athletes. This study therefore aimed to: compare wellness scores between professional ballet dancers and athletes in training and performance; report frequency of self-reported modified participation during training and performance; and report frequency of self-reported inability to participate due to pain and illness in dancers and athletes., Methods: Fourteen professional ballet dancers (mean 26 yrs, SD 2.6) and 14 sex- and age-matched professional athletes (mean 27.7 yrs, SD 2.9) recorded daily wellness (fatigue, stress, sleep quality and quantity), participation (full, rest, modified, or unable to participate) and activity (performance, training) into a wellness application on their smart phone over a 4-month period. Mixed factorial ANOVAs were conducted to assess the interaction between group (ballet dancers and athletes) and activity (performance and training) on the dependent variables (stress, fatigue, sleep quality, and sleep quantity)., Results: Stress and fatigue levels were higher for both dancers and athletes during performance compared to training periods. Dancers recorded lower sleep quantity than athletes, with no difference in sleep quality. Modified participation appears more common in dancers compared to athletes. Dancers and athletes were rarely unable to train or perform/compete over the 4 months., Conclusion: Self-reported wellness scores appear sensitive to activity type and can provide valuable information to guide intervention and recovery strategies. Further research on the impact of poor wellness on performance, illness, and injury in professional ballet is warranted.

Aim: To analyse the development of motor skill and executive function in school-aged children with and without developmental coordination disorder (DCD)., Method: Using a longitudinal design, 186 children (86 males, 100 females) aged 6 to 11 years at Time 1 were tested over a 2-year period, 52 of whom were diagnosed with DCD at Time 1 (27 males, 25 females; mean age 8y 5mo, SD 1y 6mo) using DSM-5 criteria. The McCarron Assessment of Neuromuscular Development assessed motor status at Time 1 and at 2-year follow-up (Time 2). Executive function was assessed using a well-validated measure, the Groton Maze Learning Test., Results: The DCD cohort at Time 1 had moderate incidence of executive function deficit (41%). Most importantly, at a group level, children with persisting DCD (across Times 1 and 2) also showed significantly lower levels of executive function than children with typical motor development at both time points. At an individual level, around 26% of children in this group had persisting executive function deficits relative to normal ranges of performance., Interpretation: Children with persisting DCD are at significant risk of executive function issues. The combination of motor and cognitive issues as a potential risk factor in the longer-term development of children is discussed., What This Paper Adds: Around half of children initially diagnosed with developmental coordination disorder (DCD) had the same diagnosis at 2-year follow-up. 41% of children with DCD have impaired executive function. Children with persisting DCD show poorer executive function than those with typical motor development or remitting DCD., (© 2020 Mac Keith Press.)

