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The protective effect of physical activity on breast cancer incidence may partially be mediated by inflammation. Systematic searches of Medline, EMBASE, and SPORTDiscus were performed to identify intervention studies, Mendelian randomization studies, and prospective cohort studies that examined the effects of physical activity on circulating inflammatory biomarkers in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system was used to determine the overall quality of the evidence. Thirty-five intervention studies and one observational study met the criteria for inclusion. Meta-analyses of randomized controlled trials (RCT) indicated that, compared with control groups, exercise interventions reduced levels of C-reactive protein (CRP) [standardized mean difference (SMD) = -0.27, 95% confidence interval (CI) = -0.62 to 0.08), tumor necrosis factor alpha (TNFα, SMD = -0.63, 95% CI = -1.04 to -0.22), interleukin-6 (IL6, SMD = -0.55, 95% CI = -0.97 to -0.13) and leptin (SMD = -0.50, 95% CI = -1.10 to 0.09). Owing to heterogeneity in effect estimates and imprecision, evidence strength was graded as low (CRP, leptin) or moderate (TNFα and IL6). High-quality evidence indicated that exercise did not change adiponectin levels (SMD = 0.01, 95% CI = -0.14 to 0.17). These findings provide support for the biological plausibility of the first part of the physical activity-inflammation-breast cancer pathway., (©2023 The Authors; Published by the American Association for Cancer Research.)

Perturbation of the insulin/insulin-like growth factor (IGF) signaling system is often cited as a mechanism driving breast cancer risk. A systematic review identified prospective cohort studies and Mendelian randomization studies that examined the effects of insulin/IGF signaling (IGF, their binding proteins (IGFBP), and markers of insulin resistance] on breast cancer risk. Meta-analyses generated effect estimates; risk of bias was assessed and the Grading of Recommendations Assessment, Development and Evaluation system applied to evaluate the overall quality of the evidence. Four Mendelian randomization and 19 prospective cohort studies met our inclusion criteria. Meta-analysis of cohort studies confirmed that higher IGF-1 increased risk of breast cancer; this finding was supported by the Mendelian randomization studies. IGFBP-3 did not affect breast cancer. Meta analyses for connecting-peptide and fasting insulin showed small risk increases, but confidence intervals were wide and crossed the null. The quality of evidence obtained ranged from 'very low' to 'moderate'. There were insufficient studies to examine other markers of insulin/IGF signaling. These findings do not strongly support the biological plausibility of the second part of the physical activity-insulin/IGF signaling system-breast cancer pathway. Robust conclusions cannot be drawn due to the dearth of high quality studies. See related article by Swain et al., p. 2106., (©2022 American Association for Cancer Research.)

Physical activity may reduce the risk of developing breast cancer via its effect on the insulin/insulin-like growth factor (IGF) signaling system. A systematic review searched for randomized controlled trials (RCT), Mendelian randomization and prospective cohort studies that examined the effects of physical activity on insulin/IGF signaling [IGFs, their binding proteins (IGFBP), and markers of insulin resistance] in adult women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the Grading of Recommendations Assessment, Development, and Evaluation system used to determine the overall quality of the evidence. Fifty-eight RCTs met our inclusion criteria, no observational or Mendelian randomization studies met the criteria for inclusion. Meta-analyses indicated that physical activity interventions (vs. control) reduced fasting insulin, the Homeostatic Model Assessment for Insulin Resistance and fasting glucose. Physical activity increased IGF-1, but there was no clear effect on IGFBP-3 or the ratio of IGF-1:IGFBP-3. Strong evidence was only established for fasting insulin and insulin resistance. Further research is needed to examine the effect of physical activity on C-peptide and HBA1c in women. Reductions in fasting insulin and insulin resistance following exercise suggest some biological plausibility of the first part of the physical activity-insulin/IGF signaling-breast cancer pathway. See related article by Drummond et al., p. 2116., (©2022 American Association for Cancer Research.)

We undertook a systematic review and appraised the evidence for an effect of circulating sex steroid hormones and sex hormone-binding globulin (SHBG) on breast cancer risk in pre- and postmenopausal women. Systematic searches identified prospective studies relevant to this review. Meta-analyses estimated breast cancer risk for women with the highest compared with the lowest level of sex hormones, and the DRMETA Stata package was used to graphically represent the shape of these associations. The ROBINS-E tool assessed risk of bias, and the GRADE system appraised the strength of evidence. In premenopausal women, there was little evidence that estrogens, progesterone, or SHBG were associated with breast cancer risk, whereas androgens showed a positive association. In postmenopausal women, higher estrogens and androgens were associated with an increase in breast cancer risk, whereas higher SHBG was inversely associated with risk. The strength of the evidence quality ranged from low to high for each hormone. Dose-response relationships between sex steroid hormone concentrations and breast cancer risk were most notable for postmenopausal women. These data support the plausibility of a role for sex steroid hormones in mediating the causal relationship between physical activity and the risk of breast cancer. See related reviews by Lynch et al., p. 11 and Swain et al., p. 16 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Epidemiologic research suggests that physical activity is associated with a reduced risk of breast cancer, but the causal nature of this link is not clear. Investigating mechanistic pathways can provide evidence of biological plausibility and improve causal inference. This project will examine three putative pathways (sex steroid hormones, insulin signaling, and inflammation) in a series of two-stage systematic reviews. Stage 1 used Text Mining for Mechanism Prioritisation (TeMMPo) to identify and prioritize relevant biological intermediates. Stage 2 will systematically review the findings from studies of (i) physical activity and intermediates and (ii) intermediates and breast cancer. Ovid MEDLINE, EMBASE, and SPORTDiscus will be searched using a combination of subject headings and free-text terms. Human intervention and prospective, observational studies will be eligible for inclusion. Meta-analysis will be performed where possible. Risk of bias will be assessed using the Cochrane Collaboration tool, or the ROBINS-I or ROBINS-E tool, depending on study type. Strength of evidence will be assessed using the GRADE system. In addition to synthesizing the mechanistic evidence that links physical activity with breast cancer risk, this project may also identify priority areas for future research and help inform the design and implementation of physical activity interventions. See related reviews by Swain et al., p. 16 and Drummond et al., p. 28 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

