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Joanne Stocks,1–3 Nicole KY Tang,4 David A Walsh,1–3 Sophie C Warner,1 Hollie L Harvey,1 Wendy Jenkins,1 Abhishek Abhishek,1–3 Michael Doherty,1–3 Ana M Valdes1–3 1Academic Rheumatology, University of Nottingham, Nottingham, UK; 2Arthritis Research UK Pain Centre, University of Nottingham, Nottingham, UK; 3National Institute for Health Research, Nottingham Biomedical Research Centre, Nottingham, UK; 4Department of Psychology, University of Warwick, Coventry, UK Background: Disturbed sleep is strongly correlated with chronic pain. The aim of this study was to examine the association between sleep disturbance and incident joint pain focusing on neuropathic-like pain symptoms. Methods: A total of 423 individuals who had undergone total joint replacement (TJR) for osteoarthritis were assessed at the mean time of 3.6 years post-surgery and again at 5.9 years post-TJR, using the Medical Outcomes Survey sleep subscale, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and painDETECT questionnaire instruments. Cox hazard ratios (HRs) and 95% confidence intervals (CIs) were computed adjusting for age, body mass index, sex, and use of hypnotic and analgesic medication. Results: The presence of neuropathic pain symptoms predicted incidence of disturbed sleep after adjustment for covariates and pain severity (adjusted HR [aHR] 2.01, 95% CI: 1.00–4.10; p