Background: Although surgical resection has been considered the only curative option for colorectal liver metastases, thermal ablation has recently been suggested as an alternative curative treatment. There have been no adequately powered trials comparing surgery with thermal ablation., Objectives: Main objective - to compare the clinical effectiveness and cost-effectiveness of thermal ablation versus liver resection surgery in high surgical risk patients who would be eligible for liver resection. Pilot study objectives - to assess the feasibility of recruitment (through qualitative study), to assess the quality of ablations and liver resection surgery to determine acceptable standards for the main trial and to centrally review the reporting of computed tomography scan findings relating to ablation and outcomes and recurrence rate in both arms., Design: A prospective, international (UK and the Netherlands), multicentre, open, pragmatic, parallel-group, randomised controlled non-inferiority trial with a 1-year internal pilot study., Setting: Tertiary liver, pancreatic and gallbladder (hepatopancreatobiliary) centres in the UK and the Netherlands., Participants: Adults with a specialist multidisciplinary team diagnosis of colorectal liver metastases who are at high surgical risk because of their age, comorbidities or tumour burden and who would be suitable for liver resection or thermal ablation., Interventions: Thermal ablation conducted as per local policy (but centres were encouraged to recruit within Cardiovascular and Interventional Radiological Society of Europe guidelines) versus surgical liver resection performed as per centre protocol., Main Outcome Measures: Pilot study - patients' and clinicians' acceptability of the trial to assist in optimisation of recruitment. Primary outcome - disease-free survival at 2 years post randomisation. Secondary outcomes - overall survival, timing and site of recurrence, additional therapy after treatment failure, quality of life, complications, length of hospital stay, costs, trial acceptability, and disease-free survival measured from end of intervention. It was planned that 5-year survival data would be documented through record linkage. Randomisation was performed by minimisation incorporating a random element, and this was a non-blinded study., Results: In the pilot study over 1 year, a total of 366 patients with colorectal liver metastases were screened and 59 were considered eligible. Only nine participants were randomised. The trial was stopped early and none of the planned statistical analyses was performed. The key issues inhibiting recruitment included fewer than anticipated patients eligible for both treatments, misconceptions about the eligibility criteria for the trial, surgeons' preference for one of the treatments ('lack of clinical equipoise' among some of the surgeons in the centre) with unconscious bias towards surgery, patients' preference for one of the treatments, and lack of dedicated research nurses for the trial., Conclusions: Recruitment feasibility was not demonstrated during the pilot stage of the trial; therefore, the trial closed early. In future, comparisons involving two very different treatments may benefit from an initial feasibility study or a longer period of internal pilot study to resolve these difficulties. Sufficient time should be allowed to set up arrangements through National Institute for Health Research (NIHR) Research Networks., Trial Registration: Current Controlled Trials ISRCTN52040363., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 21. See the NIHR Journals Library website for further project information., Competing Interests: Julia Brown is a member of Health Technology Assessment (HTA) Mental, Psychological and Occupational Health Methods Group, HTA Clinical Trials Committee, HTA Prioritisation Committee Methods Group and HTA Funding Committee Policy Group. Stephen Morris was formerly a member of the National Institute for Health Research (NIHR) Health Services and Delivery Research (HSDR) Research Funding Board, the NIHR HSDR Commissioned Board, the NIHR HSDR Evidence Synthesis Sub Board, the NIHR Unmet Need Sub Board, the NIHR HTA Clinical Evaluation and Trials Board, the NIHR HTA Commissioning Board, the NIHR Public Health Research (PHR) Research Funding Board and the NIHR Programme Grants for Applied Research (PGfAR) expert subpanel. Maureen Twiddy is a member of the Research for Patient Benefit North East and Yorkshire Advisory Panel. Brian Davidson is chairperson of the London NIHR Research for Patient Benefit panel. Daniel Hochhauser reports Medical Research Council CASE studentship with Merck Serono (Darmstadt, Germany). Kurinchi Gurusamy reports grants from NIHR, Cancer Research UK Multidisciplinary Award, UK Oncology Nursing Society, University College London and Wellcome Trust/Department of Health and Social Care – Health Innovation Challenge Fund 4 – Smart Surgery, during the conduct of the study.