The effect of physical activity on breast cancer risk may be partly mediated by sex steroid hormones. This review synthesized and appraised the evidence for an effect of physical activity on sex steroid hormones. Systematic searches were performed using MEDLINE (Ovid), EMBASE (Ovid), and SPORTDiscus to identify experimental studies and prospective cohort studies that examined physical activity and estrogens, progestins, and/or androgens, as well as sex hormone binding globulin (SHBG) and glucocorticoids in pre- and postmenopausal women. Meta-analyses were performed to generate effect estimates. Risk of bias was assessed, and the GRADE system was used to appraise quality of the evidence. Twenty-eight randomized controlled trials (RCT), 81 nonrandomized interventions, and six observational studies were included. Estrogens, progesterone, and androgens mostly decreased, and SHBG increased, in response to physical activity. Effect sizes were small, and evidence quality was graded moderate or high for each outcome. Reductions in select sex steroid hormones following exercise supports the biological plausibility of the first part of the physical activity-sex hormone-breast cancer pathway. The confirmed effect of physical activity on decreasing circulating sex steroid hormones supports its causal role in preventing breast cancer. See related reviews by Lynch et al., p. 11 and Drummond et al., p. 28 ., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objective: To assess the clinical and cost-effectiveness of cognitive rehabilitation for attention and memory problems in people with multiple sclerosis., Design: Multicentre, pragmatic, randomized controlled trial., Setting: Community., Participants: People with multiple sclerosis aged 18-69 years, who reported cognitive problems in daily life and had cognitive problems on standardized assessment., Interventions: A group cognitive rehabilitation programme delivered in 10 weekly sessions in comparison with usual care., Main Measures: The primary outcome was the Multiple Sclerosis Impact Scale Psychological subscale at 12 months after randomization. Secondary outcomes included measures of everyday memory problems, mood, fatigue, cognitive abilities and employment at 6 and 12 months after randomization., Results: In all, 245 participants were allocated to cognitive rehabilitation and 204 to usual care. Mean Multiple Sclerosis Impact Scale Psychological at 12 months was 22.2 (SD = 6.1) for cognitive rehabilitation and 23.4 (SD = 6.0) for usual care group; adjusted difference -0.6, 95% confidence interval (CI) = -1.5 to 0.3, P  = 0.20. No differences were observed in cognitive abilities, fatigue or employment. There were small differences in favour of cognitive rehabilitation for the Multiple Sclerosis Impact Scale Psychological at 6 months and everyday memory and mood at 6 and 12 months. There was no evidence of an effect on costs (-£808; 95% CI = -£2248 to £632) or on quality-adjusted life year gain (0.00; 95% CI = -0.01 to 0.02)., Conclusion: This rehabilitation programme had no long-term benefits on the impact of multiple sclerosis on quality of life, but there was some evidence of an effect on everyday memory problems and mood.

Background: People with multiple sclerosis have problems with memory and attention. The effectiveness of cognitive rehabilitation has not been established., Objectives: The objectives were to assess the clinical effectiveness and cost-effectiveness of a cognitive rehabilitation programme for people with multiple sclerosis., Design: This was a multicentre, randomised controlled trial in which participants were randomised in a ratio of 6 : 5 to receive cognitive rehabilitation plus usual care or usual care alone. Participants were assessed at 6 and 12 months after randomisation., Setting: The trial was set in hospital neurology clinics and community services., Participants: Participants were people with multiple sclerosis who had cognitive problems, were aged 18-69 years, could travel to attend group sessions and gave informed consent., Intervention: The intervention was a group cognitive rehabilitation programme delivered weekly by an assistant psychologist to between four and six participants for 10 weeks., Main Outcome Measures: The primary outcome was the Multiple Sclerosis Impact Scale - Psychological subscale at 12 months. Secondary outcomes included results from the Everyday Memory Questionnaire, the 30-Item General Health Questionnaire, the EuroQol-5 Dimensions, five-level version and a service use questionnaire from participants, and the Everyday Memory Questionnaire - relative version and the Modified Carer Strain Index from a relative or friend of the participant., Results: Of the 449 participants randomised, 245 were allocated to cognitive rehabilitation (intervention group) and 204 were allocated to usual care (control group). Of these, 214 in the intervention group and 173 in the control group were included in the primary analysis. There was no clinically important difference in the Multiple Sclerosis Impact Scale - Psychological subscale score between the two groups at the 12-month follow-up (adjusted difference in means -0.6, 95% confidence interval -1.5 to 0.3; p  = 0.20). There were no important differences between the groups in relation to cognitive abilities, fatigue, employment, or carer strain at follow-up. However, there were differences, although small, between the groups in the Multiple Sclerosis Impact Scale - Psychological subscale score at 6 months (adjusted difference in means -0.9, 95% confidence interval -1.7 to -0.1; p  = 0.03) and in everyday memory on the Everyday Memory Questionnaire as reported by participants at 6 (adjusted difference in means -5.3, 95% confidence interval -8.7 to -1.9) and 12 months (adjusted difference in means -4.4, 95% confidence interval -7.8 to -0.9) and by relatives at 6 (adjusted difference in means -5.4, 95% confidence interval -9.1 to -1.7) and 12 months (adjusted difference in means -5.5, 95% confidence interval -9.6 to -1.5) in favour of the cognitive rehabilitation group. There were also differences in mood on the 30-Item General Health Questionnaire at 6 (adjusted difference in means -3.4, 95% confidence interval -5.9 to -0.8) and 12 months (adjusted difference in means -3.4, 95% confidence interval -6.2 to -0.6) in favour of the cognitive rehabilitation group. A qualitative analysis indicated perceived benefits of the intervention. There was no evidence of a difference in costs (adjusted difference in means -£574.93, 95% confidence interval -£1878.93 to £729.07) or quality-adjusted life-year gain (adjusted difference in means 0.00, 95% confidence interval -0.02 to 0.02). No safety concerns were raised and no deaths were reported., Limitations: The trial included a sample of participants who had relatively severe cognitive problems in daily life. The trial was not powered to perform subgroup analyses. Participants could not be blinded to treatment allocation., Conclusions: This cognitive rehabilitation programme had no long-term benefits on quality of life for people with multiple sclerosis., Future Work: Future research should evaluate the selection of those who may benefit from cognitive rehabilitation., Trial Registration: Current Controlled Trials ISRCTN09697576., Funding: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 4. See the National Institute for Health Research Journals Library website for further project information., Competing Interests: Alan A Montgomery reports grants from the National Institute for Health Research (NIHR) and membership of the NIHR Health Technology Assessment (HTA) Clinical Evaluation and Trials Funding Board during the conduct of the study. Roshan das Nair reports membership of the NIHR Health Services and Delivery Research Board, the HTA End of Life Care and Add-on Studies Board and the NIHR Research for Patient Benefit (East Midlands), and personal fees from Biogen Inc. (Cambridge, MA, USA). Avril ER Drummond reports membership of the NIHR Clinical Lectureships panel. Cris S Constantinescu reports grants, personal fees and other from Bayer AG (Leverkusen, Germany); Biogen Inc.; Merck, Sharp & Dohme (Kenilworth, NJ, USA); Novartis International AG (Basel, Switzerland), Sanofi Genzyme (Cambridge, MA, USA) and Teva Pharmaceuticals Industries Ltd (Petah Tikva, Israel). He also reports grants and personal fees from GW Pharmaceuticals (Cambridge, UK), Morphosys (Planegg, Germany), Roche (Basel, Switzerland); and grants from Sanofi-Pasteur-MSD (Lyon, France), outside the submitted work.