Background The treatment of osteoarthritis with knee replacement aims to reduce pain and disability. However, some people experience chronic pain. Objectives To improve outcomes for people with chronic pain after knee replacement by identifying post-surgical predictors and effective interventions, characterising patient pathways and resource use, developing and evaluating a new care pathway, and exploring non-use of services. Design The programme comprised systematic reviews, national database analyses, a cohort study, intervention development, a randomised controlled trial, health economic analyses, qualitative studies and stakeholder engagement. Extensive and meaningful patient and public involvement underpinned all studies. Setting NHS, secondary care, primary care. Participants People with, or at risk of, chronic pain after knee replacement and health-care professionals involved in the care of people with pain. Interventions A care pathway for the management of people with pain at 3 months after knee replacement. Main outcome measures Patient-reported outcomes and cost-effectiveness over 12 months. Data sources Literature databases, the National Joint Registry, Hospital Episode Statistics, patient-reported outcomes, the Clinical Practice Research Datalink, the Clinical Outcomes in Arthroplasty Study, the Support and Treatment After joint Replacement randomised trial, interviews with 90 patients and 14 health-care professionals, and stakeholder events. Review methods Systematic reviews of cohort studies or randomised trials, using meta-analysis or narrative synthesis. Results In the Clinical Outcomes in Arthroplasty Study cohort, 14% of people experienced chronic pain 1 year after knee replacement. By 5 years, 65% reported no pain, 31% fluctuated and 4% remained in chronic pain. People with chronic pain had a worse quality of life, higher primary care costs, and more frequent analgesia prescriptions, particularly for opioids, than those not in chronic pain. People with chronic pain after knee replacement who made little or no use of services often felt nothing more could be done, or that further treatments may have no benefit or cause harm. People described a feeling of disconnection from their replaced knee. Analysis of UK databases identified risk factors for chronic pain after knee replacement. Pre-operative predictors were mild knee pain, smoking, deprivation, body mass index between 35 and 40 kg/m2 and knee arthroscopy. Peri- and post-operative predictors were mechanical complications, infection, readmission, revision, extended hospital stay, manipulation under anaesthetic and use of opioids or antidepressants. In systematic reviews, pre-operative exercise and education showed no benefit in relation to chronic pain. Peri-operative interventions that merit further research were identified. Common peri-operative treatments were not associated with chronic pain. There was no strong evidence favouring specific post-operative physiotherapy content. We evaluated the Support and Treatment After joint Replacement care pathway in a multicentre randomised controlled trial. We randomised 363 people with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales. At 12 months’ follow-up, the intervention group had lower mean pain severity (adjusted difference –0.65, 95% confidence interval –1.17 to -0.13; p = 0.014) and pain interference (adjusted difference –0.68, 95% confidence interval –1.29 to -0.08; p = 0.026), as measured on the Brief Pain Inventory subscales (scale 0–10). People receiving the Support and Treatment After joint Replacement pathway had lower NHS and Personal Social Services costs (–£724, 95% confidence interval –£150 to £51) and higher quality-adjusted life-years (0.03, 95% confidence interval –0.008 to 0.06) than those with usual care. The Support and Treatment After joint Replacement pathway was cost-effective with an incremental net monetary benefit at the £20,000 per quality-adjusted life-year threshold of £1256 (95% confidence interval £164 to £2348), indicating a 98.79% probability that the intervention is the cost-effective option. Participants found the Support and Treatment After joint Replacement pathway acceptable, with opportunities to receive information and discuss concerns while ensuring further treatment and support. In systematic reviews considering treatments for chronic pain after surgery we identified some unifactorial interventions that merit further research after knee replacement. Health-care professionals delivering and implementing the Support and Treatment After joint Replacement pathway valued its focus on neuropathic pain and psychosocial issues, enhanced patient care, formalised referrals, and improved pain management. Stakeholders supported pathway implementation. Limitations Database analyses were limited to factors recorded in data sets. Pain was only measured 6 months after surgery. However, analyses including large numbers of centres and patients should be generalisable across the NHS. In many studies found in systematic reviews, long-term pain was not a key outcome. Conclusions The Support and Treatment After joint Replacement pathway is a clinically effective and cost-effective, acceptable intervention for the management of chronic pain after knee replacement. Unifactorial interventions merit further study before inclusion in patient care. People with pain should be empowered to seek health care, with the support of health-care professionals. Future work Future work should include research relating to the implementation of the Support and Treatment After joint Replacement pathway into the NHS, an assessment of its long-term clinical effectiveness and cost-effectiveness and wider application, and an evaluation of new interventions for incorporation in the pathway. It will also be important to design and conduct research to improve communication between patients and health-care professionals before surgery; explore whether or not education and support can enable earlier recognition of chronic pain; consider research that may identify how to support people’s feelings of disconnectedness from their new knee; and design and evaluate a pre-surgical intervention based on risk factors. Study registration All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The Support and Treatment After joint Replacement randomised trial was registered as ISRCTN92545361. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information. Plain language summary People with severe knee osteoarthritis may have knee replacement surgery to reduce pain and disability. Although highly successful for many people, some people report long-term pain. Our research looked at why some people are more likely to have long-term pain, its personal and economic consequences, and how to prevent and treat it. We reviewed previous research; analysed UK health-care databases; interviewed and met with patients, surgeons and health-care professionals; and developed and evaluated a new care pathway for patients with pain after knee replacement. We found that about one in seven people experience significant pain 6 months after knee replacement. For many, pain fluctuates over time. Some people with long-term pain feel that nothing more can be done to help and that further treatments may even cause harm. Changes to aspects of patient health and care merit further research as they may prevent the development of long-term pain. The Support and Treatment After joint Replacement pathway comprises a detailed assessment by a trained health-care professional; referral to appropriate services, such as an orthopaedic surgeon, physiotherapist, general practitioner for treatment of depression or anxiety, or pain specialist; and telephone follow-up. A total of 363 people with pain at 3 months after their knee replacement were randomly allocated to receive either the Support and Treatment After joint Replacement pathway or their hospital’s usual care. Participants were followed for 1 year to assess their long-term pain. We also looked at health-care costs and the acceptability of the Support and Treatment After joint Replacement pathway to patients and health-care professionals. This research was supported by a dedicated patient advisory group. For people with pain after knee replacement, the Support and Treatment After joint Replacement pathway leads to reduced long-term pain severity and reduced interference with everyday life, and is acceptable to patients and health-care professionals. NHS, personal social services and patient costs were lower in the group receiving the Support and Treatment After joint Replacement pathway. Scientific summary Background Chronic pain after total knee replacement places considerable burden on individuals, society and the NHS. With nearly 100,000 patients receiving knee replacements in the NHS annually, around 20,000 patients will have chronic post-surgical pain. Pre-operative prediction of who will have chronic pain after knee replacement is of limited value, referral for assessment and care is inconsistent and varies widely, and people do not necessarily receive or seek care. This programme aimed to address these issues and provide evidence on improvements to patient care and service delivery. Objectives The programme aimed to improve outcomes for patients with chronic pain ≥ 3 months after total knee replacement. Specific programme objectives were as follows: 1.synthesise evidence on the effectiveness of interventions for preventing chronic pain after knee replacement and the treatment of chronic pain after diverse surgeries, and identify post-surgical predictors of chronic pain after knee replacement 2.characterise the long-term trajectory of chronic pain, including pain characteristics and resource use up to 5 years after total knee replacement 3.finalise an assessment process and a care pathway for patients with chronic pain after total knee replacement 4.evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for patients with chronic pain after total knee replacement 5.identify reasons for non-use of services 6.make evidence-based suggestions about the best-practice care for patients with chronic pain after total knee replacement and evaluate the implementation of these. Methods To meet the objectives, we conducted six work packages. Work package 1: systematic reviews and analysis of national databases Systematic reviews of the following were carried out: post-surgical predictors of chronic pain after total knee replacement; the effectiveness of pre-, peri- and post-operative interventions for chronic pain after total knee replacement; and the effectiveness of interventions for chronic pain after diverse surgeries. In addition, we undertook an analysis of data from the National Joint Registry (NJR) linked to Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs) databases to identify post-operative predictors of chronic pain. Work package 2: long-term follow-up and analysis of databases Using the annual follow-up of the Clinical Outcomes in Arthroplasty Study (COASt) cohort of patients with total knee replacement, we were able to collect pain and resource use data for 5 years after surgery. We also analysed the Clinical Practice Research Datalink (CPRD), linked to the Hospital Episode Statistics (HES) and Patient Reported Outcome Measures (PROMs) database, to characterise the natural history of chronic pain after total knee replacement, including resource use. Work package 3: finalisation of an assessment protocol and care pathway Consensus questionnaires completed by and meetings with health-care professionals were used to refine our previously developed intervention. We also tested intervention delivery and acceptability with 10 patients and evaluated the views of 10 health-care professional stakeholders on future implementation using a questionnaire based on the Normalisation Measure Development (NoMAD) instrument. Work package 4: randomised controlled trial The multicentre Support and Treatment After joint Replacement (STAR) randomised controlled trial was carried out with 363 participants to evaluate the clinical effectiveness and cost-effectiveness of a new care pathway for patients with chronic pain after total knee replacement. The primary follow-up time point was 12 months post randomisation and the coprimary outcomes were the Brief Pain Inventory (BPI) severity and interference scales (scored 0–10), with the minimal clinically important difference pre-specified as 1 point on either scale. Two embedded qualitative studies with 56 patients explored trial processes and acceptability of the intervention. Work package 5: qualitative study We undertook a qualitative interview study with 34 people with chronic pain after total knee replacement who made little or no use of formal health-care services and explored reasons for non-use of services. Work package 6: implementation and dissemination Interviews, based on the NoMAD instrument, were