Objective: To validate the NHSLA maternity claims taxonomy at the level of a single maternity service and assess its ability to direct quality improvement., Design: Qualitative descriptive study., Setting: Medico-legal claims between 1 January 2000 and 31 December 2016 from a maternity service in metropolitan Melbourne, Australia., Population: All obstetric claims and incident notifications occurring within the date range were included for analysis., Methods: De-identified claims and notifications data were derived from the files of the insurer of Victorian public health services. Data included claim date, incident date and summary, and claim cost. All reported issues were coded using the NHSLA taxonomy and the lead issue identified., Main Outcome Measures: Rate of claims and notifications, relative frequency of issues, a revised taxonomy., Results: A combined total of 265 claims and incidents were reported during the 6 years. Of these 59 were excluded, leaving 198 medico-legal events for analysis (1.66 events/1000 births). The costs for all claims was $46.7 million. The most common claim issues were related to management of labour (n = 63, $17.7 million), cardiotocographic interpretation (n = 43, $24.4 million), and stillbirth (n = 35, $656,750). The original NHSLA classification was not sufficiently detailed to inform care improvement programmes. A revised taxonomy and coding flowchart is presented., Conclusions: Systematic analysis of obstetric medico-legal claims data can potentially be used to inform quality and safety improvement., Tweetable Abstract: New taxonomy to target health improvement from maternity claims based on NHSLA Ten Years of Maternity Claims., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Background: Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke., Methods: This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5-42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45-60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613., Findings: Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53-1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%])., Interpretation: Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therapy., Funding: Medical Research Council., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Addressing the stigma of mental illness and its effect in the workplace is a contemporary issue in occupational health. The role of leaders is a vital but relatively unexplored dimension of this phenomenon. This study examined the effectiveness and application of an online intervention to reduce depression-related stigma in organizational leaders. A randomized controlled, "in the field" study was conducted with 196 leaders. Participants completed an online survey and were randomly assigned to either the experimental or wait-list control group. One week later, participants in the experimental group were given access to a brief online workplace mental health intervention and asked to complete a postsurvey, whereas the control group had to only complete the online postsurvey. Six months later, participants completed a follow-up online survey. Results revealed significant reductions in behavioral and affective depression-related stigma scores among leaders who completed the intervention, compared with the control group. These reductions were similar at 6 months. The factors that enabled or hindered training transfer from the intervention were examined through semistructured interviews with 16 of the participating leaders. Results showed that positive attitudes and high levels of knowledge are not sufficient to ensure leaders apply intervention learning in their work environments. Factors including the nature of the work environment, the collective readiness and capability of the organization to address these issues, the attitudes of others at work, and the broader political context affected the application of learning from the intervention. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Introduction: Previous research indicates that children with Developmental Coordination Disorder (DCD) show deficits performing online corrections, an issue exacerbated by adding inhibitory constraints; however, cross-sectional data suggests that these deficits may reduce with age. Using a longitudinal design, the aim of the study presented here was to model the coupling that occurs between inhibitory systems and (predictive) online control in typically developing children (TDC) and in those with Developmental Coordination Disorder (DCD) over an extended period of time, using a framework of interactive specialization. We predicted that TDC would show a non-linear growth pattern, consistent with re-organisation in the coupling during the middle childhood period, while DCD would display a developmental lag., Method: A group of 196 children (111 girls and 85 boys) aged between 6 and 12years participated in the study. Children were classified as DCD according to research criteria. Using a cohort sequential design, both TDC and DCD groups were divided into age cohorts. Predictive (online) control was defined operationally by performance on a Double-Jump Reaching Task (DJRT), which was assessed at 6-month intervals over two years (5 time points in total). Inhibitory control was examined using an anti-jump condition of the DJRT paradigm whereby children were instructed to touch a target location in the hemispace opposite a cued location., Results: For the TDC group, model comparison using growth curve analysis revealed that a quadratic trend was the most appropriate fit with evidence of rapid improvement in anti-reach performance up until middle childhood (around 8-9years of age), followed by a more gradual rate of improvement into late childhood and early adolescence. This pattern was evident on both chronometric and kinematic measures. In contrast, for children with DCD, a linear function provided the best to fit on the key metrics, with a slower rate of improvement than controls., Conclusion: We conclude that children with DCD require a more extended period of development to effectively couple online motor control and executive systems when completing anti-reach movements, whereas TDC show rapid improvement in early and middle childhood. These group differences in growth curves are likely to reflect a maturational lag in the development of motor-cognitive networks in children with DCD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