Background: There is currently insufficient evidence for the clinical effectiveness and cost-effectiveness of psychological therapies for post-stroke depression., Objective: To evaluate the feasibility of undertaking a definitive trial to evaluate the clinical effectiveness and cost-effectiveness of behavioural activation (BA) compared with usual stroke care for treating post-stroke depression., Design: Parallel-group, feasibility, multicentre, randomised controlled trial with nested qualitative research and a health economic evaluation., Setting: Acute and community stroke services in three sites in England., Participants: Community-dwelling adults 3 months to 5 years post stroke who are depressed, as determined by the Patient Health Questionnaire-9 (PHQ-9) or the Visual Analogue Mood Scales 'Sad' item. Exclusions: patients who are blind and/or deaf, have dementia, are unable to communicate in English, do not have mental capacity to consent, are receiving treatment for depression at the time of stroke onset or are currently receiving psychological intervention., Randomisation and Blinding: Participants were randomised (1 : 1 ratio) to BA or usual stroke care. Randomisation was conducted using a computer-generated list with random permuted blocks of varying sizes, stratified by site. Participants and therapists were aware of the allocation, but outcome assessors were blind., Interventions: The intervention arm received up to 15 sessions of BA over 4 months. BA aims to improve mood by increasing people's level of enjoyable or valued activities. The control arm received usual care only., Main Outcome Measures: Primary feasibility outcomes concerned feasibility of recruitment to the main trial, acceptability of research procedures and measures, appropriateness of baseline and outcome measures, retention of participants and potential value of conducting the definitive trial. Secondary feasibility outcomes concerned the delivery of the intervention. The primary clinical outcome 6 months post randomisation was the PHQ-9. Secondary clinical outcomes were Stroke Aphasic Depression Questionnaire - Hospital version, Nottingham Leisure Questionnaire, Nottingham Extended Activities of Daily Living, Carer Strain Index, EuroQol-5 Dimensions, five-level version and health-care resource use questionnaire., Results: Forty-eight participants were recruited in 27 centre-months of recruitment, at a recruitment rate of 1.8 participants per centre per month. The 25 participants randomised to receive BA attended a mean of 8.5 therapy sessions [standard deviation (SD) 4.4 therapy sessions]; 23 participants were allocated to usual care. Outcome assessments were completed by 39 (81%) participants (BA, n  = 18; usual care, n  = 21). Mean PHQ-9 scores at 6-month follow-up were 10.1 points (SD 6.9 points) and 14.4 points (SD 5.1 points) in the BA and control groups, respectively, a difference of -3.8 (95% confidence interval -6.9 to -0.6) after adjusting for baseline PHQ-9 score and centre, representing a reduction in depression in the BA arm. Therapy was delivered as intended. BA was acceptable to participants, carers and therapists. Value-of-information analysis indicates that the benefits of conducting a definitive trial would be likely to outweigh the costs. It is estimated that a sample size of between 580 and 623 participants would be needed for a definitive trial., Limitations: Target recruitment was not achieved, although we identified methods to improve recruitment., Conclusions: The Behavioural Activation Therapy for Depression after Stroke trial was feasible with regard to the majority of outcomes. The outstanding issue is whether or not a sufficient number of participants could be recruited within a reasonable time frame for a definitive trial. Future work is required to identify whether or not there are sufficient sites that are able to deliver the services required for a definitive trial., Trial Registration: Current Controlled Trials ISRCTN12715175., Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 23, No. 47. See the NIHR Journals Library website for further project information., Competing Interests: Shirley A Thomas and Avril ER Drummond report grants from the National Institute for Health Research (NIHR) and the Stroke Association outside the submitted work. Rebecca L Palmer is an author of the Consent Support Tool, which was piloted in the work and is discussed in the report. Roshan das Nair is a member of the NIHR Health Services and Delivery Research Board. Nicholas R Latimer is supported by the NIHR (NIHR Post Doctoral Fellowship PDF-2015-08-022). Stephen J Walters is a member of the NIHR Health Technology Assessment (HTA) Clinical Trials Board and the NIHR HTA Funding Boards Policy Group; he also reports grants from the NIHR HTA programme during the conduct of the study, personal fees from royalties, research grants from the NIHR and the Medical Research Council, personal fees from external examining fees and book royalties outside the submitted work. Cindy L Cooper is a member of the NIHR Clinical Trials Unit Standing Advisory Committee.

Objectives: The objective of this study was to test the feasibility of conducting a randomised controlled trial (RCT) of an intervention targeted at activities of daily living (ADL), delivered by an occupational therapist, in homecare reablement., Design: Feasibility parallel group RCT., Setting: Single-site local authority homecare reablement service., Participants: People referred for homecare reablement with ability to consent. Exclusion criteria were as follows: inability to speak English, receiving other community therapy services, needing two or more to assist transfer and receiving end-of-life care., Control: 'Usual care' was 6 weeks of homecare reablement delivered by social care workers (no routine health professional input)., Intervention: A targeted ADL programme, delivered by an occupational therapist incorporating goal setting, teaching/practising techniques, equipment/adaptations and provision of advice/support. This was in addition to usual care., Outcome Measures: Aspects of feasibility including eligibility, recruitment, intervention delivery, attrition and suitability and sensitivity of outcome measures. Participant outcomes were personal and extended ADL, quality of life, falls and use of health and social care services., Results: 30 participants were recruited, 15 to each arm, which was 60% of those eligible. Data from 22 (73%) were analysed at 6 months. Of the 15 participants, 13 (86%) received the intervention and were able to set one or more ADL goals. There were improvements from baseline in both groups, although overall improvements were greater in the occupational therapy (OT) intervention group. The biggest threat to feasibility was a change in service configuration during the trial, involving additional occupational therapy input, affecting usual care and recruitment., Conclusions: Despite the service reconfiguration, it was feasible to recruit and retain participants, deliver the intervention and collect outcome data that were responsive to change. The choice of primary outcome measure remains unclear. A further powered study is feasible and warranted; however, the design will require careful consideration because of ongoing national changes in service configurations., Trial Registration Number: ISRCTN21710246; Results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: There is currently insufficient evidence for the clinical and cost-effectiveness of psychological therapies for treating post-stroke depression., Methods/design: BEADS is a parallel group feasibility multicentre randomised controlled trial with nested qualitative research and economic evaluation. The aim is to evaluate the feasibility of undertaking a full trial comparing behavioural activation (BA) to usual stroke care for 4 months for patients with post-stroke depression. We aim to recruit 72 patients with post-stroke depression over 12 months at three centres, with patients identified from the National Health Service (NHS) community and acute services and from the voluntary sector. They will be randomly allocated to receive behavioural activation in addition to usual care or usual care alone. Outcomes will be measured at 6 months after randomisation for both participants and their carers, to determine their effectiveness. The primary clinical outcome measure for the full trial will be the Patient Health Questionnaire-9 (PHQ-9). Rates of consent, recruitment and follow-up by centre and randomised group will be reported. The acceptability of the intervention to patients, their carers and therapists will also be assessed using qualitative interviews. The economic evaluation will be undertaken from the National Health Service and personal social service perspective, with a supplementary analysis from the societal perspective. A value of information analysis will be completed to identify the areas in which future research will be most valuable., Discussion: The feasibility outcomes from this trial will provide the data needed to inform the design of a definitive multicentre randomised controlled trial evaluating the clinical and cost-effectiveness of behavioural activation for treating post-stroke depression., Trial Registration: Current controlled trials ISRCTN12715175.