carried out with 14 health-care professionals who implemented the intervention within the trial. An online meeting, short animated film and survey were all used to communicate findings to key stakeholders and engage health-care professionals in maximising the embedding of the intervention in practice. A range of dissemination activities to engage health-care professionals, researchers, policy-makers, patients and the public were undertaken. Patient and public involvement Patient and public involvement was integral to the programme’s design and remained at its core during the programme. We worked with an existing patient forum and developed a complementary group focusing exclusively on chronic pain after total knee replacement. Contributions of this group included the design of study materials and processes, research management and dissemination strategies. Results Work package 1: systematic reviews Our systematic review of post-operative risk factors for chronic pain after total knee replacement included 14 studies published up to October 2016, with data from 1168 people. Studies focused on acute pain, function and psychological factors. Risk factor measures and outcomes were heterogeneous. In a narrative synthesis we were unable to draw firm conclusions on potential interventions. The need for further prospective studies in representative populations was clear. Research published up to December 2018 into pre-operative interventions mainly focused on exercise and education. In the eight trials, with a total of 960 people randomised, there was no association with these interventions and long-term pain outcomes. In the peri-operative setting, we identified 44 trials published up to February 2018, with a range of 10 to 280 people randomised. Unifactorial interventions including some forms of analgesia, early rehabilitation, electrical muscle stimulation and anabolic steroids were associated with improved long-term pain outcomes. However, studies were small and merit further evaluation. There was reassurance that some common peri-operative treatments are not associated with chronic pain. Post-operative interventions evaluated in 17 trials published up to November 2016, with a total of 2485 people randomised, mainly focused on physiotherapy. There was no strong evidence favouring one format of therapy over another. There has been little research into treatments for chronic pain after total knee replacement. Considering interventions for general chronic post-surgical pain, we identified 66 randomised trials with a total of 3149 participants in our systematic review with searches up to March 2016. A more focused updated search including treatments for chronic pain after arthroplasty of the large joints was conducted in October 2020. Many unifactorial interventions have been evaluated, and specific nerve-focused treatments deserve further research. Work packages 1 and 2: analysis of national databases We undertook two analyses of linked databases to identify pre-, peri- and post-operative risk factors for chronic pain outcome. In the first analysis with NJR and HES data, the pre- and 6-month-post-operative Oxford Knee Scores (OKS) was available for 258,386 patients, 43,702 (16.9%) of whom were identified as having chronic pain at 6 months post surgery. Post-surgical predictors of chronic pain were mechanical complication of prosthesis, surgical site infection, readmission, reoperation, revision and an extended hospital stay. However, these post-surgical predictors explained only a limited amount of variability in chronic pain outcome. In the second analysis, we analysed primary care data from CPRD and secondary care data from the HES–PROMs database and included 4570 patients. At 6 months after surgery, 10.4% of patients were classified as non-responders to surgery regarding their knee pain. Expressing the effects as absolute risk differences allowed us to quantify the relative importance of individual risk factors in terms of the absolute proportions of patients achieving poor pain outcomes. Pre-operative risk factors were having only mild knee pain symptoms, currently smoking, living in the most deprived areas, having a body mass index between 35 and 40 kg/m2 and having had previous knee arthroscopy surgery. Post-operative risk factors were revision surgery and manipulation under anaesthetic within 3 months after the operation, and use of opioids and antidepressants within 3 months after surgery. Work package 2: long-term follow-up of COASt cohort and analysis of national databases We characterised the long-term trajectory of chronic pain, including pain characteristics and resource use, through the 5-year follow-up of the COASt cohort of 1581 patients with total knee replacement, and analysis of the linked CPRD and HES databases. We applied cluster analysis to data on 128,145 patients with primary total knee replacement included in the English PROMs programme to derive a cut-off point on the pain subscale of the OKS. A high-pain group was identified, defined as those with a score of ≤ 14 points on the OKS pain subscale 6 months after total knee replacement. About one in eight people experienced chronic pain 1 year after total knee replacement. Of these patients with chronic pain after surgery, after imputing significant missing data assumed to be missing at random, 65% experienced no-chronic-pain by year 5, 31% fluctuated and 4% remained in chronic pain. People with chronic pain in year 1 had worse quality of life to start with; this improved, but less rapidly than for those not in chronic pain. People with chronic pain reported slightly higher primary care consultation costs than those not in chronic pain but their prescriptions for analgesia were much more frequent, more costly to the health-care system and continued to grow even after surgery, especially prescriptions for opioids. Work package 3: finalisation of an assessment protocol and care pathway We refined and finalised the novel STAR care pathway and associated training materials. The STAR care pathway involves a clinic appointment for patients who have troublesome pain at 3 months after surgery. A specially trained extended scope practitioner (ESP) conducts a clinic assessment with the patient, comprising history, examination, radiography and questionnaire completion. Based on this assessment, which focuses on understanding the reasons for and impact of the pain, the patient is referred to the appropriate existing services for treatment, such as a surgeon, general practitioner (GP) or specialist, or receives ongoing monitoring. The ESP follows up with patients by telephone for up to 12 months. Work package 4: randomised controlled trial In a multicentre pragmatic, open randomised controlled trial, we evaluated the STAR care pathway. We screened 5036 people, randomised 363 patients with pain at 3 months after knee replacement from eight NHS Trusts in England and Wales and collected 12-month outcomes from 313 (85%) randomised participants. The sample had a mean age of 67 years, was 60% female and 94% white. Our analysis of clinical effectiveness indicated that at 12 months the intervention arm had lower mean pain severity and lower mean pain interference than the usual care arm. For pain interference at 12 months, the adjusted difference in means was –0.68 points on the Brief Pain Inventory pain interference scale [95% CI –1.29, –0.08; p = 0.026]. For pain severity at 12 months, the adjusted difference in means was –0.65 points on the Brief Pain Inventory pain severity scale [95% CI –1.17, –0.13; p = 0.014]. Our analysis of cost-effectiveness indicated that people receiving the STAR pathway from an NHS and personal social services perspective had lower costs (–£724, 95% CI -£1500 to £51) and more quality-adjusted life-years (QALYs) (0.03, 95% CI –0.008 to 0.06) than those receiving usual care. The STAR pathway was the cost-effective option: the incremental net monetary benefit at the £20,000-per-QALY threshold was £1256 (95% CI £164 to £2348). This was also the case from a patient perspective. Embedded qualitative research found that patients thought that the STAR pathway was acceptable, and patients described how it provided an opportunity for them to discuss their concerns and to receive more information about their condition while ensuring they received further treatment and ongoing support. Work package 5: qualitative study In semistructured interviews with 34 people, we found that people with chronic pain after total knee replacement who made little or no use of services did so because they became stuck in a cycle of appraisal of the validity of their need for help and concern that treatment may not be of benefit. Some were concerned that further treatment may even worsen their pain or cause further harm. When describing chronic post-surgical pain, some participants described sensations of discomfort including heaviness, numbness, pressure and tightness associated with the prosthesis, and some also reported a lack of felt connection with their knee as their movement was no longer natural and required deliberate attention, and that they had a lack of confidence in it. Work package 6: implementation and dissemination We found that health-care professionals involved in the delivery and implementation of the STAR care pathway valued its focus on the identification of neuropathic pain and psychosocial issues, enhanced patient care, formalisation and validation of referral practices and an increased knowledge of pain management. Stakeholders supported formal implementation of the STAR pathway. Whether or not this would be supported by hospital management was felt to be dependent on whether or not it was shown to be cost-effective. Conclusions: implications for health care After knee replacement, screening for pain with the OKS pain subscale beginning at 2 months after surgery can facilitate the delivery of targeted care from 3 months. Our findings indicate that the STAR care pathway can provide improved care and outcomes for people who have pain after knee replacement. To our knowledge, the STAR care pathway is the first multifactorial intervention for the treatment of post-surgical pain to have been evaluated in a randomised controlled trial. In database analyses and systematic reviews, we identified risk factors for and univariable interventions to prevent or treat chronic pain. After further research these may provide additional components to the care pathway. Our work also indicates that people with pain could be empowered to seek health care and that health-care professionals can be encouraged provide support. This could include information for people living with chronic pain to inform them that health care may provide benefit and that seeking care is not futile. Informing patients of the likely outcomes after surgery may be a key part of pre- and post-surgical care. Recommendations for research We recommend that further research addresses the following points, numbered in descending order of priority: 1.How to implement the STAR care pathway into the NHS. 2.How to improve communication between patients and professionals before surgery. 3.Whether or not patient education and supportive care can enable earlier recognition of chronic pain. 4.The STAR care pathway showed benefit to patients for both pain and interference at 6 and 12 months. Further follow-up would describe the longer-term outcomes of this intervention and the health-care resources utilised by participants. 5.How to reshape the STAR pathway for other surgeries. 6.The STAR programme focused on care after surgery. Future research could make use of the recently developing evidence base about the time before surgery as an opportunity for intervention. Specifically, we now have a greater understanding of risk factors for poor outcome and using this understanding to design and evaluate pre-surgical intervention may prove of long-term benefit to patients and health-care systems. 7.How to better manage patient’s feelings of disconnectedness from the new knee and sensations of otherness to improve incorporation of the prosthesis. 8.Promising interventions, identified in systematic reviews and suggested by our risk factor studies, should be evaluated in appropriately powered high-quality randomised controlled trials. 9.New interventions with evidence of effectiveness in the treatment of chronic pain after knee replacement should be considered as new components of multifaceted personalised care as delivered in the STAR intervention. Study registration All systematic reviews were registered on PROSPERO (CRD42015015957, CRD42016041374 and CRD42017041382). The STAR randomised trial was registered as ISRCTN92545361. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Programme Grants for Applied Research programme and will be published in full in Programme Grants for Applied Research; Vol. 11, No. 3. See the NIHR Journals Library website for further project information.