For children with Developmental Coordination Disorder (DCD), the real-time coupling between frontal executive function and online motor control has not been explored despite reported deficits in each domain. The aim of the present study was to investigate how children with DCD enlist online control under task constraints that compel the need for inhibitory control. A total of 129 school children were sampled from mainstream primary schools. Forty-two children who met research criteria for DCD were compared with 87 typically developing controls on a modified double-jump reaching task. Children within each skill group were divided into three age bands: younger (6-7 years), mid-aged (8-9), and older (10-12). Online control was compared between groups as a function of trial type (non-jump, jump, anti-jump). Overall, results showed that while movement times were similar between skill groups under simple task constraints (non-jump), on perturbation (or jump) trials the DCD group were significantly slower than controls and corrected trajectories later. Critically, the DCD group was further disadvantaged by anti-jump trials where inhibitory control was required; however, this effect reduced with age. While coupling online control and executive systems is not well developed in younger and mid-aged children, there is evidence of age-appropriate coupling in older children. Longitudinal data are needed to clarify this intriguing finding. The theoretical and applied implications of these results are discussed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Medicinal products produced from human plasma fall under the administrative batch release procedure of the competent authority. In Germany, this has been carried out since 1995 by the Paul Ehrlich Institute (PEI), the responsible state control agency for blood products. Medicinal products released for the European and national market are tested for quality, efficacy and safety. Experimental testing of the final product and the starting materials, the plasma pools, as well as control of the production documentation guarantee a constantly high product safety. In the 28,000 batches tested since the beginning of the state controlled batch release testing of these blood products at the PEI, there has been no transmission of infectious viruses (HIV, HBV and HCV) to any patient. The batch release has made a contribution to the improvement of product quality. This procedure is still an important tool to ensure safety of blood products. The PEI is integrated in the batch release network of the European Directorate for the Quality of Medicines & Health Care (EDQM) in Strasbourg. Regulations and guidelines for official control authority batch release (OCABR) ensure harmonized procedures for mutual recognition of batch release on the European level. The EU certificates and German national certificates are requested and accepted in over 70 countries worldwide. Experimental testing in the EU and the requisite certificates have developed into a seal of quality for the world market.

It has been hypothesized that the underlying mechanism of clumsy motor behaviour in children with Developmental Coordination Disorder (DCD) is caused by a deficit in the internal modelling for motor control. An internal modelling deficit can be shown on a behavioural level by a task that requires motor imagery. Motor imagery skills are suggested to be related to anticipatory action planning, but motor imagery and action planning have not been tested within the same child. In the present study, action planning and motor imagery skills were assessed in 82 children between 7 and 12 years of age. Twenty-one of these children met the criteria for DCD, which was assessed by the McCarron Assessment of Neuromuscular Development and 56 of these children were used in the control group. Motor imagery was tested by a mental rotation task of hands that were shown from a back and palm point of view. The results show that motor imagery is affected in children with DCD but only in conditions with complex task constraints (i.e., rotation of hand stimuli presented in palm view). These results provide partial support for the internal modelling deficit hypothesis. We were not able to elicit motor planning deficits in this group, however, and argue that more complex planning tasks may be needed to identify such deficits., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Primary Sjögren's Syndrome (PSS) mainly affects women (9:1 female:male ratio) and is one of the commonest autoimmune diseases with a prevalence of 0.1 - 0.6% of adult women. For patients with PSS there is currently no effective therapy that can alter the progression of the disease. The aim of the TRACTISS study is to establish whether in patients with PSS, treatment with rituximab improves clinical outcomes., Methods/design: TRACTISS is a UK multi-centre, double-blind, randomised, controlled, parallel group trial of 110 patients with PSS. Patients will be randomised on a 1:1 basis to receive two courses of either rituximab or placebo infusion in addition to standard therapy, and will be followed up for up to 48 weeks. The primary objective is to assess the extent to which rituximab improves symptoms of fatigue and oral dryness. Secondary outcomes include ocular dryness, salivary flow rates, lacrimal flow, patient quality of life, measures of disease damage and disease activity, serological and peripheral blood biomarkers, and glandular histology and composition., Discussion: The TRACTISS trial will provide direct evidence as to whether rituximab in patients with PSS leads to an improvement in patient symptoms and a reduction in disease damage and activity., Trial Registration: UKCRN Portfolio ID: 9809 ISRCTN65360827.