Background: People with multiple sclerosis have problems with memory and attention. Cognitive rehabilitation is a structured set of therapeutic activities designed to retrain an individual's memory and other cognitive functions. Cognitive rehabilitation may be provided to teach people strategies to cope with these problems, in order to reduce the impact on everyday life. The effectiveness of cognitive rehabilitation for people with multiple sclerosis has not been established., Methods: This is a multi-centre, randomised controlled trial investigating the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems for people with multiple sclerosis. Four hundred people with multiple sclerosis will be randomised from at least four centres. Participants will be eligible if they have memory problems, are 18 to 69 years of age, are able to travel to attend group sessions and give informed consent. Participants will be randomised in a ratio of 6:5 to the group rehabilitation intervention plus usual care or usual care alone. Intervention groups will receive 10 weekly sessions of a manualised cognitive rehabilitation programme. The intervention will include both restitution strategies to retrain impaired attention and memory functions and compensation strategies to enable participants to cope with their cognitive problems. All participants will receive a follow-up questionnaire and an assessment by a research assistant at 6 and 12 months after randomisation. The primary outcome is the Multiple Sclerosis Impact Scale (MSIS) Psychological subscale at 12 months. Secondary outcomes include the Everyday Memory Questionnaire, General Health Questionnaire-30, EQ-5D and a service use questionnaire from participants, and the Everyday Memory Questionnaire-relative version and Carer Strain Index from a relative or friend. The primary analysis will be based on intention to treat. A mixed-model regression analysis of the MSIS Psychological subscale at 12 months will be used to estimate the effect of the group cognitive rehabilitation programme., Discussion: The study will provide evidence regarding the clinical and cost-effectiveness of a group-based cognitive rehabilitation programme for attention and memory problems in people with multiple sclerosis., Trial Registration: ISRCTN09697576 . Registered 14 August 2014.

Objectives: To identify interventions that aim to reduce dependency in activities of daily living (ADL) in homecare service users. To determine: content; effectiveness in improving ability to perform ADL; and whether delivery by qualified occupational therapists influences effectiveness., Data Sources: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, OTseeker, PEDro, Web of Science, CIRRIE, and ASSIA., Review Methods: We included: randomised controlled trials, non-randomised controlled trials and controlled before and after studies. Two reviewers independently screened studies for inclusion, assessed risk of bias and extracted data. A narrative synthesis of the findings was conducted., Results: Thirteen studies were included, totalling 4975 participants. Ten (77%) were judged to have risk of bias. Interventions were categorised as those termed 're-ablement' or 'restorative homecare' (n=5/13); and those involving separate components which were not described using this terminology (n=8/13). Content of the intervention and level of health professional input varied within and between studies. Effectiveness on ADL: eight studies included an ADL outcome, five favoured the intervention group, only two with statistical significance, both these were controlled before and after studies judged at high risk of bias. ADL outcome was reported using seven different measures. Occupational therapy: there was insufficient evidence to determine whether involvement of qualified occupational therapists influenced effectiveness., Conclusion: There is limited evidence that interventions targeted at personal ADL can reduce homecare service users' dependency with activities, the content of evaluated interventions varies greatly., (© The Author(s) 2015.)

Background: Homecare re-ablement services have been developed by local authorities in England in response to the government agenda for health and social care. These services aim to optimize users' independence and ability to cope at home, and reduce the need for ongoing health and social care services. However, there is currently limited evidence and guidance regarding the optimum configuration and delivery of re-ablement services. In particular, the impact of occupational therapy input on service user outcomes has been highlighted as a specific research priority., Methods/design: This feasibility randomized controlled trial (RCT) will recruit 50 people from one local authority led homecare re-ablement service in England. Those who provide informed consent will be randomized to receive either usual homecare re-ablement (without routine occupational therapy input) or usual homecare re-ablement plus an enhanced program targeted at activities of daily living (ADL), delivered by an occupational therapist. The primary aim of this study is to assess the feasibility of conducting a further, powered study. The participant outcomes assessed will be independence in personal and extended ADL, health and social care-related quality of life, number of care support hours, falls, acute and residential admissions and use of health and social care services. These will be assessed at two weeks, three months and six months post-discharge from the re-ablement service., Discussion: To our knowledge, this is the first RCT of occupational therapy in homecare re-ablement services. The results of this study will lay the foundations for a further powered study. The findings will be relevant to researchers, clinicians, commissioners and users of adult social care services., Trial Registration: Current Controlled Trials registration number: ISRCTN21710246 (registered on 31March 2014).

Objective: To evaluate the cost effectiveness of a psychological adjustment group shown to be clinically effective in comparison with usual care for people with multiple sclerosis., Design: Randomized controlled trial with comparison of costs and calculation of incremental cost effectiveness ratio., Setting: Community., Participants: People with multiple sclerosis were screened on the General Health Questionnaire 12 and Hospital Anxiety and Depression Scale, and those with low mood were recruited., Interventions: Participants randomly allocated to the adjustment group received six group treatment sessions. The control group received usual care, which did not include psychological interventions., Main Measures: Outcomes were assessed four and eight months after randomization, blind to group allocation. The costs were assessed from a service use questionnaire and information provided on medication. Quality of life was assessed using the EQ-5D., Results: Of the 311 patients identified, 221 (71%) met the criteria for having low mood. Of these, 72 were randomly allocated to receive treatment and 79 to usual care. Over eight months follow-up there was a decrease in the combined average costs of £378 per intervention respondent and an increase in the costs of £297 per patient in the control group, which was a significant difference (p=0.03). The incremental cost-effectiveness ratio indicated that the cost per point reduction on the Beck depression inventory-II was £118., Conclusion: In the short term, the adjustment group programme was cost effective when compared with usual care, for people with multiple sclerosis presenting with low mood. The longer-term costs need to be assessed.

Background: There is a growing demand for services whereby individuals receive assistance from care workers for personal care within the home. This has led to the development of re-ablement or restorative homecare services that provide time-limited input aimed at reducing dependency in personal activities of daily living, and preventing or delaying the need for further homecare support. However, little is currently known about how such interventions are configured, or how they may affect individuals' ability to carry out personal care independently., Methods/design: We will seek to identify studies that compare an intervention designed to reduce dependency in personal activities of daily living with routine input or usual care as the control. We will include randomised controlled trials, nonrandomised controlled trials, and controlled before and after studies. We will also include interrupted time series studies. We shall search electronic databases in addition to searching for ongoing and unpublished studies, and where appropriate will contact key authors. Two reviewers will independently screen articles for inclusion; will assess risk of bias using quality assessment tools; and will carry out data extraction using pre-prepared forms. Any disagreements, at any stage, will be resolved by discussion and the involvement of a third reviewer if needed. We will produce a narrative summary of the results. A meta-analysis will be conducted if sufficient data are available of appropriate quality and comparability., Discussion: The findings from this review will inform future practice within homecare re-ablement services; will inform policy decisions about the structure, organisation and content of such services; and will identify areas where further research is warranted., Trial Registration: This review protocol has been registered on the PROSPERO database (CRD42013004163).