The current study proposes that personal need fulfillment (relatedness, generativity, identity, growth, and finances) predicts early and late retirement intentions. The personal needs of 160 full-time older employees were measured by personal goals, job satisfactions, job characteristics, and intrinsic motivation. Results suggest that the personal needs fulfilled by job employment remain important in retirement. The expectation for personal need fulfillment for identity, growth, and relatedness shifts from work to retirement for those who intend to retire early. The results are discussed in terms of the need for greater study of the relationship between expectations of personal need fulfillment, worker self-concept, and retirement decisions. [ABSTRACT FROM AUTHOR]

Identity, as a guiding concept for work and retirement decisions, is explored in the current study. Image theory suggests that actions that 'fit' with the goals of the trajectory image are fundamental for maintaining a positive and consistent self-identity (Beach, 1998; Beach & Mitchell, 1987). Incompatibility is the mechanism that evaluates whether retiring or continued work provides sufficient 'fit' with the goals one hopes to achieve. In the current study, the 'fit' of the trajectory image with retirement and work was measured in 238 full-time employees. Consistent with image theory predictions, individuals' perception of the incompatibility between five personal goals, within the trajectory image, and the choices of working and retiring predicted 25% of their retirement intent. Further support for goal incompatibility as a decision criterion is provided by findings showing it yielded better prediction than an alternative model based on goal facilitation, and equal prediction to an alternative model based on cost/benefit. Overall, the results are consistent with image theory and expand on continuity theory's (Atchley, 1999) concept of identity as fundamental for predicting retirement intent. [ABSTRACT FROM AUTHOR]

The current study explored the contribution of personal goals to retirement decisions. A SMARTER methodology (to assess multiattribute utility) and taxonomy of human goals were used to investigate the relationship between older workers' personal goals and their retirement intentions. Two hundred and fifty-one employees of a large university, varying in age from 55 to 77, were asked to indicate the relative importance of 29 goals and to indicate the utility they perceived in continued work and retirement as a means to achieve these goals. The results demonstrate that goal evaluations are important predictors of retirement intentions. Furthermore, goal evaluations provide an important and unique contribution to predicting retirement intentions beyond that predicted by personal and demographic variables. These results have implications for pre-retirement education and workplace application. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: In a prospective interventional study, problems with performance were evaluated in 101 consecutive patients with chronic low-back pain for more than 12 months, before and after participation in an outpatient-based multidisciplinary pain management program in Mansfield, United Kingdom. OBJECTIVES: To describe problems identified as most important by patients with chronic low-back pain and to evaluate the Canadian Occupational Performance Measure (COPM) as a tool for measuring problem-specific outcomes. SUMMARY OF BACKGROUND DATA: Patients with chronic low-back pain report difficulties with a variety of activities. The COPM permits the identification and measurement of problems of particular concern to the patient. MATERIALS AND METHODS: COPM, likert-modified Roland and Morris Disability Questionnaire, Pain Self-Efficacy Questionnaire, and 5-minute walk test were administered at baseline, immediately after, and 9 months after intervention. Differences and statistical interactions were determined by nonparametric tests. RESULTS: Participants identified 60 different types of problem activity, 45 of which were identified by nine or fewer participants. Decreased walking tolerance was the most frequently identified problem (56% of participants). Improvements were observed in all outcomes following intervention. Approximately one third of participants reported improvements two or more COPM units in overall performance and satisfaction with their performance at 9 months. Higher reported performance and satisfaction were associated with greater self-efficacy. Increased reported walking performance was associated with increased observed 5-minute walk distance (R = 0.35, P = 0.02). CONCLUSIONS: Patients with chronic low-back pain report problems with diverse activities. The COPM provides a patient-centered outcome measure that displays good external validity and responsiveness to change when addressing the individual's goals. [ABSTRACT FROM AUTHOR]

CONTEXT: Numerous studies have documented the potential effects on young audiences of violent content in media products, including movies, television programs, and computer and video games. Similar studies have evaluated the effects associated with sexual content and messages. Cumulatively, these effects represent a significant public health risk for increased aggressive and violent behavior, spread of sexually transmitted diseases, and pediatric pregnancy. In partial response to these risks and to public and legislative pressure, the movie, television, and gaming industries have implemented ratings systems intended to provide information about the content and appropriate audiences for different films, shows, and games. OBJECTIVE: To test the validity of the current movie-, television-, and video game-rating systems. DESIGN: Panel study. MEASURE: Participants used the KidScore media evaluation tool, which evaluates films, television shows, and video games on 10 aspects, including the appropriateness of the media product for children based on age. RESULTS: When an entertainment industry rates a product as inappropriate for children, parent raters agree that it is inappropriate for children. However, parent raters disagree with industry usage of many of the ratings designating material suitable for children of different ages. Products rated as appropriate for adolescents are of the greatest concern. The level of disagreement varies from industry to industry and even from rating to rating. Analysis indicates that the amount of violent content and portrayals of violence are the primary markers for disagreement between parent raters and industry ratings. CONCLUSIONS: As 1 part of a solution to the complex public health problems posed by violent and sexually explicit media products, ratings can have value if used with caution. Parents and caregivers relying on the ratings systems to guide their children's use of media products should continue to monitor content independently. Industry ratings systems should be revised with input from the medical and scientific communities to improve their reliability and validity. A single ratings system, applied universally across industries, would greatly simplify the efforts of parents and caregivers to use the system as well as the efforts of outside parties to monitor the use and validity of the system. [ABSTRACT FROM AUTHOR]

Abstract Background To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles. Methods Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture. Results Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029). Conclusions While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation.