Aim: Developmental coordination disorder (DCD) is a significant disorder of childhood, characterized by core difficulties in learning fine and/or gross motor skills, and the attendant psychosocial problems. The aim of the meta-analysis presented here (the first on DCD since 1998) was to summarize trends in the literature over the past 14 years and to identify and describe the main motor control and cognitive deficits that best discriminate children with DCD from those without., Method: A systematic review of the literature published between January 1997 and August 2011 was conducted. All available journal papers reporting a comparison between a group of children with DCD and a group of typically developing children on behavioural measures were included., Results: One hundred and twenty-nine studies yielded 1785 effect sizes based on a total of 2797 children with DCD and 3407 typically developing children. Across all outcome measures, a moderate to large effect size was found, suggesting a generalized performance deficit in children with DCD. The pattern of deficits suggested several areas of pronounced difficulty, including internal (forward) modelling, rhythmic coordination, executive function, gait and postural control, catching and interceptive action, and aspects of sensoriperceptual function., Interpretation: The results suggest that the predictive control of action may be a fundamental disruption in DCD, along with the ability to develop stable coordination patterns. Implications for theory development and intervention are discussed., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Background and Objectives: The occurrence of thromboembolic events (TEEs) with intravenous immunoglobulin lots (IVIGs) raised the question of the causative agent for these adverse events. We investigated the predominant plasma proteases in 19 IVIG lots from five manufacturers including three lots associated with adverse events., Material and Methods: The inhibitor profile of the amidolytic activity in IVIG lots was investigated with substrates S-2302 and S-2288. In immunocapture assays, prekallikrein and FXI antigen and respective active proteases were quantified. Non-activated partial thromboplastin time (NAPTT) and a modified FXIa PTT served as global and FXIa-specific clotting assays, respectively., Results: Kallikrein was identified as one major contaminant activity in IVIGs. A second activity was seen in some IVIGs with substrate S-2288, but not with S-2302. Inhibition studies excluded FXIIa, thrombin or plasmin as contaminant activity. FXI antigen was seen in all 19 IVIG lots, and FXIa activity was found as second major impurity in some IVIGs, including all lots involved in TEEs. FXIa highly correlated with a short clotting time in NAPTT., Conclusions: Kallikrein and FXIa are the major contaminants in IVIGs. FXIa was highly procoagulant, with highest level in TEE-associated IVIGs. Since the NAPTT unambiguously identified FXIa procoagulant activity in IVIGs, its implementation as a release test would improve the safety of IVIGs., (© 2011 The Author(s). Vox Sanguinis © 2011 International Society of Blood Transfusion.)

Thromboembolic adverse reactions reported after transfusion of SD-plasma in the United States (US) prompted us to perform a comparative study with SD-plasma from the US and the European (EU) market. In SD-plasma from US, residual tri-N-butyl phosphate was found, and citrate concentrations were lower than in EU-plasma. Except for substantial losses of FV, FVIII and antiplasmin found for all SD-plasmas, clotting factor activities were mainly retained. However, for SD-plasma from US, markedly elevated concentrations of lipoprotein (a) [Lp(a)], fibrin monomer and a particularly high degree of complement activation (C3a des-Arg) were observed. Furthermore, pronounced differences were found for protein S. Although SD-plasma pools from US contained nearly normal concentrations of free and bound protein S antigen, protein S activities were almost completely absent. In contrast to this, SD-plasma from EU showed a moderate loss of both protein S activity and free antigen. Antitrypsin inhibitor activities were much more diminished in SD-plasma from US than from EU. In view of a possible thrombogenicity of SD-plasma from US, the loss of protein S and elevated Lp(a) concentrations could be of significance. The very high levels of C3a des-Arg in US plasma could possibly have an additional effect, through priming platelet activation after transfusion.