Granulosa cell tumours of the ovary (GCT) express aromatase and produce oestrogens. The ovarian-specific aromatase promoter (pII) is regulated by members of the group 5A nuclear receptor family, SF-1 and LRH-1. Since both SF-1 and LRH-1 are implicated in proliferation and cancer, we hypothesised that alteration in the expression of either or both receptors may be associated with GCT. We therefore determined the expression of LRH-1, SF-1 and aromatase in a cohort of GCT, mucinous and serous cystadenocarcinomas, and normal ovaries. LRH-1 mRNA was present at low level in normal ovary and serous cystadenocarcinoma, but was elevated approximately 30-fold in GCT, and 8-fold in mucinous cystadenocarcinoma, compared to normal ovary. LRH-1 protein expression was confirmed in GCT by immunohistochemistry. SF-1 mRNA was significantly lower that of LRH-1 in all samples and not significantly altered in GCT, compared to normal ovary. Aromatase mRNA was present at low level in normal ovary and serous and mucinous cystadenocarcinoma, and significantly elevated (18-fold) in GCT compared to normal ovary. Despite the coordinate over-expression of both LRH-1 and aromatase in GCT versus normal ovary, their levels did not correlate in individual patients; rather, aromatase expression correlated with that of SF-1. Finally, although both LRH-1 and SF-1 activated aromatase promoter activity in transient transfection studies, gel-shift and chromatin immunoprecipitation data indicated that SF-1, but not LRH-1, bound to the aromatase promoter. We conclude that SF-1 regulates aromatase expression in GCT; over-expression of LRH-1 suggests that this receptor may be involved in the pathogenesis of GCT by mechanisms other than the regulation of aromatase. Its role in this disease therefore warrants further investigation., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To assess the feasibility of conducting a randomized controlled trial of occupational therapy predischarge home visits for people after stroke., Design: Randomized controlled trial and cohort study. We randomized eligible patients for whom there was clinical uncertainty about the need to conduct a home visit to a randomized controlled trial; patients for whom a visit was judged 'essential' were enrolled into a cohort study., Setting: Stroke rehabilitation unit of teaching hospital., Participants: One hundred and twenty-six participants hospitalized following recent stroke., Interventions: Predischarge home visit or structured, hospital-based interview., Main Outcome Measures: The primary objective was to collect information on the feasibility of a randomized controlled trial, including eligibility, control intervention and outcome assessments. The primary outcome measure was the Nottingham Extended Activities of Daily Living Scale at one month after discharge from hospital. Secondary outcomes included mood, quality of life and costs at one week and one month following discharge., Results: Ninety-three people were allocated to the randomized controlled trial; 47 were randomized to intervention and 46 to control. Thirty-three were enrolled into the cohort study. More people were allocated to the randomized controlled trial as the study progressed. One hundred and thirteen people (90%) received the proposed intervention, although there was a need for stricter protocol adherence. Follow-up was good: at one month 114 (90%) were assessed. There were no significant differences between the groups in the randomized controlled trial for the primary outcome measure at one month. The average cost of a home visit was £208., Conclusion: A trial is feasible and warranted given the resource implications of predischarge occupational therapy home visits.

Ovarian cancer may be the most frequently lethal gynaecological malignancy but the heterogeneous nature of the disease and the advanced stage at which it is usually diagnosed, have contributed to the paucity of information relating to its aetiology and pathogenesis. Members of the TGF-β superfamily, estrogen and NFκB have all been implicated in the development and progression of cancers from a wide range of tissues. In the ovary, TGF-β superfamily members and estrogen play key roles in maintaining normal function. To date, little is known about the capacity of NFκB to influence normal ovarian function except that it is ubiquitously expressed. In this review we will highlight the roles that inhibin/activin, estrogen and NFκB, have been attributed within carcinogenesis and examine the potential for crosstalk between these pathways in ovarian cancer pathogenesis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Numerous studies have reported on the roles of activins in gonadal regulation; however, little is known about their specific roles in early folliculogenesis. Ovarian follicular growth was investigated in 10-day cultures of day 4 postnatal whole ovaries treated with activin A (ActA; 50 ng/ml), with or without FSH (100 ng/ml) in vitro. We hypothesized that treatment with ActA±FSH would affect rates of growth and atresia in follicles. None of the treatments affected primordial follicle activation, and antral follicles were not observed after 10 days in culture. Primordial follicle numbers from all treatment groups were ∼20% of those in day 4 fresh ovaries, indicating that activation had occurred. In the presence of ActA, preantral follicle numbers increased significantly (P<0.0001). ActA alone decreased the proportion of atretic follicles in the primary and preantral classes, whereas the combined treatment of ActA+FSH increased the proportion of atretic preantral oocytes. Real-time PCR analysis revealed that follistatin, FSH receptor, and activin βA and βB subunits were all expressed at significantly higher levels in the ActA-only treated group but not in the ActA+FSH group. Here, we report novel findings supporting the role of FSH in primordial follicle survival through an action on apoptosis and a stimulatory role of ActA in the primordial to primary and preantral stages of follicle development, suggesting an inhibitory action of activin on oocyte apoptosis.

The development of a normal ovary during foetal life is essential for the production and ovulation of a high-quality oocyte in adult life. Early in embryogenesis, the primordial germ cells (PGCs) migrate to and colonise the genital ridges. Once the PGCs reach the bipotential gonad, the absence of the sex-determining region on the Y chromosome (SRY) gene and the presence of female-specific genes ensure that the indifferent gonad takes the female pathway and an ovary forms. PGCs enter into meiosis, transform into oogonia and ultimately give rise to oocytes that are later surrounded by granulosa cells to form primordial follicles. Various genes and signals are implicated in germ and somatic cell development, leading to successful follicle formation and normal ovarian development. This review focuses on the differentiation events, cellular processes and molecular mechanisms essential for foetal ovarian development in the mice and humans. A better understanding of these early cellular and morphological events will facilitate further study into the regulation of oocyte development, manifestation of ovarian disease and basis of female infertility.

Purpose: A cognitive behavioural group promoting psychological adjustment for people with multiple sclerosis (MS) was found to reduce psychological distress. Not all those offered treatment attended the group sessions. The aims were to examine the rates of attendance and to evaluate feedback from participants., Method: Participants with MS and low mood were recruited to a randomized trial comparing attendance at a psychological support group with a usual care control group. The attendance at each session was determined and those who attended were compared with those who failed to attend using a Mann-Whitney U-test or chi-squared. A sample of participants completed a telephone feedback questionnaire to determine their views of the group., Results: The 44 participants who attended four or more sessions were not significantly different from the 28 who attended fewer than four sessions on demographic variables, disability, self-efficacy or quality of life, but significantly fewer men attended than women (p = 0.03). Participants' feedback from the group was mainly positive, and no factors were identified associated with non-attendance., Conclusions: Men were less likely to attend group treatment sessions than women, but no other variables were associated with non-attendance. Attendance rates influence the effectiveness of interventions and reasons for non-attendance need to be determined.