Abstract This analysis reports on Irish regulatory policies for in vitro fertilisation (IVF) from 2004-2009, in the context of membership changes within the Medical Council of Ireland. To achieve this, the current (2009) edition of the Guide to Professional Conduct & Ethics was compared with the immediately preceding version (2004). The statutory composition of the Medical Council from 2004-2009 was also studied. Content analysis of the two editions identified the following differences: 1) The 2004 guide states that IVF "should only be used after thorough investigation has failed to reveal a treatable cause of the infertility", while the 2009 guide indicates IVF "should only be used after thorough investigation has shown that no other treatment is likely to be effective"; 2) The 2004 stipulation stating that fertilized ovum (embryo) "must be used for normal implantation and must not be deliberately destroyed" is absent from the 2009 guidelines; 3) The option to donate "unused fertilised ova" (embryos) is omitted from the 2009 guidelines; 4) The 2009 guidelines state that ART should be offered only by "suitably qualified professionals, in appropriate facilities, and according to the international best practice"; 5) The 2009 guidelines introduce criteria that donations as part of a donor programme should be "altruistic and non-commercial". These last two points represent original regulatory efforts not appearing in the 2004 edition. The Medical Practitioners Act 2007 reduced the number of physicians on the Medical Council to 6 (of 25) members. The ethical guidelines from 2004 preceded this change, while the reconstituted Medical Council published the 2009 version. Between 2004 and 2009, substantial modifications in reproductive health policy were incorporated into the Medical Council's ethical guidelines. The absence of controlling Irish legislation means that patients and IVF providers in Ireland must rely upon these guidelines by default. Our critique traces the evolution of public policy on IVF during a time when the membership of the Medical Council changed radically; reduced physician contribution to decision-making was associated with diminished protection for IVF-derived embryos in Ireland. Considerable uncertainty on IVF practice in Ireland remains.

Abstract Background Guidelines for safe gamete donation have emphasised donor screening, although none exist specifically for testing oocyte recipients. Pre-treatment assessment of anonymous donor oocyte IVF treatment in Ireland must comply with the European Union Tissues and Cells Directive (Directive 2004/23/EC). To determine the effectiveness of this Directive when applied to anonymous oocyte recipients in IVF, we reviewed data derived from selected screening tests performed in this clinical setting. Methods Data from tests conducted at baseline for all women enrolling as recipients (n = 225) in the anonymous oocyte donor IVF programme at an urban IVF referral centre during a 24-month period were analysed. Patient age at programme entry and clinical pregnancy rate were also tabulated. All recipients had at least one prior negative test for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis performed by her GP or other primary care provider before reproductive endocrinology consultation. Results Mean (±SD) age for donor egg IVF recipients was 40.7 ± 4.2 yrs. No baseline positive chlamydia, gonorrhoea or syphilis screening results were identified among recipients for anonymous oocyte donation IVF during the assessment interval. Mean pregnancy rate (per embryo transfer) in this group was 50.5%. Conclusion When tests for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis already have been confirmed to be negative before starting the anonymous donor oocyte IVF sequence, additional (repeat) testing on the recipient contributes no new clinical information that would influence treatment in this setting. Patient safety does not appear to be enhanced by application of Directive 2004/23/EC to recipients of anonymous donor oocyte IVF treatment. Given the absence of evidence to quantify risk, this practice is difficult to justify when applied to this low-risk population.

Abstract Background This investigation describes features of patients undergoing in vitro fertilisation (IVF) and embryo transfer (ET) where both gametes were obtained from anonymous donors. Methods Gamete unsuitability or loss was confirmed in both members of seven otherwise healthy couples presenting for reproductive endocrinology consultation over a 12-month interval in Ireland. IVF was undertaken with fresh oocytes provided by anonymous donors in Ukraine; frozen sperm (anonymous donor) was obtained from a licensed tissue establishment. For recipients, saline-enhanced sonography was used to assess intrauterine contour with endometrial preparation via transdermal estrogen. Results Among commissioning couples, mean±SD female and male age was 41.9 ± 3.7 and 44.6 ± 3.5 yrs, respectively. During this period, female age for non dual anonymous gamete donation IVF patients was 37.9 ± 3 yrs (p < 0.001). Infertility duration was ≥3 yrs for couples enrolling in dual gamete donation, and each had ≥2 prior failed fertility treatments using native oocytes. All seven recipient couples proceeded to embryo transfer, although one patient had two transfers. Clinical pregnancy was achieved for 5/7 (71.4%) patients. Non-transferred cryopreserved embryos were available for all seven couples. Conclusions Mean age of females undergoing dual anonymous donor gamete donation with IVF is significantly higher than the background IVF patient population. Even when neither partner is able to contribute any gametes for IVF, the clinical pregnancy rate per transfer can be satisfactory if both anonymous egg and sperm donation are used concurrently. Our report emphasises the role of pre-treatment counselling in dual anonymous gamete donation, and presents a coordinated screening and treatment approach in IVF where this option may be contemplated.

Abstract Background There is little robust evidence to test the policy assumption that housing-led area regeneration strategies will contribute to health improvement and reduce social inequalities in health. The GoWell Programme has been designed to measure effects on health and wellbeing of multi-faceted regeneration interventions on residents of disadvantaged neighbourhoods in the city of Glasgow, Scotland. Methods/Design This mixed methods study focused (initially) on 14 disadvantaged neighbourhoods experiencing regeneration. These were grouped by intervention into 5 categories for comparison. GoWell includes a pre-intervention householder survey (n = 6008) and three follow-up repeat-cross sectional surveys held at two or three year intervals (the main focus of this protocol) conducted alongside a nested longitudinal study of residents from 6 of those areas. Self-reported responses from face-to-face questionnaires are analysed along with various routinely produced ecological data and documentary sources to build a picture of the changes taking place, their cost and impacts on residents and communities. Qualitative methods include interviews and focus groups of residents, housing managers and other stakeholders exploring issues such as the neighbourhood context, potential pathways from regeneration to health, community engagement and empowerment. Discussion Urban regeneration programmes are 'natural experiments.' They are complex interventions that may impact upon social determinants of population health and wellbeing. Measuring the effects of such interventions is notoriously challenging. GoWell compares the health and wellbeing effects of different approaches to regeneration, generates theory on pathways from regeneration to health and explores the attitudes and responses of residents and other stakeholders to neighbourhood change.

Abstract Background While socio-economic status has been shown to be an important determinant of health and physical activity in adults, results for children and adolescents are less consistent. The purpose of this study, therefore, is to examine whether physical activity and sedentary behavior differs in children by socio-economic status (SES) independent of body mass index. Methods Data were from two cohorts including 271 children (117 males; 154 females) in study 1 and 131 children in study 2 (63 males; 68 females). The average age was 9.6 and 8.8 years respectively. Height and body mass were assessed according to standard procedures and body mass index (BMI, kg/m2) was calculated. Parent-reported household income was used to determine SES. Habitual, free-living physical activity (PA) was assessed by a pedometer (steps/day) in study 1 and accelerometer (time spent in moderate-to-vigorous PA) in study 2. Self-reported time spent watching TV and on the computer was used as measure of sedentary behavior. Differences in PA and sedentary behavior by SES were initially tested using ANOVA. Further analyses used ANCOVA controlling for BMI, as well as leg length in the pedometer cohort. Results In study 1, mean daily steps differed significantly among SES groups with lower SES groups approximating 10,500 steps/day compared to about 12,000 steps/day in the higher SES groups. These differences remained significant (p < 0.05) when controlling for leg length. Lower SES children, however, had higher body mass and BMI compared to higher SES groups (p < 0.05) and PA no longer remained significant when further controlling for BMI. In study 2 results depended on the methodology used to determine time spent in moderate-to-vigorous physical activity (MVPA). Only one equation resulted in significant group differences (p = 0.015), and these differences remained after controlling for BMI. Significant differences between SES groups were shown for sedentary behavior in both cohorts (P < 0.05) with higher SES groups spending less time watching TV than low SES groups. Conclusions Children from a low SES show a trend of lower PA levels and spend more time in sedentary behavior than high SES children; however, differences in PA were influenced by BMI. The higher BMI in these children might be another factor contributing to increased health risks among low SES children compared to children from with a higher SES.