Background: Proteomic technologies are evolving tools to analyze complex protein patterns that to date have been rarely applied to transfusion medicine. The analysis of prothrombin complex concentrates (PCCs) was used as a model to evaluate to what extent these technologies can detect differences in blood-derived therapeutics beyond that of standard quality control., Study Design and Methods: Three PCCs (two batches each) were individually analyzed for differences in protein content by functional assays, two-dimensional gel electrophoresis, and mass spectrometry. The results were compared to a pool of 72 normal plasma samples., Results: A highly complex protein pattern was found that varied considerably among the three PCCs: 192 spots comprising 40 different proteins were identified. Factor (F) IX activities of the three PCCs were comparable, but their F IX protein contents differed considerably. Many proteins were present in multiple spots (e.g. FII, FX, protein C, vitronectin), indicating a high degree of posttranslational modifications. In comparison with untreated pooled plasma, PCCs displayed several low-molecular-weight variants of proteins that likely constitute potential degradation products., Conclusion: Proteomic technologies allow the identification of potentially modified proteins in clotting factor concentrates, indicating that they could become a useful tool for transfusion medicine to assess the impact of processing on the integrity of blood-derived therapeutics.

To meet the increasing requirement for therapeutic antibodies to conduct clinical trials, an enhanced culture medium and fed-batch process was developed for GS-NS0 cell lines. This process was shown to produce high concentrations of monoclonal antibodies for several cell lines expressing different antibodies. Cells were adapted to growth in a glutamine- and serum-free medium containing bovine serum albumin (BSA), cholesterol, and transferrin. A number of amino acids were found to be depleted during cell culture. The concentrations of these amino acids were increased, and further cell culture analyses were performed. This process of cell growth and analysis was repeated over multiple cycles until no depletion was detected. This resulted in an amino acid supplement that was shown to be generic and enhanced antibody productivity up to 5-fold for the three cell lines tested. Transferrin was replaced using tropolone, a lipophilic iron chelator and ferric ammonium citrate. Cell growth was equivalent to that in transferrin-containing medium over the wide ranges tested. A concentrated feed solution, based on the amino acid supplement and the components of the serum- and protein-free supplements, was formulated. Addition of this feed in response to metabolic requirements resulted in a harvest titer a further 2-fold higher than the enhanced culture medium. Harvest antibody titers of up to 600 mg/L were achieved for three cell lines expressing different antibodies, representing an increase of 10-fold over the starting concentrations.

A growth inhibition assay (GIA) and an immunofluorescence test detecting deposited complement components C6 and C9 were compared for their ability to classify Borrelia isolates with respect to their resistance to non-immune human serum (NHS). In both assays a total of 34 Borrelia isolates of all three human pathogenic genospecies were tested. Interestingly, 95% of the serum-sensitive or intermediate serum-sensitive isolates belonged to the genospecies B. burgdorferi s. s. and B. garinii, whereas most B. afzelii isolates (83%) proved serum-resistant. Consequently, a strong correlation between the assignment of the isolates to the different genospecies and their degree of serum sensitivity was seen. These findings were supported strongly by the quantitative analysis of the deposited complement components and the location of the terminal complement complex on the bacterial surface as detected by means of immunoelectron microscopy. The GIA displayed an obvious lack of sensitivity to slow growing isolates, whereas the IFA allowed classification of all Borrelia isolates. Discrimination between serum-sensitive and serum-resistant isolates in the IFA was the most specific provided that the detection of C6 and C9 was incorporated into the final classification of isolates. Accordingly, both assays, turned out to be effective and reliable tools for the investigation of borrelial serum sensitivity. The IFA, however, is regarded as superior to the GIA owing to the obvious ease of performance and its rapid capability for the classification of even very slow growing isolates.