Estrogen is essential for folliculogenesis with independent roles attributed to each of the two estrogen receptors (ERs). ERβ, expressed predominantly by the ovarian granulosa cells, is required for antrum formation, preovulatory follicle maturation, expression of genes involved in ovarian differentiation (luteinizing hormone, aromatase, etc.), and follicle rupture during ovulation. Ovulatory dysfunction is associated with polymorphisms of the ERβ gene, and endocrine disruptors that selectively activate ERβ cause reproductive dysfunction and impairment fertility. ERβ may also exhibit antitumorigenic properties, with a decline in ERβ levels in epithelial ovarian cancers associated with more severe disease and poor prognosis. In this review, we examine the models that have been used to elucidate the roles ERβ plays in the ovary and consider the clinical consequences of altered ERβ expression or inappropriate activation of ERβ signaling., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Mouse gametogenetin (Ggn) is a testis-enriched gene that encodes multiple spliced transcripts giving rise to three predicted protein isoforms: GGN1, GGN2 and GGN3. Of these, GGN1 has been linked to germ cell development. Based on the spatial and temporal expression pattern of GGN1 during mouse spermatogenesis, it has been proposed as a candidate human infertility gene. Here, we report the localization of GGN1 in the human testis and ovary compared with the mouse orthologue. Within the testis, GGN1 was confined to pachytene spermatocytes and spermatids. During mid-prophase GGN1 redistributes from a solely cytoplasmic localization to both cytoplasmic and nuclear in late prophase spermatocytes and round spermatids, and is ultimately incorporated into the sperm tail. Within both mouse and human ovaries, GGN1 was localized within granulosa cells. Lower levels of expression were observed in mouse oocytes and the cumulus cells. Furthermore, to define the level of sequence variation in the fertile population and to assess the potential for an association with male infertility, we sequenced the coding region of human GGN in 100 idiopathic oligospermic infertile and 100 control men. Fifteen genetic variants were identified, of which 10 had not previously been reported. No significant associations with fertility status were observed, suggesting that variance in the GGN gene are not a common cause of oligospermic infertility in Australian men., (© 2010 The Authors. International Journal of Andrology © 2011 European Academy of Andrology.)

Background: Mood problems affect many people with multiple sclerosis (MS). The aim was to evaluate the effectiveness of a group treatment based on cognitive behavioural principles., Methods: People with MS were screened on the General Health Questionnaire 12 (GHQ-12) and Hospital Anxiety and Depression Scale (HAD). Those identified with low mood were invited to take part in a randomized trial comparing the effect of attending an adjustment group with a waiting list control. Patients allocated to the adjustment group received six 2 h group treatment sessions. Outcomes were assessed 4 and 8 months after randomization, blind to group allocation., Results: Of the 311 patients identified, 221 (71%) met the criteria for low mood and 151 (68%) agreed to take part. Hierarchical regression analyses were conducted to compare the two groups, correcting for baseline mood and disability. At 4 months, group allocation alone was a significant predictor of the primary outcome measure, the GHQ-12. At 8 months, group allocation alone was no longer a significant predictor for GHQ-12 scores, but it was when baseline GHQ-12 and Guy's Neurological Disability Scale scores were controlled for. Comparison of the area under the curve revealed significant differences between the groups for GHQ-12 (p = 0.003), HAD Anxiety (p = 0.013), HAD Depression (p = 0.004), Beck Depression Inventory (p = 0.001), MS Self-efficacy (p = 0.037) and MS Impact Scale Psychological (p = 0.012)., Conclusion: Patients receiving treatment were less distressed and had less depression and anxiety. There was some evidence of improved self-efficacy and a reduction of the impact of MS on people's lives.

Granulosa cell tumors of the ovary (GCT) represent ~5% of malignant ovarian tumors. The adult form is defined by a mutation in the FOXL2 gene. GCT exhibit many of the features of normal proliferating granulosa cells. We have profiled the expression of the 48 human nuclear receptors (NR) by quantitative RT-PCR in a panel of GCT and in two GCT-derived cell lines, COV434 and KGN. The highest level of expression is seen for COUP-TF2 with abundant expression of PPARγ, SF-1, and TR-α. Estrogen receptor (ER)-β is the most abundant of the steroid receptors with relatively high expression also of AR, ER-α, and PR. The concordance of expression for each NR across the tumors is remarkably high with same discordance between the cell lines and the tumors, particularly the COV434 line. No significant differences were observed with respect to tumor stage for NR expression. These findings provide a full profile of NR expression in GCT which will enable full characterization of their roles and potential as therapeutic targets., (© Springer Science+Business Media, LLC 2011)

Estrogen (E) plays a pivotal role in regulating the female reproductive system, particularly the ovary. However, the number and type of ovarian genes influenced by estrogen remain to be fully elucidated. In this study, we have utilized wild-type (WT) and aromatase knockout (ArKO; estrogen free) mouse ovaries as an in vivo model to profile estrogen dependent genes. RNA from each individual ovary (n = 3) was analyzed by a microarray-based screen using Illumina Sentrix Mouse WG-6 BeadChip (45,281 transcripts). Comparative analysis (GeneSpring) showed differential expression profiles of 450 genes influenced by E, with 291 genes up-regulated and 159 down-regulated by 2-fold or greater in the ArKO ovary compared to WT. Genes previously reported to be E regulated in ArKO ovaries were confirmed, in addition to novel genes not previously reported to be expressed or regulated by E in the ovary. Of genes involved in 5 diverse functional processes (hormonal processes, reproduction, sex differentiation and determination, apoptosis and cellular processes) 78 had estrogen-responsive elements (ERE). These analyses define the transcriptome regulated by E in the mouse ovary. Further analysis and investigation will increase our knowledge pertaining to how E influences follicular development and other ovarian functions.

Unlabelled: To assess the effectiveness of an environmental falls prevention intervention delivered by qualified occupational therapists or unqualified trained assessors., Design: A pilot three-armed randomized controlled trial., Setting: Airedale National Health Service Trust catchment, North and West Yorkshire, England., Participants: Two hundred thirty-eight community-dwelling adults aged 70 and older with a history of falls in the previous year., Intervention: Assessment and modification of the home environment of people at greater risk of falls., Measurements: Fear of falling was the primary outcome measure, and an analysis of covariance was conducted on the area under the curve at 12 months. As a secondary outcome, falls were analysed using negative binomial regression. Quality of life and independence in activities of daily living (ADLs) were also measured., Results: The intervention had no effect on fear of falling (P=.63). The occupational therapy group had significantly fewer falls than controls 12 months after the assessment (incidence rate ratio (IRR)=0.54, 95% confidence interval (CI)=0.36-0.83, P=.005). There was no significant effect on falls in the trained assessor group (IRR=0.78, 95% CI=0.51-1.21, P=.34)., Conclusion: Environmental assessment had no effect on fear of falling. Environmental assessment prescribed by an occupational therapist significantly reduced the number of falls in high-risk individuals whereas that prescribed by a trained assessor did not. Further research in other settings is needed to confirm this, to explore the mechanisms, and to estimate cost-effectiveness., (© 2011, Copyright the Authors. Journal compilation © 2011, The American Geriatrics Society.)