Abstract Background Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF) with donor oocytes is currently the only treatment known to be effective. Methods A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the recipient's husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day three. Results A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks' gestation. Additionally, four embryos were cryopreserved for the recipient's future use. The sister-donor achieved another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery. Conclusion POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the circumstance of sister oocyte donation.

Abstract Background This study sought to describe patient features before beginning fertility treatment, and to ascertain their perceptions relative to risk of twin pregnancy outcomes associated with such therapy. Methods Data on readiness for twin pregnancy outcome from in vitro fertilisation (IVF) was gathered from men and women before initiating fertility treatment by anonymous questionnaire. Results A total of 206 women and 204 men were sampled. Mean (± SD) age for women and men being 35.5 ± 5 and 37.3 ± 7 yrs, respectively. At least one IVF cycle had been attempted by 27.2% of patients and 33.9% of this subgroup had initiated ≥3 cycles, reflecting an increase in previous failed cycles over five years. Good agreement was noted between husbands and wives with respect to readiness for twins from IVF (77% agreement; Cohen's K = 0.61; 95% CI 0.53 to 0.70). Conclusion Most patients contemplating IVF already have ideas about particular outcomes even before treatment begins, and suggests that husbands & wives are in general agreement on their readiness for twin pregnancy from IVF. However, fertility patients now may represent a more refractory population and therefore carry a more guarded prognosis. Patient preferences identified before IVF remain important, but further studies comparing pre- and post-treatment perceptions are needed.

Abstract Background Schools are the most frequent target for intervention programs aimed at preventing child obesity; however, the overall effectiveness of these programs has been limited. It has therefore been recommended that interventions target multiple ecological levels (community, family, school and individual) to have greater success in changing risk behaviors for obesity. This study examined the immediate and short-term, sustained effects of the Switch program, which targeted three behaviors (decreasing children's screen time, increasing fruit and vegetable consumption, and increasing physical activity) at three ecological levels (the family, school, and community). Methods Participants were 1,323 children and their parents from 10 schools in two states. Schools were matched and randomly assigned to treatment and control. Measures of the key behaviors and body mass index were collected at baseline, immediately post-intervention, and 6 months post-intervention. Results The effect sizes of the differences between treatment and control groups ranged between small (Cohen's d = 0.15 for body mass index at 6 months post-intervention) to large (1.38; parent report of screen time at 6 months post-intervention), controlling for baseline levels. There was a significant difference in parent-reported screen time at post-intervention in the experimental group, and this effect was maintained at 6 months post-intervention (a difference of about 2 hours/week). The experimental group also showed a significant increase in parent-reported fruit and vegetable consumption while child-reported fruit and vegetable consumption was marginally significant. At the 6-month follow-up, parent-reported screen time was significantly lower, and parent and child-reported fruit and vegetable consumption was significantly increased. There were no significant effects on pedometer measures of physical activity or body mass index in the experimental group. The intervention effects were moderated by child sex (for fruit and vegetable consumption, physical activity, and weight status), family involvement (for fruit and vegetable consumption), and child body mass index (for screen time). The perception of change among the experimental group was generally positive with 23% to 62% indicating positive changes in behaviors. Conclusion The results indicate that the Switch program yielded small-to-modest treatment effects for promoting children's fruit and vegetable consumption and minimizing screen time. The Switch program offers promise for use in youth obesity prevention.

Abstract Introduction The ability to screen blood of early stage operable breast cancer patients for circulating tumour cells is of potential importance for identifying patients at risk of developing distant relapse. We present the results of a study of the efficacy of the immunobead RT-PCR method in identifying patients with circulating tumour cells. Results Immunomagnetic enrichment of circulating tumour cells followed by RT-PCR (immunobead RT-PCR) with a panel of five epithelial specific markers (ELF3, EPHB4, EGFR, MGB1 and TACSTD1) was used to screen for circulating tumour cells in the peripheral blood of 56 breast cancer patients. Twenty patients were positive for two or more RT-PCR markers, including seven patients who were node negative by conventional techniques. Significant increases in the frequency of marker positivity was seen in lymph node positive patients, in patients with high grade tumours and in patients with lymphovascular invasion. A strong trend towards improved disease free survival was seen for marker negative patients although it did not reach significance (p = 0.08). Conclusion Multi-marker immunobead RT-PCR analysis of peripheral blood is a robust assay that is capable of detecting circulating tumour cells in early stage breast cancer patients.

Abstract Background To present a diagnostic evaluation and treatment strategy for serous adenocarcinoma of the ovary discovered during an in vitro fertilisation (IVF) sequence, and report on reproductive outcome after tumour resection and embryo transfer. Case presentation Cycle monitoring in IVF identified an abnormal ovarian lesion which was subjected to ultrasound-guided needle aspiration. Cytology suggested malignancy, and unilateral oophorectomy was performed after formal staging. After surgery, the patient underwent an anonymous donor oocyte IVF cycle which established a viable twin intrauterine pregnancy. No recurrence of cancer has been detected in the >72 month follow-up interval; mother and twin daughters continue to do well. Conclusion Suspicious adnexal structures noted during controlled ovarian hyperstimulation for IVF warrant assessment, and this report confirms the role of aspiration cytology in such cases. If uterine conservation is possible, successful livebirth can be achieved from IVF if donor oocyes are utilised, as described here.