Phage display provides a methodology for obtaining fully human antibodies directed against human transforming growth factor-beta (TGFbeta) suitable for the treatment of fibrotic disorders. The strategy employed was to isolate a human single chain Fv (scFv) fragment that neutralises human TGFbeta2 from a phage display repertoire, convert it into a human IgG4 and then determine its TGFbeta binding and neutralisation properties and its physical characteristics. Several scFv fragments binding to TGFbeta2 were isolated by panning of an antibody phage display repertoire, and subsequent chain shuffling of the selected V(H) domains with a library of V(L) domains. The three most potent neutralising antibodies were chosen for conversion to IgG4 format. The IgG4 antibodies were ranked for their ability to neutralise TGFbeta2 and the most potent, 6B1 IgG4, was chosen for further characterisation. 6B1 IgG4 has a high affinity for TGFbeta2 with a dissociation constant of 0.89 nM as determined using the BIAcore biosensor and only 9% cross-reactivity with TGFbeta3 (dissociation constant, 10 nM). There was no detectable binding to TGFbeta1. 6B1 IgG4 strongly neutralises (IC50 = 2 nM) the anti-proliferative effect of TGFbeta2 in bioassays using TF1 human erythroleukaemia cells. Similarly, there was strong inhibition of binding of TGFbeta2 to cell surface receptors in a radioreceptor assay using A549 cells. 6B1 IgG4 shows no detectable cross-reactivity with related or unrelated antigens by immunocytochemistry or ELISA. The 6B1 V(L) domain has entirely germline framework regions and the V(H) domain has only three non-germline framework amino acids. This, together with its fully human nature, should minimise any potential immunogenicity of 6B1 IgG4 when used in therapy of fibrotic diseases mediated by TGFbeta2.

Sixteen Borrelia burgdorferi strains, including all three species, were compared in a colorimetric bactericidal assay for their ability to escape the complement-dependent bacteriolysis on incubation in normal human serum free of specific antibodies (NHS). The species B. afzelii was found to be serum resistant (EB1, EB3, FEM1, FEM2, Pko), whereas strains of the species B. garinii were found to be serum sensitive (1/B29, G1, G2, PSth, PBr, PTrob). Six strains, mainly B. burgdorferi sensu stricto, were only partially sensitive (Z25, 297, B31, PKa-I, PBi). All strains activated the complement cascade in NHS, whereas only four strains (G1, G2, PBr, PSth) could activate complement in the presence of EGTA-Mg. After complement activation, covalently bound C3 fragments (C3b, iC3b) were detected on serum-sensitive as well as serum-resistant borrelial strains. Heterogeneity, however, was observed between serum-resistant and serum-sensitive strains with respect to deposition of C6 and C9. Whereas serum-sensitive strains were strongly positive for C6 and C9 and were, therefore, killed by the terminal complement complex (TCC), serum-resistant strains were devoid of C6 and C9 on their cell surface. The serum resistance may, therefore, be due to an absent or only transient formation of TCC on the bacterial surface.

In this report we have compared the ability of 14 Borrelia burgdorferi sensu lato isolates to stimulate monocytes. From these isolates, all three human pathogen genospecies were represented. To determine the stimulatory activity of the different strains, interleukin-1 beta (IL-1 beta) was measured in the supernatant of monocyte cultures. This was achieved with borrelial strains in a ratio of 10 bacteria to 1 monocyte. In the majority of strains the stimulation induced a release of about 8000 pg/ml IL-1 beta, whereas four strains (B31, 297, EB3, 1/B29) induced more than 18,000 pg/ml IL-1 beta. We could, therefore, define two groups: low-level inductors and high-level inductors for IL-1 beta. The strains in the defined groups could not be ascribed to one distinct genospecies or a biological source. Further experiments confirmed the same differential release for tumor necrosis factor-alpha, but not for IL-6. Studies on IL-1 beta indicated that high- and low-level release of cytokine was due to differences in protein synthesis.