It remains to be established as to whether the absence of estrogen (direct) or the elevated levels of gonadotrophins and androgens (indirect) are responsible for the ArKO (aromatase knockout) ovarian phenotype. The aim of this study was to determine the effects of E(2) (17beta-estradiol) replacement, acyline (GnRH antagonist) and flutamide (anti-androgen) treatment on the ovarian phenotype of ArKO mice. E(2) replacement and acyline treatment but not flutamide treatment, reduced serum gonadotrophin levels of ArKO mice to within normal ranges. E(2) replacement improved uterine and ovarian follicular phenotypes and reduced the number of Sertoli-like filled cords by 62%. Acyline treatment reduced the number of hemorrhagic cysts and the number of Sertoli-like filled cords within ArKO ovaries. The data indicate that the absence of estrogen in concert with elevated levels of circulating gonadotrophins, principally LH, is responsible for the abnormal reproductive phenotype of the female ArKO mouse., (Crown Copyright 2010. Published by Elsevier Ireland Ltd. All rights reserved.)

The high-temperature requirement factor A (Htra) family of serine proteases is conserved from bacteria to humans. In the mouse and human, Htra3, a member of the Htra family, is transcribed into two transcripts through alternative splicing. In the rat, Htra3 is located on chromosome 14q21 and the overall intron/exon structure of Htra3 is conserved between the rat, mouse and human. Rat Htra3, similar to the mouse and human, is alternatively spliced into two transcripts (long and short). The expression and regulation of Htra3 gene and protein in the rat ovary was recently determined. The long form Htra3 has the dominant expression throughout rat ovarian postnatal development, folliculogenesis and luteinization compared to short form Htra3. The expression of the HTRA3 gene and the cellular localization of the protein in the rhesus monkey ovary were investigated. Protein expression increased during folliculogenesis and was significantly higher in the granulosa-lutein cells compared to the theca-lutein cells, suggesting a role for HTRA3 in folliculogenesis and luteinization in the primate ovary. A preliminary study has also revealed a significant decrease in HTRA3 mRNA expression in ovarian cancer and granulosa cell tumor cell lines, suggesting that HTRA3 may act as a tumor suppressor. The role of the PDZ domain, specific to the long form Htra3, and the specific substrates of Htra3 in vivo, need to be defined to better understand the roles of HtrA3 in the normal and malignant ovary., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

This review examines the evidence for a central role of oestrogen receptor beta (ERbeta or ESR2 as listed in the MGI Database) in folliculogenesis and hence reproductive biology. Knockout mouse models have been a valuable resource in this respect. The ERbeta-null mouse exhibits a granulosa cell phenotype associated with the partial arrest of folliculogenesis and ovulatory dysfunction. Phyto-oestrogens such as genistein, which preferentially activate ERbeta, have been shown to alleviate the ovarian phenotype of the oestrogen-depleted aromatase knockout mouse. In normal adult mice, genistein has been shown to cause reproductive defectives following neonatal administration. Studies of ovarian cancer have also informed the literature. A decline in ERbeta levels in epithelial ovarian cancers has been hypothesised to be associated with severity of disease and prognosis. Whereas the abundant expression of ERbeta in granulosa cell tumours (GCT) of the ovary and evidence that ERbeta signalling is transrepressed by the nuclear factor-kappaB pathway in GCT cell lines suggest a pathogenetic role for ERbeta in GCT. In recent years, studies into the impact of environmental oestrogens (either in the form of pesticides or plastics) on reproductive function have shown that ERbeta-selective toxins cause reproductive dysfunction and impair fertility. It remains to be established as to what genes are regulated by ERbeta in the ovary. Finally, ERbeta has been shown to be regulated by gonadotrophins, the pituitary hormones mediating ovarian function.

The high-temperature requirement factor A (HtrA) family of serine proteases is evolutionarily conserved from bacteria to mammals. We have previously identified Htra3 in the mouse and human (HTRA3) and reported its expression in the ovary. In this study, we analyzed the rat Htra3 gene and determined its developmental regulation in the rat ovary. We localized the rat Htra3 gene on chromosome 14q21 and identified two alternatively spliced mRNA variants. The two protein sequences deduced from these mRNAs enabled the prediction of the domain organization of the two protein isoforms. Our comparative analysis has established that the key gene features of Htra3 including its genomic structure, intron-exon junction and alternative splicing are well conserved among the mouse, rat and human. The similarities are even higher at the levels of primary protein sequence and protein domain architecture, suggesting that the functions of Htra3 are highly conserved during evolution from rodents to primates. We demonstrate that Htra3 expression in the rat ovary is developmentally regulated; expression was initiated on day 12 after birth and up-regulated during ovarian maturation with the highest levels found in the mature cycling ovary. In the mature ovary, Htra3 was expressed in granulosa cells, in a follicle-stage specific manner, with the level of expression being dependent on the positioning of the granulosa cells relative to the oocyte in late stage follicles. The luteinizing granulosa cells of the corpus luteum expressed the highest levels of Htra3. Collectively, these results suggest an important role for Htra3 in ovarian development, granulosa cell differentiation and luteinization.

Fibroblast growth factor 9 (FGF9) is widely expressed in embryos and fetuses and has been shown to be involved in male sex determination, testicular cord formation, and Sertoli cell differentiation. Given its male gender bias, the ovary has not been reported to express FGF9, nor has a role in ovarian function been explored. We report here that FGF9 mRNA and protein are present in the rat ovary and provide evidence that supports a role for FGF9 in ovarian progesterone production. FGF9 mRNA levels as determined by real-time PCR were high in 4-d-old rat ovaries, thereafter declining and stabilizing at levels approximately 30% of d 4 levels at d 12-25. Levels of FGF9 mRNA in the ovary were significantly higher than that present in adult testis, at all ages studied. The FGF9 receptors FGFR2 and FGFR3 mRNAs were present in postnatal and immature rat ovary and appeared to be constitutively expressed. FGF9 protein was localized to theca, stromal cells, and corpora lutea and FGFR2 and FGFR3 proteins to granulosa cells, theca cells, oocytes, and corpora lutea, by immunohistochemistry. Follicular differentiation induced by gonadotropin treatment reduced the expression of FGF9 mRNA by immature rat ovaries, whereas the estrogen-stimulated development of large preantral follicles had no significant effect. In vitro, FGF9 stimulated progesterone production by granulosa cells beyond that elicited by a maximally stimulating dose of FSH. When the granulosa cells were pretreated with FSH to induce LH receptors, FGF9 was found not to be as potent as LH in stimulating progesterone production, nor did it enhance LH-stimulated production. The combined treatments of FSH/FGF9 and FSH/LH, however, were most effective at stimulating progesterone production by these differentiated granulosa cells. Analyses of steroidogenic regulatory proteins indicate that steroidogenic acute regulatory protein and P450 side chain cleavage mRNA levels were enhanced by FGF9, providing a mechanism of action for the increased progesterone synthesis. In summary, the data are consistent with a paracrine role for FGF9 in the ovary.