Abstract Objective To review utilisation of elective embryo cryopreservation in the expectant management of patients at risk for developing ovarian hyperstimulation syndrome (OHSS), and report on reproductive outcome following transfer of thawed embryos. Materials and methods Medical records were reviewed for patients undergoing IVF from 2000–2008 to identify cases at risk for OHSS where cryopreservation was electively performed on all embryos at the 2 pn stage. Patient age, total number of oocytes retrieved, number of 2 pn embryos cryopreserved, interval between retrieval and thaw/transfer, number (and developmental stage) of embryos transferred (ET), and delivery rate after IVF were recorded for all patients. Results From a total of 2892 IVF cycles undertaken during the study period, 51 IVF cases (1.8%) were noted where follicle number exceeded 20 and pelvic fluid collection was present. Elective embryo freeze was performed as OHSS prophylaxis in each instance. Mean (± SD) age of these patients was 32 ± 3.8 yrs. Average number of oocytes retrieved in this group was 23 ± 8.7, which after fertilisation yielded an average of 14 ± 5.7 embryos cryopreserved per patient. Thaw and ET was performed an average of 115 ± 65 d (range 30–377 d) after oocyte retrieval with a mean of 2 ± 0.6 embryos transferred. Grow-out to blastocyst stage was achieved in 88.2% of cases. Delivery/livebirth rate was 33.3% per initiated cycle and 43.6% per transfer. Non-transferred blastocysts remained in cryostorage for 24 of 51 patients (46.1%) after ET, with an average of 3 ± 3 blastocysts refrozen per patient. Conclusion OHSS prophylaxis was used in 1.8% of IVF cycles at this institution; no serious OHSS complications were encountered during the study period. Management based on elective 2 pn embryo cryopreservation with subsequent thaw and grow-out to blastocyst stage for transfer did not appear to compromise embryo viability or overall reproductive outcome. For these patients, immediate elective embryo cryopreservation and delay of ET by as little as 30 d allowed for satisfactory conclusion of the IVF sequence, yielding a livebirth-delivery rate (per ET) >40%.

Abstract Background Although several previous projects have attempted to address the issue of child obesity through school-based interventions, the overall effectiveness of school-based programs on health-related outcomes in youth has been poor. Thus, it has been suggested that multi-level interventions that aim to influence healthy lifestyle behaviors at the community, school and family levels may prove more successful in the prevention of childhood obesity. Methods/Design This paper describes the rationale, design, and implementation of a community-, school-, and family-based intervention aimed at modifying key behaviors (physical activity, screen time (Internet, television, video games), and nutrition) related to childhood obesity among third through fifth graders in two mid-western cities. The intervention involves a randomized study of 10 schools (5 intervention and 5 control schools). The intervention is being conducted during the duration of the academic year – approximately 9 months – and includes baseline and post-intervention measurements of physical activity, dietary intake, screen time and body composition. Discussion We hope this report will be useful to researchers, public health professionals, and school administrators and health professionals (nurses and physical/health educators) seeking to develop similar prevention programs. It is obvious that more collaborative, inter-disciplinary, multi-level work is needed before a proven, effective intervention package to modify behaviors related to childhood obesity can be generally recommended. It is our hope that SWITCH is a step in that direction. Trial Registration ClinicalTrials.gov NCT00685555

Abstract Background Gene expression patterns in the brain are strongly influenced by the severity and duration of physiological stress at the time of death. This agonal effect, if not well controlled, can lead to spurious findings and diminished statistical power in case-control comparisons. While some recent studies match samples by tissue pH and clinically recorded agonal conditions, we found that these indicators were sometimes at odds with observed stress-related gene expression patterns, and that matching by these criteria still sometimes results in identifying case-control differences that are primarily driven by residual agonal effects. This problem is analogous to the one encountered in genetic association studies, where self-reported race and ethnicity are often imprecise proxies for an individual's actual genetic ancestry. Results We developed an Agonal Stress Rating (ASR) system that evaluates each sample's degree of stress based on gene expression data, and used ASRs in post hoc sample matching or covariate analysis. While gene expression patterns are generally correlated across different brain regions, we found strong region-region differences in empirical ASRs in many subjects that likely reflect inter-individual variabilities in local structure or function, resulting in region-specific vulnerability to agonal stress. Conclusion Variation of agonal stress across different brain regions differs between individuals, revealing a new level of complexity for gene expression studies of brain tissues. The Agonal Stress Ratings quantitatively assess each sample's extent of regulatory response to agonal stress, and allow a strong control of this important confounder.

Abstract Background The type 1 (microbial) rhodopsins are a diverse group of photochemically reactive proteins that display a broad yet patchy distribution among the three domains of life. Recent work indicates that this pattern is likely the result of lateral gene transfer (LGT) of rhodopsin genes between major lineages, and even across domain boundaries. Within the lineage in which the microbial rhodopsins were initially discovered, the haloarchaea, a similar patchy distribution is observed. In this initial study, we assess the roles of LGT and gene loss in the evolution of haloarchaeal rhodopsin ion pump genes, using phylogenetics and comparative genomics approaches. Results Mapping presence/absence of rhodopsins onto the phylogeny of the RNA polymerase B' subunit (RpoB') of the haloarchaea supports previous notions that rhodopsins are patchily distributed. The phylogeny for the bacteriorhodopsin (BR) protein revealed two discrepancies in comparison to the RpoB' marker, while the halorhodopsin (HR) tree showed incongruence to both markers. Comparative analyses of bacteriorhodopsin-linked regions of five haloarchaeal genomes supported relationships observed in the BR tree, and also identified two open reading frames (ORFs) that were more frequently linked to the bacteriorhodopsin gene than those genes previously shown to be important to the function and expression of BR. Conclusion The evidence presented here reveals a complex evolutionary history for the haloarchaeal rhodopsins, with both LGT and gene loss contributing to the patchy distribution of rhodopsins within this group. Similarities between the BR and RpoB' phylogenies provide supportive evidence for the presence of bacteriorhodopsin in the last common ancestor of haloarchaea. Furthermore, two loci that we have designated bacterio-opsin associated chaperone (bac) and bacterio-opsin associated protein (bap) are inferred to have important roles in BR biogenesis based on frequent linkage and co-transfer with bacteriorhodopsin genes.

Abstract Background Immunomagnetic enrichment followed by RT-PCR (immunobead RT-PCR) is an efficient methodology to identify disseminated carcinoma cells in the blood and bone marrow. The RT-PCR assays must be both specific for the tumor cells and sufficiently sensitive to enable detection of single tumor cells. We have developed a method to test RT-PCR assays for any cancer. This has been investigated using a panel of RT-PCR markers suitable for the detection of breast cancer cells. Methods In the assay, a single cell line-derived tumor cell is added to 100 peripheral blood mononuclear cells (PBMNCs) after which mRNA is isolated and reverse transcribed for RT-PCR analysis. PBMNCs without added tumor cells are used as specificity controls. The previously studied markers epidermal growth factor receptor (EGFR), mammaglobin 1 (MGB1), epithelial cell adhesion molecule (EpCAM/TACSTD1), mucin 1 (MUC1), carcinoembryonic antigen (CEA) were tested. Two new epithelial-specific markers ELF3 and EphB4 were also tested. Results MUC1 was unsuitable as strong amplification was detected in 100 cell PBMNC controls. Expression of ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 was found to be both specific for the tumor cell, as demonstrated by the absence of a signal in most 100 cell PBMNC controls, and sensitive enough to detect a single tumor cell in 100 PBMNCs using a single round of RT-PCR. Conclusions ELF3, EphB4, EpCAM, EGFR, CEA and MGB1 are appropriate RT-PCR markers for use in a marker panel to detect disseminated breast cancer cells after immunomagnetic enrichment.