Three sunscreen ingredients, derivatives of benzylidene camphor, were tested for photomutagenic potential. These were benzenesulfonic acid, 4-[(4,7,7,-trimethyl-3-oxo-bicyclo [2.2.1] hept-2-ylidene) methyl] (Mexoryl SL), 4-(2-oxo 3-bornylidenemethyl) phenyl trimethylammonium methyl sulphate (Mexoryl SO) and 3,3'-(1,4-phenylenedimethylidyne) bis [7,7-dimethyl-2-oxo-bicyclo [2.2.1] heptane-1-methanesulfonic acid] (Mexoryl SX). Two complementary assay systems were used, one involving the induction of reverse mutations in Escherichia coli strain WP2, the other measuring the induction of chromosome damage in Chinese hamster ovary (CHO) cells. Irradiation with UVA and/or UVB was provided by an Osram Ultra-Vitalux sunlamp. None of the three sunscreens, tested either to the limit of solubility or toxicity, gave any indication of photomutagenicity in either assay, under conditions in which the positive control compound, 8-methoxypsoralen, was extremely photomutagenic. It is concluded that Mexoryls SL, SO and SX can be exposed to UV light without producing photomutagenicity measurable using a bacterial reverse mutation or a mammalian chromosome aberration assay.

Two complementary assay systems have been adapted for the detection of compounds which may form mutagenic photoproducts during exposure to UV light from an Osram Ultra-Vitalux sunlamp as used in the evaluation of the effectiveness of sun filters. The effects of UVA and of UVB were evaluated. A bacterial plate test using Escherichia coli strain WP2 allowed the bacteria, co-plated with test chemical in soft agar, to be irradiated with various doses of UV light. Mutagenesis was assessed by scoring numbers of tryptophan-independent colonies. The chosen reference compound was 8-methoxypsoralen (8-MOP) which was non-mutagenic alone at the highest dose tested (1000 micrograms/plate). Following simultaneous exposure of bacteria to 8-MOP and doses of UV light which alone had little effect, large numbers of revertants were scored. Numbers of mutants were dependent upon the doses of both 8-MOP and of UV light. The second test system involved the exposure of Chinese hamster ovary cells to UV light in the presence of test chemical to determine the clastogenic effects of photoproducts. Treatment with 8-MOP alone up to 50 micrograms/ml was not clastogenic but concomitant exposure to non-damaging doses of UV light caused large increases in the incidence of chromosome aberrations of all types. Damage was again dependent on the doses of both components. Two additional photoactive compounds, para-aminobenzoic acid and chlorpromazine both show photoclastogenic but not photomutagenic properties. These two complementary assay systems take advantage of using no-effect levels of UV light as a baseline against which photomutagenicity readily can be compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Experience with 146 in-situ vein bypass procedures for obliterative arterial disease are reviewed to determine the specific complication of the technique. Vein wall injury with the Hall valvulotome occurred in 6 patients (4%) and vein patching of a stenosed femoral vein was required in 2 patients. Residual arteriovenous fistulae occurred in 24 patients (16.5%) of whom 9 had an associated graft thrombosis distal to the fistula of which 6 were corrected by thrombectomy and fistula ligation. Perioperative thrombosis occurred in 29 grafts (20%) and was more common in the femoropopliteal group (23/80) than in the femorocrural group (6/66) (P less than 0.01, X2 = 7.55). Fourteen of the femoropopliteal and two of the femorocrural thromboses were corrected resulting in an immediate patency of 89% and 94% respectively with the cumulative patency at one year being 77.5% and 79%. Complications of the in-situ bypass technique remain despite having largely overcome the problems of valve disruption. However, until a standard method emerges careful note must be made of technique and complications when considering reports of in-situ bypass patency.

Investigation of the uptake and metabolism of drugs by organs such as the liver may allow assessment of specific aspects of organ function. Rifampicin, when orally administered, is transported into the hepatocyte from portal blood and thence passes, with its deacetylated metabolite, into the systemic circulation and into bile. This paper reports an investigation of the pharmacokinetics of a sub-therapeutic oral dose of rifampicin in healthy subjects, in patients with cirrhosis and in subjects with Gilbert's syndrome. The areas under the plasma concentration curves (AUC) in patients with cirrhosis were significantly greater than in healthy subjects. Subjects with Gilbert's syndrome had decreased AUCs compared with healthy subjects and were clearly distinguished from patients with cirrhosis. Rifampicin concentration in serum was measured by HPLC using a novel direct injection technique.