Background: Occupational therapy aims to help people reach their maximum level of function and independence in all aspects of daily life., Objectives: To determine whether occupational therapy focused specifically on personal activities of daily living improves recovery for patients following stroke., Search Strategy: We searched the Cochrane Stroke Group Trials Register (last searched January 2006). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to March 2006), EMBASE (1980 to March 2006), CINAHL (1983 to March 2006), PsycLIT (1974 to March 2006), AMED (1985 to March 2006), Wilson Social Sciences Abstracts (1984 to March 2006) and the following Web of Science databases: Science Citation Index (1945 to March 2006), Social Science Citation Index (1956 to March 2006) and Arts and Humanities Citation Index (1975 to March 2006). In an effort to identify further published, unpublished and ongoing trials we searched The Occupational Therapy Research Index and Dissertation Abstracts register, scanned reference lists of relevant articles, contacted authors and researchers and handsearched relevant journals., Selection Criteria: We identified randomised controlled trials of an occupational therapy intervention (compared to usual care or no care) where stroke patients practiced personal activities of daily living, or performance in activities of daily living was the focus of the occupational therapy intervention., Data Collection and Analysis: Two review authors independently selected trials and extracted data for pre-specified outcomes. The primary outcomes were the proportion of patients who had deteriorated or were dependent in personal activities of daily living and performance in personal activities of daily living at the end of follow up., Main Results: We identified 64 potentially eligible trials and included 10 studies (1348 participants). Occupational therapy interventions reduced the odds of a poor outcome (Peto odds ratio 0.67 (95% confidence interval (CI) 0.51 to 0.87; P = 0.003). and increased personal activity of daily living scores (standardised mean difference 0.18 (95% CI 0.04 to 0.32; P = 0.01). For every 11 (95% CI 7 to 30) patients receiving an occupational therapy intervention to facilitate personal activities of daily living, one patient was spared a poor outcome., Authors' Conclusions: Patients who receive occupational therapy interventions are less likely to deteriorate and are more likely to be independent in their ability to perform personal activities of daily living. However, the exact nature of the occupational therapy intervention to achieve maximum benefit needs to be defined.

The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The role of progestins in follicular growth and development is limited, its action confined largely to ovulation, although direct effects on granulosa cell function have been reported. Consistent with these findings, progesterone receptor knockout mice are infertile because they cannot ovulate. Androgens have been shown to promote early follicular growth, but also to impede follicular development by stimulating atresia and apoptosis. The inability of androgens to transduce a signal in mice lacking androgen receptors culminates in reduced fertility. Oestrogens are known to exert effects on granulosa cell growth and differentiation in association with gonadotrophins. Studies with oestrogen receptor knockouts and oestrogen depleted mice have shown us that oestrogen is essential for folliculogenesis beyond the antral stage and is necessary to maintain the female phenotype of ovarian somatic cells. In summary, the action of steroids within the ovary is based on the developmental status of the follicle. In the absence of any single sex steroid, ovarian function and subsequently fertility, are compromised.

Ovarian development begins back in the embryo with the formation of primordial germ cells and their subsequent migration and colonisation of the genital ridges. Once the ovary has been defined structurally, the primordial germ cells transform into oocytes and become housed in structures called follicles (in this case, primordial follicles), a procedure that, in most mammals, occurs either shortly before or during the first few days after birth. The growth and differentiation of follicles from the primordial population is termed folliculogenesis. Primordial follicles give rise to primary follicles that transform into preantral follicles, then antral follicles (secondary follicles) and, finally (preovulatory) Graafian follicles (tertiary follicles) in a co-ordinated series of transitions regulated by hormones and local intraovarian factors. Members of the transforming growth factor-beta (TGFbeta) superfamily have been shown to play important roles in this developmental process starting with the specification of primordial germ cells by the bone morphogenetic proteins through to the recruitment of primordial follicles by anti-Mullerian hormone and, potentially, growth and differentiation factor-9 (GDF9) and, finally, their transformation into preantral and antral follicles in response to activin and TGF-beta. Developmental and mutant mouse models have been used to show the importance of this family of growth factors in establishing the first wave of folliculogenesis.

The physiology of inhibin has been investigated using rodent and ruminant animal models in both in vitro and in vivo studies. Inhibin was originally defined as a substance that causes selective suppression of follicle-stimulating hormone (FSH) secretion by pituitary gonadotropes. Although this definition is still valid, it fails to encompass the breadth of inhibin's actions. In addition to its endocrine action on pituitary FSH secretion, inhibin has a local paracrine action in its target tissues. The inhibin alpha subunit appears to play an important role in determining whether inhibin or activin is produced in cells. More recently, transgenic and knockout mouse models have highlighted the importance of inhibin for fertility and the inhibin alpha subunit for tumor suppression. Whether inhibin exerts its effects by a direct action on the gonad or by regulating FSH secretion, it is clear that inhibin is essential for normal reproductive function. In this article, we review the rodent and ruminant models employed to investigate inhibin physiology and examine the potential of inhibin-based vaccines to enhance gonadal function.

Objective: To undertake a detailed analysis of therapy provided in a multicentred randomized controlled trial of activities of daily living (ADL) and leisure (TOTAL), testing the hypothesis that specific interventions given in the trial affected specific aspects of outcome., Subjects: Three hundred and nine stroke patients who had been randomly allocated to receive either occupational therapy aimed at ADL activities (n = 156) or leisure (n = 153)., Measures: Number, duration and type of activity undertaken per patient. Barthel Index, Extended Activities of Daily Living Scale (EADL) and Nottingham Leisure Questionnaire (NLQ) six months after entry to the study., Method: Activities that had been used in treatment were coded and categorized. Frequently used activities identified. These activities were matched to items from the six-month outcome measures. Patient independence in these outcome items was compared between the leisure and ADL groups., Results: Three hundred and nine therapy record forms were returned. Patients received a median of ten sessions with a median duration of 55 minutes. The ADL group received significantly more, mobility training, transfer training, cleaning, dressing, cooking and bathing training (chi-squared, p < 0.05). Sport, creative activities, games, hobbies, gardening, entertainment and shopping were used significantly more in the leisure group (chi-squared, p < 0.05) than the ADL group. Fifteen items from the outcome measures were identified as specific to these interventions. There were no statistically significant differences in outcome on these 15 items between the ADL and leisure groups (chi-squared, p > 0.05)., Conclusions: We found no evidence that specific ADL or leisure interventions led to improvements in specific relevant outcomes. We believe that these findings should prompt a review of the relationship between process and outcome of occupational therapy.