Background: Schools are the most frequent target for intervention programs aimed at preventing child obesity; however, the overall effectiveness of these programs has been limited. It has therefore been recommended that interventions target multiple ecological levels (community, family, school and individual) to have greater success in changing risk behaviors for obesity. This study examined the immediate and short-term, sustained effects of the Switch program, which targeted three behaviors (decreasing children's screen time, increasing fruit and vegetable consumption, and increasing physical activity) at three ecological levels (the family, school, and community).Methods: Participants were 1,323 children and their parents from 10 schools in two states. Schools were matched and randomly assigned to treatment and control. Measures of the key behaviors and body mass index were collected at baseline, immediately post-intervention, and 6 months post-intervention.Results: The effect sizes of the differences between treatment and control groups ranged between small (Cohen's d = 0.15 for body mass index at 6 months post-intervention) to large (1.38; parent report of screen time at 6 months post-intervention), controlling for baseline levels. There was a significant difference in parent-reported screen time at post-intervention in the experimental group, and this effect was maintained at 6 months post-intervention (a difference of about 2 hours/week). The experimental group also showed a significant increase in parent-reported fruit and vegetable consumption while child-reported fruit and vegetable consumption was marginally significant. At the 6-month follow-up, parent-reported screen time was significantly lower, and parent and child-reported fruit and vegetable consumption was significantly increased. There were no significant effects on pedometer measures of physical activity or body mass index in the experimental group. The intervention effects were moderated by child sex (for fruit and vegetable consumption, physical activity, and weight status), family involvement (for fruit and vegetable consumption), and child body mass index (for screen time). The perception of change among the experimental group was generally positive with 23% to 62% indicating positive changes in behaviors.Conclusion: The results indicate that the Switch program yielded small-to-modest treatment effects for promoting children's fruit and vegetable consumption and minimizing screen time. The Switch program offers promise for use in youth obesity prevention. [ABSTRACT FROM AUTHOR]

Objectives: To develop a protocol for largescale analysis of synovial fluid proteins, for the identification of biological networks associated with subtypes of osteoarthritis., Methods: Synovial Fluid To detect molecular Endotypes by Unbiased Proteomics in Osteoarthritis (STEpUP OA) is an international consortium utilising clinical data (capturing pain, radiographic severity and demographic features) and knee synovial fluid from 17 participating cohorts. 1746 samples from 1650 individuals comprising OA, joint injury, healthy and inflammatory arthritis controls, divided into discovery (n = 1045) and replication (n = 701) datasets, were analysed by SomaScan Discovery Plex V4.1 (>7000 SOMAmers/proteins). An optimised approach to standardisation was developed. Technical confounders and batch-effects were identified and adjusted for. Poorly performing SOMAmers and samples were excluded. Variance in the data was determined by principal component (PC) analysis., Results: A synovial fluid standardised protocol was optimised that had good reliability (<20% co-efficient of variation for >80% of SOMAmers in pooled samples) and overall good correlation with immunoassay. 1720 samples and >6290 SOMAmers met inclusion criteria. 48% of data variance (PC1) was strongly correlated with individual SOMAmer signal intensities, particularly with low abundance proteins (median correlation coefficient 0.70), and was enriched for nuclear and non-secreted proteins. We concluded that this component was predominantly intracellular proteins, and could be adjusted for using an 'intracellular protein score' (IPS). PC2 (7% variance) was attributable to processing batch and was batch-corrected by ComBat. Lesser effects were attributed to other technical confounders. Data visualisation revealed clustering of injury and OA cases in overlapping but distinguishable areas of high-dimensional proteomic space., Conclusions: We have developed a robust method for analysing synovial fluid protein, creating a molecular and clinical dataset of unprecedented scale to explore potential patient subtypes and the molecular pathogenesis of OA. Such methodology underpins the development of new approaches to tackle this disease which remains a huge societal challenge., Competing Interests: YD, TAP, PH, SL, AS, NKA, DF, BM, AMV, SK, VB, JMA and VK declare no conflicts of interest. FW has received consultancy fees from Pfizer, and has a leadership role at the Medical Research Council (panel member) and Osteoarthritis and Cartilage (Associate Editor). LSL has received consultancy fees from Arthro Therapeutics AB, and is an advisory board member of AstraZeneca (non consortium member). LJD has received consultancy fees from Nightingale Health PLC. TLV has no conflicts to declare with the exception of grant income for STEpUP OA from industry partners (see above). RAM is a shareholder of AstraZeneca. SB and JM are employees and shareholders of Novartis (consortium members). MK has received support for attending the Gordon Research Conference, OARSI meeting, International Cartilage Repair Society, Munster University, is a board member of the Dutch Arthritis Society (Chair of Visitation Board), and has a leadership role at Osteoarthritis Research Society International (Board of Directors Member). CTA has received consultancy fees from Novartis, and has received honoraria for educational purposes also from Novartis. DAW has received consultancy fees from GlaxoSmithKline plc, AKL Research & Development Limited, Pfizer Ltd, Eli Lilly and Company, Contura International, and AbbVie Inc, has received honoraria for educational purposes from Pfizer Ltd and AbbVie Inc, is a board member of UKRI (Director) and Versus Arthritis Advanced Pain Discovery Platform. “This does not alter our adherence to PLOS ONE policies on sharing data and materials (see also Data Availability statement)”., (Copyright: © 2024 Deng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pain, the primary complaint in rheumatoid arthritis (RA), is multifaceted, and may be driven by inflammatory disease activity and central sensitisation. We aimed to ascertain what proportion of RA pain severity is explained by markers of inflammation and quantitative sensory testing (QST) indices of central sensitisation., Methods: This was a cross-sectional analysis of data from individuals with clinically active RA. Pain severity was assessed using numerical rating scales and inflammation via 28-joint Disease Activity Score (DAS28) and Ultrasound (Greyscale, Power Doppler). Pain sensitivity was assessed by 'static' (tibialis anterior or brachioradialis pressure pain detection threshold-PPT-TA/PPT-BR) and 'dynamic' (temporal summation-TS, conditioned pain modulation-CPM) QST. Bivariate associations used Spearman's correlation coefficients, and multivariable linear regression models determined relative contributions to pain severity., Results: In bivariate analyses of N = 96 (age 65 ± 10y, 77% females) people with RA, pain severity was significantly associated with inflammation indices (r = 0.20 to 0.55), and CPM (r=-0.26). In multivariable models that included TS, CPM, age, sex, and body mass index, inflammation indices remained significantly associated with pain severity. Multivariable models explained 22 to 27% of pain variance. Heterogeneity was apparent for associations with pain between subscores for pain now, strongest or average over the past 4-weeks., Conclusions: In individuals with clinically active RA, markers of inflammatory disease activity best explain RA pain with only marginal contributions from QST indices of central sensitisation. Although inflammation plays a key role in the experience of RA pain, the greater proportion of pain severity remains unexplained by DAS28 and ultrasound indices of inflammation., (© 2024. The Author(s).)